Clinical trial NCT02019264
Conditions: Cardiovascular Disease High Cardiovascular Risk Obesity Overweight Type 2 Diabetes
Keywords: Diabetes Cardiovascular Disease Multiple Cardiovascular Risk Factors Obesity Overweight MACE Conversion to Diabetes
Sponsor: Eisai Inc.
Start date: 2014-01-24; Completion date: 2018-05-14
Enrollment: 14673 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in overweight and obese subjects with cardiovascular (CV) disease and/or multiple CV risk factors.

Detailed description:
Approximately 12,000 subjects will be randomized to two treatment groups in a ratio of 1:1, stratified by the presence of established CV disease (approximately 80%) or CV risk factors without established CV disease (approximately 20%). Subjects will receive lorcaserin HCl 10 mg BID or placebo BID. The study will consist of 2 phases: Prerandomization and Randomization. The Prerandomization Phase will last up to 30 days and consist of one visit during which subjects will be screened for eligibility. The Randomization Phase will consist of two periods: Treatment and Follow-up. The Treatment Period will last for approximately 5 years with approximately 18 visits and Follow-up period is 30 (+ or - 10 days) from the end of treatment visit.

Arms: arm 1: APD356 10 mg twice daily arm 2: Placebo twice daily
Interventions: intervention 1: Lorcaserin hydrochloride intervention 2: Placebo
Intervention descriptions: intervention 1: APD356 10 mg twice daily intervention 2: Placebo twice daily

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol
(Protocol Amendment 02)
APD356-G000-401
Eisai
FINAL (v7.0):  30 Mar 2017
Page i of xvi
CONFIDENTIAL
REVISION HISTORY
Revision History
Previous Version (Amendment 01): V6.0
Current Version (Amendment 02): V7.0
Date of Revisions: 30 Mar 2017
Change
Rationale
Affected Protocol Section(s)
Grammatical, 
typographical, 
and formatting changes 
Throughout
The 
primary 
objective 
of 
conversion to Type 2 diabetes 
mellitus was changed to a 
secondary objective
The timelines to demonstrate
the primary endpoint for 
conversion 
to 
Type 
2 
diabetes are not as initially
projected, due to the low rate 
of conversion 
SYNOPSIS
Primary Objectives
Secondary Objectives
Study Design
Secondary Endpoints
Primary Safety and 
Efficacy and Key 
Secondary Analyses
Primary Endpoint 
Analyses
Secondary Endpoint 
Analysis 
Interim Analysis
Sample Size Rationale 
Section 8.1
Section 8.2
Section 9.1
Section 9.7.1.1
Section 9.7.1.6
Section 9.7.2
Section 9.7.3
Removed 
HbA1c
from 
the 
Exploratory Objective
In order to have a broader 
assessment 
of 
glycemic 
benefit 
in 
subjects
with 
diabetes
SYNOPSIS
Exploratory Objectives
Section 8.3
Added fasting plasma glucose
(FPG), fasting insulin levels, 
and 
homeostatic 
model 
To better assess lorcaserin 
glycemic benefit
SYNOPSIS
Exploratory Endpoints


Clinical Study Protocol
(Protocol Amendment 02)
APD356-G000-401
Eisai
FINAL (v7.0):  30 Mar 2017
Page ii of xvi
CONFIDENTIAL
Revision History
Previous Version (Amendment 01): V6.0
Current Version (Amendment 02): V7.0
Date of Revisions: 30 Mar 2017
Change
Rationale
Affected Protocol Section(s)
assessment-insulin 
resistance 
(HOMA-IR)
Section 9.7.1.1
Multiple testing procedure was 
updated to reflect the change in 
the primary objective
SYNOPSIS
Primary Safety and 
Efficacy and Key 
Secondary Analyses
List of Abbreviations
Section 9.7.1.6
The renal objective for the 
overall population has been 
added
and 
reorganized
for 
clarification
To 
better 
assess 
the 
lorcaserin renal beneficial 
effect in the total study 
population
SYNOPSIS

Secondary Objectives

Secondary Endpoints

Secondary Endpoint 
Analyses
Section 8.2
Section 9.7.1
Details of the interim analysis 
are outlined 
in 
the Study 
Integrity Charter
Clarification
SYNOPSIS
Interim Analysis
Section 9.4.6
Section 9.7.3
Removed the clarification of 
major adverse cardiovascular 
events 
(MACE)+ 
events 
accruing after 11 months after 
460 
MACE 
events 
have 
occurred
Not needed
SYNOPSIS
Interim Analysis
Section 9.7.3
Updated the timing of the
interim analysis date
Update
SYNOPSIS
Study Design
Interim Analysis
Section 9.1
Section 9.7.3


Clinical Study Protocol
(Protocol Amendment 02)
APD356-G000-401
Eisai
FINAL (v7.0):  30 Mar 2017
Page iii of xvi
CONFIDENTIAL
Revision History
Previous Version (Original Protocol): V5.0
Current Version (Amendment 01): V6.0
Date of Revisions: 06 Aug 2015
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, and 
formatting changes 
Throughout
Revised total number of study sites
Fewer 
study 
sites 
are 
needed for completion of 
the study
SYNOPSIS, Sites
Section 6
Section 9.3
Reclassified 
the 
secondary 
objective 
related 
to 
glycemic 
control to allow for assessment in 
subject 
subpopulations 
as 
an 
exploratory objective.  
Allow for identification of 
patient subpopulations
in 
which lorcaserin may have 
greater efficacy
SYNOPSIS, Secondary Objectives
Section 8.2
Added exploratory objective to 
evaluate 
AACE 
and 
ACE 
obesity-related complications
Facilitate 
evaluation 
of 
lorcaserin effects in relation 
to 
widely 
accepted 
endpoints
SYNOPSIS, Exploratory Objectives
Section 8.3
Provided specific instructions that 
the 1st dose should be taken at 
Visit 2
To 
clarify 
instructions 
pertaining to initiation of 
study medication
SYNOPSIS, Study Design
Section 9.1
Section 9.1.2.1
Section 9.4.1
Section 9.5.2.1, Table 4
Add contents related to diabetes 
adjudication and confirmatory test 
needed
SYNOPSIS, Assessments
Section 9.5.1.3
Changed the designation, clinical 
trial safety database, to clinical 
trial database
To correct terminology
SYNOPSIS, Study Design
Section 9.5.1.3
Section 9.5.1.5
Revised 
inclusion 
criterion 
pertaining 
to 
established 
CV 
disease (MI or stroke) and stable 
antidiabetic medication, such that 
randomization (not screening) is 
the point of reference
To minimize unnecessary 
exclusion of prospective 
subjects
SYNOPSIS, Inclusion Criterion #3
Section 9.3.1
Defined renal impairment with To provide a more precise 
SYNOPSIS, Inclusion Criterion #3


Clinical Study Protocol
(Protocol Amendment 02)
APD356-G000-401
Eisai
FINAL (v7.0):  30 Mar 2017
Page iv of xvi
CONFIDENTIAL
Revision History
Previous Version (Original Protocol): V5.0
Current Version (Amendment 01): V6.0
Date of Revisions: 06 Aug 2015
Change
Rationale
Affected Protocol Section(s)
reference to estimated glomerular 
filtration rate rather than clearance
definition of this criterion 
SYNOPSIS, Exclusion Criterion #5
Section 9.3.1
Section 9.3.2
Clarified the circumstances under 
which subjects with high levels of 
hsCRP would be allowed to enter 
the study
To allow recruitment of 
subjects who have high 
hsCRP but are suitable for 
inclusion in the study.
SYNOPSIS, Inclusion Criterion #3
Section 9.3.1
Clarified 
that 
known 
severe 
valvular disease does not need to 
result in exclusion if corrected by 
valve repair or replacement 
To minimize unnecessary 
exclusion of prospective 
subjects
SYNOPSIS, Exclusion Criterion #4
Section 9.3.2
Deleted 
moderate 
renal 
insufficiency 
from 
Exclusion 
Criterion #5
To allow recruitment of 
subjects 
who 
have 
moderate 
renal 
insufficiency 
but 
are 
nonetheless 
suitable 
for 
study inclusion. 
SYNOPSIS, Exclusion Criterion #5
Section 9.3.2
Revised wording for exclusion 
criterion and prohibited therapies
and 
drugs 
pertaining 
to 
serotonergic drugs
For clarity 
SYNOPSIS, Exclusion Criterion #8
Section 9.3.2
Deleted 
cyproheptadine, 
amoxapine, TCAs, and mirtazapine 
from the list of drugs known to 
increase the risk for cardiac 
valvulopathy and/or PH
Correction
SYNOPSIS, Exclusion Criterion #9 
and Concomitant Drug/Therapy
Section 9.3.2
Section 9.4.7.2
Revised the list of prohibited drugs 
and 
clarified 
restrictions 
on 
serotonergic drugs
To 
provide 
more 
appropriate restrictions on 
concomitant drug treatment
SYNOPSIS, Exclusion Criterion #8
Section 9.3.2
Section 9.4.7.2
Clarified 
instances 
where 
the 
exclusion criterion for enrollment 
in other clinical trials does not 
apply
To minimize unnecessary 
exclusion of prospective 
subjects
SYNOPSIS, Exclusion Criterion 
#14
Section 9.3.2
Added 
exclusion 
for 
bariatric 
surgery performed within 1 year of 
screening
Study 
results could 
be 
confounded by significant 
weight loss resulting from 
recent bariatric surgery.
SYNOPSIS, Exclusion Criterion 
#15
SYNOPSIS, Concomitant Drug
Therapy


Clinical Study Protocol
(Protocol Amendment 02)
APD356-G000-401
Eisai
FINAL (v7.0):  30 Mar 2017
Page v of xvi
CONFIDENTIAL
Revision History
Previous Version (Original Protocol): V5.0
Current Version (Amendment 01): V6.0
Date of Revisions: 06 Aug 2015
Change
Rationale
Affected Protocol Section(s)
Section 9.3.2
Updated the exclusion criterion 
defining women of childbearing 
potential
Updated per Eisai Safety 
SYNOPSIS, Exclusion Criterion 
#18
Section 9.3.2
Specified 
that 
valvular 
regurgitation ratings are to be 
applied 
to 
substudy 
echocardiograms
To 
clarify 
method 
for 
evaluating 
 
valvular 
regurgitation
SYNOPSIS, Safety Assessments
Section 9.5.1.5
Added an analysis of proportion of 
subjects 
who 
have 
worsened 
valvulopathy at 1 year and yearly 
thereafter  and had FDA-defined 
valvulopathy at Baseline as a 
secondary endpoint
Evaluate whether lorcaserin 
treatment worsens FDA-
defined 
valvulopathy 
hypertension 
in 
subjects 
who 
have 
existing 
valvulopathy at baseline
SYNOPSIS, Secondary Endpoints 
& Secondary Endpoints Analyses
Section 9.7.1.1
Section 9.7.1.6
Eliminated 
provisions 
for 
representative 
of 
subject 
to 
participate in informed consent
It is expected that all 
subjects will be capable of
providing informed consent 
on their own.
Section 5.3
Deleted phrase “if applicable” 
from 
explanation 
of 
contact 
information
Deleted unnecessary phrase
Section 6
Changed the study population for 
conversion 
to 
diabetes 
to 
prediabetes population
To select a proper high 
diabetes risk population for 
the conversion to diabetes
Section 7.1
Define terminology of “Sponsor 
Notification of Study Completion” 
as 
announcement 
of 
study 
closeout.
Clarify the definition of 
study completion
Section 9.1
Section 9.1.2.2
Section 9.5.1.5
Section 9.5.2.1, Table 4 footnotes
Section 9.5.4.1
Section 9.5.5.1
Added 
instruction 
that 
a 
confirmatory test is needed for 
subjects with new onset of diabetes
Further instruction of the 
confirmatory 
test 
was 
needed
Section 9.3.1
Modified dosing instructions to 
allow for temporarily reduced 
dosing for nonserious AEs likely 
To 
enhance 
subject 
tolerability  and improve 
study retention
Section 9.4.5.1


Clinical Study Protocol
(Protocol Amendment 02)
APD356-G000-401
Eisai
FINAL (v7.0):  30 Mar 2017
Page vi of xvi
CONFIDENTIAL
Revision History
Previous Version (Original Protocol): V5.0
Current Version (Amendment 01): V6.0
Date of Revisions: 06 Aug 2015
Change
Rationale
Affected Protocol Section(s)
related to drug treatment
Changed 
study 
medication 
instructions to separate the 2 daily 
doses by at least 6 hours 
To enhance compliance by 
eliminating 
unnecessary 
reference to mealtime
Section 9.4.5
Added guidelines for managing 
renal 
dysfunction 
or 
hepatic 
abnormalities
To provide specific  safety 
guidance in the event that 
subjects 
develop 
severe 
renal 
dysfunction, 
or 
significant 
hepatic 
abnormalities
Section 9.4.5.1
Added instructions to allow re-
initiation of study drug after 
discontinuation of the second of 
2 serotonergic drugs (more than 
1 serotonergic drug is prohibited)
To minimize unnecessary 
instances 
of 
failure 
to 
complete study
SYNOPSIS, Concomitant 
Medications
Section 9.4.7.2
Added 
DEA-223 
form 
as 
controlled substance registration 
certificate form
Correction
Section 9.4.9
Clarified exclusion on basis of 
prohibited drugs of abuse.  Stated 
that 
nicotine 
use 
is 
not 
exclusionary.
For clarity
Section 9.5.1.2
AEs and Events Associated with 
Special Situations from AEs and 
Other Events of Interest
Title updated per sponsor 
template
Section 9.5.1.5
Deletion pertaining to duration of 
AE/SAE data collection
Updated per Eisai Safety
Standard
Section 9.5.1.5
Deleted the statement, “Worsens 
(increases) to Grade 02 or higher 
based on the sponsor’s grading for 
laboratory values.”
Simplified reporting rules.  
Abnormal labs will still be 
reported as AE’s based on 
the other criteria in the 
protocol and also will be 
analyzed 
based 
on 
the 
central laboratory values
Section 9.5.1.5
Deleted instructions pertaining to 
the 
requirement 
to 
categorize 
certain ECG findings as AEs
Simplified reporting rules. 
ECG abnormalities will be 
reported as AE’s consistent 
with the other criteria for 
AE reporting within the 
Section 9.5.1.5


Clinical Study Protocol
(Protocol Amendment 02)
APD356-G000-401
Eisai
FINAL (v7.0):  30 Mar 2017
Page vii of xvi
CONFIDENTIAL
Revision History
Previous Version (Original Protocol): V5.0
Current Version (Amendment 01): V6.0
Date of Revisions: 06 Aug 2015
Change
Rationale
Affected Protocol Section(s)
protocol and do not require 
a separate section. 
Hospitalization for administration 
of study drug or insertion of access 
for administration of study drug 
removed 
from 
list 
of 
hospitalizations that are not SAEs
Removed 
because 
not 
applicable for this study.
Section 9.5.1.5
Clarified 
that 
subjects 
who 
permanently
discontinue 
study 
drug are to complete the EOT visit 
within 30 days.
Clarification
Section 9.5.1.5
Moved 
euphoria 
and 
suicidal 
ideation from study specific AEs 
of interest to ‘SAEs and Events 
Associated with Special Situations’
Euphoria 
and 
suicidal 
ideation are listed under 
‘SAEs 
and 
Events 
Associated 
with 
Special 
Situations’ 
pertaining 
to 
study-specific 
AEs 
of 
interest, 
allowing 
investigators to report these 
events correctly.
Section 9.5.4.4
Updated description of study-
specific events of interest and 
instructions for reporting these 
events
To 
provide 
clearer 
guidance for the correct 
reporting of study-specific 
events of interest
Section 9.5.1.5
Section 9.5.4.4
Revised description of valvular 
heart 
disease 
to 
distinguish 
between new onset and worsened 
valvular heart disease
To allow for evaluation of 
new onset and worsened 
valvular heart disease
Section 9.5.4.4
Revised description of pulmonary 
hypertension 
 
to 
distinguish 
between new onset and worsened 
pulmonary hypertension
To allow for evaluation of 
new onset and worsened 
pulmonary hypertension
Section 9.5.4.4
Revised footnote b in Schedule of 
Procedures/Assessments pertaining 
to unscheduled visits to allow for 
assessments required by state-
controlled substance requirements
Compliance with possible 
local regulations
Section 9.5.2.1, Table 4
Added 
that 
renal 
function 
parameters and glycemic profile 
To enhance surveillance of 
possible 
renal-related 
Section 9.5.2.1, Table 4, footnote f


Clinical Study Protocol
(Protocol Amendment 02)
APD356-G000-401
Eisai
FINAL (v7.0):  30 Mar 2017
Page viii of xvi
CONFIDENTIAL
Revision History
Previous Version (Original Protocol): V5.0
Current Version (Amendment 01): V6.0
Date of Revisions: 06 Aug 2015
Change
Rationale
Affected Protocol Section(s)
should be collected at all visits 
changes
Specified that SAE collection for 
30 days after the last drug dose 
applies only to subjects taking 
study drug at the time of study 
completion
Some subjects may have 
discontinued 
study 
drug 
before study completion, 
such 
that 
the 
30-day 
interval for SAE collection 
may not be applicable.
Section 9.5.4.1
Deleted component of “misuse” 
definition 
pertaining 
to 
prescription drugs
This is a clinical study, 
therefore these statements 
are not applicable.
Section 9.5.4.4
Deleted instructions for reporting 
of 
significant 
laboratory 
abnormality
Simplified reporting rules.  
Laboratory 
abnormalities 
will be reported  as AEs 
based 
on 
the 
other 
instructions in the protocol 
and also will be analyzed 
using the central laboratory 
data.
Section 9.5.4.4
Relocated language to allow for re-
initiation
Note that new content is provided.
To minimize unnecessary 
instances 
of 
failure 
to 
complete study
Section 9.5.5.1
Section 9.5.5.2


Clinical Study Protocol
(Protocol Amendment 02)
APD356-G000-401
Eisai
FINAL (v7.0):  30 Mar 2017
Page ix of xvi
CONFIDENTIAL
Revisions in Version 5.0 
Date:  21 Oct 2013
Change
Rationale
Affected Protocol Sections
Removed timing of evaluation from 
the 
objective 
for 
diabetes-related 
microvascular complications
Not needed in objective
●Synopsis
-Exploratory Objectives, 2nd bullet
●Section 8.3
Deleted duration of Follow-up Period
Clarification, as it may vary 
among subjects
●Synopsis
-Study Design
●Section 9.1
Qualified the EOS Visit for subjects 
who complete treatment
Clarification
●Synopsis
-Study 
Design
-Duration of Study Phases and 
Treatment
●Section 9.1
●Table 4 (Notes)
Referred reviewer to the SAP for 
details of analyses
Clarification
●Synopsis
-Analysis Sets, 1st  bullet
●Section 9.7.1.2
Revised window for EOS visit 
Larger window is needed
●Section 9.1.2.2
●Table 4 (footnote c)
Added serum creatinine and cystatin C 
assessment at EOT
Correction
●Table 4
Revised
last timepoint for other 
biomarkers sampling
Correction
●Table 4
Revised “EOS” to “the end of the 
study”
Clarification
●Synopsis
-Exploratory Endpoints, 2nd bullet
●Section 
9.7.1.1, 
Exploratory 
Endpoints
Changed timing of first subject 
screened
Correction
●Synopsis
-Study 
Period 
and 
Phase 
of 
Development
-Study Design
Revised MACE-related objective of 
the study
Correction; MACE+ includes 
components of MACE
●Synopsis
-Secondary 
Objectives, 
MACE-
related; 
1st
bullet
-Section 8.2
Qualified supportive endpoint for 
effects on conversion to diabetes to 
include its sequelae
Correction
●Synopsis
-Secondary 
Objectives
-Supportive 
endpoints 
for 
conversion to T2DM
●Section 8.2
●Section 
9.7.1.1 
(Supportive 
endpoints for conversion to T2DM)
Estimated number of subjects who 
Not needed in objectives; needs 
●Synopsis


Clinical Study Protocol
(Protocol Amendment 02)
APD356-G000-401
Eisai
FINAL (v7.0):  30 Mar 2017
Page x of xvi
CONFIDENTIAL
Revisions in Version 5.0 
Date:  21 Oct 2013
Change
Rationale
Affected Protocol Sections
will have ECHO assessments and 
revised 
timing 
of 
evaluation 
of
echocardiographically 
determined 
heart valve and pulmonary artery 
pressure changes
to be qualified elsewhere
-Exploratory Objectives, 4th bullet
-Study Design
●Section 8.3, 4th bullet
●Section 9.1
●Section 9.5.1.5
●Table 4 (footnote d)
Revised text regarding reduced –
calorie diet and physical activity 
program
Clarification
●Synopsis
-Study Design
●Section 9.1
Qualified definition of hypertension
Clarification
●Synopsis
-Inclusion 
Criteria, 
#3 
(OR
  scenario) “a”
●Section 9.3.1
Qualified criteria for T2DM
Clarification 
for 
the 
stabilization of treatment of 
diabetes and rescreening in 
enrollment.
●Synopsis
-Inclusion #3
●Section 9.3.1
Added 
use 
of 
lorcaserin 
within 
6 months prior to Screening as an 
exclusion criterion
New restriction since it is an 
approved drug
●Synopsis
-Exclusion #11
●Section 9.3.2
Revised text and added FPG and 
additional components of the ADA 
diagnostic criteria to
the primary 
efficacy/safety assessments
Clarification 
●Synopsis
-Primary 
Safety/Efficacy 
Assessments
●Section 
9.5.1.3 
(Conversion 
to 
Diabetes)
Revised timing of last hsCRP and 
fibrinogen assessments from EOS to 
EOT
EOT assessments will collect 
samples 
if 
a 
subject 
discontinues 
the 
treatment 
earlier.
●Synopsis
-Biomarker Assessments
●Section 
9.5.1.4 
(Biomarker 
Assessments)
●Table 4
Redefined 
conversion 
to 
T2DM 
primary endpoint
Clarification 
●Synopsis
-
Statistical 
Methods 
(Primary 
Endpoints, 2nd bullet)
●Section 9.7.1.1 Primary Endpoints, 
2nd bullet)
Included an option to have other 
biomarkers 
collected 
for 
future 
research.  
Clarification for how subjects 
sign the informed consent
●Section 5.3
Revised window for EOS visit
Safety requires at least 30 days
follow-up.
●Section 9.1.2.2
●Table 4


Clinical Study Protocol
(Protocol Amendment 02)
APD356-G000-401
Eisai
FINAL (v7.0):  30 Mar 2017
Page xi of xvi
CONFIDENTIAL
Revisions in Version 5.0 
Date:  21 Oct 2013
Change
Rationale
Affected Protocol Sections
Deleted schedule footnote; re-lettered 
following footnote and revised in table
Correction
●Table 4 (footnote i)
Revised 
language 
related 
to 
withdrawal of consent to specify the 
appropriate CRF and point of contact 
for confirmation.
Clarification of the procedure
●Section 9.5.5.2
Revised language for completion of 
study treatment
Correction
Section 9.7.1.3
Added “approximately” symbol for 
EOT
Clarification
●Figure 1
Removed cross-reference to footnote e 
on ECHO assessment
ECHO 
assessments 
will 
continue 
after 
a 
subject 
discontinues study treatment
●Table 4
Delete hematology tests at EOS
They are not required
●Table 4
Add HbA1c, FPG, and Fasting insulin 
level at EOS
To collect more data for 
diabetes conversion
●Table 4.
Added FPG at unscheduled visits
To collect more data for 
diabetes conversion
●Table 4
Revised footnote language pertaining 
to renal function parameters 
Clarification.
Table 4 (footnote f)
Added generic name of Belviq
Correction
●Protocol Signature page
●Figure 1
Specified reporting of MACE and 
MACE+ 
to 
the 
Sponsor 
Pharmacovigilance Dept.
Clarification
●Synopsis
-Study Design
●Section 9.5.1.3
●Section 9.5.1.5
Revised 
language 
regarding 
AE 
reporting
Clarification
●Section 9.5.1.5
Revised 
timeframe 
for 
reporting 
pregnancy/exposure 
through 
breastfeeding
Clarification
●Section 9.5.4.3


Clinical Study Protocol
(Protocol Amendment 02)
APD356-G000-401
Eisai
FINAL (v7.0):  30 Mar 2017
Page xii of xvi
CONFIDENTIAL
Revisions in Version 4.0 
Date:  03 Oct 2013
Change
Rationale
Affected Protocol Sections
Ensured sampling for/measurement of 
creatinine at appropriate timepoints
Measurement 
of 
creatinine 
should be in parallel with 
cystatin C 
●Table 4, footnote g
Revised timing from EOT to EOS for 
evaluating the effect of lorcaserin on 
microvascular complications
Correction
●Synopsis
-Exploratory Objectives
●Section 8.3
Qualified biomarkers evaluated as an 
exploratory endpoint
Because all biomarkers are not 
assessed on a yearly basis; 
correction
●Synopsis
-Exploratory Endpoints
●Section 9.7.1.1
Revised analysis of eGFR and ACR 
from EOT to EOS
Correction
●Synopsis
-Exploratory 
Endpoints
-Exploratory Endpoints Analyses
●Section 9.7.1.1
●Section 9.7.1.6
Removed “percent” and “percentage” 
for change from Baseline
Clarification
●Synopsis
-Exploratory 
Endpoints
-Secondary 
Endpoints 
Analyses
-Exploratory Endpoints Analyses
●Section 9.7.1.1
●Section 9.7.1.6
Removed 
secondary 
reasons 
for 
discontinuation 
on 
the 
Subject 
Disposition CRF for documenting 
study completion
Not required
●Section 9.7.1.3
Removed 
reference 
to 
a 
6-digit 
randomization number
A different number of digits 
may be used
●Section 9.4.3
Made participation in a reduced-
calorie diet and increased physical 
activity program required
Clarification 
●Synopsis
-Study Design
●Section 9.1
Stipulated a separate ICF for other 
biomarker sampling/analysis
Requirement for separate ICF; 
correction
●Section 5.3
Revised timing of last sampling for 
hsCRP, 
fibrinogen 
and 
other 
biomarkers from EOT to EOS
Correction
●Synopsis
-Biomarker assessments
●Section 9.5.1.4
●Table 4
●Appendix 5
Qualified when ECGs will be obtained
Clarification
●Section 9.5.1.5
Specified duration of the Follow-up 
Period
Clarification
●Synopsis
-Study Design
●Section 9.1
Added text for the sensitivity analysis
To improve the sensitivity 
●Synopsis


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Change
Rationale
Affected Protocol Sections
analysis, additional language 
added since the FDA-approved 
protocol
-Primary Endpoints Analyses
●Section 9.7.1.6
Revised 
protocol 
definition 
of 
regression of CKD
Correction
●Synopsis
-PD Assessments
●Section 9.5.1.4
Separated hematology from chemistry 
in laboratory tests in the schedule
Because renal function tests 
(chemistry) will be done at 
some visits where hematology 
is not required
●Table 4
Revised 
existing 
footnote 
for 
assessments conducted via telephone 
contact
Clarification
●Table 4 (footnote j)
Added a footnote to stipulate the need 
to perform renal function tests in 
subjects who discontinue study drug 
early
Clarification, as this is a 
requirement
●Table 4 (footnote f)
Designate assessments not needed 
after end of treatment for subjects who 
discontinue study drug early
FDA recommendation
●Table 4 (footnote e)
Removed modified clinic visit 
The information this column 
provides is captured instead in 
the footnoted assessments.
●Table 4
Added FPG as an indicator of 
glycemic control
Correction
●Section 9.5.1.3
Qualified use of Form FDA 1572
Non-North American sites will 
not use this form, so an 
alternative 
option 
must 
be 
added.
●Section 9.4.9
●Section 9.6.1
●Section 11.6
Revised molecular formula
Correction
●Section 9.4.2.1
Revised 
primary 
and 
secondary 
endpoints for conversion to T2DM
Based on discussion with the 
CVOT Advisory Board and 
consultants. It also was decided 
to 
use 
full 
2013 
ADA 
guidelines for definition of 
conversion to T2DM.
●Synopsis
-Primary 
Endpoints
-Secondary Endpoints
●Section 9.7.1.1
●Section 10
Increased the number of sites in the 
study
To increase enrollment in order 
to meet in a timely manner, the 
FDA-specified 
number 
of 
events required to be reported 
in the designated timeframe.
●Synopsis
-Sites
●Section 6
●Section 9.3


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Date:  03 Oct 2013
Change
Rationale
Affected Protocol Sections
MDRD equation replaced with CKD-
EPI formula for renal assessments
Based on recommendation from 
CVOT Advisory Board; eGFR 
calculated with the CKD-EPI 
formula 
is 
more 
accurate, 
particularly in overweight or 
obese populations.
●Synopsis
-Inclusion 
Criteria, 
#3 
(OR
  scenario) 
“c”
-Exclusion 
Criteria 
#5
-PD Assessments
●List of Abbreviations and Definition 
of Terms
●Section 9.3.1
●Section 9.3.2
●Section 9.5.1.4
●Section 10
Revised and qualified definitions for 
albuminuria
Based on recommendation from 
CVOT 
Advisory 
Board; 
albuminuria is variable, so 2
consecutive 
assessments 
are 
required
●Synopsis
-PD Assessments
●Section 9.5.1.4 
●Section 9.7.1.4
Added serum cystatin C as a PD 
assessment in a subset of subjects to 
calculate eGFR
Based on recommendation from 
CVOT 
Advisory 
Board; 
provides more accurate eGFR 
in the sub- population with high 
nephropathy 
risk 
and 
may 
provide correct reference for 
creatinine-based eGFR,
since 
eGFR 
 
calculated 
from
creatinine may not be accurate 
due to that muscle loss would 
result in decreased creatinine.
●Synopsis
-PD Assessments
●Section 9.5.1.4
●Table 3
Revised 
supportive 
endpoints 
for 
glycemic and end-organ benefits
Based on recommendation from 
CVOT 
Advisory 
Board; 
endpoint revision was made to 
align with changes made for the 
definition of albuminuria. 
●Synopsis
-Secondary Endpoints
●Section 9.7.1.1
Revised 
language 
around 
ECHO 
objectives and assessments
Because ECHO
assessments 
will 
stop 
after 
460 MACE 
events 
are 
reached; 
new 
language 
since 
the 
FDA-approved protocol
●Synopsis
-Study 
Design
-Exploratory Objectives
●Section 8.3
●Section 9.1
●Section 9.5.1.5
●Table 4
Added an appendix for the biomarker 
substudy
For completeness
●Appendix 5
Added 
an 
appendix 
for 
For completion
●Appendix 6


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Change
Rationale
Affected Protocol Sections
pharmacogenomic research
Revised molecular formula
Correction
●Section 9.4.2.1


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Revisions in Version 3.0 
Date:  14 Jun 2013
Change
Rationale
Affected Protocol Sections
Clarified 
definition 
of 
“On-
Treatment plus 30 Days Analysis 
Set”
To address FDA comment
●Synopsis – Analysis Sets
●Section 9.7.1.2


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Revisions in Version 2.0
Date:  14 Jun 2013
Change
Rationale
Affected Protocol Sections
Clarified reporting of MACE, SAEs 
and vital status until EOS for 
subjects 
who 
prematurely 
discontinue study drug
To address FDA comment
●Section 9.5.1.5
●Section 9.5.5.2
Clarified actions to be taken in the 
case of a subject withdrawing 
consent
To address FDA comment
●Section 9.5.5.2
Clarified 
wording 
inclusion 
of 
subjects with established CV disease
To address FDA comment 
●Synopsis, Inclusion Criteria, #3
●Section 9.3.1
Revised the upper limit of HbA1c for 
subjects with T2DM
To address FDA comment 
●Synopsis, Inclusion Criteria, #3
●Section 9.3.1
Added text to address the risk of 
hypoglycemia in subjects taking 
certain concomitant medications
To address FDA comment
●Section 9.4.7.2
Clarified timing of baseline ECHOs 
to account for subjects who may be 
excluded
To address FDA comment
●Table 4, footnote “e” (Schedule of 
Procedures/Assessments
●Section 9.5.1.5
Specified all cancers to be reported 
as study-specific AEs of interest
To address FDA comment
●Section 9.5.1.5
●Section 9.5.4.3
Added ACR ≥30 as a potential CV 
risk factor to inclusion criteria
To address FDA comment
●Synopsis, Inclusion Criteria, #3
●Section 9.3.1
Reduced 
frequency 
of 
(safety) 
laboratory assessments after 1 year
To address FDA comment
●Table 4
Aligned categories for albuminuria 
to the KDIGO 2012 guidelines
To address FDA comment
●Synopsis
●Section 9.5.1.4
Added details of adjunctive lifestyle 
program
To address FDA comment
●(new) Appendix 4
Added the On-Treatment plus 30 
Days Analysis Set
To address FDA comment
●Synopsis
●Section 9.7.1.2
●Section 9.7.1.6
Added all-cause mortality as a 
secondary endpoint
To address FDA comment
●Synopsis
●Section 9.7.1.2
●Section 9.7.1.6
Added 
language 
for 
defining, 
reporting, 
and 
treating 
hypoglycemia
To address FDA comment
●Section 9.4.7.2
●Section 9.5.4
●Section 9.5.4.2
Described type of investigators 
wanted to participate in the study
Clarification
●Synopsis
Revised primary efficacy objective
Clarification
●Synopsis, Analysis Sets
●Section 8.1


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Date:  14 Jun 2013
Change
Rationale
Affected Protocol Sections
Reorganized secondary objectives to 
support primary objectives, with 
subsequent 
reorganization 
of 
endpoints and analyses to align with 
the objectives
Clarification
●Synopsis
●Section 8.2
●Section 9.7.1.1
●Section 9.7.1.6
Revised 
concomitant 
medication 
language with regard to use of 
serotonergic drugs, drugs for the 
treatment 
of 
hypertension, 
dyslipidemia, and diabetes, and 
drugs associated with an increased 
risk of valvulopathy
Clarification
●Synopsis
●Section 9.4.7.2
Reduced Screening Period from 
42 days to 30 days
30 days is sufficient
●Synopsis
●Section 9.1
●Section 9.1.1
●Figure 1
●Table 4
Revised language on reporting of 
MACE and MACE+
Clarification
●Synopsis
●Section 9.5.1.3
Revised 
language 
regarding 
completion 
of 
the 
study, 
MACE/MACE+ reporting, and the 
interim analysis
Clarification
●Synopsis
●Section 9.1
Revised date of first subject in and 
last subject out
Correction
●Synopsis
●Section 9.1
Identified 
specific 
examples 
of 
drugs known to increase the risk of 
valvulopathy as exclusion criteria
Clarification
●Synopsis
●Section 9.3.2
Updated contraception language in 
exclusion criteria
Correction
●Synopsis
●Section 9.3.2
Removed the C-SSRS assessment
To address FDA comment to 
reduce safety assessments
●Synopsis, Exclusion Criteria #10
●Section 9.3.2, Exclusion Criteria #10
●Synopsis, Safety Assessments
●Section 9.5.1.5, Safety Assessments
●List of Abbreviations
●Synopsis, Safety Analyses
●Section 9.7.1.8, Safety Analyses
●Table 4


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Revisions in Version 2.0
Date:  14 Jun 2013
Change
Rationale
Affected Protocol Sections
Reduced frequency of visits after 
2 years to every 4 months
To address FDA comment to 
reduce safety assessments
●Table 4
●Synopsis/Study Design
●Section 9.1
●Section 9.1.2.1
●Section 9.4.1
Reduced frequency of vital signs
To address FDA comment to 
reduce safety assessments
●Table 4
Removed FPG at 3 and 18 months
Not required at these visits
●Table 4
Removed 
Other 
Biomarkers 
sampling at Month 36
Not required
●Table 4
Added 3 additional exploratory 
analyses
Correction
●Synopsis
●Section 9.7.1.6
Revised one of the conditions for 
completion of the study
Correction
●Synopsis
●Section 9.1
●Section 9.7.3
Revised definition for end of the 
study for purposes of reporting to 
the IRB/IEC/CA
Correction
●Section 5.1
Removed 
Early 
Discontinuation 
Visit; edited table note to Table 4 to 
identify procedures for subjects who 
prematurely discontinue study drug
A separately identified visit is not 
needed.
●Table 4, “Note”
Added Modified Clinic Visit
This visit is for subjects who 
prematurely 
discontinue 
study 
drug, but are being followed 
clinically.
●Table 4
Revised text regarding criteria for 
antidiabetic treatments at time of 
screening
Correction
●Synopsis, inclusion criterion 3
●Section 9.3.1
●Section 9.4.7
Revised 
definition 
for 
newly 
developed albuminuria
Correction
●Synopsis
●Section 9.5.1.4
Revised Classification of Causality 
of Adverse Events
Facilitate reporting of AEs 
●Section 9.5.1.5
Revised text related to safety 
reporting to remove the use of forms
Alignment 
with 
use 
of 
an 
electronic gateway which will be 
used for reporting
●Section 9.5.1.5
●Section 9.5.4.1
Revised text pertaining to analysis 
of ECGs
Correction
●Section 9.7.1.8
Updated clinical laboratory tests
Clarification
●Table 3


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Revisions in Version 2.0
Date:  14 Jun 2013
Change
Rationale
Affected Protocol Sections
Revised 
study-specific 
adverse 
events of interest
In response to discussion with 
FDA to appropriately assess and  
report AEs of interest
●Section 9.5.1.5
●Section 9.5.4.3
Added provision for Telephone 
Visit
For subjects who cannot attend a 
clinic visit in person
●Section 9.1
●Table 4
●Section 9.5.5
Removed 
Pharmacogenomics 
appendix
This 
plan 
will 
be 
provided 
separately.
●Appendix 3
Removed endpoint definitions for 
hospitalizations
These will be provided separately 
from the protocol for the CEC.
●(previous) Appendix 4
Updated List of Abbreviations
In response to  all revisions made 
post-FDA review
●Section 4
Revised date and document version
Update
●Throughout protocol


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1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
APD356-G000-401
Study Protocol Title:
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Evaluate the Effect of Long-Term Treatment with BELVIQ (lorcaserin HCl) on 
the Incidence of Major Adverse Cardiovascular Events and Conversion to 
Type 2 Diabetes Mellitus in Obese and Overweight Subjects with 
Cardiovascular Disease or Multiple Cardiovascular Risk Factors
Sponsor:   
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, New Jersey 07677
USA
Eisai Limited
European Knowledge Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN
UK
Investigational 
Product Name:
APD356/BELVIQ® (lorcaserin hydrochloride)
Indication:
Obesity
Phase:
Phase 3b/4
Approval Date:
V1.0
04 Feb 2013 (original protocol)
V2.0
14 Jun 2013 (original protocol)
V3.0
14 Jun 2013 (original protocol)
V4.0
03 Oct 2013 (original protocol)
V5.0
21 Oct 2013 (original protocol)
V6.0
06 Aug 2015 (Amendment 01)
V7.0
30 Mar 2017 (Amendment 02)
IND Number:
69888
EudraCT Number:
2013-000324-34
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
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 Effect of Long-Term 
Treatment with BELVIQ (lorcaserin HCl) on the Incidence of Major Adverse Cardiovascular Events and 
Conversion to Type 2 Diabetes Mellitus in Obese and Overweight Subjects with Cardiovascular Disease or Multiple 
Cardiovascular Risk Factors
Investigators
Physicians who treat patients with obesity, diabetes, or cardiovascular disease and who have experience in 
conducting clinical studies
Sites
Approximately 500 sites, multinationally (revised per Amendment 01)
Study Period and Phase of Development
Approximately 60 months from first subject screened (~December 2013) to last subject’s last visit/last assessment 
(~October 2018)
Phase 3b/4
Objectives
Primary Objectives
Safety:

To demonstrate that, in obese and overweight subjects with cardiovascular (CV) disease and/or multiple 
CV risk factors, lorcaserin HCl 10 mg administered twice daily (BID) does not increase the incidence of 
major adverse cardiovascular events (MACE = myocardial infarction [MI], or stroke, or CV death) 
compared to placebo, with a noninferiority margin for the hazard ratio of 1.4
Efficacy:
(revised per Amendment 02)

To demonstrate that, in obese and overweight subjects with CV disease and/or multiple CV risk factors,
lorcaserin HCl 10 mg BID reduces the incidence of MACE+ (MACE or hospitalization for unstable angina 
or heart failure (HF), or any coronary revascularization) compared to placebo
Secondary Objectives
Key Secondary Objective

To confirm that, in subjects with prediabetes at Baseline based on the 2013 ADA guideline, lorcaserin HCl 
10 mg BID reduces the incidence of conversion to type 2 diabetes mellitus (T2DM) compared to placebo 
(revised per Amendments 01 and 02)


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Other Secondary Objectives (revised per Amendment 02)
MACE and MACE+ Related: (revised per Amendment 02)

To determine whether the rates of the individual events comprising the MACE+ endpoints are different in 
subjects on lorcaserin compared to those on placebo

To determine whether lorcaserin reduces all-cause mortality compared with placebo
Diabetes and Prediabetes Related:  (revised per Amendment 02)

To evaluate the effect of lorcaserin HCl 10 mg BID compared to placebo on conversion to normal glucose 
homeostasis at 1 year and yearly thereafter in subjects with prediabetes at Baseline (revised per 
Amendment 01)

To evaluate whether in all subjects without any type of diabetes at Baseline, lorcaserin HCl 10 mg BID 
reduces the incidence of conversion to T2DM compared to placebo (revised per Amendments 01 and 02)

To confirm that, in subjects with T2DM at Baseline, lorcaserin HCl 10 mg BID improves glycemic control 
(HbA1c) compared to placebo at 6 months
Renal Related:  (revised per Amendment 02)

To evaluate the long-term effect of lorcaserin HCl compared to placebo on renal function in all subjects 
(revised per Amendment 01)

To evaluate the long-term effect of lorcaserin HCl compared to placebo on renal function in subjects with 
T2DM at Baseline

To evaluate the long-term effect of lorcaserin HCl compared to placebo on renal function in subjects with 
prediabetes at Baseline (revised per Amendment 02)
Safety Objectives (revised per Amendment 02)

To evaluate echocardiographically determined cardiac valvular function and pulmonary arterial pressure 
changes associated with treatment with lorcaserin HCl 10 mg BID compared to placebo at 1 year

To evaluate the long-term safety of lorcaserin HCl 10 mg BID
Exploratory Objectives

To explore the effects of long-term treatment with lorcaserin HCl 10 mg BID on improving CV risk factors 
associated with obesity (eg, body weight, dyslipidemia, insulin level, hypertension, inflammatory 
biomarkers) compared with placebo at 1 year and yearly thereafter

To evaluate the effect of lorcaserin HCl on other diabetes-related microvascular complications (retinopathy
and neuropathy compared to placebo in subjects with prediabetes, or T2DM at Baseline at EOS. (revised 
per Amendment 01)

To explore, in subjects with a diagnosis of Non-Alcoholic Fatty Liver Disease (NAFLD) at Baseline, the 
effects of long-term treatment with lorcaserin HCl 10 mg BID on liver function compared with placebo at 
1 year and yearly thereafter

To evaluate echocardiographically determined heart valve and pulmonary artery pressure changes 
associated with treatment with lorcaserin HCl 10 mg BID compared to placebo at 2 years and yearly 
thereafter 

To collect and store DNA samples which may be used for examination of the impact of genetic variation on 
weight loss, the response to lorcaserin HCl, susceptibility to diabetes, and the risk of developing CV and 
other end-organ disease and their associated risk factors (for participating countries/sites where ethics and 
regulatory approval is obtained)


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
To collect and store serum and plasma biomarker samples which may be used for examination of the 
impact of different metabolic and CV pathologic processes on weight loss, the response to lorcaserin HCl, 
susceptibility to diabetes, and the risk of developing CV and other end-organ disease and their associated 
risk factors (for participating countries/sites where ethics and regulatory approval is obtained)

To explore the effects of long-term treatment with lorcaserin HCl (10 mg BID) on improvement of obesity 
related complications, as defined by the 2014 Advanced Framework for a New Diagnosis of Obesity as a 
Chronic Disease (American Association of Clinical Endocrinologists [AACE] and American College of 
Endocrinology [ACE]) (eg, pre diabetes, metabolic syndrome, hypertriglyceridemia/dyslipidemia, and 
potentially others) (revised per Amendment 01)

To demonstrate that lorcaserin HCl 10 mg BID improves glycemic control, and/or reduction in OAD 
medications for the subjects treated with OADs, compared to placebo at 6 months in the following 
subpopulations of patients with T2DM:
o
Subjects with T2DM with an HbA1c>7% at Baseline
o
Subjects with T2DM who have not been treated with antidiabetic agents at Baseline
o
Subjects with T2DM who are on Monotherapy with an oral antidiabetic agent at Baseline
o
Subjects with early T2DM (duration of diagnosis of diabetes is less than 5 years) at Baseline 
Study Design
This will be a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in overweight and 
obese subjects with CV disease and/or multiple CV risk factors.  Approximately 12,000 subjects will be randomized 
to 2 treatment groups in a ratio of 1:1, stratified by the presence of established CV disease (~80%) or CV risk factors 
without established CV disease (~20%). The 80% of subjects in the established CV disease strata will consist of a 
group with T2DM (approximately 30% of the total number of subjects in the study) and a group without T2DM 
(approximately 50% of the total number of subjects in the study).  The 20% of subjects in the strata with CV risk 
factors but without established CV disease will all have T2DM, as well as additional risk factors. Therefore,
approximately 50% of the total number of subjects in the study will have T2DM.
Subjects will receive lorcaserin HCl 10 mg BID or placebo BID for approximately 5 years.  Throughout the duration 
of the study, subjects will be provided with instructions regarding a reduced-calorie diet and increased physical 
activity program. Echocardiography will be performed on a subset of approximately 3600 subjects at Baseline and 
at 6, 12, 18, 24 months, and yearly thereafter.  Acquisition of new ECHO data in all subjects will cease when at least
1000 subjects have completed the Month 36 echocardiographic assessment.  (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 
will consist of 2 periods:  Treatment and Follow-up.  The Treatment Period will last for approximately 5 years with 
approximately 18 visits.  The first dose should be taken at Randomization Visit 2.  (revised per Amendment 01)  The 
Follow-up Period extends from the end of treatment (EOT) visit to the EOS visit. Sponsor Notification of Study 
Completion will occur once 1401 MACE+ events, 460 MACE events, and a median treatment duration of 2.5 years
have accrued.  (revised per Amendment 02)  This is expected to occur on or before October 2018.  Following this 
announcement (“Sponsor Notification of Study Completion”), sites will be instructed to bring subjects who remain 
on treatment for an EOT visit.  An EOS visit will occur approximately 30 days later for subjects on treatment at 
Sponsor Notification of Study Completion.  (revised per Amendment 01)  Subjects who are still being followed in 
the study but have already discontinued study medication ≥30 days before will return for an EOS visit.  Subjects 
who are still being followed in the study but who discontinued study medication within the last 30 days will return 
for an EOS visit approximately 30 days after their last dose of study medication.
During this study, the endpoints of MACE and MACE+ will need to be reported in an expedited fashion by 
investigators to the Clinical Endpoint Committee (CEC) and to the Eisai Product Safety Department. 
MACE/MACE+ events will be recorded on the adverse event (AE) case report form, but these events will not be 
considered as AEs, nor will they be recorded as serious adverse events (SAEs) in the clinical trial database or be 
required to be reported to regulatory authorities in an expedited timeframe, with the exception of MACE or MACE+ 


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events that are considered by the investigator to be at least possibly related to the study drug (ie, where there is 
evidence to suggest a causal relationship).  (revised per Amendment 01)
All subjects will continue in the study until study completion rather than for a prespecified number of visits. 
Subjects will remain in the study even after their first nonfatal MACE event. Subjects who discontinue treatment 
prematurely will be followed up for safety until study completion (ie, they will attend the remaining study visits for 
safety assessments).

In order to reduce intra- and inter-site variability, the CEC will centrally review each potential MACE and 
MACE+ event to ensure standardization of data collection and interpretation of such events reported 
throughout the study.  The CEC will determine whether each potential event meets criteria for MACE or 
MACE+.  The CEC will remain blinded to treatment allocation and its activities and the criteria for 
classification of MACE/MACE+ events will be documented in the CEC Charter.
When 460 adjudicated MACE events have occurred, an interim analysis will be conducted on MACE events. It will 
be conducted to establish whether the primary safety objective (MACE noninferiority) has been achieved.  This 
analysis will be performed by an independent statistician and governed by an independent Data Monitoring 
Committee (DMC) and is anticipated to occur on or before (approximately) July 2017. (revised per Amendment 02)  
If the primary safety objective has been achieved, the trial will continue for evaluation of additional endpoints as 
delineated in the objectives.
As required by some regulatory agencies, the following estimates are provided:
●
The study will begin in December 2013.
●
460 MACE events are expected to occur on or before December 2017; the interim analysis is anticipated to 
occur on or before (approximately) July 2017. (revised per Amendment 02).
●
The study will terminate when 1401 MACE+ events have occurred and when there has been a median 
treatment duration of 2.5 years have accrued.  (revised per Amendment 02)  This is expected to occur on or 
before October 2018
●
The estimated period for each subject on study is anticipated to be approximately 60 months.
Number of Subjects
Approximately 18,000 subjects will be screened to provide 12,000 randomized subjects.
Inclusion Criteria
1.
Body mass index (BMI) ≥27kg/m2 
2.
Subjects able and willing to comply with a reduced-calorie diet and an increased physical activity program
3.
Age ≥40 years with established CV disease as defined by 1 of the following:
a.
History of documented MI or ischemic stroke >1 month before Randomization (revised per 
Amendment 01)
b.
History of peripheral artery disease as manifested by symptomatic claudication with an 
ankle-brachial pressure index of <0.85 
c.
History of revascularization (coronary, carotid, or peripheral artery)
d.
Significant unrevascularized coronary arterial stenosis defined as ≥50% in 2 or more coronary 
arteries
OR
Age ≥55 years for women or ≥50 years for men who have T2DM without established CV disease plus at 
least 1 of the following CV risk factors: 
a.
Hypertension, defined as systolic blood pressure (SBP) >140 or diastolic blood pressure (DBP)


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>90, or currently receiving therapy for documented hypertension
b.
Dyslipidemia, defined as low density lipoprotein-cholesterol (LDL-C) >130 mg/dL, or high 
density lipoprotein-cholesterol (HDL-C) <40 mg/dL, or currently taking prescription 
lipid-lowering therapy for documented dyslipidemia
c.
Estimated glomerular filtration rate (eGFR) ≥30 to ≤60 mL/min/1.73 m2 per the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) equation (revised per Amendment 01)
d.
High sensitivity C-reactive protein (hsCRP) > 3 mg/L detected by the central laboratory in the 
absence of known acute or chronic inflammatory conditions (eg, infection, rheumatologic disease)
(revised per Amendment 01)
e.
Urinary albumin-to-creatinine ratio (ACR) ≥30 μg/mg in spot urine
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.  A new 
diagnosis of T2DM (ie, discovered at Screening) should be based on the 2013 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) 
o
2-hour plasma glucose ≥200 mg/dL (11.1mmol/L) by an oral glucose tolerance test (OGTT)
All T2DM subjects must have an HbA1c <10% at Screening.  If subjects are being treated, or upon diagnosis 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.
(revised per Amendment 01) Minimal changes are defined as a change in insulin dose 
<10% of daily dose, 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 01)
4.
Provide written informed consent
5.
Willing and able to comply with all aspects of the protocol
Exclusion Criteria
1.
Current moderate or greater symptoms of congestive cardiac failure (New York Heart Association [NYHA] 
class III or IV)
2.
Known left ventricular (LV) ejection fraction <20%
3.
Current moderate or greater symptoms of pulmonary hypertension (PH) (World Health Organization 
[WHO] functional Class III and IV)
4.
Known severe valvular disease defined by clinical diagnosis and/or most recent echocardiography.  History 
of severe valvular disease is allowed if it has been corrected by valve replacement or repair. (revised per 
Amendment 01)
5.
Severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2 per the CKD-EPI 
equation based on ideal body weight), or end-stage renal disease (ESRD) (revised per Amendment 01)
6.
Severe hepatic impairment (Child-Pugh score 10 to 15)
7.
Use of other products intended for weight loss including prescription drugs, over-the-counter (OTC) drugs, 


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and herbal preparations within 1 month prior to Screening
8.
Use of more than 1 serotonergic drug within 1 month before Screening or during the screening window,
including, but not limited to: (revised per Amendment 01)
a.
selective serotonin reuptake inhibitors (SSRIs)
b.
serotonin norepinephrine reuptake inhibitors (SNRIs)
c.
tricyclic antidepressants (TCAs) 
d.
bupropion
e.
triptans 
f.
St. John’s Wort and tryptophan 
g.
Monoamine oxidase inhibitors [MAOIs] 
h.
linezolid
i.
dextromethorphan
j.
lithium
k.
tramadol
l.
antipsychotics or other dopamine antagonists 
9.
Use of drugs known to increase the risk for cardiac valvulopathy within 6 months prior to Screening 
including, but not limited to:
pergolide, ergotamine, methysergide, or cabergoline (revised per 
Amendment 01)
10. History or evidence of clinically significant disease (eg, malignancy, cardiac, respiratory, gastrointestinal, 
renal, or psychiatric disease) that in the opinion of the investigator(s) could affect the subject’s safety, 
interfere with the study assessments, or result in a life expectancy of less than 1 year
11. Use of lorcaserin HCl within 6 months prior to Screening or hypersensitivity to lorcaserin HCl or any of the 
excipients
12. History of alcohol dependence or abuse within 2 years prior to Visit 1 (Screening)
13. Recreational drug use within the 2 years prior to Visit 1 (Screening)
14. Currently enrolled in another clinical trial or used any investigational drug or device within 30 days 
preceding informed consent (the exclusion criterion will not apply if the subjects are no longer in follow-up 
and have discontinued use of an investigational drug or device for at least 30 days. It will not apply if
subjects are enrolled in registries or observational studies). (revised per Amendment 01)
15. Planned bariatric surgery or bariatric surgery performed within 1 year before screening  (revised per 
Amendment 01)
16. Subjects considered by the investigator to have insufficient motivation to remain in a long-term clinical 
trial or who are considered likely to drop out for nonmedical reasons, (eg, social issues)
17. Females must not be breastfeeding or pregnant at Visit 1 (Screening) or Visit 2 (Baseline) (as documented 
by a negative beta-human chorionic gonadotropin [β-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.
18. All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic 
for at least 12 consecutive months, in the appropriate age group and without other known or suspected 
cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy or bilateral 
oophorectomy, all with surgery at least 1 month before dosing).  Females of childbearing potential are 
defined as those who: (revised per Amendment 01)

Had unprotected sexual intercourse within 30 days before study entry

Do not agree to use a highly effective method of contraception (eg, total abstinence, an intrauterine 


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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.

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.

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.
Study Treatment
Test drug 
Lorcaserin HCl will be provided as blue, round, film-coated biconvex tablets, one 10-mg tablet to be administered 
orally, BID
Comparator Drug
Lorcaserin HCl-matching placebo, 1 tablet to be administered orally, BID
Duration of Study Phases and Treatment
Prerandomization Phase:  approximately 30 days
Randomization Phase:

Treatment Period:  approximately 5 years

Follow-up Period:  30 days +10 days after last dose of study drug for subjects who complete study 
treatment (revised per Amendment 02)
Concomitant Drug/Therapy 
The following are prohibited as concomitant medications:

Other products intended for weight loss including prescription drugs, OTC drugs, and herbal preparations 
are prohibited as concomitant medications.  Any drug that has a risk for serotonin syndrome in its label, or 
that has been associated with a risk of serotonin syndrome including OTC drugs, should be used only when 
clearly indicated and within approved dose ranges and durations, as specified in the appropriate labeling.  
More than 1 additional serotonergic agent is prohibited in combination with lorcaserin HCl (eg, an SSRI, 
antipsychotic, and lorcaserin).  (revised per Amendment 01)
Serotonergic drugs include, but are not limited to:  (revised per Amendment 01)
a.
selective serotonin reuptake inhibitors (SSRIs)
b.
serotonin norepinephrine reuptake inhibitors (SNRIs)
c.
tricyclic antidepressants (TCAs) 
d.
bupropion
e.
triptans 
f.
St. John’s Wort and tryptophan 
g.
Monoamine oxidase inhibitors [MAOIs]
h.
Linezolid
i.
dextromethorphan
j.
lithium
k.
tramadol
l.
antipsychotics or other dopamine antagonists 

If a second nonstudy serotonergic agent is required by the subject during the study, temporarily discontinue 
study drug and, if possible, wait 3 days after study drug has been discontinued before starting the second 
serotonergic agent.


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
If the subject discontinues treatment with the 2nd, nonstudy serotonergic agent, lorcaserin HCl may be 
restarted when the 2nd serotonergic agent has been discontinued for at least 15 days, with the following 
exceptions, which must be discontinued for longer periods of time before restarting study drug. 
o
-30 days: fluoxetine, phenelzine, and isocarboxazid; 
o
-90 days: the injectable formulation of fluphenazine, haloperidone, paliperidone, and 
zuclopenthixol.  

If a subject requires treatment with an agent that has a documented correlation with increased incidence of 
cardiac valvulopathy and/or PH (eg, pergolide, ergotamine, methysergide, or cabergoline), lorcaserin HCl 
should be stopped.  (revised per Amendment 01)  If the subject discontinues treatment with the other agent, 
lorcaserin HCl may be restarted as long as the other agent has been discontinued for at least 1 month.
(revised per Amendment 01)
The following concomitant medication guidelines/restrictions will apply:
o
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.
Assessments
Safety/Efficacy Assessments (revised per Amendment 02)
Potential MACE will be recorded throughout the study and assessed by the CEC for the primary safety endpoint.
Blood samples for measurement of HbA1c and FPG will be collected at Screening, Baseline, and specified 
timepoints throughout the study.  HbA1c, FPG, and when available, additional components of the ADA diagnostic 
criteria will be assessed. All potential cases of conversion to diabetes will undergo central review of relevant 
supporting data.  (revised per Amendment 01)
Potential MACE+ events will be recorded throughout the study and assessed by the CEC for a primary efficacy 
endpoint.  
Pharmacokinetic Assessments
Not applicable
Pharmacodynamic Assessments
The following will be measured for assessment of CV risk factors:
1.
Body weight, BMI, waist and hip circumference
2.
SBP, DBP, heart rate (HR) 
3.
Triglycerides, total cholesterol, HDL-C, LDL-C
4.
FPG, fasting insulin
The following parameters related to renal function will be assessed:

Urinary ACR:
o
ACR will be measured in spot urine
o
The following are the definitions of newly developed, worsening, and regression of albuminuria which 
need to be documented in 2 consecutive scheduled or non-scheduled assessments at least 30 days 
apart:
-
Newly developed albuminuria, defined as first evidence of microalbuminuria (ACR ≥30 μg/mg in 
spot urine) or macroalbuminuria (ACR ≥300 μg/mg), and ACR value increases ≥30% from 


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previous assessment during treatment 
-
Worsening albuminuria, defined as when subjects with microalbuminuria at Baseline develop 
macroalbuminuria, and ACR value increases ≥30% from previous assessment during treatment
-
Regression of albuminuria, defined as when subjects with macroalbuminuria at Baseline develop 
microalbuminuria or non-albuminuria, or subjects with microalbuminuria at Baseline become 
non-albuminuric, and ACR value decreases ≥30% from previous assessment during treatment

Estimated glomerular filtration rate (eGFR): 
o
eGFR will be calculated by the CKD-EPI equation based on creatinine measurement in the total 
population and/or cystatin C measurement in a selected population.  The full criteria for determining 
whether creatinine, cystatin C, or an algorithm incorporating both will be used to estimate GFR will be 
detailed in the statistical analysis plan (SAP).
o
Definitions for newly developed, worsening, and regression of chronic kidney disease (CKD) in the 
absence of acute, transient, kidney injury
-
Newly developed CKD, defined as when a subject with eGFR ≥90 mL/min per 1.73 body surface 
area (BSA) and without kidney damage at Baseline changes to CKD Stage 1 or higher classified 
by the 2002 National Kidney Foundation (NKF) guidelines, where kidney damage referred to in 
the guideline is defined as the emergence of microalbuminuria as defined above, during treatment
-
Worsening of CKD, defined as when a subject with CKD Stage 1 or higher defined by NKF 
guidelines worsens to higher CKD stages (eGFR ≥90 with albuminuria at Baseline decreases to 
<90, or eGFR 60 to 89 at Baseline becomes <60, or eGFR 30 to 59 at Baseline becomes 
<30 mL/min per 1.73 BSA) during treatment
-
Regression of CKD, defined as when a subject with CKD Stage 1 or higher at Baseline improves 
to normal or lower stages by NKF guideline (eGFR ≥90 with albuminuria at Baseline improves to 
eGFR ≥90 without albuminuria, or eGFR 60 to 89 at Baseline becomes eGFR ≥90 with or without 
albuminuria, or eGFR between 30 to 59 at Baseline improves to 60 mL/min per 1.73 BSA) 
during treatment

Serum creatinine: 
o
Doubling of serum creatinine concentration, defined as when a subject’s creatinine value is at least 
2 times the Baseline value and ≥1.5mg/dL during treatment

Serum cystatin C:
o
Serum cystatin C will be measured to estimate eGFR in the population of subjects who are in CKD 
Stage 1 or 2 at Baseline.  CKD Stage 1 or 2 is defined as albuminuria and eGFR 60 mL/min per 
1.73 BSA.
Additional diabetes-related microvascular complications will be assessed by monitoring AEs associated with 
retinopathy and neuropathy.  (revised per Amendment 01)
The following parameters related to non-alcoholic fatty liver disease (NAFLD) will be measured:  aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, gamma glutamyl transpeptidase 
(GGT), total and direct bilirubin.
Obesity-related complications that are not assessed by any of the objective measures listed in this protocol may be 
evaluated using data from AE reporting, changes in concomitant medications, or reports of changes in medical 
history.  (revised per Amendment 01)


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Biomarker Assessments
The following inflammatory biomarkers will be assessed to further define the CV risk study population and to 
investigate potential correlation with changes in CV risk factors, MACE, and MACE+, as well as weight loss and
susceptibility to diabetes:

hsCRP will be measured at the time of Screening and will be followed up yearly through EOT.

Fibrinogen will be measured at the time of randomization and will be followed up yearly through EOT.

Other biomarkers related to obesity, diabetes, CV disease, and associated risk factors may be evaluated in 
serum and plasma samples in selected countries, where applicable.
Pharmacogenomic Assessments
A blood sample for potential investigation of genetic variability associated with genotypes relating to response to 
lorcaserin HCl, weight loss, susceptibility to diabetes, and CV and other end-organ disease and their associated risk 
factors will be taken at the time of randomization in the study, where applicable.
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and SAEs; laboratory evaluation for 
hematology, blood chemistry, and urinalysis; periodic measurement of vital signs and electrocardiograms (ECGs); 
and the performance of physical examinations.
In addition, echocardiography will be performed in a subset of subjects at predefined visits. Valvular regurgitation 
as assessed in the echocardiogram substudy 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.  (revised per 
Amendment 01)  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. 
Other Assessments
None
Bioanalytical Methods
Not applicable


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Statistical Methods
Study Endpoints
Primary Endpoints

Time from randomization to first occurrence of MACE (first occurrence of any of the following events:  
MI, stroke, or CV death)

Time from randomization to first occurrence of MACE+ (first occurrence of any of the following events:  
MACE or hospitalization for unstable angina or HF, or any coronary revascularization) (revised per 
Amendment 02)
Key Secondary Endpoint (revised per Amendment 02)

Time from randomization to conversion to T2DM, defined as first occurrence of any component of the 
2013 ADA diagnostic criteria in subjects with prediabetes at Baseline. 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 
subsequently  confirmed on repeat laboratory testing:  (revised per Amendments 01 and 02)
o
HbA1c ≥6.5% 
o
FPG≥126 mg/dL (7.0 mmol/L) 
o
2-hour plasma glucose ≥200mg/dL (11.1 mmol/L) by an OGTT
Investigators should make every effort to obtain central lab confirmatory testing no later than 6 weeks after meeting 
any of the above criteria.  Abnormalities of any 1 of the above 3 criteria on repeat testing constitutes diagnostic 
confirmation of diabetes.  Subjects who have been started on anti-diabetic medications following abnormalities in 
preliminary testing do not require confirmatory testing.  (revised per Amendments 01 and 02)
Other Secondary Endpoints (revised per Amendment 02)
MACE and MACE + Related:  (revised per Amendment 02)

Time from randomization to first occurrence of each of the individual components of MACE+

Time from randomization to first occurrence of all-cause mortality
Diabetes and Prediabetes Related (revised per Amendment 02)

Time from randomization to conversion to normal glucose homeostasis (HbA1c ≤5.6% and fasting plasma 
glucose <100 mg/dL without any antidiabetic treatment) in subjects with prediabetes at Baseline (revised 
per Amendments 01 and 02)

Time from randomization to conversion to T2DM in subjects without any type of diabetes at Baseline  
(revised per Amendment 01)

Change from Baseline in HbA1c at 6 months in subjects with T2DM at Baseline
Renal Related (revised per Amendment 02)

Time from randomization to first occurrence of 2 consecutive assessments within the same component of 
the composite endpoint or time to first occurrence of renal transplant or renal death, on scheduled or 
nonscheduled visits at least 30 days apart, indicative of new onset renal impairment or worsening of 
existing renal impairment (first occurrence of any of the following events:  microalbuminuria, 
macroalbuminuria, worsening albuminuria, newly developed CKD or worsening of CKD, or doubling of 
serum creatinine, as defined above, or any of the following:  ESRD, renal transplant, renal death) in all 
subjects (revised per Amendment 02)

Time from randomization to first occurrence of 2 consecutive assessments within the same component of 


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the composite endpoint or time to first occurrence of renal transplant or renal death,, on scheduled or 
nonscheduled visits at least 30 days apart, indicative of new onset renal impairment or worsening of 
existing renal impairment (first occurrence of any of the following events:  microalbuminuria, 
macroalbuminuria, worsening albuminuria, newly developed CKD or worsening of CKD, or doubling of 
serum creatinine, as defined above, or any of the following:  ESRD, renal transplant, renal death) in 
subjects with prediabetes at Baseline (revised per Amendments 01 and 02)

Time from randomization to first occurrence of 2 consecutive assessments within the same component of 
the composite endpoint or time to first occurrence of renal transplant or renal death,, on scheduled or 
nonscheduled visits at least 30 days apart, indicative of new onset renal impairment or worsening of 
existing renal impairment (first occurrence of any of the following events:  microalbuminuria, 
macroalbuminuria, worsening albuminuria, newly developed CKD or worsening of CKD, or doubling of 
serum creatinine, as defined above, or any of the following:  ESRD, renal transplant, renal death) in 
subjects with T2DM at Baseline (revised per Amendment 02)

Time from randomization to first occurrence of 2 consecutive assessments, on scheduled or nonscheduled 
visits at least 30 days apart, indicative of improvement in renal function (first occurrence of regression of 
albuminuria or regression of CKD) in subjects with T2DM at Baseline 
Secondary Safety Endpoints Assessing Cardiac Valve Function and Pulmonary Arterial Pressure:  
(revised per Amendment 02)

Proportion of subjects without Food and Drug Administration (FDA)-defined valvulopathy at Baseline who 
develop FDA-defined valvulopathy at 1 year

Proportion of subjects with FDA-defined valvulopathy confirmed by documented objective assessments at 
Baseline who demonstrate worsened FDA-defined valvulopathy at 1 year (revised per Amendment 01)

Change from Baseline in estimated pulmonary artery systolic pressure at 1 year
Exploratory Endpoints:

Change from Baseline in CV risk factors at 1 year and yearly thereafter (eg, body weight, dyslipidemia, 
insulin level, hypertension, and applicable biomarkers of CV risk and other end-organ diseases)

Change from Baseline in eGFR and ACR at 1 year, yearly thereafter, and at the end of the study

Change from Baseline in LFTs (AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin) at 1 year 
and yearly thereafter

Proportion of subjects without FDA-defined valvulopathy at Baseline who develop FDA-defined 
valvulopathy at 2 years and yearly thereafter 

Change from Baseline in estimated pulmonary artery systolic pressure at 2 years and yearly thereafter 

Proportions of subjects with at least a 1-stage reduction in an obesity-related complication (prediabetes, 
metabolic syndrome, T2DM, hypertension, and hypertriglyceridemia/dyslipidemia) at 1 year and EOS; 
incidence of other obesity-related complications will be collected through AE reports, medical history, and 
use of concomitant medications, based on 2014 Advanced Framework for a New Diagnosis of Obesity as a 
Chronic Disease (American Association of Clinical Endocrinologists [AACE] and American College of 
Endocrinology [ACE]). (revised per Amendment 01)

Change from Baseline in HbA1c, FPG, fasting insulin levels, and homeostatic model assessment-insulin 
resistance (HOMA-IR) at 6 months in the following subpopulations of subjects with T2DM at Baseline:
(revised per Amendments 01 and 02)
o
Subjects with (HbA1c >7%) at Baseline
o
Subjects who have not been treated with antidiabetic agents at Baseline 
o
Subjects who are on monotherapy with oral antidiabetic agent at Baseline 


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o
Subjects with early T2DM (duration of diagnosis of diabetes is less than 5 years) at Baseline. 

Proportion of subjects with reduction in the number of OAD medications or reduction in the dosage of 
OAD medications at 6 months in the following subpopulations of subjects with T2DM at Baseline: (revised 
per Amendment 01)
o
Subjects with (HbA1c >7%) at Baseline
o
Subjects who are on monotherapy with oral antidiabetic agent at Baseline 
o
Subjects with early T2DM (duration of diagnosis of diabetes is less than 5 years) at Baseline. 

Proportions of subjects with prediabetes at Baseline who develop new diagnosis of diabetic retinopathy or 
new diagnosis of diabetic neuropathy by EOS (revised per Amendment 01)

Proportions of subjects with T2DM at Baseline who develop new diagnosis of diabetic retinopathy or new 
diagnosis of diabetic neuropathy by EOS (revised per Amendment 01)
Analysis Sets
The Safety Analysis Set will be the group of subjects who received at least 1 dose of study drug and had at least 
1 postdose safety assessment.
The Intent-to-Treat set (ITT) will be the group of all randomized subjects regardless of whether they took study drug 
or not.

Total Time Analysis Set:  Using the ITT, events are counted that occur while subjects are on and off 
treatment. Subjects with no events who discontinue early or complete the study will be censored at their 
last study contact (see details in the SAP).  This will be used for the primary analysis.

On-Treatment plus 30 Days Analysis Set:  Using the ITT, events are counted that occur while subjects are 
on treatment and up to 30 days from their last dose.  Subjects with no events who discontinue early or 
complete the study will be censored at their last dose day plus 30 days.

On-Treatment Analysis Set:  Using the ITT, events are counted that occur while subjects are on treatment.  
Subjects with no events who discontinue early or complete the study will be censored at their last dose day.

Prediabetes Analysis Set: This set includes all subjects in the ITT set without a history of any type of 
diabetes and who are prediabetic at Baseline.  Definition of prediabetes will be found in the SAP.  (revised 
per Amendment 01)

Nondiabetes Analysis Set: This set includes all subjects in the ITT set without a history of any type of 
diabetes at Baseline.  Definition of nondiabetes will be found in the SAP.  (revised per Amendment 01)
T2DM Analysis Set: This set will be all subjects in the ITT who have T2DM at Baseline.
FDA-defined Valvulopathy Analysis Set:  This set will be all subjects in the ITT without FDA-defined valvulopathy 
at Baseline.  The data from this study will be pooled with the data from the 3 pivotal lorcaserin HCl studies 
(APD356-009, -010, and -011).
The Pharmacodynamic (PD) Analysis Set will be the group of subjects who have both baseline and at least 
1 postbaseline assessment of at least 1 PD parameter.
Primary Safety and Efficacy and Key Secondary Analyses (revised per Amendment 02)
The primary endpoints, MACE, and MACE+, will be analyzed using a Cox proportional hazards model that 
includes factors for treatment and stratification variable (presence of established CV disease or CV risk factors 
without established CV disease).  (revised per Amendment 02)  For secondary and exploratory endpoints a 2-sided α 
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460 adjudicated MACE events have been recorded; the other analyses will be conducted when 1401 adjudicated 
MACE+ events have been recorded, and the study has completed.  (revised per Amendment 02)
Sequential Gatekeeping Testing Procedure
The following closed sequential gatekeeping testing procedure (SGTP) will be used to control the family-wise error 
rate (FWER) at α = 0.05 (2-sided) in testing the 2 primary endpoints (MACE and MACE+) and 1 key secondary 
endpoint, conversion to T2DM.  (revised per Amendment 02)
Let H01 be the gatekeeping null hypothesis for noninferiority testing of the MACE endpoint using a noninferiority 
margin of 1.4.
Let H02 and H03 be the null hypotheses for superiority testing: MACE+ and conversion to T2DM, respectively.  
(revised per Amendment 02)
The SGTP testing hierarchy is presented below.  (revised per Amendment 02)

STEP1:  At the interim analysis, test the noninferiority hypothesis for MACE, H01 (α = 0.025, 1-sided).  If 
H01 is rejected, then proceed to STEP2, otherwise stop testing and the trial will be stopped.

STEP2:  At study completion the hypothesis H02 (α = 0.05, 2-sided) is tested first. If the hypothesis is 
rejected, then proceed to test H03 (α = 0.05, 2-sided). If H02 is not rejected, then testing stops at this point.   
The flowchart below presents the SGTP:
Primary Endpoint Analyses

Time to MACE:  The estimate of the hazard ratio of lorcaserin HCl to placebo and the corresponding 
1-sided 97.5% confidence interval (CI) will be calculated.  Noninferiority of lorcaserin HCl to placebo will 
be declared if the upper limit of the 97.5% CI is less than the noninferiority margin of 1.4.  The Total Time 
Analysis Set will be used as the primary analysis at the interim analysis.  (revised per Amendment 02)   The 
On-Treatment Analysis Set and the On-Treatment plus 30 Days Analysis Set will be used as sensitivity 
analyses at study completion.  (revised per Amendment 02)


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
Time to MACE+:  The estimate of the hazard ratio of lorcaserin HCl to placebo and the corresponding 
2-sided 95% CI will be calculated.  The Total Time Analysis Set will be used as the primary analysis.  
(revised per Amendment 02)  The On-Treatment Analysis and the On-Treatment plus 30 Days Analysis Set 
will be used as sensitivity analyses.
The incidence rate difference and the incidence rate ratio between lorcaserin HCl and placebo will also be analyzed 
as supportive analysis for the primary endpoints above, at study completion. (revised per Amendment 02)
Sensitivity analyses will be performed at study completion for the MACE and MACE+ endpoints using the Total 
Time Analysis Set.  (revised per Amendment 02)  This sensitivity analysis will not count a MACE or MACE+ event 
that occurs after the subject starts another weight reduction medication or undergoes bariatric surgery.  (revised per 
Amendment 02)
Key Secondary Endpoint Analysis (revised per Amendment 02)

Time to conversion to T2DM:  The estimate of the hazard ratio of lorcaserin HCl to placebo and the 
corresponding 2-sided 95% CI will be calculated.  The Prediabetes and Total Time Analyses Sets will be 
used as the primary for this analysis. The Prediabetes along with the On-Treatment Analysis Set and the 
On-Treatment plus 30 Days Analysis Set will be used as a sensitivity analysis at study completion.
(revised per Amendment 02)
Secondary Endpoint Analyses 
For the following endpoints, a Cox proportional hazards model with factors for treatment and stratification variable 
(presence of established CV disease or CV risk factors without established CV disease) will be used.  The estimate 
of the hazard ratio of lorcaserin HCl to placebo and the corresponding 2-sided 95% CI will be calculated.  
o
The time-to-event of each component of MACE+. The Total Time Analysis Set will be used as the 
primary analysis.  The On-Treatment Analysis Set and the On-Treatment plus 30 Days Analysis Set will 
be used as sensitivity analyses.
o
Time-to-event of all-cause mortality. The Total Time Analysis Set will be used as the primary analysis.  
The On-Treatment Analysis Set and the On-Treatment plus 30 Days Analysis Set will be used as 
sensitivity analyses.
o
Time-to-event of new onset renal impairment or worsening existing renal impairment in all subjects.
The ITT Analysis Set will be used for this analysis.  (revised per Amendment 02)
o
Time-to-event of new onset renal impairment or worsening existing renal impairment in subjects with 
T2DM at Baseline.  The T2DM Analysis Set will be used for this analysis.
o
Time-to-event of new onset renal impairment or worsening existing renal impairment in subjects with 
prediabetes at Baseline.  The Prediabetes Analysis Set will be used for this analysis.  (revised per 
Amendment 01)
o
Time-to-event of improvement in renal function.  The T2DM Analysis Set will be used for this analysis.
o
Time-to conversion to T2DM in subjects without any type of diabetes at Baseline.  The Nondiabetes 
Analysis Set will be used for this analysis.   (revised per Amendment 01)
o
Time to conversion to normal glucose homeostasis (HbA1c ≤5.6% and fasting plasma glucose 
<100 mg/dL without any antidiabetic treatment).  The Prediabetes Analysis Set will be used for this 
analysis.  (revised per Amendments 01 and 02)

Change from Baseline in HbA1c at 6 months in subjects with T2DM at Baseline will be analyzed using an 
analysis of covariance (ANCOVA) model with treatment and stratification variable (presence of 
established CV disease or CV risk factors without established CV disease) as factors, and baseline HbA1c, 
as a covariate.  Comparison between lorcaserin HCl and placebo will be made at 6 months.  The estimated 
treatment difference between lorcaserin HCl and placebo and the 2-sided 95% CI will be calculated.  The 


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T2DM Analysis Set will be used for this analysis.  (revised per Amendment 01)

The proportion of subjects who meet FDA-defined valvulopathy in echocardiographically determined heart 
valve changes will be analyzed using logistic regression including treatment as a factor and baseline BMI 
as a covariate.  Comparison between lorcaserin HCl and placebo will be made at 1 year.  The FDA-defined 
Valvulopathy Analysis Set will be used for this analysis.

The proportion of subjects with FDA-defined valvulopathy at Baseline who demonstrate worsened 
FDA-defined valvulopathy at 1 year will be analyzed using logistic regression including treatment as a 
factor and baseline BMI as a covariate.  A comparison between lorcaserin HCl and placebo will be made at 
1 year.  The ITT analysis set in subjects with FDA-defined valvulopathy at Baseline will be used for this 
analysis.  (revised per Amendment 01)

The change from Baseline in echocardiographically-determined pulmonary arterial systolic pressure will be 
analyzed using a mixed-effects model with repeated measures with treatment as a factor and baseline BMI 
as a covariate.  Comparison between lorcaserin HCl and placebo will be made at 1 year and the 
corresponding 2-sided 95% CI will be calculated.  The ITT will be used for this analysis.  (revised per 
Amendment 01)
Exploratory Endpoint Analyses

The change from Baseline in CV risk factors (body weight, BMI, waist and hip circumference, 
dyslipidemia, insulin level, hypertension, inflammatory biomarkers) will be analyzed using a mixed-effects 
model with repeated measures with treatment and stratification variable (presence of established CV 
disease or CV risk factors without established CV disease) as factors.  Comparison between lorcaserin HCl 
and placebo will be made at 1 year.  The ITT will be used for this analysis.

For subjects with NAFLD at Baseline, the change from Baseline in LFTs (AST, ALT, alkaline 
phosphatase, GGT, total and direct bilirubin) will be analyzed using a mixed-effects model with repeated 
measures with treatment and stratification variable (presence of established CV disease or CV risk factors 
without established CV disease) as factors.  Comparison between lorcaserin HCl and placebo will be made 
at 1 year.  The ITT will be used for this analysis.

The proportion of subjects who meet FDA-defined valvulopathy in echocardiographically determined heart 
valve changes will be analyzed using logistic regression including treatment as a factor and baseline BMI 
as a covariate.  Comparison between lorcaserin HCl and placebo will be made at 2 years and yearly 
thereafter.  The FDA-defined Valvulopathy Analysis Set will be used for this analysis.

The change from baseline in eGFR and ACR will be analyzed using a mixed-effects model with repeated 
measures with treatment as a factor and baseline value as a covariate.  Comparison of the trajectories for 
lorcaserin HCl and placebo will be made at 1 year, yearly thereafter, and at EOS.  The ITT will be used for 
this analysis.

The change from Baseline in echocardiographically-determined pulmonary arterial systolic pressure will be 
analyzed using a mixed-effects model with repeated measures with treatment as a factor and baseline BMI 
as a covariate.  Comparison between lorcaserin HCl and placebo will be made at 2 years and yearly 
thereafter.  The ITT will be used for this analysis.

Change from Baseline in HbA1c, FPG, fasting insulin levels, and HOMA-IR at 6 months in subjects with 
T2DM at Baseline will be analyzed using an ANCOVA model with treatment and stratification variable 
(presence of established CV disease or CV risk factors without established CV disease) as factors, and 
baseline HbA1c, as a covariate.  Comparison between lorcaserin HCl and placebo will be made at 6 months.  
The estimated treatment difference between lorcaserin HCl and placebo and the 2-sided 95% CI will be 
calculated.  The T2DM Analysis Set will be used for this analysis, in the following subpopulations.
(revised per Amendments 01 and 02)


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o
Subjects with (HbA1c>7%) at Baseline
o
Subjects who have not been treated with antidiabetic agents at Baseline 
o
Subjects who are on monotherapy with oral antidiabetic agents at Baseline.
o
Subjects with early T2DM (duration of diagnosis of diabetes is less than 5 years) at Baseline.

Proportion of subjects with reduction in the number of OAD medications or reduction in the dosage of 
OAD medications in the following subpopulations of subjects with T2DM at Baseline will be analyzed
using logistic regression including treatment as factor.  Comparison between lorcaserin HCl and placebo 
will be made at 6 months. The T2DM Analysis Set will be used for this analysis, in the following 
subpopulations: (revised per Amendment 01)
o
Subjects with (HbA1c >7%) at Baseline
o
Subjects who are on monotherapy with oral antidiabetic agent at Baseline 
o
Subjects with early T2DM (duration of diagnosis of diabetes is less than 5 years) at Baseline. 

Proportions of subjects with at least a 1-stage reduction in an obesity-related complication (prediabetes, 
metabolic syndrome, T2DM, hypertension, and hypertriglyceridemia/dyslipidemia), incidence of other
obesity-related complications will be collected through AE reports, medical history, and use of concomitant
medications, will be analyzed using logistic regression including treatment as factor.  Comparison between 
lorcaserin HCl and placebo will be made at 1 year and EOS.  The Safety Analysis Set will be used for this 
analysis.  (revised per Amendment 01)
Logistic regression including treatment as factor will be used for the following endpoints.  Comparison between 
lorcaserin HCl and placebo will be made at EOS.  (revised per Amendment 01)
The Prediabetes Analysis Set will be used for the following analyses:   (revised per Amendment 01)

Proportions of subjects with prediabetes at Baseline who develop new diagnosis of diabetic retinopathy at 
EOS (revised per Amendment 01)

Proportions of subjects with prediabetes at Baseline who develop new diagnosis of diabetic neuropathy at 
EOS  (revised per Amendment 01)  
The T2DM Analysis Set will be used for the following analyses:  (revised per Amendment 01)

Proportions of subjects with T2DM at Baseline who develop new diagnosis of diabetic retinopathy at EOS  
(revised per Amendment 01)

Proportions of subjects with T2DM at Baseline who develop new diagnosis of diabetic neuropathy at EOS  
(revised per Amendment 01)
Pharmacokinetic Analyses
Not applicable
Pharmacodynamic Analyses
A PD analysis plan may be defined and reported separately.
Biomarker Analyses
A biomarker analysis plan may be defined and reported separately.
Pharmacogenomic Analyses
A pharmacogenomic analysis plan may be defined and reported separately.


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Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs (including changes from 
baseline in physical examination), out-of-normal-range laboratory safety test variables, abnormal ECG findings, 
along with change from Baseline in laboratory safety test variables, ECGs, suicidality and vital sign measurements
will be summarized yearly by treatment group using descriptive statistics.
The incidence of AEs of interest will be summarized separately.  In addition, for each AE of interest, Kaplan-Meier 
curves and median time and 95%CI will be presented.  The Safety Analysis Set will be used for this analysis.
Other Analyses

Not applicable
Interim Analysis
There will be 1 interim analysis; when 460 adjudicated MACE events have occurred, the primary analysis for 
MACE will be conducted.  This will be the analysis to rule out a hazard ratio of 1.4.  The study will continue to 
accrue events until the required number of MACE+ have occurred.  (revised per Amendment 02)  Sensitivity 
analysis for MACE endpoint will be performed after all the MACE+ events have accrued.  (revised per 
Amendment 02)  At the time of MACE+ analyses, there will be approximately 600 MACE events.
The interim analysis for MACE endpoint will be performed by an independent statistician and governed by an 
independent DMC and is anticipated to occur on or before (approximately) Jul 2017.  (revised per Amendment 02)  
The interim analysis will be conducted to establish whether the MACE primary objective has been achieved.  To 
maintain the integrity and  credibility of the trial, procedures will be implemented to ensure the DMC and 
independent statistician have sole access to evolving information from the clinical trial regarding comparative 
efficacy and safety data aggregated by treatment group.  Full details of the DMC procedures including primary 
responsibilities of the DMC, its relationship with other trial components, its membership, and the purpose and 
timing of its meetings will be documented in the DMC Charter.  These details will also include procedures to ensure 
confidentiality and proper communication (as outlined in the Study Integrity Charter), the safety and statistical 
monitoring guidelines to be implemented by the DMC, and an outline of the content of the closed reports and open 
reports that will be provided to the DMC.  (revised per Amendment 02)
At the interim analysis for MACE, the estimate of the hazard ratio of lorcaserin HCl to placebo and the 
corresponding 97.5% CI will be calculated.  Noninferiority between lorcaserin HCl and placebo will be declared if 
the upper limit of the 97.5% CI is less than or equal to the noninferiority margin of 1.4.  If the upper limit of the 
97.5% CI is greater than 1.4, then lorcaserin HCl will be declared as not noninferior to placebo and the trial will 
stop.
If noninferiority between lorcaserin HCl and placebo is confirmed when 460 adjudicated MACE events are observed 
at approximately 43 months from the start of the study, then the study will be continued to observe 1401 MACE+ 
events at approximately 54 months from the start of the study, and a minimum median treatment duration of 
2.5 years have accrued.  (revised per Amendment 02)  The events for MACE+ and T2DM will be tested according 
to the SGTP described previously, upon study completion.  (revised per Amendment 02)
Sample Size Rationale
A sample size of 12,000 subjects should provide the required power for the primary endpoints and key secondary 
endpoint as follows:
Primary Endpoints (revised per Amendment 02)

For 460 MACE events to have occurred by approximately 43 months from start of the study, providing 
95% power to exclude a noninferiority margin of 1.4, assuming an annual background rate of 1.5%, 
15-month accrual period, 5% annual drop-out rate, α = 0.025, and a 1-sided test

For 1401 MACE+ events to have occurred by approximately 54 months from the start of the study, 
providing >85% power to detect a 15% risk reduction with lorcaserin HCl, assuming an annual background 


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rate of 3.5%, 15-month accrual period, 5% annual drop-out rate, α = 0.05, and a 2-sided test
Key Secondary Endpoint (revised per Amendment 02)

For 457 events of conversion to T2DM in subjects who are prediabetic at the time of enrollment (~33%) to 
have occurred by approximately 54 months from the start of the study, providing 86% power to detect a 
25% risk reduction with lorcaserin HCl, assuming an annual background rate of 4%, 15-month accrual 
period, 5% annual drop-out rate, α = 0.05 and a 2-sided test.  


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3
TABLE OF CONTENTS
REVISION HISTORY
i
1
TITLE PAGE
1
2
SYNOPSIS
2
3
TABLE OF CONTENTS
21
LIST OF IN-TEXT TABLES
24
LIST OF IN-TEXT FIGURES
24
LIST OF APPENDICES
24
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
25
5
ETHICS
28
5.1
Institutional Review Boards/Independent Ethics Committees
28
5.2
Ethical Conduct of the Study
28
5.3
Subject Information and Informed Consent
29
6
INVESTIGATORS AND STUDY PERSONNEL
31
7
INTRODUCTION
32
7.1
Study Rationale
33
8
STUDY OBJECTIVES
35
8.1
Primary Objectives
35
8.2
Secondary Objectives
35
8.3
Exploratory Objectives
36
9
INVESTIGATIONAL PLAN
38
9.1
Overall Study Design and Plan
38
9.1.1
Prerandomization Phase
40
9.1.2
Randomization Phase
40
9.1.2.1
Treatment Period
41
9.1.2.2
Follow-up Period
41
9.2
Discussion of Study Design
41
9.3
Selection of Study Population
42
9.3.1
Inclusion Criteria
42
9.3.2
Exclusion Criteria
43
9.3.3
Removal of Subjects From Therapy or Assessment
45
9.4
Treatments
45
9.4.1
Treatments Administered
45
9.4.2
Identity of Investigational Product
46
9.4.2.1
Chemical Name, Structural Formula of BELVIQ
46
9.4.2.2
Comparator Drug
46
9.4.2.3
Labeling for Study Drug
46
9.4.2.4
Storage Conditions
47
9.4.3
Method of Assigning Subjects to Treatment Groups
48
9.4.4
Selection of Doses in the Study
48


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9.4.5
Timing of Dose for Each Subject
48
9.4.5.1
Dose Reduction, Interruption, and Restarting of Study 
Drug  (revised per Amendment 01)
48
9.4.6
Blinding
50
9.4.7
Prior and Concomitant Therapy
50
9.4.7.1
Drug-Drug Interactions
51
9.4.7.2
Prohibited Concomitant Therapies and Drugs
51
9.4.8
Treatment Compliance
53
9.4.9
Drug Supplies and Accountability
53
9.5
Study Assessments
55
9.5.1
Assessments
55
9.5.1.1
Demography
55
9.5.1.2
Baseline Assessments
55
9.5.1.3
Primary Safety/Efficacy Assessments
55
9.5.1.4
Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic/Pharmacogenetic Assessments
56
9.5.1.5
Safety Assessments
59
9.5.2
Schedule of Procedures/Assessments
67
9.5.2.1
Schedule of Procedures/Assessments
67
9.5.3
Appropriateness of Measurements
72
9.5.4
Reporting of SAEs, Hypoglycemia, Pregnancy, and Other 
Events of Interest
72
9.5.4.1
Reporting of SAEs
72
9.5.4.2
Reporting of Hypoglycemia
73
9.5.4.3
Reporting of Pregnancy and Exposure to Study Drug 
Through Breastfeeding
73
9.5.4.4
Reporting of Events Associated with Special Situations
74
9.5.4.5
Expedited Reporting
76
9.5.4.6
Breaking the Blind
76
9.5.4.7
Regulatory Reporting of AEs
76
9.5.5
Completion/Discontinuation of Subjects
76
9.5.5.1
Premature Discontinuation of Study Drug
76
9.5.5.2
Discontinuation from Study Procedures/Withdrawal of 
Consent
77
9.5.6
Abuse or Diversion of Study Drug
78
9.5.7
Confirmation of Medical Care by Another Physician
78
9.6
Data Quality Assurance
78
9.6.1
Data Collection
79
9.6.2
Clinical Data Management
79
9.7
Statistical Methods
79
9.7.1
Statistical and Analytical Plans
79
9.7.1.1
Study Endpoints
79
9.7.1.2
Definitions of Analysis Sets
83
9.7.1.3
Subject Disposition
83


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9.7.1.4
Demographic and Other Baseline Characteristics
84
9.7.1.5
Prior and Concomitant Therapy
84
9.7.1.6
Primary Safety and and Key Secondary Efficacy 
Analyses (revised per Amendment 02)
85
9.7.1.7
Secondary Endpoint Analyses
87
9.7.1.8
Exploratory Endpoints Analyses
88
9.7.1.9
Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic/Pharmacogenetic Analyses
90
9.7.1.10
Safety Analyses
91
9.7.2
Determination of Sample Size
93
9.7.3
Interim Analysis
93
9.7.4
Other Statistical/Analytical Issues
94
9.7.5
Procedure for Revising the Statistical Analysis Plan
94
10
REFERENCE LIST
95
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES)
96
11.1
Changes to the Protocol
96
11.2
Adherence to the Protocol
96
11.3
Monitoring Procedures
96
11.4
Recording of Data
97
11.5
Identification of Source Data
97
11.6
Retention of Records
98
11.7
Auditing Procedures and Inspection
98
11.8
Handling of Study Drug
98
11.9
Publication of Results
99
11.10 Disclosure and Confidentiality
99
11.11 Discontinuation of Study
99
11.12 Subject Insurance and Indemnity
100
12
APPENDICES
101


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LIST OF IN-TEXT TABLES
Table 1
Approximate Stratification of Subjects
38
Table 2
Treatments Administered
45
Table 3
Clinical Laboratory Tests
64
Table 4
Schedule of Procedures/Assessments in Study APD356-G000-401
68
LIST OF IN-TEXT FIGURES
Figure 1
Study Design Schematic
40
Figure 2
Measuring Tape Position for Waist Circumference
65
Figure 3
Flowchart for SGTP
86
LIST OF APPENDICES
Appendix 1
WHO Functional Classification of Pulmonary Hypertension
102
Appendix 2
Classification of Chronic Kidney Disease
103
Appendix 3
Sponsor’s Grading for Laboratory Values
104
Appendix 4
APD356-G000-401 Healthy Lifestyle Program
106
Appendix 5
Biomarker Research
107
Appendix 6
Pharmacogenetic Research
116


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
(revised per Amendments 01 and 02)
Abbreviation
Term
AACE
American Association of Clinical Endocrinologists
ACE
American College of Endocrinology
ACR
albumin-to-creatinine ratio
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BID
twice daily
BMI
body mass index
BNP
B-type natriuretic peptide
BP
blood pressure
BSA
body surface area
CA
Competent Authority
CAD
coronary artery disease
CEC
Clinical Endpoint Committee
CFR
Code of Federal Regulations
CI
confidence interval
CKD
chronic kidney disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CV
cardiovascular
CVD
cardiovascular disease
CVOT
cardiovascular outcomes trial
DEA
Drug Enforcement Administration
DMC
Data Monitoring Committee
DPP
Diabetes Prevention Program
eGFR
estimated glomerular filtration rate
ECG
electrocardiogram
EER
Estimated Energy Requirement
EOS
end of study
EOT
end of treatment
ESRD
end-stage renal disease
EU
European Union


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Abbreviation
Term
FDA
Food and Drug Administration
FPG
fasting plasma glucose
FWER
family-wise error rate
GCP
Good Clinical Practice
GGT
gamma glutamyl transpeptidase
HbA1c
glycosylated hemoglobin
HDL-C
high density lipoprotein-cholesterol
HF
heart failure
HR
heart rate
hsCRP
high sensitivity C-reactive protein
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IL
interleukin
IND
Investigational New Drug
IRB
Institutional Review Board
ITT
Intent-to-Treat
IxRS
interactive voice and/or web response system
LDL-C
low density lipoprotein-cholesterol
LFTs
liver function tests
LNH
low/normal/high
LV
left ventricular
MACE
major adverse cardiovascular events
MACE+
MACE or hospitalization for unstable angina or heart failure, or 
any coronary revascularization
MAOI
monoamine oxidase inhibitor
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MRI
magnetic resonance imaging
SGTP
sequential gatekeeping testing procedure
NAFLD
Non-Alcoholic Fatty Liver Disease
NKF
National Kidney Foundation
OGTT
oral glucose tolerance test
OTC
over-the-counter
PD
pharmacodynamic
PGx
pharmacogenomics
PH
pulmonary hypertension
PI
principal investigator
PK
pharmacokinetic


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Abbreviation
Term
PT
preferred term
QTc
corrected QT interval
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SNRI
serotonin norepinephrine reuptake inhibitor
SOC
system organ class
SOP
standard operating procedure
SSRI
selective serotonin reuptake inhibitor
SUSAR
Suspected, Unexpected, Serious Adverse Reaction
T2DM
type 2 diabetes mellitus
TCA
tricyclic antidepressant
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
TIMI
Thrombolysis in Myocardial Infarction
TNF-
tumor necrosis factor-alpha
ULN
upper limit of normal
US
United States
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 
(ICH) E6 (Good Clinical Practice [GCP]), Section 3, and any local regulations.  Any protocol 
amendment or revision to the ICF will be resubmitted to the IRB/IEC for review and approval, 
except for changes involving only logistical or administrative aspects of the study (eg, change in 
clinical research associates [CRAs], change of telephone numbers).  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 must be sent to the Principal Investigator
(PI) (or if regionally required, the head of the medical institution) 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 (or if 
regionally required, the head of the medical institution) 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 (or if regionally required, the investigator and the relevant IRB via the head 
of the medical institution) 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 database lock. 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 GCP guidelines as required by 
the following:


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●
Principles of the World Medical Association Declaration of Helsinki 2008
●
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 (US) 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
●
A waiver from the IRBs/IECs will be obtained before study initiation for non-US studies 
conducted under an Investigational New Drug (IND) application.
●
European GCP Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies 
conducted within any European Union (EU) country.  All Suspected, Unexpected,
Serious Adverse Reactions (SUSARs) will be reported, as required, to the Competent 
Authorities of all involved EU member states, if applicable.
●
Other applicable regulatory authorities’ requirements or directives
This study will be conducted in accordance with national and local laws (eg, Drug and Narcotics 
laws of the countries where study sites are located).
5.3
SUBJECT INFORMATION AND INFORMED CONSENT
As part of administering the informed consent document, the investigator must explain to each 
subject the nature of the study, its purpose, the procedures involved, the expected duration, the 
potential risks and benefits involved, any potential discomfort, potential alternative procedures or 
courses of treatment available to the subject, and the extent of maintaining confidentiality of the 
subject’s records.  (revised per Amendment 01)  Each subject must be informed that participation 
in the study is voluntary, that he/she may withdraw from the study at any time, and that 
withdrawal of consent will not affect his/her subsequent medical treatment or relationship with 
the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and dating it 
and will be given a copy of the signed document.  If a subject is unable to read, an impartial 
witness should be present during the entire informed consent discussion. 
(revised per 
Amendment 01)  After the ICF and any other written information to be provided to subjects is 
read and explained to the subject, and after the subject has orally consented to participate 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. (revised per Amendment 01) 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.


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An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH E6, 
Section 4, and all applicable local regulations.  Each subject must sign an approved ICF before 
study participation, including an option to have other biomarkers collected for future research.  
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.
Subjects will be asked to sign a separate ICF for the collection of pharmacogenomic samples.


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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 500 multinational investigational sites.  (revised per Amendment 01)
The name and telephone and fax numbers of the medical monitor and other contact personnel at 
the sponsor and of the contract research organizations (CROs) will be listed in the Investigator 
Study File provided to each site. (revised per Amendment 01)


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7
INTRODUCTION
Obesity has reached global epidemic proportions as the prevalence has nearly doubled from 
20 years ago. According to the World Health Organization (WHO), more than 1 billion adults 
worldwide are overweight, and at least 300 million are obese.1 In the US, more than one-third of 
adults (35.7%) and almost 17% of children and adolescents are obese.2 Obesity is a major risk 
factor for life threatening diseases such as type 2 diabetes mellitus (T2DM), heart attack, stroke, 
and some forms of cancer.  For example, the age-adjusted relative risk of developing T2DM is 
approximately 10-fold higher for men with a body mass index (BMI) of 30 kg/m2 relative to men 
with a BMI <23 kg/m2 and the risk is even higher for women, where a BMI of 30 kg/m2 is 
associated with an approximately 30-fold higher risk.3,4 Obesity is a major cause of morbidity 
and mortality, and it is estimated that there are 300,000 obesity-related deaths annually in the US 
alone.5
It is well established that modest weight reductions of 5% to 10% of body weight can decrease 
blood pressure (BP) and total blood cholesterol, improve glucose tolerance in diabetic patients 
and those with impaired glucose tolerance prone to develop diabetes, and reduce the severity of
obstructive sleep apnea. Given the rise in the prevalence of obesity, even modest weight loss can 
be important to the overall health. 
Current approaches to weight management include life style modification, pharmacotherapy and 
invasive bariatric procedures.  Lifestyle modification involving a combination of diet, exercise, 
and behavioral change is the preferred and essential strategy for weight management in obese 
and overweight individuals. Although behavior 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 behavioral changes 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 beneficial effects 
of many available agents are in part offset by side effects that can include increased BP (agents 
with sympathomimetic activity) or unpleasant gastrointestinal events (orlistat). 
Over the past 2 decades there have been numerous attempts to develop safe and effective drugs 
for weight management.  However, most have failed to gain approval or have been withdrawn 
from the market due to serious safety concerns.  Furthermore, no agent has demonstrated long-
term cardiovascular (CV) benefit.
APD356/BELVIQ® (lorcaserin hydrochloride) 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 greater than or equal to 30 kg/m2 (obese), or adult patients with a BMI 


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greater than or equal to 27 kg/m2 (overweight) in the presence of at least 1 weight-related 
comorbid condition.
The Phase 3 clinical evaluation of lorcaserin HCl in clinical trials of more than 7700 patients, 
including 604 patients with 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 lorcaserin HCl 10 mg twice daily (BID) dose met prespecified 
primary endpoints for weight loss:

A significantly greater proportion of patients taking lorcaserin HCl lost ≥5% of baseline 
body weight at 1 year as compared to placebo

The mean weight loss at 1 year in patients taking lorcaserin HCl was significantly greater 
than that in patients taking placebo

A significantly greater proportion of patients taking lorcaserin HCl lost ≥10% of baseline 
body weight at 1 year as compared to placebo

The weight loss efficacy was supported in each trial by favorable trends in multiple other 
measures of CV risk, glycemic control and quality of life.  

Glycosylated hemoglobin (HbA1c) was statistically significantly reduced by 0.5% among 
patients with T2DM compared to placebo.
Based on the results of the Phase 3 data, BELVIQ (lorcaserin HCl) has a favorable benefit-risk 
profile as a pharmacological agent for weight management in obese and overweight patients.
The overall efficacy and safety profile of BELVIQ (lorcaserin HCl) makes it an ideal 
pharmacological agent for weight management, potentially leading to a long term CV benefit.
7.1
STUDY RATIONALE
The sample size and duration of this cardiovascular outcomes trial (CVOT) allows us to design 
the study not only to meet FDA’s requirements but, in addition, to evaluate additional 
indications. 
In the previously pooled Phase 3 dataset from Studies APD356-009 and 
APD356-011 (the 2 nondiabetic studies, total n=7190), BELVIQ (lorcaserin HCl) significantly 
improved BMI, waist circumference, serum lipid profiles, BP, glycemic parameters, and other 
markers of CV risk (high sensitivity C-reactive protein [hsCRP], fibrinogen).  These findings 
suggest that rather than there being a risk of an increase in CV events, it is possible that through 
improvement in risk parameters, BELVIQ (lorcaserin HCl) may have a favorable impact on CV 
risk, and therefore a reduction in major adverse cardiovascular events (MACE)+ is included in 
the study as a coprimary endpoint.
By selecting a large diabetes subpopulation within a population of otherwise high CV risk 
subjects, this study will be able to evaluate the safety of BELVIQ (lorcaserin HCl) in patients 
with type 2 diabetes and additional CV risk, contributing to satisfying the requirement of 
establishing CV safety for a potential future diabetes indication.


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In a historic clinical trial, Diabetes Prevention Program (DPP)6, a 5% weight loss translated to a 
significant decrease in the incidence of new diabetes. In the pooled Phase 3 dataset from studies 
APD356-009 and APD356-011 (the 2 nondiabetic studies, total n=7190), weight loss was 
significantly greater than 5% in the BELVIQ-treated group.  In the prediabetes subpopulation 
(25% of the total combined population) of the aforementioned studies, BELVIQ (lorcaserin HCl) 
statistically significantly decreased the incidence of newly developed T2DM (HbA1c ≥6.5). In 
addition, the 2 studies demonstrated that BELVIQ (lorcaserin HCl) improves fasting glucose, 
HbA1c, and insulin resistance in these insulin-resistant nondiabetic populations. In the current 
proposed study, there is a significant prediabetic obese population (approximately 25% to 35% 
of the total population), which allows confirmation of the Phase 3 trial findings. (revised per 
Amendment 01) 
In addition, the large sample size and long follow-up duration in this 
subpopulation provides the opportunity to demonstrate BELVIQ (lorcaserin HCl) not only can 
delay conversion to T2DM, but also delay the progression of renal impairment due to diabetes, 
which will confirm that the effect is indeed due to glycemic benefit, not due to improvement of 
other risk factors.
In the APD356-010 trial (n=508), BELVIQ (lorcaserin HCl) significant improved glycemic
control across all BMI categories on top of standard diabetes treatment. The proposed substudy 
in T2DM subjects at Baseline treated with oral anti-diabetics (OADs) allow confirmation of the 
Phase 3 trial finding that BELVIQ (lorcaserin HCl) improves glycemic control in this diabetic 
subpopulation. The large sample size (the diabetes population at Baseline is about 50% of the 
total population) allows further demonstration of the independent effect of glycemic benefit from 
other improvement in weight reduction-related risk factors.


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8
STUDY OBJECTIVES
8.1
PRIMARY OBJECTIVES
Safety:

To demonstrate that, in obese and overweight subjects with CV disease and/or multiple 
CV risk factors, lorcaserin HCl 10 mg administered BID does not increase the incidence 
of MACE (myocardial infarction [MI], or stroke, or CV death) compared to placebo, with 
a noninferiority margin for the hazard ratio of 1.4 
Efficacy:
(revised per Amendment 02)

To demonstrate that, in obese and overweight subjects with CV disease and/or multiple 
CV risk factors, lorcaserin HCl 10 mg BID reduces the incidence of MACE+ (MACE or 
hospitalization for unstable angina or heart failure
(HF),
or any coronary 
revascularization) compared to placebo
8.2
SECONDARY OBJECTIVES
Key Secondary Objective

To confirm that, in subjects with prediabetes at Baseline based on the 2013 ADA 
guideline, lorcaserin HCl 10 mg BID reduces the incidence of conversion to T2DM 
compared to placebo (revised per Amendments 01 and 02)
Other Secondary Objectives (revised per Amendment 02)
MACE and MACE+ Related:  (revised per Amendment 02)

To determine whether the rates of the individual events comprising the MACE+ 
endpoints are different in subjects on lorcaserin compared to those on placebo

To determine whether lorcaserin reduces all-cause mortality compared with placebo
Diabetes and Prediabetes Related:  (revised per Amendment 02)

To evaluate the effect of lorcaserin HCl 10 mg BID compared to placebo on conversion 
to normal glucose homeostasis at 1 year and yearly thereafter in subjects with prediabetes 
at Baseline (revised per Amendment 01)

To evaluate whether in all subjects without any type of diabetes at Baseline, lorcaserin 
HCl 10 mg BID reduces the incidence of conversion to T2DM compared to placebo 
(revised per Amendment 01)

To confirm that, in subjects with T2DM at Baseline, lorcaserin HCl 10 mg BID improves
glycemic control (HbA1c) compared to placebo at 6 months


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Renal Related:  (revised per Amendment 02)

To evaluate the long-term effect of lorcaserin HCl compared to placebo on renal function 
in all subjects (revised per Amendment 01)

To evaluate the long-term effect of lorcaserin HCl compared to placebo on renal function
in subjects with T2DM at Baseline

To evaluate the long-term effect of lorcaserin HCl compared to placebo on renal function 
in subjects with prediabetes at Baseline (revised per Amendment 02)
Safety Objectives (revised per Amendment 02)

To evaluate echocardiographically determined cardiac valvular function and pulmonary 
arterial pressure changes associated with treatment with lorcaserin HCl 10 mg BID
compared to placebo at 1 year

To evaluate the long-term safety of lorcaserin HCl 10 mg BID
8.3
EXPLORATORY OBJECTIVES

To explore the effects of long-term treatment with lorcaserin HCl 10 mg BID on 
improving CV risk factors associated with obesity (eg, body weight, dyslipidemia, insulin 
level, hypertension, inflammatory biomarkers) compared with placebo at 1 year and 
yearly thereafter

To evaluate the effect of BELVIQ (lorcaserin HCl) on other diabetes-related 
microvascular complications (retinopathy and neuropathy) compared to placebo in 
subjects with prediabetes or T2DM at Baseline at EOS.  (revised per Amendment 01)

To explore in subjects with a diagnosis of Non-Alcoholic Fatty Liver Disease (NAFLD) 
at Baseline, the effects of long-term treatment with lorcaserin HCl 10 mg BID on liver 
function compared with placebo at 1 year and yearly thereafter

To evaluate echocardiographically determined heart valve and pulmonary artery pressure 
changes associated with treatment with lorcaserin HCl 10 mg BID compared to placebo
at 2 years and yearly thereafter 

To collect and store DNA samples which may be used for examination of the impact of 
genetic variation on weight loss, the response to lorcaserin HCl, susceptibility to diabetes, 
and the risk of developing CV and other end-organ disease and their associated risk 
factors (for participating countries/sites where ethics and regulatory approval is obtained)

To collect and store serum and plasma biomarker samples which may be used for 
examination of the impact of different metabolic and CV pathologic processes on weight 
loss, the response to lorcaserin HCl, susceptibility to diabetes, and the risk of developing 
CV and other end-organ disease and their associated risk factors (for participating 
countries/sites where ethics and regulatory approval is obtained)


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
To explore the effects of long-term treatment with lorcaserin HCl (10 mg BID) on 
improvement of obesity-related complications, as defined by the 2014 Advanced 
Framework for a New Diagnosis of Obesity as a Chronic Disease (American Association 
of Clinical Endocrinologists [AACE] and American College of Endocrinology [ACE]) 
(eg, prediabetes, metabolic syndrome, hypertriglyceridemia/dyslipidemia, and potentially 
others) (revised per Amendment 01)

To demonstrate that lorcaserin HCl 10 mg BID improves glycemic control, and/or
reduction in OAD medications for the subjects treated with OADs compared to placebo 
at 6 months in the following subpopulations of patients with T2DM:  (revised per 
Amendments 01 and 02)
o
Subjects with T2DM with an (HbA1c>7%) at Baseline
o
Subjects with T2DM who have not been treated with antidiabetic agents at 
Baseline
o
Subjects with T2DM who are treated with mono oral antidiabetic agent at 
Baseline
o
Subjects with early T2DM (duration of diagnosis of diabetes is less than 5 years) 
at Baseline. 


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9
INVESTIGATIONAL PLAN
9.1
OVERALL STUDY DESIGN AND PLAN
This will be a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 
overweight and obese subjects with CV disease and/or multiple CV risk factors.  Approximately 
12,000 subjects will be randomized to 2 treatment groups in a ratio of 1:1, stratified by the 
presence of established CV disease (~80%) or CV risk factors without established CV disease 
(~20%). The 80% of subjects in the established CV disease strata will consist of a group with 
T2DM (approximately 30% of the total number of subjects in the study) and a group without 
T2DM (approximately 50% of the total number of subjects in the study).  The 20% of subjects in 
the strata with CV risk factors but without established CV disease will all have T2DM, as well as 
additional risk factors.   Therefore, approximately 50% of the total number of subjects in the 
study will have T2DM (Table 1).  
Table 1
Approximate Stratification of Subjects (revised per Amendment 02)
CV Disease
CV Disease Risk Factors
Total
T2DM
30%
20%
50%
No T2DM
50%
0%
50%
Total
80%
20%
100%
CV = cardiovascular, T2DM = type 2 diabetes mellitus.
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 will consist of 2 periods:  Treatment and Follow-up.  The 
Treatment Period will last for approximately 5 years with approximately 18 visits.  The first dose 
should be taken at Visit 2. (revised per Amendment 01)  The Follow-up Period extends from the 
end of treatment (EOT) visit to the EOS visit.  Sponsor Notification of Study Completion will 
occur once 1401 MACE+ events, 460 MACE events, and median treatment duration of 2.5 years
have accrued.
This is expected to occur on or before October 2018.  Following this 
announcement (“Sponsor Notification of Study Completion”), sites will be instructed to bring 
subjects who remain on treatment for an EOT visit.  An EOS visit will occur approximately 
30 days later for subjects on treatment at Sponsor Notification of Study Completion. (revised per 
Amendment 01)  Subjects who are still being followed in the study but have already 
discontinued study medication ≥30 days before will return for an EOS visit.  Subjects who are 
still being followed in the study but who discontinued study medication within the last 30 days 
will return for an EOS visit approximately 30 days after their last dose of study medication.  
Subjects will receive lorcaserin HCl 10 mg BID or placebo BID for approximately 5 years.  
Throughout the duration of the study, subjects will be provided with instructions regarding a 
reduced-calorie 
diet 
and 
increased 
physical 
activity 
program
(see
Appendix 
4). 
Echocardiography will be performed on a subset of subjects at Baseline and at 6, 12, 18, and 
24 months, and yearly thereafter. Acquisition of new ECHO data in all subjects will cease when 


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at least 1000 subjects have completed the Month 36 echocardiographic assessment.  (revised per 
Amendment 02)
All subjects will continue in the study until study completion, rather than for a prespecified 
number of visits. Subjects who prematurely discontinue study drug will continue in the study for 
all subsequent study visits until study completion and are to complete visit procedures as 
indicated in Table 4.  It is preferred that these visits are in person.  However, if the subject is 
unable to attend a visit in person, a telephone visit may be performed.  The outcome of the 
telephone visit must be clearly documented in the source record.  At a minimum, the site should 
attempt to have the subject return for an in-person visit at least once per year.  The study will 
terminate when 1401 MACE+ events have occurred and when there has been a median treatment 
duration of 2.5 years have accrued.  (revised per Amendment 02)  This is expected to occur on or 
before October 2018. 
When 460 adjudicated MACE events have occurred, an interim analysis will be conducted on 
MACE events (see Section 9.7.3).  It will be conducted to establish whether the primary safety 
objective (MACE noninferiority) has been achieved.  This analysis will be performed by an 
independent statistician and governed by an independent Data Monitoring Committee (DMC)
and is anticipated to occur on or before (approximately) July 2017.  (revised per 
Amendment 02).  If the primary safety objective has been achieved, the trial will continue for 
evaluation of additional endpoints as delineated in the objectives.
An overview of the study design is presented in Figure 1.


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Figure 1
Study Design Schematic
BID = twice daily; EOS = end of study; EOT = end of treatment; R = randomization.
9.1.1
Prerandomization Phase
The Prerandomization Phase will last up to 30 days and consist of 1 visit during which subjects 
will be screened for eligibility and continue until randomization or exclusion.  The purpose of the 
Prerandomization Phase is to obtain informed consent and to establish protocol eligibility.  
Informed consent will be obtained after the study has been fully explained to each subject and 
before the conduct of any screening procedures or assessments.  Procedures to be followed when 
obtaining informed consent are detailed in Section 5.3.
Subjects must be overweight or obese with CV disease or other CV risk factors and must meet 
all inclusion and exclusion criteria.  The Screening Disposition case report form (CRF) page 
must be completed to indicate whether the subject is eligible to participate in the study and to 
provide reasons for screen failure, if applicable.
9.1.2
Randomization Phase
The duration of the Randomization Phase will be approximately 56 months and will include 
2 periods:  Treatment and Follow-up.  Subjects whose screening assessments and evaluations are 
completed and reviewed by the investigator and who continue to meet all of the 
Period:
R
Lorcaserin HCl 10 mg BID
Day -30
Day 1
EOS
Treatment
Placebo BID
~5 years
EOT
Phase:
Prerandomization
Randomization
Follow-
up


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inclusion/exclusion criteria will enter the Randomization Phase.  Subjects will be randomized in 
a 1:1 ratio to receive lorcaserin HCl 10 mg BID or placebo.
9.1.2.1
Treatment Period
The Treatment Period will last for approximately 5 years with approximately 18 visits.  The first 
dose should be taken at the Randomization visit (Visit 2).  (revised per Amendment 01) During 
the Treatment Period, subjects will continue treatment with the dose of lorcaserin HCl 10 mg or 
placebo BID in blinded fashion.
9.1.2.2
Follow-up Period
For subjects who remain in the study through the Sponsor Notification of Study Completion, the 
Follow-up Period will begin immediately after the EOT assessments have been completed, and 
will consist of 1 EOS visit, occurring 30 days 10 days after last dose of study drug for subjects 
who complete study treatment.
(revised per Amendments 01 and 02)  See Section 9.3.3 for 
procedures for subjects who prematurely discontinue study drug.
9.2
DISCUSSION OF STUDY DESIGN
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.
A placebo control is 
considered appropriate because study drug treatment will be adjunctive to all standard-of-care 
therapies for background CV risk factors.
The population selected for the study targets high CV risk obese patients in order to demonstrate 
that BELVIQ (lorcaserin HCl) does not cause an increase in MACE events and may even reduce 
MACE+ events within the study period. There is significant linkage between obesity and 
diabetes and most T2DM subjects are obese. T2DM with CV risk factors confers greater CV 
risk. Inclusion of 50% of subjects with diabetes with additional CV risk factors in the total study 
population will ensure that the population is representative of patients with more advanced 
diabetes, and may also help to establish the CV safety profile for BELVIQ (lorcaserin HCl) if a
diabetes indication is pursued in the future. In addition, the sample size of this population allows 
the evaluation of BELVIQ’s short term effects on glycemic control.
The sample size of nondiabetic subjects (50% of the total study population) allows further 
confirmation of BELVIQ’s benefit in delaying conversion from nondiabetes to diabetes and 
further explores BELVIQ’s benefit in delaying diabetes progression in the long follow-up study 
duration. In addition, it may also help to establish the clinical significance of reduction of 
conversion to diabetes by the assessment of T2DM-specific induced renal impairment and its 
progression.


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9.3
SELECTION OF STUDY POPULATION
Approximately 18,000 subjects will be screened to provide 12,000 randomized subjects at 
approximately 500 sites in regions that include North America, South America, Europe, and the 
Asia-Pacific.  (revised per Amendment 01)
9.3.1
Inclusion Criteria
1. BMI ≥27 kg/m2 
2. Subjects able and willing to comply with a reduced-calorie diet and an increased physical 
activity program
3. Age ≥40 years with established CV disease as defined by 1 of the following:
a.
History of documented MI or ischemic stroke >1 month before Randomization
(revised per Amendment 01)
b. History of peripheral artery disease as manifested by symptomatic claudication with 
an ankle-brachial pressure index of <0.85 
c.
History of revascularization (coronary, carotid, or peripheral artery)
d. Significant unrevascularized coronary arterial stenosis defined as ≥50% in 2 or more 
coronary arteries
OR
Age ≥55 years for women or ≥50 years for men who have T2DM without established CV 
disease plus at least 1 of the following CV risk factors:
a.
Hypertension, defined as systolic blood pressure (SBP) >140 or diastolic blood 
pressure (DBP) >90, or currently receiving therapy for documented hypertension
b. Dyslipidemia, defined as low density lipoprotein-cholesterol (LDL-C) >130 mg/dL, 
or high density lipoprotein-cholesterol (HDL-C) <40 mg/dL7 or currently taking 
prescription lipid-lowering therapy for documented dyslipidemia
c.
Estimated glomerular filtration rate (eGFR) ≥30 to ≤60 mL/min/1.73 m2 per the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation8 (revised 
per Amendment 01)
d. hsCRP >3 mg/L9 detected by the central laboratory in the absence of known acute or 
chronic inflammatory conditions (eg, infection, rheumatologic disease) (revised per 
Amendment 01)
e.
Urinary albumin-to-creatinine ratio (ACR) ≥30 μg/mg in spot urine


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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.  A new diagnosis of T2DM (ie, discovered at Screening) 
should be based on the 2013 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:  (revised per Amendments 01 and 02)

HbA1c ≥6.5% 

fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L) 

2-hour plasma glucose ≥200 mg/dL (11.1mmol/L) by an oral glucose tolerance test 
(OGTT)
All T2DM subjects must have an HbA1c <10% at Screening.  If subjects are being treated, or 
upon diagnosis need to be treated with antidiabetic agents, the T2DM treatment regimen must be 
stable for at least 3 months prior to 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. (revised per amendment 01)  Minimal changes are defined as a change in 
insulin dose <10% of daily dose, 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 01)
4. Provide written informed consent
5. Willing and able to comply with all aspects of the protocol
9.3.2
Exclusion Criteria
1. Current moderate or greater symptoms of congestive cardiac failure (New York Heart 
Association [NYHA] class III or IV)
2. Known left ventricular (LV) ejection fraction <20%
3. Current moderate or greater symptoms of pulmonary hypertension (PH) (WHO 
functional Class III and IV)10 (see Appendix 1)
4. Known severe valvular disease defined by clinical diagnosis and/or most recent 
echocardiography.  History of severe valvular disease is allowed if it has been corrected 
by valve replacement or repair. (revised per Amendment 01)
5. Severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2 per 
the CKD-EPI equation based on ideal body weight),  or end-stage renal disease (ESRD)
(revised per Amendment 01)
6. Severe hepatic impairment (Child-Pugh score 10 to 15)
7. Use of other products intended for weight loss including prescription drugs, over-the-
counter (OTC) drugs, and herbal preparations within 1 month prior to Screening


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8. Use of more than 1 serotonergic drug within 1 month before Screening, or during the 
screening window, including but not limited to: (revised per Amendment 01)
a.
selective serotonin reuptake inhibitors (SSRIs)
b. serotonin norepinephrine reuptake inhibitors (SNRIs)
c.
tricyclic antidepressants (TCAs) 
d. bupropion
e.
triptans
f.
St. John’s Wort and tryptophan 
g. Monoamine oxidase inhibitors (MAOIs)
h. linezolid
i.
dextromethorphan
j.
lithium
k. tramadol
l.
antipsychotics or other dopamine antagonists 
9. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months prior to 
Screening including, but not limited to: 
pergolide, ergotamine, methysergide, or
cabergoline (revised per Amendment 01)
10. History or evidence of clinically significant disease (eg, malignancy, cardiac, respiratory, 
gastrointestinal, renal or psychiatric disease) that in the opinion of the investigator(s) 
could affect the subject’s safety, interfere with the study assessments, or result in a life 
expectancy of less than 1 year
11. Use of lorcaserin HCl within 6 months prior to Screening or hypersensitivity to lorcaserin 
HCl or any of the excipients
12. History of alcohol dependence or abuse within 2 years prior to Visit 1 (Screening)
13. Recreational drug use within the 2 years prior to Visit 1 (Screening)
14. Currently enrolled in another clinical trial or used any investigational drug or device 
within 30 days preceding informed consent (the exclusion criterion will not apply if the 
subjects are no longer in follow-up and have discontinued use of an investigational drug 
or device for at least 30 days. It will not apply if subjects are enrolled in registries or 
observational studies.) (revised per Amendment 01)
15. Planned bariatric surgery or bariatric surgery performed within 1 year before screening  
(revised per Amendment 01)
16. Subjects considered by the investigator to have insufficient motivation to remain in a 
long-term clinical trial or who are considered likely to drop out for nonmedical reasons 
(eg, social issues)
17. Females must not be breastfeeding or pregnant at Visit 1 (Screening) or Visit 2 (Baseline) 
(as documented by a negative beta-human chorionic gonadotropin [ß-hCG]).  A separate 


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Baseline assessment is required if a negative screening pregnancy test was obtained more 
than 72 hours before the first dose of study drug.
18. All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age 
group and without other known or suspected cause) or have been sterilized surgically (ie, 
bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at 
least 1 month before dosing).  Females of childbearing potential are defined as those 
who: (revised per Amendment 01)

Had unprotected sexual intercourse within 30 days before study entry

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.

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.

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.
9.3.3
Removal of Subjects From Therapy or Assessment
Refer to Section 9.5.5 (Completion/Discontinuation of Subjects).
9.4
TREATMENTS
9.4.1
Treatments Administered
The following treatments will be administered to subjects in this study (Table 2).  Study drug 
will be dispensed at each study visit starting at the Randomization Visit (Visit 2, at which time
the first dose should be taken; see Table 4).  (revised per Amendment 01)
Table 2
Treatments Administered
Drug Name
Strength
Oral Dose Form
Number 
Dispensed 
and 
Frequency
Duration
lorcaserin HCl
10 mg
Tablet
1 × 10 mg tablet, BID, orally
≈ 5 years
Placebo 
(to 
match 
lorcaserin HCl 10 mg)
N/A
lorcaserin HCl-matched 
tablet
1 tablet, BID, orally
≈ 5 years
BID = twice daily, N/A = not applicable.


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9.4.2
Identity of Investigational Product
BELVIQ (lorcaserin hydrochloride) is a (US) Drug Enforcement Administration (DEA) 
Scheduled IV Drug Product (C – IV).
Test drug and placebo will be supplied by the sponsor in labeled containers.  The sponsor will 
provide the study drugs packaged in a double-blind configuration.  Lorcaserin HCl tablets will be 
supplied as blue, round, film-coated, biconvex tablets containing 10 mg of drug substance and 
excipients (silicified microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, 
magnesium stearate, Opadry II blue).  Identical matching tablets will be provided for placebo.
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·0.5H2O
●
Molecular weight:  241.16 g/mol
●
Structural formula:  
9.4.2.2
Comparator Drug
Placebo matched to lorcaserin HCl 10-mg tablets will be the comparator drug in the study.
9.4.2.3
Labeling for Study Drug
Lorcaserin HCl will be labeled in accordance with text that is in full regulatory compliance with 
each participating country and will be translated into the required language(s) for each of those 
countries.
The clinical study labels will contain, but are not limited to:
1. Name, address and telephone number of the Sponsor
2. Pharmaceutical dosage form, route of administration, quantity of dosage units, identifier, 
and potency
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4. Protocol number
5. Directions of use (if applicable)
6. Storage conditions
7. Storage restrictions (if applicable)
8. Expiration date (if applicable, and not required for US)
9. The appropriate controlled drug symbol (where required per local regulation)
10. CAUTION: Federal law prohibits the transfer of this drug to any person other than the 
patient for whom it was prescribed (US sites) 
All packaging and labeling will be performed according to Good Manufacturing Practice (GMP) 
and GCP guidelines. A separate manual, detailing clinical supplies responsibilities, including the 
dispensing procedure, will be signed between an approved contract packaging and labeling 
vendor and the Sponsor.
Study drug must be stored as instructed on the study drug label and in accordance with the DEA
Regulations for Scheduled III - V Drugs (US sites).
All relevant site-specific guidelines and
country-specific labeling requirements must be followed. Study drug must be kept in a secure
location 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 all discrepancies.
A Drug Dispensing Log must be kept current and should contain the following information:

Identification (subject ID number and initials) of subject to whom the study drug was 
dispensed

The dates and lot numbers 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 (or if regionally required, the head 


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of the medical institution) is responsible for ensuring that the temperature is monitored 
throughout the total duration of the study and that records are maintained.
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, stratified by the presence of established CV disease (roughly 80%) or CV risk 
factors without established CV disease (approximately 20%). Each treatment group will receive 
either lorcaserin HCl or placebo BID.  Randomization will be performed centrally by an 
interactive voice and/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 (Visit 2), 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 of Doses in the Study
The dose selected for this study is 10 mg BID, which is the FDA-approved dose for BELVIQ
(lorcaserin HCl). 
9.4.5
Timing of Dose for Each Subject
Subjects should take the study medication twice daily at least 6 hours apart (revised per 
Amendment 01) and be encouraged to take the study medication with an adequate amount of 
water (8 oz or 240 mL).
9.4.5.1
Dose 
Reduction, 
Interruption,
and 
Restarting 
of 
Study 
Drug
(revised per Amendment 01)
Dose Reduction to 10 mg QD

Subjects who experience intolerable nonserious AEs believed to be related to study drug, 
in the opinion of the investigator, may be dosed at 10 mg QD. 

Subjects should take 1 tablet (lorcaserin 10 mg or placebo) QD for up to 7 days.  

After 7 days of 10 mg QD dose, subjects will resume to twice daily dosing. Subjects 
should be encouraged to remain on 10 mg BID for 7 days following QD dosing before 
dose reduction may be considered again.

The temporary reduced dosing option may be implemented for the subject up to 3 times.

Subjects who have attempted the temporary 10 mg QD dose reduction and escalation to 
the standard 10 mg BID dose regimen 3 times and confirmed that they can tolerate the 
10 mg QD dose but cannot tolerate the 10 mg BID dose are allowed to stay on prolonged 


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10 mg QD dose regimen for the remainder of their participation in the study. Please 
contact the Thrombolysis in Myocardial Infarction (TIMI) Hotline before initiation of 
prolonged once daily dosing. 

Subjects on prolonged 10 mg QD dose regimen may resume 10 mg BID at any time if it 
is safe to do so in investigators’ opinion. Subjects who had previously discontinued 
study drug due to a nonserious AE considered to be related to study drug can also be 
re-initiated on study drug starting with a temporary 10 mg QD dose regimen. Subjects 
are encouraged to try 10 mg BID, but if that cannot be tolerated, then the prolonged 
10 mg QD dose regimen can be considered.  

Utilization of dose reduction will be recorded in the applicable subject’s chart for source 
documentation purposes and captured in the eCRF.
Dose Interruption for Renal and Hepatic Abnormalities 
Severe Renal Dysfunction (revised per Amendment 01)
o
If eGFR <30 mL/min/1.73 m2, continue study drug but repeat eGFR within 1 week. 
o
If eGFR still <30 mL/min/1.73 m2 on repeat measurement, temporarily discontinue 
study drug. 

Follow-up after study drug discontinuation due to severe renal dysfunction: 
o
Recheck eGFR per clinical practice 
o
Consider re-initiation of study drug with resolution of reversible cause of acute 
kidney injury and when eGFR ≥30ml/min/1.73 m2 on at least 2 consecutive 
measurements spaced at least 1 week apart. 
Significant Hepatic Abnormalities 

Temporarily discontinue study drug if there is any evidence for hepatic dysfunction defined 
as either:
o
Clinical evidence for severe acute hepatitis associated with either ALT elevation 
>5x upper limit of normal (ULN) or total bilirubin level >3xULN.
o
Known chronic hepatic disease with an increase in the Child-Pugh Score to ≥10. 
http://www.mdcalc.com/child-pugh-score-for-cirrhosis-mortality/

Confirm the new or worsening hepatic dysfunction with repeat liver function tests (LFTs)
and determine its cause. Repeat LFTs weekly until the clinical picture resolves and 
laboratory values are stable for at least 2 weeks, or until it is determined that the hepatic 
dysfunction is chronic. 


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Consider re-initiation of study drug with resolution of a reversible cause of liver injury and 
improvement of lab abnormalities to values below thresholds listed above.
Restarting of Study Drug
Study drug should be restarted at the standard BID dosing unless study drug was discontinued 
due to an AE considered related to the study drug.  Those individuals can be started on QD
dosing as per the instructions above.  Subjects discontinued from study drug due to a serious or
severe AE considered to be related to study drug by the investigator should not be restarted on 
study drug.  Prior to restarting study drug for subjects who have been discontinued, consideration 
should be given as to whether the subject has developed any conditions (eg, change in medical 
status, use of concomitant medications, lack of contraception) exclusionary to taking study drug. 
(see Section 9.4.7.2 for specific instructions concerning restart of study drug for individuals 
requiring a second nonstudy drug serotonergic agent).  
9.4.6
Blinding
During the Randomization Phase, subjects and all personnel involved with the conduct and 
interpretation of the study, including investigators, site personnel, and sponsor staff will be 
blinded to the treatment codes.  Randomization data will be kept strictly confidential, filed 
securely by an appropriate group with the sponsor or CRO and accessible only to authorized 
persons (eg, Eisai Global Safety) until the time of unblinding, per SOP.
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 9.5.4.6.  If possible, before breaking the blind, the investigator 
should consult with the sponsor or designee to ascertain the necessity of breaking the code.
An interim analysis will be conducted during the trial when 460 adjudicated MACE events have 
been reported.  To maintain the integrity and credibility of the trial, procedures will be 
implemented to ensure the DMC and independent statistician have sole access to evolving 
information from the clinical trial regarding comparative efficacy and safety data aggregated by 
treatment group.  Full details of the DMC procedures including primary responsibilities of the 
DMC, its relationship with other trial components, its membership, and the purpose and timing 
of its meetings will be documented in the DMC Charter.  These details will also include 
procedures to ensure confidentiality and proper communication (as outlined in the Study 
Integrity Charter), the safety and statistical monitoring guidelines to be implemented by the 
DMC, and an outline of the content of the closed reports  and open reports  that will be provided 
to the DMC.  (revised per Amendment 02)
9.4.7
Prior and Concomitant Therapy
Any medication (including OTC medications) or therapy administered to the subject during the 
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established CV disease taken by the subject during the 90 days before first dose/administration of 
study drug, and any other medications taken by the subject during the 30 days before first 
dose/administration of study drug will be recorded on the Prior and Concomitant Medication 
CRF or Non-Pharmacological Procedures CRF.  Exact doses of these medications and duration 
of treatment prior to the study must be recorded, as well as any changes in dosing during the 
study. 
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.
Any antidiabetic agents taken by diabetic subjects prior to randomization must be stabilized for 
3 months with minimal changes.  Minimal changes are defined as no change in insulin dose 
10% of daily dose, no change in dose frequency, no add-on or reduction of anti-diabetic agents,
and the subject has not been hospitalized due to hypo-, or hyperglycemic events.
See Section 9.4.7.2 for specific restrictions on the use of concomitant therapies.
9.4.7.1
Drug-Drug Interactions
Not applicable
9.4.7.2
Prohibited Concomitant Therapies and Drugs

The following are prohibited as concomitant medications:  Other products intended for 
weight loss including prescription drugs, OTC drugs, and herbal preparations are 
prohibited as concomitant medications.  Any drug that has a risk for serotonin syndrome 
in its label, or that has been associated with a risk of serotonin syndrome including OTC 
drugs, should be used only when clearly indicated and within approved dose ranges and 
durations, as specified in the appropriate labeling.  More than 1 additional serotonergic 
agent is prohibited in combination with lorcaserin HCl (eg an SSRI, antipsychotic and 
lorcaserin).  (revised per Amendment 01)  
Serotonergic drugs include, but are not limited to: (revised per Amendment 01)
a.
selective serotonin reuptake inhibitors (SSRIs)
b. serotonin norepinephrine reuptake inhibitors (SNRIs)
c.
tricyclic antidepressants (TCAs) 
d. bupropion
e.
triptans 
f.
St. John’s Wort and tryptophan 
g. Monoamine oxidase inhibitors [MAOIs]
h.
linezolid
i.
dextromethorphan


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j.
lithium
k. tramadol
l.
antipsychotics or other dopamine antagonists 

If a second nonstudy serotonergic agent is required by the subject during the study, 
temporarily discontinue study drug and, if possible, wait 3 days after study drug has been 
discontinued before starting the second serotonergic agent.

If the subject discontinues treatment with the 2nd nonstudy serotonergic agent, lorcaserin 
HCl may be restarted when the 2nd serotonergic agent has been discontinued for at least
15 days, with the following exceptions, which must be discontinued for longer periods of 
time before restarting study drug. 

-30 days: fluoxetine, phenelzine, and isocarboxazid; 

-90 days: the injectable formulation of fluphenazine, haloperidone, paliperidone, 
and zuclopenthixol.  

If a subject requires treatment with an agent that has a documented correlation 
with increased incidence of cardiac valvulopathy and/or PH (eg, pergolide, 
ergotamine, methysergide, or cabergoline) lorcaserin HCl should be stopped.  
(revised per Amendment 01)  If the subject discontinues treatment with the other 
agent, lorcaserin HCl may be restarted as long as the other agent has been 
discontinued for at least 1 month. (revised per Amendment 01)
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, 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.  (revised per Amendment 01)  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 


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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:
o
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.

Use of serotonergic drugs:
o
The US Prescribing Information for BELVIQ (lorcaserin HCl) allows for concomitant 
use of serotonergic drugs with extreme caution, noting that if concomitant 
administration of lorcaserin HCl with an agent that affects the serotonergic 
neurotransmitter system is clinically warranted, extreme caution and careful 
observation of the patient is advised, particularly during treatment initiation and dose 
increases.  
For the purposes of this clinical study, any drug that has a risk for serotonin syndrome in its 
label, or that has been associated with a risk of serotonin syndrome in the medical literature, 
including OTC drugs, should be used only when clearly indicated and within approved dose 
ranges and durations as specified in the appropriate labeling.  More than 1 additional 
serotonergic agent is prohibited in combination with lorcaserin HCl.
See Section 9.4.8 for 
instructions related to study drug discontinuation and restart if a subject requires treatment with a 
second nonstudy drug serotonergic agent.  (revised per Amendment 01)
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  CRAs will 
review treatment compliance during site visits and at the completion of the study.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:
●
A signed and dated confidentiality agreement
●
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator
●
Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/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 
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●
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 FDA Form 1572 or equivalent
●
Financial Disclosure form(s) for the PI and all subinvestigators listed on Form FDA 1572
or equivalent
●
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 trials agreement
●
Where required, a copy of the regulatory authority approval for the country in which the 
study is being conducted, and the Import License 
●
A Controlled Substance Registration Certificate, form DEA-223 (US sites only)  (revised 
per Amendment 01)
The investigator and the study staff will be responsible for the accountability of all study drugs 
(dispensing, inventory, and record keeping) following the sponsor’s instructions and adherence 
to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not enrolled 
in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study drugs, 
dispensing of study drugs to the subject, collection and reconciliation of unused study drugs that 
are either returned by the subjects or shipped to site but not dispensed to subjects, and return of 
reconciled study drugs to the sponsor or (where applicable) destruction of reconciled study drugs 
at the site.  This includes, but may not be limited to:  (a) documentation of receipt of study drugs, 
(b) study drugs dispensing/return reconciliation log, (c) study drugs accountability log, (d) all 
shipping service receipts, (e) documentation of returns to the sponsor, and (f) certificates of 
destruction for any destruction of study drugs/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 and inventory records must be made available, upon request, for inspection by a 
designated representative of the sponsor or a representative of a health authority (eg, FDA, 
Medicines and Healthcare Products Regulatory Agency [MHRA]).  As applicable, all unused 
study drugs and empty and partially empty containers from used study drugs are to be returned to 
the investigator by the subject and together with unused study drugs that were shipped to the site 
but not dispensed to subjects are to be returned to the sponsor’s designated central or local depots 
during the study or at the conclusion of the study, unless provision is made by the sponsor for 


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destruction of study drugs and containers at the site.  Destruction at the site will only occur under 
circumstances where regulation or supply type prohibits the return of study drugs to the central 
or local depots.  Approval for destruction to occur at the site must be provided by the sponsor in 
advance.  Upon completion of drug accountability and reconciliation procedures by the site’s 
personnel and documentation procedures by the sponsor’s personnel, study drugs that are to be 
returned to the sponsor’s designated central or local depots must be boxed and sealed and 
shipped back to the central or local depots following all local regulatory requirements. In some 
regions, study drugs may be removed from the site and hand delivered to the central or local 
depot by sponsor representatives.  Where study drugs are approved for destruction at the site, 
destruction will occur following the site’s standard procedures and certificates of destruction will 
be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
STUDY ASSESSMENTS
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, and race/ethnicity.
9.5.1.2
Baseline Assessments
MEDICAL, CARDIOVASCULAR, AND DIABETES HISTORY
Pertinent medical and surgical history and current medical conditions will be recorded at the 
Screening Visit.  All pertinent medical and surgical history must be noted in the Medical History 
and Current Medical Conditions CRF.
Specifically, CV and diabetes history must be recorded at Screening.  For subjects with T2DM at 
Screening, duration of disease and treatment history since becoming diabetic must be recorded 
(see Section 9.4.7).
URINE DRUG SCREENING
A urine sample will be collected for testing for common drugs of use/abuse: (eg, cocaine, 
cannabinoids, phencyclidine, nicotine/cotinine, opioids [as a group], benzodiazepines,
barbiturates, and amphetamines).  Nicotine use (ie, cotinine positive on urine screen) is not 
exclusionary.  In the absence of prescription use without concern for abuse, positive testing for 
other common drugs of use/abuse is exclusionary on the basis of Exclusion Criterion No. 12 
(Section 9.3.2) and should result in screen failure.  (revised per Amendment 01)
9.5.1.3
Primary Safety/Efficacy Assessments
MACE/MACE+ EVENTS
Potential MACE/MACE+ events will be recorded throughout the study.  


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During this study, the endpoints of MACE and MACE+ will need to be reported in an expedited 
fashion by investigators to the Clinical Endpoint Committee (CEC) and to the Eisai Product 
Safety Department.  MACE/MACE+ events will be recorded on the Adverse Event (AE) case 
report form, but these events will not be considered as AEs, nor will they be recorded as serious 
adverse events (SAEs) in the clinical trial database or be required to be reported to regulatory 
authorities in an expedited timeframe, with the exception of MACE or MACE+ events that are 
considered by the investigator to be at least possibly related to the study drug (ie, where there is 
evidence to suggest a causal relationship).  (revised per Amendment 01)
Details of which events to report, how to report, and the required supporting documentation will 
be detailed in a separate manual provided to the sites.
In order to reduce intra- and intersite variability, the CEC will centrally review each potential 
MACE and MACE+ event to ensure standardization of data collection and interpretation of such 
events reported throughout the study.  The CEC will determine whether each potential event 
meets criteria for MACE or MACE+.  The CEC will remain blinded to treatment allocation and 
its activities and the criteria for classification of MACE/MACE+ events will be documented in 
the CEC Charter.
CONVERSION TO DIABETES
HbA1c and FPG will be measured in blood samples collected at Screening, Baseline, and 
specified timepoints throughout the study.
HbA1c, FPG and when available, additional components of the ADA diagnostic criteria will be 
assessed. All potential cases of conversion to diabetes will undergo central review of relevant 
supporting data. (revised per Amendment 01)
9.5.1.4
Pharmacokinetic, 
Pharmacodynamic, 
and 
Pharmacogenomic/Pharmacogenetic 
Assessments
PHARMACOKINETIC ASSESSMENTS
Not applicable
PHARMACODYNAMIC ASSESSMENTS  
The following will be measured for assessment of CV risk factors:
1. SBP, DBP, heart rate (HR)
2. Triglycerides, total cholesterol, HDL-C, LDL-C
3. FPG, fasting insulin
The following parameters related to renal function will be assessed.

Urinary ACR


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o
ACR will be measured in spot urine.
o
The following are the definitions of newly developed, worsening, and regression of 
albuminuria which need to be documented in 2 consecutive scheduled or 
nonscheduled assessments at least 30 days apart:
-
Newly developed albuminuria, defined as first evidence of microalbuminuria 
(ACR ≥30 μg/mg in spot urine) or macroalbuminuria (ACR ≥300 μg/mg),11 and 
ACR value increases ≥30% from previous assessment during treatment
-
Worsening albuminuria, defined as when subjects with microalbuminuria at 
Baseline develop macroalbuminuria, and ACR value increases ≥30% from 
previous assessment during treatment
-
Regression of albuminuria, defined as when subjects with macroalbuminuria at 
Baseline develop microalbuminuria or non-albuminuria, or subjects with 
microalbuminuria at Baseline become non-albuminuric, and ACR value decreases 
≥30% from previous assessment during treatment


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
Estimated glomerular filtration rate (eGFR):
o
eGFR will be calculated by the CKD-EPI equation based on creatinine measurement 
in the total population and/or cystatin C measurement in a selected population. The 
full criteria for determining whether creatinine, cystatin C, or an algorithm 
incorporating both will be used to estimate GFR will be detailed in the statistical 
analysis plan (SAP).
o
Definitions for newly developed, worsening, and regression of chronic kidney disease 
(CKD)12 (see Appendix 2) in the absence of acute, transient, kidney injury
-
Newly developed CKD, defined as when a subject with eGFR ≥90 mL/min per 
1.73 body surface area (BSA) and without kidney damage at Baseline changes to 
CKD Stage 1 or higher classified by the 2002 National Kidney Foundation (NKF) 
guidelines, where kidney damage referred to in the guideline is defined as the 
emergence of microalbuminuria as defined above, during treatment
-
Worsening of CKD, defined as when a subject with CKD Stage 1 or higher 
defined by NKF guidelines worsens to higher CKD stages (eGFR ≥90 with 
albuminuria at Baseline decreases to <90, or eGFR 60 to 89 at Baseline becomes 
<60, or eGFR 30 to 59 at Baseline becomes <30 mL/min per 1.73 BSA) during 
treatment
-
Regression of CKD, defined as when a subject with CKD Stage 1 or higher at 
Baseline improves to normal or lower stages by NKF guideline (eGFR ≥90 with 
albuminuria at Baseline improves to eGFR ≥90 without albuminuria, or eGFR 
60 to 89 at Baseline becomes eGFR ≥90 with or without albuminuria, or eGFR 
between 30 to 59 at Baseline improves to 60 mL/min per 1.73 BSA) during 
treatment

Serum creatinine:
o
Doubling of serum creatinine concentration, defined as when a subject’s creatinine 
value is at least 2 times the Baseline value and ≥1.5mg/dL during treatment

Serum cystatin C:
o
Serum cystatin C will be measured to estimate eGFR in the population of subjects 
who are in CKD Stage 1 or 2 at Baseline.  CKD Stage 1 or 2 is defined as 
albuminuria and eGFR 60 mL/min per 1.73 BSA
Additional diabetes-related microvascular complications will be assessed by monitoring AEs 
associated with retinopathy and neuropathy .  (revised per Amendment 01) 
The following parameters related to NAFLD will be measured:  aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), alkaline phosphatase, gamma glutamyl transpeptidase 
(GGT), total and direct bilirubin


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Obesity-related complications that are not assessed by any of the objective measures listed in this 
protocol may be evaluated using data from AE reporting, changes in concomitant medications, or 
reports of changes in medical history.  (revised per Amendment 01)
BIOMARKER ASSESSMENTS
The following inflammatory biomarkers will be assessed to further define the CV risk study 
population and to investigate potential correlation with changes in CV risk factors, MACE, and 
MACE+, as well as weight loss and susceptibility to diabetes:

hsCRP will be measured at the time of Screening and will be followed up yearly through 
EOT.

Fibrinogen will be measured at the time of randomization and will be followed up yearly
through EOT.

For subjects who provide consent, other biomarkers related to obesity, diabetes, CV 
disease, and associated risk factors will be evaluated in serum and plasma samples in 
selected countries, where applicable (see Appendix 5).
PHARMACOGENOMIC ASSESSMENTS
A blood sample for potential investigation of genetic variability associated with genotypes 
relating to response to lorcaserin HCl, weight loss, susceptibility to diabetes, and CV and other 
end-organ disease and their associated risk factors will be taken at the time of randomization in 
the study, where applicable.  DNA samples may be used to examine the role of genetic 
variability in subject’s absorption, distribution, metabolism, and excretion, or the development of 
AEs (see Appendix 6).
Variation in lorcaserin HCl
exposure or AEs may be evaluated by correlation of 
single-nucleotide polymorphisms with pharmacokinetic (PK), safety or pharmacodynamic (PD) 
data.  
A pharmacogenomics plan will be provided separately.
Subjects who decline to give informed consent for pharmacogenomic/genetic analysis can 
participate in the study.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular 
monitoring of hematology, blood chemistry, and urinalysis; periodic measurement of vital signs 
and electrocardiograms (ECGs); and performance of physical examinations.  Additional safety 
assessments specific to this study will include echocardiography.


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AES AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
(revised per Amendment 01)
An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation 
subject administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is lorcaserin HCl. 
The criteria for identifying AEs 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
●
Any new disease or exacerbation of an existing disease 
●
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
●
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, whether prescribed in the protocol or not.
A laboratory result should be considered by the investigator to be an AE if it:
●
Results in the withdrawal of study drug
●
Results in withholding of study drug pending some investigational outcome
●
Results in an intervention, based on medical evaluation (eg, potassium supplement for 
hypokalemia)
●
Results in any out-of-range laboratory value (Sponsor’s Grading for Laboratory Value 
provided as reference in Appendix 3) that in the investigator’s judgment fulfills the 
definitions of an AE with regard to the subject’s medical profile
(revised per 
Amendment 01)
All AEs observed during the study will be reported on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the subject 
signs the study ICF through the end of the study. (revised per Amendment 01)
MACE and MACE+ events and other study-specific AEs of interest will be followed until EOS.
(revised per Amendment 01)
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.  Any laboratory abnormality considered 
to constitute an AE should be reported on the Adverse Event CRF. 


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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. 
(revised per Amendment 01)
All AEs must be followed for at least 30 days after Sponsor Notification of Study Completion, or 
until resolution, whichever comes first.  (revised per Amendment 01)
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 AES
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see SAEs and 
Other Events of Interest, Section 9.5.1.5 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
Causality will be based on the response to the following question:
Was there a reasonable possibility that the drug caused the adverse event? Yes/No


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Where Yes = related and No = Not related
SAES AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
(revised per Amendment 01)
A serious adverse event (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 1 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.
The study-specific events that are listed on the Reporting of Events Associated with Special 
Situations (Section 9.5.4.4) should always be considered as SAEs 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).  If the event does not meet other serious criteria, it should be reported under the 
serious criterion of Important Medical Event.  (revised per Amendment 01)
Study-specific AEs of interest which are always to be reported as SAEs are included in the list 
on the Reporting of Events Associated with Special Situations (Section 9.5.4.4). (revised per 
Amendment 01)
In addition to the list on the Reporting of Events Associated with Special Situations 
(Section 9.5.4.4), other 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; and any treatment-emergent significant laboratory abnormality (revised per 
Amendment 01)
During this study, the endpoints of MACE and MACE+ will need to be reported in an expedited 
fashion by investigators to the CEC and to the Eisai Product Safety Department, but will not be 


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recorded as SAEs in the clinical trial database or be required to be reported to regulatory 
authorities in an expedited timeframe, with the exception of MACE or MACE+ events that are 
considered by the investigator to be at least possibly related to the study drug (ie, where there is 
evidence to suggest a causal relationship). (revised per Amendment 01)
All MACE and MACE+ events are to be reported on the AE CRF and the MACE/MACE+ 
section of the CRF, but will not be considered as AEs.
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:

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration)

(revised per Amendment 01)

Hospitalization for routine maintenance of a device (eg, battery replacement) that was 
in place before study entry
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, are 
summarized in Table 3.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 4) shows the visits and timepoints at 
which blood for clinical laboratory tests and urine for urinalysis will be collected in the study.


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Table 3
Clinical Laboratory Tests
Category
Parameters
Hematology
hematocrit, hemoglobin, platelets, RBC count, and WBC count with 
differential (bands, basophils, eosinophils, lymphocytes, monocytes, 
neutrophils)
Chemistry
Electrolytes
bicarbonate, chloride, potassium, sodium 
Liver function tests
ALT, alkaline phosphatase, AST, direct bilirubin, total bilirubin, GGT
Renal function parameters
blood urea/blood urea nitrogen, creatinine
Other
albumin, calcium, globulin, glucose, lactate dehydrogenase, LDL-C, 
HDL-C, phosphorus, total cholesterol, total protein, triglycerides, uric 
acid,
Urinalysis
glucose, ketones, protein, RBCs, WBCs, albumin and creatinine for 
ACR
Other
HbA1c, serum cystatin C, fasting insulin, FPG, hsCRP, fibrinogen, 
serum pregnancy, urine drug screen
ACR = albumin-to-creatinine ratio; ALT = alanine aminotransferase, AST = aspartate aminotransferase, FPG = 
fasting plasma glucose; GGT = gamma glutamyl transpeptidase, HbA1c = glycosylated hemoglobin, HDL-C = 
high density lipoprotein-cholesterol, hsCRP = high sensitivity C-reactive protein, LDL-C = low density 
lipoprotein-cholesterol, 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 AEs and Other Events of Interest [Section 9.5.1.5]) and the CRF Completion Guidelines.  In 
these instances, the AE corresponding to the laboratory abnormality will be recorded on the 
Adverse Event CRF.
Laboratory abnormalities meeting the criteria of SAEs (see SAEs and Other Events of Interest 
[Section 9.5.1.5]), must be reported to the sponsor in the same manner as SAEs (see Reporting of 
SAEs [Section 9.5.4.1]).  In addition, the laboratory report must be provided to the sponsor, as 
regionally required.
VITAL SIGNS AND HEIGHT/WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], pulse [beats per minute], and 
weight (kg) will be obtained at the visits designated on the Schedule of Procedures/Assessments 
(Table 4) by a validated method.  BP and pulse will be measured after the subject has been 
sitting for 15 minutes.  All BP measurements should be performed on the same arm, preferably 
by the same person.


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Height will be measured at Screening for calculation of BMI.  Additionally, waist and hip 
circumference 
will 
be 
measured 
at 
the 
visits 
designated 
on 
the 
Schedule 
of 
Procedures/Assessments (Table 4).
The waist and hip circumferences will be measured to the nearest integer.  For a given subject 
and as much as is possible, the same site personnel should measure the waist and hip throughout 
the study to avoid variability in the method of measurement.  All measurements will be reported 
in centimeters (cm).  Each measurement will be made and recorded 3 times at each scheduled 
assessment; the average of the 3 values will be reported. In order to standardize the method 
used, measurements should be obtained as follows: 
Waist Measurement:  waist measurement will be done according to the National Heart, Lung, 
and Blood Institute (NHLBI) Guideline in the Identification, Evaluation, and Treatment of 
Overweight and Obesity in Adults.13  To define the level at which the waist circumference is 
measured, a bony landmark is first located and marked.  The subject stands and the examiner, 
positioned at the right of the subject, palpates the upper hip bone to locate the right iliac crest.  
Just above the uppermost lateral border of the right iliac crest, a horizontal mark is drawn, and 
then crossed with a vertical mark on the midaxillary line.  The measuring tape is placed in a 
horizontal plane around the abdomen at the level of this marked point on the right side of the 
trunk.  The plane of the tape is parallel to the floor and the tape is snug, but does not compress 
the skin.  The measurement is made at a normal minimal respiration (Figure 2).
Hip Measurement:  With a tape measure, measure the distance around the largest extension of 
the buttocks.
Figure 2
Measuring Tape Position for Waist Circumference


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PHYSICAL EXAMINATIONS
Physical examinations (targeted or symptom directed) will be performed as designated on the
Schedule of Procedures/Assessments (Table 4).  A targeted physical examination will include 
evaluations of the heart and lungs, abdomen, and limbs. Examinations of other systems will only 
be required in the presence of clinical symptoms related to this region.  Documentation of the 
physical examination will be included in the source documentation at the site.  Significant 
findings at the Screening Visit will be recorded on the Medical History and Current Medical 
Conditions CRF.  Changes from screening physical examination findings that meet the definition 
of an AE will be recorded on the Adverse Events CRF.
ELECTROCARDIOGRAMS
ECGs will be obtained as designated on the Schedule of Procedures/Assessments if subjects 
come to the study visit in person (Table 4). 
Newly occurring Q-waves will be reported and evaluated as potential silent MI; suspected events 
will be adjudicated by the CEC.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see AEs and 
Other Events of Interest [Section 9.5.1.5]) and the CRF Completion Guidelines.  In these 
instances, the AE corresponding to the ECG abnormality will be recorded on the Adverse Events 
CRF.
ECG abnormalities meeting the criteria of SAEs (see SAEs and Other Events of Interest 
[Section 9.5.1.5]), must be reported to the sponsor in the same manner as SAEs (see Reporting of 
SAEs [Section 9.5.4.1]).  In addition, the ECG report must be provided to the sponsor, as 
regionally required.
ECHOCARDIOGRAM
Echocardiograms will be obtained on a subset of approximately 3600 subjects at selected sites as 
designated on the Schedule of Procedures/Assessments (Table 4).  Acquisition of new ECHO
data in all subjects will cease when at least 1000 subjects have completed the Month 36
echocardiographic assessment.  (revised per Amendment 02)
To maintain consistency with echocardiographic assessments conducted in the lorcaserin HCl
Phase 3 program, and to allow pooling of Phase 3 data with that from the proposed study, the 
categories for echocardiographic assessments of aortic and mitral valve regurgitation will remain 
the same as in the Phase 3 program.  Valvular regurgitation as assessed on substudy 
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.
(revised per 
Amendment 01)  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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In this study, echocardiographic images will be acquired in a subset of subjects to establish the 
cardiac
safety of lorcaserin HCl.  Standardized training will be provided for all
echocardiographers, and will implement centralized procedures for collecting, analyzing, and
reporting echocardiographic data. All echocardiograms will be over-read by 2 blinded central 
readers (primary and secondary).
Baseline echocardiograms will be performed in between Visits 1 and 2, after the results of 
screening assessments have been obtained but prior to randomization, and subject eligibility is 
confirmed.
PREGNANCY TEST
During Screening, blood samples for pregnancy testing will be collected for women of 
childbearing potential (as defined in Section 9.3.1, Inclusion Criterion No. 5).  A urine 
pregnancy test will be performed at the time of randomization.
TOBACCO HISTORY AND USE
History of tobacco use will be captured at Baseline.  Changes in smoking status will be captured 
yearly thereafter. 
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 4 presents the schedule of procedures/assessments for the study.


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Table 4
Schedule of Procedures/Assessments in Study APD356-G000-401
Phase
Pre-
randomization
Randomization
Period
Screening
Treatment
F/U
Visit 
1
2a
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
EOT
EOS
Unschb
Monthc
Days 
-30 to -1
Day 1
3
6
9
12
15
18
21
24
28
32
36
40
44
48
52
56
Assessment
(revised per 
Amendment 01)
Informed consent
X
Demography
X
Medical history 
X
Cardiovascular history
X
Diabetes history
X
Tobacco history/use
X
X
X
X
X
X
Inclusion/ exclusion 
criteria
X
X
Physical examination
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist/hip 
circumference
X
X
X
X
X
X
X
Echocardiogramd
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
Hematology laboratory 
testse
X
X
X
X
X
X
X
Chemistry laboratory 
tests e,f
X
X
X
X
X
X
X
X


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Table 4
Schedule of Procedures/Assessments in Study APD356-G000-401
Phase
Pre-
randomization
Randomization
Period
Screening
Treatment
F/U
Visit 
1
2a
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
EOT
EOS
Unschb
Monthc
Days 
-30 to -1
Day 1
3
6
9
12
15
18
21
24
28
32
36
40
44
48
52
56
Assessment
(revised per 
Amendment 01)
Serum cystatin C/serum 
creatinine f,g
X
X
X
X
X
X
X
Urinalysis incl. ACRf
X
X
X
X
X
X
X
PGx sampling (where 
applicable)
X
HbA1c samplingf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting plasma glucosef
X
X
X
X
X
X
X
X
X
X
Fasting insulin levelf
X
X
X
X
X
X
X
X
X
Other biomarker 
sampling (where 
applicable)
X
X
X
X
hsCRP
X
X
X
X
X
X
Fibrinogen
X
X
X
X
X
X
Urine drug screen
X
Pregnancy testh
X
X
Diet and exercise 
counseling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
IxRSe
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior/concomitant 
medicationsi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 4
Schedule of Procedures/Assessments in Study APD356-G000-401
Phase
Pre-
randomization
Randomization
Period
Screening
Treatment
F/U
Visit 
1
2a
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
EOT
EOS
Unschb
Monthc
Days 
-30 to -1
Day 1
3
6
9
12
15
18
21
24
28
32
36
40
44
48
52
56
Assessment
(revised per 
Amendment 01)
Study drug dispensinge
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect study 
medicatione
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug accounting & 
compliance e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE monitoring i
<---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------->
MACE/MACE+ 
reporting i
<---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------->
(revised per Amendment 01)
Notes:  Upon Sponsor Notification of Study Completion (ie, trial completion), sites will be instructed to bring subjects who remain on treatment for an EOT visit.  An EOS visit will occur 
approximately 30 days later for subjects on treatment at Sponsor Notification of Study Completion.
Subjects who prematurely discontinue study drug are to complete the EOT visit within approximately 30 days, and will continue in the study for all subsequent study visits until study completion.  
If the next scheduled visit after EOT assessments is <30 days, subjects can skip that visit and return for the next subsequent visit (eg, if the EOT is 15 days prior to the scheduled Month 36 visit, 
they can skip Month 36, and come in at Month 40).  All procedures and assessments should be performed at subsequent visits until EOS except where footnoted in assessment column.  Upon 
Sponsor Notification of Study Completion, subjects who prematurely discontinued study medication ≥30 days before will return for an EOS visit.  Subjects who are still being followed in the study 
but who discontinued study medication within 30 days of Sponsor Notification of Study Completion will return for an EOS visit approximately 30 days after their last dose of study medication.
ACR = albumin-to-creatinine ratio; AE = adverse event, ECG = electrocardiogram, EOS = end of study; EOT = end of treatment; F/U = Follow-up; HbA1c = glycosylated hemoglobin, hsCRP = 
high sensitivity C-reactive protein; incl. = including; IxRS = interactive voice and/or web response system; MACE = major adverse cardiovascular events; MACE+ = MACE or hospitalization for 
unstable angina or heart failure, and any coronary revascularization; PGx = pharmacogenomics, Unsch = unscheduled. 
a.
Visit 2 = Baseline/Randomization.  The first dose should be taken at this visit.  (revised per Amendment 01)
b.
Assessments are only to be performed if clinically indicated or necessary due to state controlled substance requirements.  (revised per Amendment 01)
c.
Window ±10 days for all visits after Visit 2, other than the EOS visit which has a window of 10 days.  Month is shown unless otherwise indicated; 1 month = approximately 30 days.
d.
Only for a subset of subjects at selected sites.  Baseline echocardiograms will be performed in between Visits 1 and 2, after the results of screening assessments have been obtained but prior to 
randomization, and subject eligibility is confirmed.  ECHOs will be performed until at least 1000 subjects have completed the Month 36 echocardiographic assessment.  (revised per 
Amendment 02)


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Table 4
Schedule of Procedures/Assessments in Study APD356-G000-401
Phase
Pre-
randomization
Randomization
Period
Screening
Treatment
F/U
Visit 
1
2a
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
EOT
EOS
Unschb
Monthc
Days 
-30 to -1
Day 1
3
6
9
12
15
18
21
24
28
32
36
40
44
48
52
56
Assessment
(revised per 
Amendment 01)
e.
For subjects who discontinue study drug early, these assessments will be stopped after the EOT visit.
f.
Renal function parameters and glycemic profile should be obtained at all specified visits, regardless of study drug status. (revised per Amendment 01)
g.
Serum cystatin C will be measured at Baseline and yearly thereafter in the subpopulation with CKD Stage 1 or 2 at Baseline.  Serum creatinine will be measured in chemistry blood samples if 
chemistry assessments are performed.
h.
Serum pregnancy tests will be conducted at Screening.  A urine pregnancy test will be conducted at randomization. 
i.
These assessments should be done if a telephone contact is performed in lieu of a clinic visit. 


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9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements used to meet the requirements for conducting 
a CVOT.
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, vital signs and assessment of AEs, are standard evaluations to ensure 
subject safety.  Serial echocardiogram assessments on a subset of subjects at selected sites are 
included in the study per requirement by the FDA. 
9.5.4
Reporting of SAEs, Hypoglycemia, Pregnancy, and Other Events of Interest
9.5.4.1
Reporting of SAEs
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported as soon as possible but no later than 24 hours from the time the 
investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected through the end of 
study.  For those subjects taking study drug at the time of study completion (“Sponsor 
Notification of Study Completion”), SAEs should be collected for 30 days after the last dose. 
(revised per Amendment 01)
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 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 be as complete 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 24 hours 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 report.
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 or 
designated CRO to be filed in the sponsor’s Trial Master File.


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9.5.4.2
Reporting of Hypoglycemia
Patient-reported episodes of hypoglycemia or decreased blood sugar should be captured on the 
eCRF according to the following guidelines:

Mild 
hypoglycemia 
is 
defined 
as 
capillary 
glucose 
≥55
to
<65
mg/dL 
(≥3.0 - <3.3 mmol/L) that the subject is able to treat himself/herself; or, if glucose is not 
measured, symptoms of hypoglycemia that resolve with administration of oral 
carbohydrates. 

Moderate hypoglycemia is defined as capillary glucose <55 mg/dL (<3.0 mmol/L) that 
the subject is able to treat himself/herself.

Severe hypoglycemia is defined as a symptomatic capillary glucose <40 mg/dL
(<2.2mmol/L) OR a capillary glucose ≤65 mg/dL AND needed help from another person 
OR required intravenous glucose

Catastrophic hypoglycemia is defined as severe hypoglycemia that resulted in 
life-threatening injury to the subject or another person, hospitalization, and/or death.  
This should be reported as a SAE.
Additionally, adverse events of hypoglycemia should be further specified in the eCRF adverse 
event term as “symptomatic” or “asymptomatic”.  
See Section 9.4.7.2 for directions on the recommendations for possible adjustment to 
antihyperglycemic medication doses in response to reported episodes of hypoglycemia.
9.5.4.3
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 Reporting of SAEs [Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported as soon as 
possible but no later than 24 hours from the date the investigator becomes aware of the 
pregnancy.  The contact information for the reporting of pregnancies and exposure to study drug 
through breastfeeding is provided in the Investigator Study File.  All pregnancies must be 
followed to outcome.  The outcome of the pregnancy must be reported as soon as possible but no 
later than 24 hours from the date the investigator becomes aware of the outcome.


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A subject who becomes pregnant must be discontinued from study treatment. 
9.5.4.4
Reporting of Events Associated with Special Situations
(revised per Amendment 01)
REPORTING OF AES ASSOCIATED WITH STUDY DRUG OVERDOSE, MISUSE, ABUSE, OR 
MEDICATION ERROR
AEs associated with study drug overdose, misuse, abuse, and medication error refer to AEs 
associated with uses of the study drug outside of that specified by the protocol.  Overdose,
misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher than the 
protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with the
protocol (revised per Amendment 01)
Abuse
Sporadic or persistent intentional excessive use of study drug accompanied 
by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study drug use 
or subject harm while the study drug is in the control of site personnel or the
subject
All AEs associated with an overdose should be captured on the Adverse Event CRF.  AEs
associated with overdose, misuse, abuse, or medication error should be reported using the 
procedures detailed in Reporting of SAEs (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 in an 
expedited manner but should be noted as nonserious in the report and on the Adverse Event 
CRF.
(revised per Amendment 01)
REPORTING OF STUDY-SPECIFIC EVENTS
All study specific AEs of interest should be reported using the procedures detailed in Reporting 
of SAEs (Section 9.5.4.1).  (revised per Amendment 01)
The Study-specific events below should always be considered as SAEs 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),  If the event does not meet other serious criteria, then it should be 
reported under the serious criteria of Important Medical Event.  (revised per Amendment 01)


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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) (revised per Amendment 01)

Psychosis

Suicidal behavior (revised per Amendment 01)

Priapism

New symptoms or worsening symptoms of valvular heart disease
(revised per 
Amendment 01)

New or worsening symptomatic pulmonary hypertension   (revised per Amendment 
01)

Malignant neoplasms, with the exception of basal cell and squamous cell carcinomas of 
the skin

Fibroadenomas of the breast or ductal carcinoma in sit
Additionally, the following additional study specific AEs 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 
non-serious on the Adverse Event CRF: (revised per Amendment 01)

Suicidal ideation  (revised per Amendment 01)

Euphoria (revised per Amendment 01)
Asymptomatic new onset or worsened valvular heart disease as demonstrated by 
objective assessment, eg, echocardiography or cardiac catheterization.  New onset valvular 
disease is defined as subjects who develop mild or greater aortic insufficiency and 
moderate or greater grading for all other valvular lesions (eg, mitral regurgitation, aortic 
stenosis) on imaging in subjects without any valvular disease at Baseline.  Worsened 
valvular disease is defined in subjects who have existing FDA defined valvulopathy at 
Baseline increase in severity of regurgitation or stenosis as demonstrated by objective 
assessments (eg, imaging assessments such as magnetic resonance imaging [MRI], 
echocardiography, or cardiac catherization). (revised per Amendment 01)

Asymptomatic new onset or worsened pulmonary hypertension as documented by 
echocardiography or cardiac catheterization.  New onset of pulmonary hypertension is 
defined as estimated pulmonary artery or right ventricular systolic pressure greater than 


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40 mmHg or mean pulmonary artery pressure equal-or-greater than 25 mmHg in the 
subjects without any pulmonary hypertension at Baseline.  Worsening pulmonary 
hypertension is defined in subjects who have documented objective assessment 
pulmonary hypertension at Baseline as an increase in pulmonary artery systolic pressure, 
or mean artery pressure by more than 10 mmHg. (revised per Amendment 01)
9.5.4.5
Expedited Reporting
The sponsor must inform investigators (or, as regionally required, the head of the medical 
institution) 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.
9.5.4.6
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.
9.5.4.7
Regulatory Reporting of AEs
AEs will be reported by the sponsor or a third party acting on behalf of the sponsor to regulatory 
authorities in compliance with local and regional law and established guidance.  The format of 
these reports will be dictated by the local and regional requirements.
All studies that are conducted within any European country will comply with European GCP
Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All SUSARs will be reported, as 
required, to the competent authorities of all involved European member states.
9.5.5
Completion/Discontinuation of Subjects
9.5.5.1
Premature Discontinuation of Study Drug
A subject may decide to discontinue receiving the study drug at any time for any reason.  The 
investigator may discontinue a subject from receiving the study drug at any time for safety or 
administrative reasons.  The reason for premature discontinuation of study drug will be 
documented.
Discontinuation from receiving study drug does not mean that the subject is withdrawn from the 
study.  Subjects who prematurely and permanently discontinue study drug are to complete the 
EOT visit within approximately 30 days as defined in the Schedule of Procedures/Assessments 
(Table 4).  (revised per Amendment 01)  Subjects who prematurely discontinue study drug will 
continue in the study for all subsequent study visits until study completion and are to complete 
visit procedures as indicated in Table 4.  It is preferred that these visits are conducted in person.  


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However, if the subject is unable to attend a visit in person, a telephone visit may be performed.  
The outcome of the telephone visit must be clearly documented in the source record.  At a 
minimum, the site should attempt to have the subject return for an in-person clinic visit at least 
once per year. 
Upon Sponsor Notification of Study Completion, subjects who prematurely discontinued study 
medication ≥30 days before will return for an EOS visit.  Subjects who are still being followed in 
the study but who discontinued study medication within 30 days of Sponsor Notification of 
Study Completion will return for an EOS visit approximately 30 days after their last dose of 
study medication. (revised per Amendment 01)
Unless he or she withdraws consent for any type of follow-up contact, a subject who has ceased 
to return for visits may 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.  This information will be recorded in the CRF.  
Patient finder services will be utilized to identify updated contact information when the site 
cannot locate a missing subject.
For subjects who prematurely discontinue from study drug, the reasons will be documented in 
the CRF and source documentation.  Study drug disposition information will be collected on the 
Early Discontinuation from Study Drug CRF.
Restart of Study Drug 
Whenever possible, restart of study drug should be encouraged. Subjects discontinued from 
study drug due to a serious or severe adverse event considered to be related to study drug by the 
investigator should not be restarted on study drug.  Prior to restarting study drug on subjects who 
have been discontinued, consideration should be given as to whether the subject has developed 
any conditions (eg, change in medical status, use of concomitant medications, lack of 
contraception) exclusionary to taking study drug. See specific instructions in Section 9.4.5.1 for 
instructions on dosing when restarting study drug and Section 9.4.7.2 for instructions concerning 
restart of study drug for individuals requiring a second non study drug serotonergic agent.  Even 
if a premature EOT visit was completed due to the discontinuation of study drug, this should not 
prevent complete study follow-up procedures including the final EoT/Closing Visit, following 
restart of randomized treatment.  (revised per Amendment 01)
9.5.5.2
Discontinuation from Study Procedures/Withdrawal of Consent
A subject may elect to discontinue all participation in the study at any time for any reason.  
(revised per Amendment 01)
Only subjects who refuse any and all types of contact (eg, visits, telephone calls, medical record 
reviews) will be considered to have withdrawn consent for all clinical follow-up.  It is expected 
that this would be extremely unusual.  The site must contact the TIMI Hotline to confirm 
withdrawal of consent, at which time the Withdrawal of Consent CRF will be made available for 


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completion.  A final assessment for vital status using publically available data will be performed 
at the end of the study for all subjects who withdraw consent for all clinical follow-up, when 
allowed by law, regulation, or local authorities.
The investigator may also withdraw a subject from the study only in the event of exceptional 
circumstances.  This must be documented by the site, signed by the investigator, and reviewed by 
the sponsor/designee before it is considered to take effect.
All subjects who prematurely discontinue all study procedures (ie, withdraw consent) are to 
complete the EOS Visit procedures indicated in the schedule of procedures/assessments
(Table 4).
For subjects who prematurely discontinue from the study, the reasons will be documented in the 
CRF and source documentation.  Study disposition information will be collected on the Subject 
Disposition CRF.
A subject removed from the study for any reason may not be replaced.
9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator will report any concern about abuse or diversion of study drug.
AEs associated with abuse or diversion will be appropriately reported as AEs and monitored per 
Section 9.5.1.5.  Abuse is always to be captured as an AE.
Sites will be assessed for the appropriateness of study drug storage and retrieval at the time of 
site selection.  Required policies and procedures will be clearly communicated to the site to 
assess the site’s capabilities and adherence to storage, dispensing, reconciliation, and retention of 
study drug.
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.


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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
or equivalent 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
Statistical analyses will be performed by the sponsor or designee after the study is completed and 
the database is locked and released for unblinding.  Statistical analyses will be performed using 
SAS software or other validated statistical software as required.  Details of the statistical 
analyses will be included in a separate statistical analysis plan.
9.7.1
Statistical and Analytical Plans
The statistical analyses of the APD356-G000-401 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 for the interim analysis.
9.7.1.1
Study Endpoints
PRIMARY ENDPOINTS

Time from randomization to first occurrence of MACE (first occurrence of any of the 
following events: MI, stroke, or CV death)

Time from randomization to first occurrence of MACE+ (first occurrence of any of the 
following events: MACE or hospitalization for unstable angina or HF, or any coronary 
revascularization) (revised per Amendment 02)


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KEY SECONDARY ENDPOINT 
(revised per Amendment 02)

Time from randomization to conversion to T2DM, defined as first occurrence of any 
component of the 2013 ADA diagnostic criteria14 in subjects with prediabetes at 
Baseline.  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 subsequently confirmed on repeat laboratory testing:  (revised per Amendments 01
and 02)

HbA1c ≥6.5% 

FPG ≥126 mg/dL (7.0 mmol/L)

2-hour plasma glucose ≥200mg/dL (11.1 mmol/L) by an OGTT
Investigators should make every effort to obtain central lab confirmatory testing no later than 
6 weeks after meeting any of the above criteria.  Abnormalities of any 1 of the above 3 
criteria on repeat testing constitutes diagnostic confirmation of diabetes.  Subjects who have 
been started on anti-diabetic medications following abnormalities in preliminary testing do 
not require confirmatory testing.  (revised per Amendments 01 and 02)
OTHER SECONDARY ENDPOINTS (REVISED PER AMENDMENT 02)
MACE and MACE+ Related:  (revised per Amendment 02)

Time from randomization to first occurrence of each of the individual components of 
MACE+

Time from randomization to first occurrence of all-cause mortality
Diabetes and Prediabetes Related (revised per Amendment 02)

Time from randomization to conversion to normal glucose homeostasis (HbA1c ≤5.6%
and fasting plasma glucose <100 mg/dL without any antidiabetic treatment) in subjects 
with prediabetes at Baseline (revised per Amendments 01 and 02)

Time from randomization to conversion to T2DM in subjects without any type of 
diabetes at Baseline  (revised per Amendment 01)

Change from Baseline in HbA1c at 6 months in subjects with T2DM at Baseline
Renal Related (revised per Amendment 02)

Time from randomization to first occurrence of 2 consecutive assessments within the 
same component of the composite endpoint or time to first occurrence of renal transplant 
or renal death, on scheduled or nonscheduled visits at least 30 days apart, indicative of 
new onset renal impairment or worsening of existing renal impairment (first occurrence 
of any of the following events:  microalbuminuria, macroalbuminuria, worsening 


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albuminuria, newly developed CKD or worsening of CKD, or doubling of serum 
creatinine, as defined above, or any of the following:  ESRD, renal transplant, renal 
death) in all subjects.  (revised per Amendment 02)

Time from randomization to first occurrence of 2 consecutive assessments within the 
same component of the composite endpoint or time to first occurrence of renal transplant 
or renal death,, on scheduled or nonscheduled visits at least 30 days apart, indicative of 
new onset renal impairment or worsening of existing renal impairment (first occurrence 
of any of the following events:  microalbuminuria, macroalbuminuria, worsening 
albuminuria, newly developed CKD or worsening of CKD, or doubling of serum 
creatinine, as defined above, or any of the following:  ESRD, renal transplant, renal 
death) in subjects with prediabetes at Baseline (revised per Amendments 01 and 02)  

Time from randomization to first occurrence of 2 consecutive assessments within the 
same component of the composite endpoint or time to first occurrence of renal transplant 
or renal death,, on scheduled or nonscheduled visits at least 30 days apart, indicative of 
new onset renal impairment or worsening of existing renal impairment (first occurrence 
of any of the following events:  microalbuminuria, macroalbuminuria, worsening 
albuminuria, newly developed CKD or worsening of CKD, or doubling of serum 
creatinine, as defined above, or any of the following:  ESRD, renal transplant, renal 
death) in subjects with T2DM at Baseline (revised per Amendment 02)

Time from randomization to first occurrence of 2 consecutive assessments, on scheduled 
or nonscheduled visits at least 30 days apart, indicative of improvement in renal function 
(first occurrence of regression of albuminuria or regression of CKD) in subjects with 
T2DM at Baseline
Secondary Safety Endpoints Assessing Cardiac Valve Function and Pulmonary Arterial 
Pressure:  (revised per Amendment 02)

Proportion of subjects without FDA-defined valvulopathy at Baseline who develop 
FDA-defined valvulopathy at 1 year

Proportion of subjects with FDA-defined valvulopathy confirmed by documented 
objective assessments at Baseline who demonstrate worsened FDA-defined valvulopathy 
at 1 year (revised per Amendment 01)

Change from Baseline in estimated pulmonary artery systolic pressure at 1 year
EXPLORATORY ENDPOINTS

Change from Baseline in CV risk factors at 1 year and yearly thereafter (eg, body 
weight, dyslipidemia, insulin level, hypertension, and applicable biomarkers of CV risk
and other end-organ diseases)

Change from Baseline in eGFR and ACR at 1 year, yearly thereafter, and at the end of 
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
Change from Baseline in LFTs (AST, ALT, alkaline phosphatase, GGT, total and direct 
bilirubin) at 1 year and yearly thereafter

Proportion of subjects without FDA-defined valvulopathy at Baseline who develop 
FDA-defined valvulopathy at 2 years and yearly thereafter

Change from Baseline in estimated pulmonary artery systolic pressure at 2 years and 
yearly thereafter 

Proportions of subjects with at least a 1-stage reduction in an obesity-related 
complication 
(prediabetes, 
metabolic 
syndrome, 
T2DM, 
hypertension, 
and 
hypertriglyceridemia/dyslipidemia) at 1 year and EOS; incidence of other
obesity-related complications will be collected through AE reports, medical history, and 
use of concomitant medications, based on 2014 Advanced Framework for a New 
Diagnosis of Obesity as a Chronic Disease (American Association of Clinical 
Endocrinologists [AACE] and American College of Endocrinology [ACE]). (revised per 
Amendment 01)

Change from Baseline in HbA1c, FPG, fasting insulin levels, and homeostatic model 
assessment-insulin resistance (HOMA-IR) at 6 months in the following subpopulations of 
subjects with T2DM at Baseline:  (revised per Amendments 01 and 02)
o
Subjects with (HbA1c>7%) at Baseline
o
Subjects who have not been treated with antidiabetic agents at Baseline
o
Subjects who are on monotherapy with oral antidiabetic agent at Baseline
Subjects with early T2DM (duration of diagnosis of diabetes is less than 
5 years) at Baseline. 

Proportion of subjects with reduction in the number of OAD medications or reduction in 
the dosage of OAD medications at 6 months in the following subpopulations of subjects 
with T2DM at Baseline: (revised per Amendment 01)
o
Subjects with (HbA1c >7%) at Baseline
o
Subjects who are on monotherapy with oral antidiabetic agent at Baseline 
o
Subjects with early T2DM (duration of diagnosis of diabetes is less than 5 years) 
at Baseline. 

Proportions of subjects with prediabetes at Baseline who develop new diagnosis of 
diabetic retinopathy or new diagnosis of diabetic neuropathy by EOS  (revised per 
Amendment 01)

Proportions of subjects with T2DM at Baseline who develop new diagnosis of diabetic 
retinopathy or new diagnosis of diabetic neuropathy by EOS  (revised per 
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9.7.1.2
Definitions of Analysis Sets
The Safety Analysis Set will be the group of subjects who received at least 1 dose of study drug 
and had at least 1 postdose safety assessment.
The Intent-to-Treat set (ITT) will be the group of all randomized subjects regardless of whether 
they took study drug or not.

Total Time Analysis Set:  Using the ITT, events are counted that occur while subjects are 
on and off treatment. Subjects with no events who discontinue early or complete the 
study will be censored at their last study contact (see details in the SAP). This will be
used for the primary analysis.

On-Treatment plus 30 Days Analysis Set:  Using the ITT, events are counted that occur 
while subjects are on treatment and up to 30 days from their last dose. Subjects with no 
events who discontinue early or complete the study will be censored at their last dose day 
plus 30 days.

On-Treatment Analysis Set:  Using the ITT, events are counted that occur while subjects 
are on treatment.  Subjects with no events who discontinue early or complete the study 
will be censored at their last dose day.

Prediabetes Analysis Set:  This set includes all subjects in the ITT set without a history of 
any type of diabetes and who are prediabetic at Baseline.  Definition of prediabetes will 
be found in the SAP.  (revised per Amendment 01)

Nondiabetes Analysis Set: This set includes all subjects in the ITT set without a history 
of any type of diabetes at Baseline.  Definition of nondiabetes will be found in the SAP.  
(revised per Amendment 01)
T2DM Analysis Set: This set will be all subjects in the ITT who have T2DM at Baseline.
FDA-defined Valvulopathy Analysis Set:  This set will be all subjects in the ITT without 
FDA-defined valvulopathy at Baseline.  The data from this study will be pooled with the data 
from the 3 pivotal lorcaserin HCl studies (APD356-009, -010, and -011).
The PD Analysis Set will be the group of subjects who have both baseline and at least 
1 postbaseline assessment of at least 1 PD parameter.
9.7.1.3
Subject Disposition
The number of subjects screened and the number (percent) of subjects who failed screening and
the reasons for screen failure will be summarized, based on data reported on the Screening
Disposition CRF. The distribution of the number of randomized subjects enrolled by each site
will be summarized for each randomized treatment group.
The primary reasons for screen


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failures; did not meet inclusion/exclusion criteria, AE, lost to follow-up, withdrawal of consent, 
and other, will be presented.
For study completion, the number (percent) of randomized and treated subjects who completed 
the study and who discontinued from the study will be summarized according to the primary 
reason for discontinuation based on data reported on the Subject Disposition (Study Phase) CRF. 
The number (percent) will be presented by treatment group and total for subjects; randomized, 
not treated, treated, who completed the study, and discontinued from the study. The reasons for 
discontinuation from the study will be documented in the CRF and source documentation.
Completion of Study Treatment: the number (percent) of randomized and treated subjects who 
completed study treatment and who discontinued from study treatment will be summarized 
according to the primary reason for discontinuation, based on data reported on both the Subject 
Disposition (Study Phase) CRF and Early Discontinuation from Study Drug CRF. The number 
(percent) will be presented by treatment group and total for subjects; randomized, not treated, 
treated, who completed study treatment, and discontinued from study 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 Safety Analysis Set, ITT for subjects who 
are prediabetic (HbA1c 5.7% to <6.5%) or have normal glucose homeostasis (HbA1c ≤5.6% at 
Baseline), ITT for subjects who have T2DM at Baseline, and ITT will be summarized for each 
treatment group using descriptive statistics. Continuous demographic and baseline variables 
include age, height, weight, waist and hip circumference, duration of comorbid conditions (none, 
hypertension, dyslipidemia, sleep apnea, coronary artery disease (CAD)/CV disease), duration of 
T2DM, HbA1c, and BMI. Categorical variables include sex, age group (<65 years, ≥65 years), 
race, ethnicity, HbA1c (prediabetes: 5.7% to <6.5%; normal glucose homeostasis:  ≤5.6%), BMI 
(<30 kg/m2, 30 to <35 kg/m2, ≥35 kg/m2), baseline body weight (by quartiles), presence of 
comorbid conditions (none, hypertension, dyslipidemia, sleep apnea, CAD/CV disease), CV risk 
factors, presence of T2DM, tobacco use, albuminuria (normal: 
ACR <30μg/mg;
microalbuminuria:  ACR 30 to 299 μg/mg; macroalbuminuria: 
ACR ≥300 μg/mg), GFR 
(mL/min per 1.73 m2 BSA); kidney damage with normal or increased GFR ≥90; kidney damage 
with mildly decreased GFR 60 to 89; moderately decreased GFR 30 to 59; severely decreased 
GFR 15 to 29; kidney failure GFR <15 or dialysis; and type of diabetes medication used.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD).  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 (ATC) 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 (1) started before the 
first dose of study drug and were continuing at the time of the first dose of study drug, or 


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(2) started on or after the date of the first dose of study drug for at least 30 days after study 
completion/early termination.  All medications will be presented in subject data listings.
9.7.1.6
Primary Safety and and Key Secondary Efficacy Analyses (revised per Amendment 02)
The primary endpoints, MACE, and MACE+, will be analyzed using a Cox proportional hazards 
model that includes factors for treatment and stratification variable (presence of established CV 
disease or CV risk factors without established CV disease).  (revised per Amendment 02) For 
secondary and exploratory endpoints a 2-sided α = 0.05 significance level will be used.  The 
MACE analysis (“interim” analysis) will be conducted when 460 adjudicated MACE events have 
been recorded; the other analyses will be conducted when 1401 adjudicated MACE+ events have 
been recorded, and the study has completed.  (revised per Amendment 02)
Sequential Gatekeeping Testing Procedure (revised per Amendment 02)
The following closed sequential gatekeeping testing procedure (SGTP) will be used to control 
the family-wise error rate (FWER) at α = 0.05 (2-sided) in testing the 2 primary endpoints
(MACE and MACE+) and 1 key secondary endpoint, conversion to T2DM.  (revised per 
Amendment 02)  
Let H01 be the gatekeeping null hypothesis for noninferiority testing of the MACE endpoint 
using a noninferiority margin of 1.4.
Let H02, and H03 be the null hypotheses for superiority testing: MACE+ and conversion to 
T2DM, respectively.  (revised per Amendment 02)
The SGTP testing hierarchy is presented below.  (revised per Amendment 02)

STEP1:  At the interim analysis, test the noninferiority hypothesis for MACE, H01 (α = 
0.025, 1-sided).  If H01 is rejected, then proceed to STEP2, otherwise stop testing and 
the trial will be stopped.

STEP2:  At study completion, the hypotheses H02 (α = 0.05, 2-sided), is tested first.  If 
the hypothesis is rejected, then proceed to test H03 (α = 0.05, 2-sided).  If H02 is not 
rejected, then testing stops at this point. 
Figure 3 presents the SGTP.  (revised per Amendment 02)


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Figure 3
Flowchart for SGTP
MACE = major adverse cardiovascular events, MACE+ = MACE or hospitalization for unstable angina or heart 
failure, or any coronary revascularization; SGTP = sequential gatekeeping testing procedure; T2DM = type 2 
diabetes mellitus.
PRIMARY ENDPOINT ANALYSES

Time to MACE:  The estimate of the hazard ratio of lorcaserin HCl to placebo and the 
corresponding 1-sided 97.5% confidence interval (CI) will be calculated.  Noninferiority 
of lorcaserin HCl to placebo will be declared if the upper limit of the 97.5% CI is less 
than the noninferiority margin of 1.4.  The Total Time Analysis Set will be used as the 
primary analysis at the interim analysis.  (revised per Amendment 02)  The On-Treatment 
Analysis Set and the On-Treatment plus 30 Days Analysis Set will be used as  sensitivity 
analyses at study completion.  (revised per Amendment 02)

Time to MACE+:  The estimate of the hazard ratio of lorcaserin HCl to placebo and the 
corresponding 2-sided 95% CI will be calculated.  The Total Time Analysis Set will be 
used as the primary analysis.  (revised per Amendment 02)  The On-Treatment Analysis
Set and the On-Treatment plus 30 Days Analysis Set will be used as sensitivity analyses.


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The incidence rate difference and the incidence rate ratio between lorcaserin and placebo will 
also be analyzed as supportive analysis for the primary endpoints above at study completion. 
(revised per Amendment 02)
Sensitivity analysis will be performed at study completion for the MACE and MACE+ endpoints 
using the Total Time Analysis Set.  (revised per Amendment 02)  This sensitivity analysis will 
not count a MACE or MACE+ event that occurs after the subject starts another weight reduction 
medication or undergoes bariatric surgery.  (revised per Amendment 02)
KEY SECONDARY ENDPOINT ANALYSIS (revised per Amendment 02)

Time to conversion to T2DM:  The estimate of the hazard ratio of lorcaserin HCl to 
placebo and the corresponding 2-sided 95% CI will be calculated.  The Prediabetes and 
Total Time Analyses Sets will be used as the primary for this analysis.  The Prediabetes 
along with the On-Treatment Analysis Set and the On-Treatment plus 30 Days Analysis 
Set will be used as a sensitivity analysis at study completion (revised per 
Amendment 02).
9.7.1.7
Secondary Endpoint Analyses
For the following endpoints, a Cox proportional hazards model with factors for treatment and 
stratification variable (presence of established CV disease or CV risk factors without 
established CV disease) will be used.  The estimate of the hazard ratio of lorcaserin HCl to 
placebo and the corresponding 2-sided 95% CI will be calculated.
o
The time-to-event of each component of MACE+. The Total Time Analysis Set 
will be used as the primary analysis.  The On-Treatment Analysis Set and the 
On-Treatment plus 30 Days Analysis Set will be used as sensitivity analyses.
o
Time-to-event of all-cause mortality. The Total Time Analysis Set will be used as 
the primary analysis.  The On-Treatment Analysis Set and the On-Treatment plus 
30 Days Analysis Set will be used as sensitivity analyses.
o
Time-to-event of new onset renal impairment or worsening existing renal 
impairment in all subjects.  The ITT Analysis Set will be used for this analysis.  
(revised per Amendment 02)
o
Time-to-event of new onset renal impairment or worsening existing renal 
impairment in subjects with T2DM at Baseline.  The T2DM Analysis Set will be 
used for this analysis.  
o
Time-to-event of new onset renal impairment or worsening existing renal 
impairment in subjects with prediabetes at Baseline.  The Prediabetes Analysis 
Set will be used for this analysis.  (revised per Amendment 01)
o
Time-to-event of improvement in renal function.  The T2DM Analysis Set will be 
used for this analysis.


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o
Time-to conversion to T2DM in subjects without any type of diabetes at Baseline.  
The Nondiabetes Analysis Set will be used for this analysis.  (revised per 
Amendment 01)
o
Time to conversion to normal glucose homeostasis (HbA1c ≤5.6% and fasting 
plasma glucose <100 mg/dL without any antidiabetic treatment).  The Prediabetes 
Analysis Set will be used for this analysis.  (revised per Amendments 01 and 02)

Change from Baseline in HbA1c at 6 months in subjects with T2DM at Baseline will be 
analyzed using an analysis of covariance (ANCOVA) model with treatment and 
stratification variable (presence of established CV disease or CV risk factors without 
established CV disease) as factors, and baseline HbA1c, as a covariate.  Comparison 
between lorcaserin HCl and placebo will be made at 6 months.  The estimated treatment 
difference between lorcaserin HCl and placebo and the 2-sided 95% CI will be 
calculated.  The T2DM Analysis Set will be used for this analysis.  (revised per 
Amendment 01)

The proportion of subjects who meet FDA-defined valvulopathy in echocardiographically 
determined heart valve changes will be analyzed using logistic regression including 
treatment as a factor and baseline BMI as a covariate.  Comparison between lorcaserin 
HCl and placebo will be made at 1 year.  The FDA-defined Valvulopathy Analysis Set
will be used for this analysis.

The proportion of subjects with FDA-defined valvulopathy at Baseline who demonstrate 
worsened FDA-defined valvulopathy will be analyzed using logistic regression including 
treatment as a factor and baseline BMI as a covariate.  A comparison between lorcaserin 
HCl and placebo will be made at 1 year.  The ITT analysis set in subjects with 
FDA-defined valvulopathy at Baseline will be used for this analysis.  (revised per 
Amendment 01)

The change from Baseline in echocardiographically-determined pulmonary arterial 
systolic pressure will be analyzed using a mixed-effects model with repeated measures 
with treatment as a factor and baseline BMI as a covariate.  Comparison between 
lorcaserin HCl and placebo will be made at 1 year and the corresponding 2-sided 95% CI 
will be calculated.  (revised per Amendment 01)  The ITT will be used for this analysis.  
9.7.1.8
Exploratory Endpoints Analyses

The change from Baseline in CV risk factors (body weight, BMI, waist and hip 
circumference, dyslipidemia, insulin level, hypertension, inflammatory biomarkers) will 
be analyzed using a mixed-effects model with repeated measures with treatment and 
stratification variable (presence of established CV disease or CV risk factors without 
established CV disease) as factors.  Comparison between lorcaserin HCl and placebo will 
be made at 1year.  The ITT will be used for this analysis.

For subjects with NAFLD at Baseline, the change from Baseline in liver function tests 
(AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin) will be analyzed using 


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a mixed-effects model with repeated measures with treatment and stratification variable 
(presence of established CV disease or CV risk factors without established CV disease) 
as factors.  Comparison between lorcaserin HCl and placebo will be made at 1 year.  The 
ITT will be used for this analysis.

The proportion of subjects who meet FDA-defined valvulopathy in echocardiographically 
determined heart valve changes will be analyzed using logistic regression including 
treatment as a factor and baseline BMI as a covariate.  Comparison between lorcaserin 
HCl and placebo will be made at 2 years and yearly thereafter.  The FDA-defined 
Valvulopathy Analysis Set will be used for this analysis.

The change from baseline in eGFR and ACR will be analyzed using a mixed-effects 
model with repeated measures with treatment as a factor and baseline value as a 
covariate.  Comparison of the trajectories for lorcaserin HCl and placebo will be made at 
1 year, yearly thereafter, and at EOS.  The ITT will be used for this analysis.

The change from Baseline in echocardiographically-determined pulmonary arterial 
systolic pressure will be analyzed using a mixed-effects model with repeated measures 
with treatment as a factor and baseline BMI as a covariate.  Comparison between 
lorcaserin HCl and placebo will be made at 2 years and yearly thereafter.  The ITT will 
be used for this analysis.

Change from Baseline in HbA1c,FPG, fasting insulin levels, and HOMA-IR at 6 months 
in subjects with T2DM at Baseline will be analyzed using an ANCOVA model with 
treatment and stratification variable (presence of established CV disease or CV risk 
factors without established CV disease) as factors, and baseline HbA1c, as a covariate.  
Comparison between lorcaserin HCl and placebo will be made at 6 months.  The 
estimated treatment difference between lorcaserin HCl and placebo and the 2-sided 95% 
CI will be calculated.  The T2DM Analysis Set will be used for this analysis, in the 
following subpopulations. (revised per Amendments 01 and 02)
o
Subjects with (HbA1c>7%) at Baseline
o
Subjects who have not been treated with antidiabetic agents at Baseline
o
Subjects who are on monotherapy with oral antidiabetic agent at Baseline
o
Subjects with early T2DM (duration of diagnosis of diabetes is less than 5 years) 
at Baseline.

Proportion of subjects with reduction in the number of OAD medications or reduction in 
the dosage of OAD medications in the following subpopulations of subjects with T2DM 
at Baseline will be analyzed using logistic regression including treatment as factor.  
Comparison between lorcaserin HCl and placebo will be made at 6 months.  The T2DM 
Analysis Set will be used for this analysis, in the following subpopulations: (revised per 
Amendment 01)
o
Subjects with (HbA1c >7%) at Baseline
o
Subjects who are on monotherapy with oral antidiabetic agent at Baseline 


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o
Subjects with early T2DM (duration of diagnosis of diabetes is less than 5 years) 
at Baseline. 

Proportions of subjects with at least a 1-stage reduction in an obesity-related 
complication 
(prediabetes, 
metabolic 
syndrome, 
T2DM, 
hypertension, 
and 
hypertriglyceridemia/dyslipidemia), incidence of other obesity-related complications will 
be collected through AE reports, medical history, and use of concomitant medications, 
will be analyzed using logistic regression including treatment as factor.  Comparison 
between lorcaserin HCl and placebo will be made at 1 year and EOS.  The Safety 
Analysis Set will be used for this analysis.  (revised per Amendment 01)
Logistic regression including treatment as factor will be used for the following endpoints.  
Comparison between lorcaserin HCl and placebo will be made at EOS.  (revised per 
Amendment 01)
The Prediabetes Analysis Set will be used for the following analyses:  (revised per 
Amendment 01)

Proportions of subjects with prediabetes at Baseline who develop new diagnosis of 
diabetic retinopathy at EOS. (revised per Amendment 01)

Proportions of subjects with prediabetes at Baseline who develop new diagnosis of 
diabetic neuropathy at EOS.  (revised per Amendment 01)  
The T2DM Analysis Set will be used for the following analyses:  (revised per Amendment 01)

Proportions of subjects with T2DM at Baseline who develop new diagnosis of diabetic 
retinopathy at EOS.  (revised per Amendment 01)

Proportions of subjects with T2DM at Baseline who develop new diagnosis of diabetic 
neuropathy at EOS.  (revised per Amendment 01) 
9.7.1.9
Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic/Pharmacogenetic Analyses
PHARMACOKINETIC ANALYSES
Not applicable
PHARMACODYNAMIC ANALYSES
A PD analysis plan may be defined and reported separately.
BIOMARKER ANALYSES
A biomarker analysis plan may be defined and reported separately.
PHARMACOGENOMIC ANALYSES
A pharmacogenomic analysis plan may be defined and reported separately.


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9.7.1.10 Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  The incidence of AEs 
(including changes from baseline in physical examination), out-of-normal-range laboratory 
safety test variables, abnormal ECG findings, along with change from Baseline in laboratory 
safety test variables, ECGs, and vital sign measurements summarized yearly by treatment group 
using descriptive statistics.
EXTENT OF EXPOSURE
Cumulative exposure to study drug will be summarized by the number and percentage of
subjects (remaining in study) exposed to study drug in days or other time units by treatment
group. In addition, the number of days or other time units of exposure will be summarized
descriptively as a continuous variable. The average dose and relative dose intensity (actual dose
administered divided by planned dose) will be summarized by month and overall study.
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  AEs will be coded to the MedDRA lower level term (LLT) closest to the verbatim 
term.  The linked MedDRA PT and primary system organ class (SOC) are also captured in the 
database.
A treatment-emergent AE (TEAE) is defined as an AE that emerges during treatment, having 
been absent at pretreatment (Baseline) or 
●
Re-emerges 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.
TEAEs will be summarized by treatment group on the Safety Analysis Set.  The incidence of 
TEAEs will be reported as the number (percentage) of subjects with TEAEs by SOC and PT.  A 
subject will be counted only once within 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 TEAEs will also be summarized by relationship to study drug 
(possibly related, probably related, and not related).
AEs will be summarized by the following subgroups:  age (<65 years, ≥65 years), sex (male, 
female), race (white, black, other), and T2DM at Baseline (with and without).


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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 SAEs will be summarized by 
MedDRA SOC and PT for each treatment group.  A subject data listing of all SAEs will be 
provided.
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT for each treatment group.  A subject data listing 
of all AEs leading to discontinuation from study drug will be provided.
The incidence of AEs of interest will be summarized separately.  In addition, for each AE of 
interest, Kaplan-Meier curves and median time and 95% CI will be presented.  The Safety 
Analysis Set will be used for this analysis.
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 Safety Assessments (Laboratory 
Measurements), the actual value and the change from baseline to each postbaseline visit and to 
the EOT (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 will be summarized 
using frequencies (number and percentage of subjects), and changes from baseline to each 
postbaseline visit and to EOT 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 EOT.  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 3 (Sponsor’s Grading for Laboratory Values) 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.


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VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, diastolic and systolic BP, pulse, weight) and 
changes from Baseline will be presented by visit and treatment group.  Descriptive statistics and 
changes from Baseline will also be presented by visit and treatment group for waist and hip
circumference. 
ECGS
Abnormal ECG findings will be presented as shifts from baseline (normal/abnormal clinically 
significant/abnormal not clinically significant) to post baseline (normal/abnormal clinically 
significant/abnormal not clinically significant) visits. The number and percent of subjects will be 
presented.
9.7.2
Determination of Sample Size
A sample size of 12,000 subjects should provide the required power for the primary endpoints as 
follows:  (revised per Amendment 02)

For 460 MACE events to have occurred by approximately 43 months from start of the 
trial, providing 95% power to exclude a noninferiority margin of 1.4, assuming an annual 
background rate of 1.5%, 15-month accrual period, 5% annual drop-out rate, α = 0.025, 
and a 1-sided test

For 1401 MACE+ events to have occurred by approximately 54 months from the start of 
the trial, providing >85% power to detect a 15% risk reduction with lorcaserin HCl, 
assuming an annual background rate of 3.5%, 15-month accrual period, 5% annual 
drop-out rate, α = 0.05, and a 2-sided test (revised per Amendment 02)
Key Secondary Endpoint (revised per Amendment 02)

For 457 events of conversion to T2DM in subjects who are prediabetic at the time of 
enrollment (~33%) to have occurred by approximately 54 months from the start of the 
study, providing 86% power to detect a 25% risk reduction with lorcaserin HCl, 
assuming an annual background rate of 4%, 15-month accrual period, 5% annual dropout 
rate, α = 0.05 and a 2-sided test.  (revised per Amendment 02)
9.7.3
Interim Analysis
There will be 1 interim analysis - when 460 adjudicated MACE events have occurred, the
primary analysis for MACE will be conducted.  This will be the analysis to rule out a hazard 
ratio of 1.4.  The study will continue to accrue events until the required number of MACE+ have
occurred.  (revised per Amendment 02)  Sensitivity analysis at study completion will be 
performed for the MACE endpoint after all the MACE+ events have accrued. (revised per 
Amendment 02)  At the time of MACE+ analyses, there will be approximately 600 MACE 
events.


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The interim analysis for MACE endpoint will be performed by an independent statistician and 
governed by an independent DMC and is anticipated to occur on or before (approximately) Jul 
2017.  (revised per Amendment 02)  The interim analysis will be conducted according to a DMC 
Charter to establish whether the MACE primary objective has been achieved.
To maintain the integrity and credibility of the trial, procedures will be implemented to ensure 
the DMC and independent statistician have sole access to evolving information from the clinical 
trial regarding comparative efficacy and safety data aggregated by treatment group.  Full details 
of the DMC procedures including primary responsibilities of the DMC, its relationship with 
other trial components, its membership, and the purpose and timing of its meetings will be 
documented in the DMC Charter.  These details will also include procedures to ensure 
confidentiality and proper communication (as outlined in the Study Integrity Charter), the safety 
and statistical monitoring guidelines to be implemented by the DMC, and an outline of the 
content of the closed reports and open reports that will be provided to the DMC.  (revised per 
Amendment 02)
At the interim analysis for MACE, the estimate of the hazard ratio of lorcaserin HCl to placebo 
and the corresponding 97.5% CI will be calculated.  Noninferiority between lorcaserin HCl and 
placebo will be declared if the upper limit of the 97.5% CI is less than or equal to the 
noninferiority margin of 1.4.  If the upper limit of the 97.5% CI is greater than 1.4, then 
lorcaserin HCl will be declared as not noninferior to placebo and the trial will stop.
If noninferiority between lorcaserin HCl and placebo is confirmed when 460 adjudicated MACE 
events are observed at approximately 43 months from the start of the study, then the study will 
be continued to observe 1401 MACE+ events at approximately 54 months from the start of the 
study, and a median treatment duration of 2.5 years have accrued. (revised per Amendment 02)  
The events for MACE+ and T2DM will be tested according to the SGTP described previously, 
upon study completion.
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
1. World Health Organization Global Strategy on Diet, Physical Activity and Health.  Fact 
Sheet: Obesity and Overweight. 2003.
2. Ogden CL, Carroll, MD, Kit, BK, Flegal KM.  Prevalence of Obesity in the United 
States, 2009-2010.  NCHS Data Brief, No, 82.  January 2012.
3. Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight Gain as a Risk Factor for 
Clinical Diabetes Mellitus in Women. Ann Intern Med 1995;122:481-6. 
4. Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willet WC. Obesity, fat distribution, 
and weight gain as risk factors for clinical diabetes in men. Diabetes Care 1994;17:961-9.
5. Marx J. Cellular Warriors at the Battle of the Bulge. Science 2003 February
7;299(5608):846-9.
6. Hamman RF, Wing RR, Edelstein SL, Lachin JM, Bray GA, Delahanty L, et al. Effect of 
Weight Loss with Lifestyle Intervention on Risk of Diabetes. Diabetes Care September 
2006; 29 (9):2102-7.
7. Morton J, Zoungas S, Li Q, Patel AA, Chalmers J, Woodward M, et al.  Low HDL 
Cholesterol and the Risk of Diabetic Nephropathy and Retinopathy. Diabetes Care 
2012;35(11):2201-6.
8. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A 
new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-12.
9. Bruno G, Fornengo P, Novelli G, Panero F, Perotto M, Segre O, et al.  C-reactive Protein 
and 5-year Survival in Type 2 Diabetes: the Casale Monferrato Study.  Diabetes. 2009 
Apr;58(4):926-33.
10. McGoon M, Gutterman D, Steen V, Barst R, McCrory DC, Fortin TA, et al. Screening, 
Early Detection, and Diagnosis of Pulmonary Arterial Hypertension: ACCP Evidence-
Based Clinical Practice Guidelines. Chest. 2004;126:14S-34S.
11. KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic 
Kidney Disease. 2012.
12. National Kidney Foundation Kidney Disease Outcome Quality Initiative Clinical Practice 
Guidelines for Chronic Kidney Disease:  Evaluation, Classification, and Stratification.  
2002.
13. National Institutes of Health Clinical Guidelines on the Identification, Evaluation, and 
Treatment of Overweight and Obesity in Adults, September 1998.
14. American Diabetes Association Position Statement:  Standards of Medical Care – 2013. 
Diabetes Care, Volume 36, Supplement 1, January 2013.


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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 or appropriate study team member 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 (or if regionally required, the head of the medical institution) 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 (or, if regionally 
required, the head of the medical institution) 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 (or if regionally 
required, the head of the medical institution) 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, computed tomography scans, magnetic resonance images, 
radioactive images, ECGs, rhythm strips, electroencephalograms, 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 dipsticks)
●
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 the source document.  Any correction to entries made on the 
CRF must be documented in a valid audit trail where the correction is dated, the individual 
making the correction is identified, the reason for the change is stated, and the original data are 
not obscured.  Only data required by the protocol for the purposes of the study should be 
collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor and 
retain a copy of the CRFs.
11.5 IDENTIFICATION OF SOURCE DATA
All data to be recorded on the CRF must reflect the corresponding source documents. 


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11.6 RETENTION OF RECORDS
The circumstances of completion or termination of the study notwithstanding, the investigator 
(or if regionally required, the head of the medical institution or the designated representative) 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 or equivalent, 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 drug will be supplied to the investigator (or a designated pharmacist) by the sponsor.  
Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored 
according to the conditions specified on the drug labels.  The investigator (or a designated 
pharmacist) must maintain an accurate record of the shipment and dispensing of the study drug 
in a drug accountability ledger, a copy of which must be given to the sponsor at the end of the 
study.  An accurate record of the date and amount of study drug dispensed to each subject must 
be available for inspection at any time.  The CRA will visit the site and review these documents 
along with all other study conduct documents at appropriate intervals once study drug has been 
received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form to 
the sponsor’s CRA.


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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 APPENDICES


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Appendix 1
WHO Functional Classification of Pulmonary Hypertension
World Health Organization Classification of Functional Status of Patients with PH 
Class
Description
I
Patients with PH in whom there is no limitation of usual physical activity; ordinary physical activity does not cause 
increased dyspnea, fatigue, chest pain, or presyncope.
II
Patients with PH who have mild limitation of physical activity. There is no discomfort at rest, but normal physical 
activity causes increased dyspnea, fatigue, chest pain, or presyncope.
III
Patients with PH who have a marked limitation of physical activity. There is no discomfort at rest, but less than 
ordinary activity causes increased dyspnea, fatigue, chest pain, or presyncope.
IV
Patients with PH who are unable to perform any physical activity at rest and who may have signs of right ventricular 
failure. Dyspnea and/or fatigue may be present at rest, and symptoms are increased by almost any physical activity.
PH = pulmonary hypertension.


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Appendix 2
Classification of Chronic Kidney Disease
Chronic Kidney Disease: A Clinical Action Plan
Stage
Description
GFR
(mL/min/1.73m2)
Action*
At increased risk
90
(with CKD risk factors)
Screening
CKD risk reduction
1.
Kidney 
damage
with normal or
GFR
90
Diagnosis 
and 
treatment
Treatment 
of 
comorbid 
conditions,
slowing 
progression,
CVD risk reduction
2.
Kidney 
damage
with mild
GFR
60-89
Estimating progression
3.
Moderate
GFR
30-59
Evaluating and treating complications
4.
Severe
GFR
15-29
Preparation 
for 
kidney
replacement therapy
5.
Kidney Failure
<15
(or dialysis) 
Replacement (if uremia present)
Shaded area identifies patients who have chronic kidney disease; unshaded area designates individuals who are at 
increased risk for developing chronic kidney disease. Chronic kidney disease is defined as either kidney damage or 
GFR <60 mL/min/1.73 m2 for 
3 months. Kidney damage is defined as pathologic abnormalities or markers of 
damage, 
including 
abnormalities 
in 
blood 
or 
urine 
tests 
or 
imaging 
studies.
* 
Includes 
actions 
from 
preceding 
stages.
Abbreviations: GFR, glomerular filtration rate; CKD, chronic kidney disease; CVD, cardiovascular disease.


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Appendix 3
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 x 109/L
< LLN – 3000/mm3
< 3.0 – 2.0 x 109/L
< 3000 – 2000/mm3
< 2.0 – 1.0 x 109/L
< 2000 – 1000/mm3
< 1.0 x 109/L
< 1000/mm3 
Lymphocytes 
< LLN – 800/mm3 
< LLN – 0.8 x 109/L
< 800 – 500/mm3
< 0.8 – 0.5 x 109/L
< 500 – 200/mm3
< 0.5 – 0.2 x 109/L
< 200/mm3
< 0.2 x 109/L
Neutrophils 
< LLN – 1.5 x 109/L
< LLN – 1500/mm3
< 1.5 – 1.0 x 109/L
< 1500 – 1000/mm3
< 1.0 – 0.5 x 109/L
< 1000 – 500/mm3 
< 0.5 x 109/L
< 500/mm3 
Platelets
< LLN – 75.0 x 109/L
< LLN – 75,000/mm3
< 75.0 – 50.0 x 109/L
< 75,000 – 50,000/mm3
< 50.0 – 25.0 x 109/L
< 50,000 – 25,000/mm3
< 25.0 x 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 x ULN
> 3.0 – 5.0 x ULN
> 5.0 – 20.0 x ULN
> 20.0 x ULN
ALT
> ULN – 3.0 x ULN
> 3.0 – 5.0 x ULN
> 5.0 – 20.0 x ULN
> 20.0 x ULN
AST
> ULN – 3.0 x ULN
> 3.0 – 5.0 x ULN
> 5.0 – 20.0 x ULN
> 20.0 x ULN
Bicarbonate, serum-low 
< LLN – 16 mmol/L
< 16 – 11 mmol/L
<11 – 8 mmol/L
< 8 mmol/L 
Bilirubin (hyperbilirubinemia)
> ULN – 1.5 x ULN 
> 1.5 – 3.0 x ULN
> 3.0 – 10.0 x ULN 
> 10.0 x 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 x ULN
> 1.5 – 3.0 x ULN
> 3.0 – 6.0 x ULN
> 6.0 x ULN
GGT (γ-Glutamyl transpeptidase) 
> ULN – 3.0 x ULN
> 3.0 – 5.0 x ULN
> 5.0 – 20.0 x ULN
> 20.0 x 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 
(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


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Grade 1
Grade 2
Grade 3
Grade 4
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, LLN = lower limit of normal, N/A = not applicable, ULN = upper limit of normal, WBC = 
white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).


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Appendix 4
APD356-G000-401 Healthy Lifestyle Program
Program Overview
All subjects in Study 401 will participate in a standardized weight management program
consisting of intensive multi-component behavior therapy. The therapy will focus on healthy 
eating, physical activity, and lifestyle changes that will facilitate weight loss and weight 
maintenance.
The objectives of this program are as follows: 
•
Develop a moderate-intensity weight management program for all lorcaserin HCl study 
participants
•
Standardize the weight management program across all study sites
•
Maximize patient retention


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Appendix 5
Biomarker Research
Drug Substance
BELVIQ(lorcaserin hydrochloride)
Study Code
APD356-G000-401
Edition Number 
Version 3
Date
2013-08-28


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1 
BACKGROUND 
AND 
RATIONALE 
FOR 
BIOMARKER 
RESEARCH
Obesity is a major risk factor for cardiovascular (CV) disease and other comorbidities, including 
diabetes, hypertension and hyperlipidemia.  Mounting evidence suggests that excess adiposity 
leads to increased morbidity via pathologic activation of inflammatory, and subsequently 
thrombotic and metabolic, pathways.  Observations supporting this mechanism are (1) that 
circulating mediators of inflammation, such as IL-6 and TNF-, participate in vascular injury 
and insulin resistance and (2) that several of these inflammatory mediators are secreted by 
adipocytes and adipose tissue-derived macrophages. These inflammatory processes are reflected 
in the correlation between adiposity and high sensitivity C-reactive protein (hsCRP), a strong 
marker of systemic and vascular inflammation associated with cardiovascular risk.  
Biomarkers of inflammation, metabolic dysregulation, and atherothrombosis have proven useful 
in identifying patients at risk of developing incident cardiovascular disease or diabetes as well as 
recurrent cardiovascular events in patients with stable atherosclerotic disease.  However, less is 
known about the potential of these biomarkers to make similar predictions in the setting of 
obesity.  
In addition to their role in prognostication, biomarkers that identify patients at higher risk for 
major adverse clinical outcomes can provide opportunity for guiding therapy. Patients at higher 
risk for cardiovascular events will have the greatest absolute risk reduction for a given relative 
risk reduction from a therapy and hence require a smaller number needed to treat to prevent a 
major event. Moreover, pathobiologically relevant biomarkers may identify a specific subset of 
patients who enjoy a larger relative risk reduction with a given pharmacotherapeutic 
intervention, and thus an even greater absolute risk reduction.
In addition to established biomarkers, new insights into the mechanistic pathways of obesity, 
diabetes and atherothrombosis have led to ongoing identification of novel cardiovascular and 
metabolic biomarkers. Using novel biomarkers that reflect the inflammatory, thrombotic, 
vascular, metabolic, and hemodynamic mediators of risk in patients with obesity and 
atherosclerotic risk factors, it may be possible to noninvasively characterize the participation of 
these different pathobiologic contributors in an individual patient and to monitor response to 
therapy. 
As such, this large study of well-characterized, obese subjects with CV risk factors (including 
diabetes) or established CV disease presents a unique opportunity to investigate circulating 
biomarkers for their pathobiologic insight as well as their value for risk stratification, therapeutic 
guidance and disease monitoring.  
The biomarker categories of interest for this study are broadly threefold: (1) those related to 
adiposity and metabolic dysregulation, (2) those related to dysglycemia and its complications, 
such as markers of glycation and renal dysfunction, and (3) those related to cardiovascular 
disease such as markers of atherosclerosis, ischemia, inflammation, thrombosis, hemodynamic 
stress and lipid dysregulation.  Selected examples for each of these areas follow below.


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Markers of adiposity include adiponectin, interleukin-6 (IL-6), and resistin.  Adiponectin is 
secreted by adipocytes and is thought to play a role insulin sensitivity, lipid metabolism and 
inflammation.  Interestingly, in patients with established coronary disease (as determined by 
angiography), lower levels of adiponectin independently predicted major adverse cardiac events.  
Furthermore, in primary prevention populations, higher concentrations of adiponectin are 
associated with lower risks of cardiovascular disease and the risk of developing incident T2DM.  
IL-6 is a pro-inflammatory cytokine released by adipose tissue and is the major stimulant for 
hepatic generation of CRP.  Elevated levels of IL-6 were shown to be associated with increased 
risk of myocardial infarction in a large cohort of apparently healthy men.  A third adipokine, 
resistin, is thought to mediate insulin resistance and metabolic dysfunction.  Several studies have 
shown a relationship between resistin and major adverse cardiovascular events in both stable 
CAD and ACS populations.
Markers of dysglycemia and its sequelae include advanced glycation end products (AGEs), 
receptor for AGE (RAGE) and amino acids/metabolites. In patients with type II diabetes, 
elevated glucose levels lead to the dysregulation of physiologic metabolic pathways resulting in 
the production and accumulation of pathologic glycolated proteins, AGEs.  Elevated levels of 
AGE/RAGE have a variety of pathologic consequences such as oxidizing LDL, promoting 
atherosclerosis, and decreasing NO production.  Accordingly, AGE and RAGE have been shown 
to be prognostic markers for vascular disease in both diabetic and non-diabetic populations. 
Recent studies found that metabolite levels, specifically several branched chain and aromatic 
amino acids, can predict development of diabetes in normoglycemic individuals as well as 
incident cardiovascular disease.
Markers of cardiovascular disease and inflammation include high-sensitivity cardiac troponin, 
natriuretic peptides, hsCRP and fibrinogen.  Cardiac troponin, used commonly for diagnosis of 
AMI, has been shown to predict worsened cardiovascular outcomes in stable individuals with 
cardiovascular risk factors.  Elevated levels of natriuretic peptides (BNP or the amino-terminal 
fragment of the prohormone [NT-proBNP]) are closely associated with mortality and/or heart 
failure across a broad range of individuals, ranging from the general population to patients with 
acute coronary syndromes and decompensated heart failure.  An interesting interplay between 
natriuretic peptides and obesity has been recognized.  Natriuretic peptides levels are lower in 
obese patients compared with non-obese patients, an effect that may be mediated by increased 
clearance of natriuretic peptides by adipose tissue.  Conversely, it appears that natriuretic 
peptides may influence adipose tissue through moderation of lipid metabolism.  hsCRP, a marker 
of inflammation, predicts risk of first MI in healthy cohorts and future coronary events in stable 
patients.  Furthermore, elevated hsCRP levels in obesity are prognostic for development of 
cardiovascular disease and predictive of progression to type II diabetes. Fibrinogen, an acute 
phase reactant that has a central role in coagulation and platelet aggregation, is a marker for CV 
risk factors and predicts future cardiovascular disease.  Notably, lorcaserin hydrochloride therapy 
has been shown to decrease hsCRP and fibrinogen levels.  
The evaluation of biomarkers in subjects in this trial may provide important insight into 
pathobiology of obesity, diabetes and cardiovascular disease, improve our ability to risk stratify 


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subjects, and provide information that can be used to tailor therapy. This study may also provide 
additional insights into the possible mechanistic pathways leading to CV benefit with lorcaserin 
hydrochloride.
2.
OBJECTIVES
Aim 1: To evaluate the effect of treatment with lorcaserin hydrochloride compared to placebo on 
the change in baseline biomarkers of adiposity and metabolic dysregulation, dysglycemia and its 
complications, and CV risk (atherosclerosis, ischemia, inflammation, thrombosis, hemodynamic 
stress and lipid dysregulation) over the data acquisition period. 
We hypothesize that lorcaserin hydrochloride will improve circulating concentrations of 
biomarkers of these conditions/processes over time compared to placebo.
Aim 2: To evaluate the prognostic performance of established and novel biomarkers of adiposity 
and metabolic dysregulation, dysglycemia and its complications, and CV risk (atherosclerosis, 
ischemia, inflammation, thrombosis, hemodynamic stress and lipid dysregulation) individually 
and in combination (multimarker approach).  
We hypothesize that baseline biomarkers can identify subgroups of overweight or obese subjects 
at increased risk of major adverse cardiovascular outcomes and/or the development of diabetes.  
Furthermore, we hypothesize that a multi-marker approach can improve discrimination, 
accuracy, and net reclassification improvement of models predicting the development or 
progression of these disorders.  
Aim 3: To evaluate whether obese subjects identified at higher risk on the basis of biomarkers 
experience greater absolute and/or relative risk reduction in major adverse cardiovascular 
outcomes and/or the development of diabetes with lorcaserin HCl versus placebo. 
We hypothesize that subjects with the highest risk biomarker profiles will observe greatest 
benefit from treatment with lorcaserin hydrochloride.
Aim 4: To evaluate the prognostic significance of the change in the levels of established and 
novel biomarkers of adiposity, inflammation, hemodynamic stress, myocardial ischemia/necrosis 
and metabolism between baseline and 6 month, and whether changes in biomarker concentration 
identify subjects with greater benefit with lorcaserin HCl versus placebo.
We hypothesize that the change in levels of biomarkers between baseline and 6 months can 
identify subgroups of overweight or obese subjects at increased risk of major adverse 
cardiovascular outcomes and/or the development of diabetes, who are likely to derive greater 
benefit from treatment with lorcaserin HCl. 
3 
BIOLOGIC RESEARCH PLAN AND PROCEDURES
This appendix to the Clinical Study Protocol has been subjected to peer review according to 
Eisai standard procedures.  Collection of the biomarker samples will be bound by the sample 


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principles and processes outlined in the main study protocol.  Sample collection for biomarker 
analysis is required as per the study protocol unless the collection and use of the samples is 
prohibited by specific country laws.
3.1 
Selection of biologic research population
3.1.1 Study selection record
All subjects will be asked to participate in this biologic research (except where prohibited by 
local regulations). Participation is voluntary and if a subject declines to participate there will be 
no penalty or loss of benefit. The subject will not be excluded from any aspect of the main 
Clinical Study Protocol.
3.1.2 Inclusion criteria
For inclusion in this biologic research, subjects must fulfill all of the inclusion criteria described 
in the main Clinical Study Protocol.
3.1.3
Exclusion criteria
Exclusion from this biologic research may be for any of the exclusion criteria specified in the 
main Clinical Study Protocol.
3.1.4 Discontinuation of subjects from this biologic research
Subjects may withdraw from this biologic research at any time, independent of any decision 
concerning participation in other aspects of the main study. Voluntary discontinuation will not 
prejudice further treatment. Procedures for discontinuation are outlined in the main Clinical 
Study Protocol.
3.2 
Collection of samples for biologic research
All subjects in participating countries will be asked to participate in this biologic research at 
Visit 2. If the patient agrees to participate, blood samples will be taken at Visit 2
(Randomization/Baseline) and the remaining visits indicated on the schedule in the main Clinical 
Study Protocol.

Blood samples for isolation of serum and plasma will be obtained as follows:
o
Visit 2: Serum (10-mL draw); EDTA-anticoagulated plasma (6-mL draw x 2)
o
Remaining visits:  Serum (10-mL draw); EDTA-anticoagulated plasma (6-mL draw)

Samples will be frozen at -20°C or colder until shipped to the central laboratory on dry ice.
These procedures are detailed in the Laboratory Manual of Operations.
3.3 
Coding and storage of samples
The biomarker samples will be labeled (or “coded”) with a study specific code to maintain 
patient confidentiality. Samples do not carry any patient identifying information. Samples will be 
stored for up to 20 years after the completion of the study (defined as submission of the clinical 
study report [CSR] to the appropriate regulatory agencies).  At the end of the storage period, 


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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.
3.4 
Analytic Plan
3.4.1 Biomarkers of interest
Analysis will be performed of biomarkers of adiposity and metabolic dysregulation, dysglycemia 
and its complications, and CV risk (atherosclerosis, ischemia, inflammation, thrombosis, and 
hemodynamic stress) to address the specific 4 aims listed above.  A detailed analytic plan will be 
developed.  Candidate biomarkers are listed below, from which a subset will be measured based 
on the scientific evidence at the time of testing.
Biomarkers of Adiposity/Obesity and Metabolic Dysregulation: 

Adipokines (eg, adiponectin, leptin, resistin, angiotensinogen, IL-6, TNF-)

Mediators of appetite (eg, Orexin A, neuropeptide Y, -melanocyte stimulating hormone, 
agouti-related protein)

Biomarkers of 
Lipid Dysregulation/Insulin Resistance (eg,
Lipoproteins and 
modified/oxidized lipoproteins, Lp(a))
Dysglycemia and its complications

Glycation end products and associated receptors (eg, AGE, RAGE)
Biomarkers of Cardiovascular Risk
Biomarkers of Oxidative Stress: 

Myeloperoxidase

ADMA and other arginine metabolism products
Biomarkers of Endothelial Function: 

VCAM-1, ICAM-1, vWF, E-selectin
Biomarkers of Ischemia/Injury: 

Cardiac troponin, FABP
Biomarkers of Inflammation and Atherothrombosis:

hs-CRP

Fibrinogen

phospholipases (eg, Lp-PLA2 and sPLA2)

metalloproteinases (eg, PAPP-A, MMP-9, MMP-11)

cytokines (eg, IL-1β, IL-1Ra, IL-6, IL-18, GDF-15, PlGF) 

chemotactic molecules (eg, MCP-1)

sCD40L


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Biomarker of Renal Dysfunction: 

Cystatin-C, FGF-23, NGAL
Biomarkers of Hemodynamic Stress: 

Natriuretic peptides (eg, BNP, ANP and their NT-prohormones) 

MR-adrenomedullin, C-terminal proendothelin 1, copeptin

ST-2

Galectin-3
Specific biomarkers to be tested will depend on the totality of published data at the time analyses 
are ready to commence. Other markers of these processes may be added or substituted as new 
evidence comes to light. In addition to analysis of existing biomarkers, proteomics and 
metabolomic analyses may be performed on samples to develop and test novel protein markers 
of cardiovascular outcomes. The biomarker samples may be used for discovery and/or validation 
to identify biomarkers that, for evaluation of response and/or safety-related outcomes as well as 
for use in diagnostic development.  
Sample processing and analysis will be performed by laboratories under the direction of the 
Sponsor and/or designee.  Processing, analysis, and storage will be performed at secure 
laboratory facilities to protect the validity of the data and maintain subject privacy. Samples will 
only be used for the purposes described in this protocol.
3.4.2 Biomarker Testing
Biomarkers will be measured in all subjects at baseline with serial testing at three additional 
timepoints.  Testing at serial timepoints may be expanded.


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4 
ETHICAL AND REGULATORY REQUIREMENTS
The principles for ethical and regulatory requirements for the study, including this biologics 
research component, are outlined in Section 5 of the main Clinical Study Protocol.
Informed consent
The biologic component of this study is optional and the patient may participate in other 
components of the main study without participating in the biologic component. The principal 
investigator(s) is responsible for ensuring that consent is given freely and that the patient 
understands that they may freely discontinue from the biologic aspect of the study at any time.
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 or its agents 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 biomarker samples will be coded.  
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.
Given the research nature of the 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 subjects or their physicians.
5 
DATA MANAGEMENT


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Biomarker data from the designated laboratory will be merged with the clinical database for 
statistical analysis.
The results from this biologic research may be reported in the CSR for the main study, or in a 
separate report as appropriate.
Some or all of the clinical datasets from the main study may be merged with the biologic data in 
a suitable secure environment separate from the clinical database.
6 
STATISTICAL ANALYSIS PLAN
The biomarker analyses are exploratory in nature.  A sample size of approximately 
10,000 subjects (assuming 80%-90% participation) will provide 80% power to detect a relative 
risk of ≥1.2 for the primary endpoint of MACE and secondary endpoint of MACE+ for subjects 
above versus those below the median level of a biomarker.  These values are in keeping with risk 
estimates and interactions seen with other biomarkers and represent the thresholds of clinical 
importance.  


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Appendix 6
Pharmacogenetic Research
Drug Substance
BELVIQ(lorcaserin hydrochloride)
Study Code
APD356-G000-401
Edition Number 
Version 2
Date
2013-08-28


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1
BACKGROUND AND RATIONALE 
Subjects enrolled in this clinical study will have the option to have samples collected for genetic 
analysis. Genetic variations affect the risk of developing cardiovascular disease (eg, myocardial 
infarction) and metabolic disease (eg, diabetes).  Furthermore, genetic variants may alter the 
clinical efficacy and/or the safety profile of specific pharmacotherapy, either directly by 
affecting the pharmacokinetics or pharmacodynamics of the drug in question, or indirectly by 
altering the risk of developing outcomes the drug may prevent. 
2
GENETIC RESEARCH OBJECTIVES 
The objective of this research is to collect deoxyribonucleic acid (DNA) for research into 
genes/genetic variation that may influence response (eg, distribution, safety, tolerability and 
efficacy, including effects on obesity and the development and progression of secondary 
complications of obesity) to treatment with lorcaserin and genetic factors that may influence 
susceptibility to obesity, cardiovascular disease, and diabetes mellitus, and/or associated 
cardiovascular conditions and their risk factors.
The pharmacogenomic 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/resistance.  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.
3
GENETIC RESEARCH PLAN AND PROCEDURES 
3.1
Selection of genetic research population 
3.1.1
Study selection record 
All subjects will be asked to participate in this genetic research. Participation is voluntary and if 
a subject declines to participate there will be no penalty or loss of benefit. The subject will not be 
excluded from any aspect of the main study.
3.1.2
Inclusion criteria 
For inclusion in this genetic research, subjects must fulfill all of the inclusion criteria described 
in the main Clinical Study Protocol and: 

Provide informed consent for the genetic sampling and analyses. 
3.1.3
Exclusion criteria 
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main Clinical Study Protocol or any of the following: 

Previous bone marrow transplant 

Whole blood transfusion within 120 days of genetic sample collection 


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3.1.4
Discontinuation of subjects from this genetic research 
Subjects may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study. Voluntary discontinuation will not 
prejudice further treatment. Procedures for discontinuation are outlined in the main Clinical 
Study Protocol. 
3.2
Collection of samples for genetic research 
The blood sample (10 ml EDTA) for genetic research will be obtained from the subjects at 
Visit 2 (Randomization/Baseline). Although genotype is a stable parameter, early sample 
collection is preferred to avoid introducing bias through excluding subjects who may withdraw 
due to an adverse event (AE). If for any reason the sample is not drawn at baseline, it may be 
taken at any visit until the last study visit at the discretion of the investigator and site staff.
Only 1 sample should be collected per subject for genetics during the study. Samples will be 
collected, labeled, stored and shipped as detailed in the Laboratory Manual of Operations 
3.3
Coding and storage of DNA samples 
No subject-identifying information (eg, initials, date of birth, government identifying number) 
will be associated with the sample.  The DNA samples 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 key linking the sample ID to the subject 
number will be maintained separately from the sample. Laboratory personnel performing genetic 
analysis will not have access to the key.  
All genetic samples will be stored under secure conditions with restricted access at Eisai, the 
designated vendor, and/or a contracted third party working with them on this study. Samples will 
be stored for up to 20 years after the completion of the study (defined as submission of the 
clinical study report [CSR] 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.
3.4
Genetic testing
There are genetic variants that increase the risk of the development of particular disease states 
(eg, degrees of obesity, cardiovascular disease, and type 2 diabetes mellitus), and lorcaserin may 
offer particular benefit among patients with these polymorphisms.  Genes will be evaluated both 
in relation to the disease state and to the properties of the study drug, and testing may include:
1. Body mass index and obesity: FTO, BDNF, MC4R. 
2. Cardiovascular disease as well as the risk of recurrent events: CDKN2A, SORT1, and 
CXCL12; additionally, a genetic risk score derived from 13 common variants has been 
successfully used to stratify risk for incident cardiovascular disease and MI in prospective 


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cohorts.  An additional 13 loci have now been identified, and these composite scores can 
also be used.
3. Development and severity of type 2 diabetes mellitus: TCF7L2, WFS1, and KCNQ1 as 
well as a composite genetic score will be evaluated.
4. Drug disposition and putative drug target: HTR2C.
5. Unbiased genetic studies may add further understanding of the mechanisms related to 
degrees of obesity, cardiovascular disease, and type 2 diabetes mellitus as well as 
lorcaserin’s modification of these particular entities.  Discovery studies using a gene 
array could be performed.
4
ETHICAL AND REGULATORY REQUIREMENTS 
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in the main Clinical Study Protocol. 
4.1
Informed consent 
The genetic component of this study is optional and the subject may participate in other 
components of the main study without participating in the genetic component. To participate in 
the genetic component of the study the subject must sign and date both the consent form for the 
main study and the genetic component of the study. Subjects may freely discontinue from the 
genetic aspect of the study at any time. 
4.2
Subject data protection 
Individual genotype results will not be provided to subjects, any insurance company, any 
employer, their family members, general physician or any other third party, unless required to do 
so by law. 
Samples will only be used for the purposes described in this protocol.  Laboratories contracted to 
perform the analysis will not retain rights to the samples beyond those necessary to perform the
specified analysis and will not transfer or sell those samples.  
5
DATA MANAGEMENT 
Any genotype data generated in this study will be in appropriate secure system within Eisai, the 
designated vendor, and/or a contracted third party working with them on this study.   
Steps will be taken 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:


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
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.
The genetic material is for research use only and not clinical care. Therefore, these results will 
not be disclosed to the subjects or their physicians.
6
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
The number of subjects that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A statistical analysis 
plan will be prepared where appropriate. 


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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
APD356-G000-401
Study Protocol Title:
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Evaluate the Effect of Long-Term Treatment with BELVIQ (lorcaserin HCl) on 
the Incidence of Major Adverse Cardiovascular Events and Conversion to Type 2 
Diabetes Mellitus in Obese and Overweight Subjects with Cardiovascular 
Disease or Multiple Cardiovascular Risk Factors
Investigational Product 
Name:
APD356/BELVIQ (lorcaserin hydrochloride)
IND Number:
69888
EudraCT Number:
2013-000324-34
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
APD356-G000-401
Study Protocol Title:
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Evaluate the Effect of Long-Term Treatment with 
BELVIQ (lorcaserin HCl) on the Incidence of Major Adverse 
Cardiovascular Events and Conversion to Type 2 Diabetes 
Mellitus in Obese and Overweight Subjects with Cardiovascular 
Disease or Multiple Cardiovascular Risk Factors 
Investigational Product
Name:
APD356/BELVIQ (lorcaserin hydrochloride)
IND Number:
69888
EudraCT Number:
2013-000324-34
I have read this protocol and agree to conduct this trial 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.
Medical Institution
Investigator
Signature
Date

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CONFIDENTIAL 
 
Previous Version: V2.0 
Current Version:  V3.0  
Date of Revisions:  18 May 2018 
Change 
Rationale 
Affected Section(s) 
Age groups: 
From <65, ≥ 65 yrs.  
To: <65, , ≥ 65 to < 75, , ≥ 75 yrs. 
To evaluate safety in 
subjects  75, as per 
Clinical Team and TIMI 
 
Section 5.2.4 
 
Section 5.3.4, 
Table 2 
Re wording definition of concomitant 
medication 
For clarity 
 
Section 5.2.6 
   From: Risk Scores( 0,1-2, and 3) 
To:   Risk Scores( 0,1-2, and 3 or greater) 
Clarity 
 
Section 5.3.4, 
Table 3 
 
Section 8 
Risk Score Table added weight of “1” to 
Prior MI 
As per TIMI group 
 
Section 8 
Deleted paragraph 
“All MACE or MACE+ events will be 
recorded in the CRF, however, only 
MACE or MACE+ events that are 
considered by the investigator to be at 
least possibly related to the study drug 
will be included in all AE summary tables, 
see Section 5.3.6 for more details.” 
 
 
As per discussions with 
clinical team and safety 
group it was decided that 
all AEs will presented in 
tables and listings. 
 
Section 5.6.2 
Newly Developed Albuminuria definition
As per clinical needed to 
include Newly Developed 
Albuminuria definition in 
Table 4 
 
Section 8.2.1, 
Table 4 
Censoring slides for On-Treatment – 30days 
During validation it was 
found that for subjects who 
complete Study on Drug 
without experiencing an 
event with be censored on 
EOS visit instead of EOT 
visit.  
 
Section 13.2.1 
Censoring slides for On-Treatment  
During validation it was 
found that for subjects who 
premature discontinuation 
of Study on Drug without 
experiencing an event with 
be censored on EOT visit 
instead of EOS visit.  
 
Section 13.2.1 


 
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FINAL V3.0   18 May 2018 
 
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CONFIDENTIAL 
 
Previous Version: V2.0 
Current Version:  V3.0  
Date of Revisions:  18 May 2018 
Change 
Rationale 
Affected Section(s) 
Algorithms for categorizing subjects into one 
of the following categories; 
 Subjects 
without 
Any 
Type 
of 
Diabetes at Baseline 
 Subject who are Pre-diabetic at 
Baseline 
 Subject who are Normoglycemic at 
Baseline 
 Subjects who are T2DM at Baseline 
 
Subjects who are T1DM at Baseline 
 
Subjects who are DM at Baseline 
In order to ensure that all 
subjects are place into one 
of the categories 
 
Section 8 
Change wording on censoring algorithm in 
subjects who started a weight reduction drug 
or had bariatric surgery. 
In order to capture subjects 
who started a weight 
reduction drug or had 
bariatric surgery prior to 
randomization their 
censoring time is set to 
randomization date.  In 
addition, for subjects who 
experienced an event after 
stopping a weight reduction 
drug the event will be 
counted. 
 
Section 8.5.2.4 
Exploratory 
Endpoint: 
Obesity 
Staging 
analysis will not be performed 
 Proportions of subjects with at 
least a 1-stage reduction in an 
obesity-related complication 
(prediabetes, metabolic syndrome, 
T2DM, hypertension, and 
hypertriglyceridemia/dyslipidemia)
, incidence of other obesity-related 
complications will be collected 
This population will show 
no change since Obesity 
Stage will be 1 for all 
subjects.  In addition the 
study is not collecting all of 
the Obesity Staging 
variables to make a reliable 
interpretation. 
 
Section 7 


 
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(Statistical Analysis Plan) 
 
 
FINAL V3.0   18 May 2018 
 
Page 3 of 67 
CONFIDENTIAL 
 
Previous Version: V2.0 
Current Version:  V3.0  
Date of Revisions:  18 May 2018 
Change 
Rationale 
Affected Section(s) 
through AE reports, medical 
history, and use of concomitant 
medications, will be analyzed 
using logistic regression including 
treatment as factor. Comparison 
between lorcaserin HCl and 
placebo will be made at 1 year and 
EOS. The odds ratio, p-value and 
2-sided 95% CI will be calculated.  
The ITT Analysis Set will be used 
for this analysis. 
 
Exploratory 
Endpoint: 
Obesity 
Staging 
analysis will not be performed 
Proportion of subjects with reduction in 
the number of OAD medications or 
reduction 
in 
the 
dosage 
of 
OAD 
medications 
in 
the 
following 
subpopulations of subjects with T2DM at 
Baseline 
It would be difficult to 
interpret results and data 
was not collected  in order 
to answer this question 
 
Section 7 
Included sentence “In addition, systolic and 
diastolic 
blood 
pressure 
will 
be 
summarized by clinically notable changes 
(see Section 8): 
As per clinical 
 
Section 5.6.4 
Definition of clinically notable changes for 
systolic and diastolic blood pressure was 
added. 
As per clinical 
 
Section 8 
 
 
 
 
 
 


 
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Previous Version:  V1.0 
Current Version:  V2.0  
Date of Revisions:  31 March 2017 
Change 
Rationale 
Affected Section(s) 
As per protocol Amendment 02 
Protocol was Amendment to 
remove conversion to T2DM 
as a co-primary endpoint and 
secondary endpoints were re-
grouped 
 
Section 3.1, 3.2 
 
Section 4 
 
Section 5.1 
 
Section 5.3.3 
 
Section 5.4.1 
 
Section 5.4.2 
Treatment compliance was change 
to consider subjects on BID or QD 
dosing as complaint 
As per protocol subjects who 
experienced an AE are 
allowed to diminish dose 
from BID to QD dosing 
 
Section 5.2.7 
Baseline diabetic medications 
categories 
As per TIMI and Eisai 
Clinical 
 
Section 5.3.4, Table 2 
Added Risk Scores criteria to CV 
risk level 
As per TIMI and Eisai 
Clinical 
 
Section 5.3.4, Table 3 
Added paragraph on Adjudication 
of Conversion to Diabetes Events 
To point out that conversion 
to diabetes  events will be 
adjudicated by the CEC and 
to reference the Conversion 
to diabetes CEC charter 
 
Section 5.3.6 
Added sensitivity analyses for 
subjects who prematurely 
discontinued 
FDA ask us to add multiple 
imputation for the MACE 
(Superiority)  and MACE+ 
endpoints for subjects who 
discontinued the study 
prematurely at Study 
Completion.  
 
Section 5.4.1.1 
 
For Subjects that start another 
weight reduction medication “or 
undergoes bariatric surgery” 
As per TIMI and Eisai 
Clinical 
 
Section 5.4.1.1 
 
For Subjects who permanently 
down titrate from BID dosing to 
QD dosing 
As per TIMI and Eisai 
Clinical the analyses sets 
where change from Total 
Time to On-treatment and 
on-treatment plus 30 days 
 
Section 5.4.1.1 
Clarification on how MACE or 
MACE+ events will be recorded 
in the CRF and reported in CSR 
tables 
As per Eisai Saety group 
 
Section 5.6.2 
Added the word “Central” 
It was agree with clinical to 
only summarized Central 
Lab data 
 
Section 5.6.3 


 
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FINAL V3.0   18 May 2018 
 
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CONFIDENTIAL 
 
Previous Version:  V1.0 
Current Version:  V2.0  
Date of Revisions:  31 March 2017 
Change 
Rationale 
Affected Section(s) 
OAD change to “non-insulin 
glucose lowering or anti-diabetic 
agent” 
As per TIMI and eisai 
clinical 
 
Section 5.8 
Exploratory endpoint at least 1-
stage reduction in an obesity 
related complication.  The 
Safety analysis set was replace 
with the ITT analysis set 
As per TIMI and Eisai 
clinical 
 
Section 5.8 
Interim Analysis, at the end of 
the second paragraph,  added 
reference to the Study Integrity 
Charter 
More transparency 
 
Section 6 
Interim Analysis: remove all 
sensitivity analyses 
As requested by FDA 
 
Section 6.1.1 
Treatment compliance was 
change to consider subjects on 
BID or QD dosing as complaint 
As per protocol subjects 
who experienced an AE 
are allow to fo from BID 
to QD dosing 
 
Section 8 
Added secondary prevention 
risk scores 
As per TIMI/clinical 
 
Section 8 
On treatment definition updated 
As per discussions with 
TIMI and Eisai clinical 
 
Section 8 
Subjects who completed the 
study  on study drug definition 
updated 
As per discussions with 
TIMI and Eisai clinical 
 
Section 8 
Subjects who completed the 
study  definition updated 
As per discussions with 
TIMI and Eisai clinical 
 
Section 8 
Subjects who are T2DM at 
Baseline definition updated 
As per discussions with 
TIMI and Eisai clinical 
 
Section 8 
Determination of conversion to 
T2DM updated 
To reference the CEC 
charter 
 
Section 8.3.1 
Determination of conversion to 
normal glucse updated 
As per discussions with 
TIMI and Eisai clinical 
 
Section 8.3.2 
Events that occur after database 
lock will not be adjudicated and 
will not be included in the 
primary analyses 
As per discussions with 
TIMI and Eisai clinical 
 
Section 8.5 
Events that occur after with 
draw of consent will be 
included if they are found 
through vital status search prior 
to database lock 
As per discussions with 
TIMI and Eisai clinical 
 
Section 8.5 


 
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FINAL V3.0   18 May 2018 
 
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CONFIDENTIAL 
 
Previous Version:  V1.0 
Current Version:  V2.0  
Date of Revisions:  31 March 2017 
Change 
Rationale 
Affected Section(s) 
Interim Analysis: Censoring 
scheme updated to only include 
MACE analysis and remove 
sensitivity analyses 
As requested by FDA
 
Section 8.5.1 
Table 6 Total Time on Study 
Censoring updated to include 
“Death” 
As per discussions with 
TIMI and Eisai clinical 
 
Section 8.5.2.1 
Inserted  “first abnormal 
laboratory test as per the 
Diabetes CEC Charter , 
Appendix  13.81.4” in the first 
paragraph 
As per discussions with 
TIMI and Eisai clinical 
 
Section 8.5.2.2 
Table 7 updated 
As per discussions with 
TIMI and Eisai clinical 
 
Section 8.5.2.3 
Bariatric surgery included 
As per discussions with 
TIMI and Eisai clinical 
 
Section 8.5.2.4 
Deleted reference on alpha 
sharing MTP 
Protocol was Amendment to 
remove conversion to T2DM 
as a co-primary endpoint. 
Therefore this procedure is 
not applicable.
 
Section 12 
Added “ and Integrity Charter” 
to heading 
Included Study Integrity 
charter 
 
Appendix 13.3.2 
Made reference to Conversion 
to T2DM Charter 
Included CEC Charter for 
conversion to T2DM 
 
Appendix 13.1.4 
Added The associations 
between body weight or BMI 
change from Baseline and the 
presence of FDA-defined 
valvulopathy analysis 
As per discussions with 
TIMI and Eisai clinical 
 
Section 5.4.3 
 
 


 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
APD356-G000-401 
Study Protocol 
Title: 
A Randomized, Double-blind, Placebo-controlled, Parallel-group Study 
to Evaluate the Effect of Long-term Treatment with BELVIQ (lorcaserin 
HCl) on the Incidence of Major Adverse Cardiovascular Events and 
Conversion to Type 2 Diabetes Mellitus in Obese and Overweight 
Subjects with Cardiovascular Disease or Multiple Cardiovascular Risk 
Factors 
 
 
Date: 
18 May 2018 
Version: 
Final 3.0 


 
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SIGNATURE PAGE 
Author  
 
[electronic signature in eDMS]  
Signature 
Date:  ______________ 
 
 
 
Approval 
Biostatistics Head of  
 
[electronic signature in eDMS] 
Signature 
Date: ________________ 
Study Director: 
 
[electronic signature in eDMS] 
Signature 
Date: ________________ 
PPD
PPD
PPD


 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS 
9 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
12 
3 
INTRODUCTION 
14 
3.1 
Primary Objectives 
14 
3.2 
Secondary Objectives 
14 
3.2.1 
Exploratory Objectives 
15 
3.3 
Overall Study Design and Plan 
16 
3.3.1 
Prerandomization Phase 
18 
3.3.2 
Randomization Phase 
19 
3.3.2.1 
Treatment Period 
19 
3.3.2.2 
Follow-up Period 
19 
4 
DETERMINATION OF SAMPLE SIZE 
19 
5 
STATISTICAL METHODS 
20 
5.1 
Study Endpoints 
20 
5.1.1 
Primary Endpoints 
20 
5.1.2 
Key Secondary Endpoint (revised per Amendment 02) 
20 
5.1.3 
Other Secondary Endpoints (revised per Amendment 02) 
21 
5.1.4 
Exploratory Endpoints 
22 
5.2 
Study Subjects 
23 
5.2.1 
Definitions of Analysis Sets 
23 
5.2.2 
Subject Disposition 
24 
5.2.3 
Protocol Deviations 
25 
5.2.4 
Demographic and Other Baseline Characteristics 
25 
5.2.5 
Medical History 
26 
5.2.6 
Prior and Concomitant Therapy 
26 
5.2.7 
Treatment Compliance 
26 
5.3 
Data Analysis General Considerations 
27 
5.3.1 
Pooling of Centers 
27 
5.3.2 
Assessment of Effect Modification 
27 
5.3.3 
Multiple Comparisons/Multiplicity 
27 
5.3.4 
Examination of Subgroups 
28 
5.3.5 
Handling of Missing Data, Drop-outs, and Outliers 
31 
5.3.6 
Other Considerations 
32 
5.4 
Efficacy Analyses 
32 
5.4.1 
Primary Endpoint Analyses 
33 
5.4.1.1 
Additional Sensitivity Analyses at Study Completion 
33 
5.4.2 
Key Secondary Analysis (revised per Amendment 02) 
34 
5.4.3 
Secondary Endpoint Analyses 
34 
5.4.4 
Other Efficacy Analyses 
36 
5.5 
Pharmacokinetic, Pharmacodynamic and Pharmacogenomic / 
Pharmacogenetic 
36 


 
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5.5.1 
Pharmacokinetic Analyses 
36 
5.5.2 
Pharmacodynamic Analyses 
36 
5.5.3 
Biomarker Analyses 
36 
5.5.4 
Pharmacogenomic/Pharmacogenetic Analyses 
37 
5.6 
Safety Analyses 
37 
5.6.1 
Extent of Exposure 
37 
5.6.2 
Adverse Events 
37 
5.6.3 
Laboratory Values 
38 
5.6.4 
Vital Signs 
39 
5.6.5 
Electrocardiograms 
39 
5.7 
Other Analyses 
39 
5.8 
Exploratory Endpoint Analyses 
39 
6 
INTERIM ANALYSES 
42 
6.1 
Interim analysis Statistical Analysis Plan 
42 
6.1.1 
Primary Endpoint Analysis for time to MACE 
43 
7 
CHANGES IN THE PLANNED ANALYSES 
43 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
44 
8.1 
Calculation of GFR 
47 
8.2 
Determination of Renal Impairment or improvement 
48 
8.2.1 
Determination of new onset or worsening of Renal Impairment 
48 
8.2.2 
Determination of Improvement of Renal function 
49 
8.3 
Determination of conversion to T2DM or to normal glucose homeostasis 
50 
8.3.1 
Determination of conversion to T2DM 
50 
8.3.2 
Determination of conversion to normal glucose homeostasis 
50 
8.4 
FDA Defined Valvulopathy and pulmonary arterial pressure 
50 
8.4.1 
Worsened FDA-defined valvulopathy 
51 
8.5 
Censoring 
51 
8.5.1 
Censoring at Interim Analysis for MACE 
52 
8.5.2 
Censoring at Study Completion 
52 
8.5.2.1 
Censoring for MACE, MACE+, each Component of 
MACE, and All-Cause Mortality 
52 
8.5.2.2 
Censoring for Conversion to T2DM 
53 
8.5.2.3 
Censoring for Secondary Time-to-Event Endpoints 
54 
8.5.2.4 
Censoring for Sensitivity Analysis Time-to-Event 
Endpoints 
55 
8.6 
Definition of Visit Windows 
55 
8.7 
Protocol Deviations 
56 
9 
PROGRAMMING SPECIFICATIONS 
57 
10 
STATISTICAL SOFTWARE 
57 
11 
MOCK TABLES, LISTINGS AND GRAPHS (TLGS) 
57 
12 
REFERENCES 
58 
13 
APPENDICES 
59 


 
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13.1 
Sponsor’s Grading for Determining Markedly Abnormal Laboratory 
Results 
59 
13.2 
Classification of Chronic Kidney Disease 
61 
13.1 
Charters and Retention Plan to prevent missing data 
62 
13.1.1 
CEC Charter 
62 
13.1.2 
DMC Charter and Integrity Charter 
62 
13.1.3 
Retention Plan to prevent missing data 
62 
13.1.4 
Conversion to Type II Diabetes Adjudication Charter 
62 
13.2 
Diagrams of Censoring Algorithms 
63 
13.2.1 
Censoring at Interim Analysis 
63 
13.2.2 
Censoring at Study Completion 
63 
13.3 
Adverse Event Start and End Date Imputation Algorithm 
65 
13.4 
Concomitant Medication Start and End Date Imputation Algorithm 
66 
 


 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation Term 
ACR 
albumin-to-creatinine ratio 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ALT 
alanine transaminase  
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic class 
BELVIQ 
Lorcaserin HCL 
BID 
twice daily 
BMI 
body mass index 
BSA 
body surface area 
CAD 
coronary artery disease 
CI 
confidence interval 
CKD 
chronic kidney disease 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
CSR 
clinical study report 
CV 
cardiovascular 
DMC 
data monitoring committee 
DSMB 
data safety monitoring board 
ECHO 
echocardiography 
EOS 
end of study 
EOT 
end of Treatment 
ESRD 
end-stage renal disease 
FDA 
Food and Drug Administration 
FAS 
full analysis set 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transpeptidase 
HbA1c 
glycosylated hemoglobin 
ITT 
Intent-to-Treat 
LOCF 
last observation carried forward 
LSM 
least squares mean 
LFT 
liver function test 
MACE 
major adverse cardiac events (myocardial infarction [MI], or stroke, or CV 
death) 
MACE+ 
MACE or hospitalization for unstable angina or heart failure, or any coronary 
revascularization 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 


 
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Abbreviation Term 
MI 
myocardial infarction 
MMRM 
Mixed Model with Repeated Measures 
MTP 
multiple testing procedure 
NAFLD 
Non-Alcoholic Fatty Liver Disease 
NKF 
National Kidney Foundation 
NI 
non-inferiority 
OAD 
Oral anti-diabetic 
PD 
pharmacodynamic 
PH 
proportional hazard 
PK 
pharmacokinetic 
PMM 
Pattern Mixture Models 
ROW 
Rest of World 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SE 
standard error  
SI 
Système International 
TEAE 
treatment-emergent adverse event 
TLG 
tables, listings, and graphs 
T2DM 
Type II Diabetes Mellitus 
WHO 
World Health Organization 
 


 
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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-G000-401; A 
Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Effect of 
Long-term Treatment with BELVIQ (lorcaserin HCl) on the Incidence of Major Adverse 
Cardiovascular Events and Conversion to Type 2 Diabetes Mellitus in Obese and Overweight 
Subjects with Cardiovascular Disease or Multiple Cardiovascular Risk Factors. 
3.1 
PRIMARY OBJECTIVES 
When 460 adjudicated MACE (composite of cardiovascular death, myocardial infarction or 
stroke) events have accrued, an interim analysis will be conducted to establish whether the 
primary safety objective (MACE non-inferiority) has been achieved (see Section 6).   This 
analysis will be performed by an independent statistician and governed by the independent 
Data Monitoring Committee (DMC) and is anticipated to occur on or before (approximately) 
July 2017.  If the primary safety objective has been achieved, the trial will continue u n t i l  
1401 MACE+ events, and 2.5 years median treatment duration.  This is expected to occur on or 
before October 2018.  The primary efficacy objectives will be assessed at Study Completion.    
 
Safety: 
 To demonstrate that, in obese and overweight subjects with CV disease and/or multiple 
CV risk factors, lorcaserin HCl 10 mg administered BID does not increase the 
incidence of MACE (myocardial infarction [MI], or stroke, or CV death) compared to 
placebo, with a non-inferiority margin for the hazard ratio of 1.4.  
 
Efficacy: 
 
(revised per Amendment 02) 
 To demonstrate that, in obese and overweight subjects with CV disease and/or 
multiple CV risk factors, lorcaserin HCl 10 mg BID reduces the incidence of MACE+ 
(MACE or hospitalization   for   unstable   angina   or   heart   failure   (HF),   or   
any    coronary revascularization) compared to placebo 
 
3.2 
SECONDARY OBJECTIVES 
Key Secondary Objective: 
 To confirm that, in subjects with pre-diabetes at Baseline based on 2013ADA guideline, 
lorcaserin HCl 10 mg BID reduces the incidence of conversion to type 2 diabetes mellitus 
(T2DM) compared to placebo (revised per Amendments 01 and 02) 


 
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Other Secondary Objectives (revised per Amendment 02) 
MACE and MACE+ Related: (revised per Amendment 02) 
 
 To determine  whether  the  rates  of  the  individual  events  comprising  the  MACE+ 
endpoints are different in subjects on lorcaserin compared to those on placebo 
 To determine whether lorcaserin reduces all-cause mortality compared with placebo 
Diabetes and Prediabetes Related: (revised per Amendment 02) 
 
 To evaluate the effect of lorcaserin HCl 10 mg BID compared to placebo on conversion 
to normal glucose homeostasis at 1 year and yearly thereafter in subjects with prediabetes 
at Baseline (revised per Amendment 01) 
 To evaluate whether in all subjects without any type of diabetes at Baseline, lorcaserin 
HCl 10 mg BID reduces the incidence of conversion to T2DM compared to placebo 
(revised per Amendment 01) 
 
  To confirm that, in subjects with T2DM at Baseline, lorcaserin HCl 10 mg BID 
improves glycemic control (HbA1c) compared to placebo at 6 months 
 
Renal Related:  (revised per Amendment 02) 
 
 To evaluate the long-term effect of lorcaserin HCl compared to placebo on renal function 
in all subjects  
 
 To evaluate the long-term effect of lorcaserin HCl compared to placebo on renal function 
in subjects with T2DM at Baseline 
 
 To evaluate the long-term effect of lorcaserin HCl compared to placebo on renal function 
in subjects with prediabetes at Baseline (revised per Amendments 01 and 02) 
 
Safety Objectives: (revised per Amendment 02) 
 
 To evaluate echocardiographically determined cardiac valvular function and pulmonary 
arterial pressure changes associated with treatment with lorcaserin HCl 10 mg BID 
compared to placebo at 1 year 
 
 To evaluate the long-term safety of lorcaserin HCl 10 mg BID 
 
3.2.1 
Exploratory Objectives 
 
 To explore the effects of long-term treatment with lorcaserin HCl 10 mg BID on 
improving CV risk factors associated with obesity (eg, body weight, dyslipidemia, insulin 


 
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level, hypertension, inflammatory biomarkers) compared with placebo at 1 year and 
yearly thereafter 
 To evaluate the effect of BELVIQ (lorcaserin HCl) on other diabetes-related 
microvascular complications (retinopathy and neuropathy compared to placebo in 
subjects with prediabetes, or T2DM at Baseline at EOS. (revised per Amendment 01) 
 To explore, in subjects with a diagnosis of Non-Alcoholic Fatty Liver Disease (NAFLD) 
at Baseline, the effects of long-term treatment with lorcaserin HCl 10 mg BID on liver 
function compared with placebo at 1 year and yearly thereafter 
 To evaluate echocardiographically determined heart valve and pulmonary artery pressure 
changes associated with treatment with lorcaserin HCl 10 mg BID compared to placebo 
at 2 years and yearly thereafter  
 To collect and store DNA samples which may be used for examination of the impact of 
genetic variation on weight loss, the response to lorcaserin HCl, susceptibility to diabetes, 
and the risk of developing CV and other end-organ disease and their associated risk 
factors (for participating countries/sites where ethics and regulatory approval is obtained) 
 To collect and store serum and plasma biomarker samples which may be used for 
examination of the impact of different metabolic and CV pathologic processes on weight 
loss, the response to lorcaserin HCl, susceptibility to diabetes, and the risk of developing 
CV and other end-organ disease and their associated risk factors (for participating 
countries/sites where ethics and regulatory approval is obtained) 
 To explore the effects of long-term treatment with lorcaserin HCl (10 mg BID) on 
improvement of obesity related complications, as defined by the 2014 Advanced 
Framework for a New Diagnosis of Obesity as a Chronic Disease (American Association 
of Clinical Endocrinologists [AACE] and American College of Endocrinology [ACE]) 
(eg, pre diabetes, metabolic syndrome, hypertriglyceridemia/dyslipidemia, and 
potentially others) (revised per Amendment 01) 
 To demonstrate that lorcaserin HCl 10 mg BID improves glycemic control, and/or 
reduction in OAD medications for the subjects treated with OADs, compared to placebo 
at 6 months in the following subpopulations of patients with T2DM: 
o Subjects with T2DM with an HbA1c>7% at Baseline  
o Subjects with T2DM who have not been treated with antidiabetic agents at 
Baseline 
o Subjects with T2DM who are on Monotherapy with an oral antidiabetic agent at 
Baseline 
o Subjects with early T2DM (duration of diagnosis of diabetes is less than 5 years) 
at Baseline  
3.3 
OVERALL STUDY DESIGN AND PLAN 
This will be a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 
overweight and obese subjects with CV disease and/or multiple CV risk factors. Approximately 
12,000 subjects will be randomized to 2 treatment groups in a ratio of 1:1, stratified by the 
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(~20%).  The 80% of subjects in the established CV disease strata will consist of a group with 
T2DM (approximately 30% of the total number of subjects in the study) and a group without 
T2DM (approximately 50% of the total number of subjects in the study).  The 20% of subjects in 
the strata with CV risk factors but without established CV disease will all have T2DM, as well as 
additional risk factors.  Therefore, approximately 50% of the total number of subjects in the 
study will have T2DM (Table 1). 
 
Table 1  Approximate Stratification of Subjects 
 
CV Disease 
CV Disease Risk 
Total 
T2DM 
30% 
20% 
50% 
No T2DM 
50% 
0% 
50% 
Total 
80% 
20% 
100% 
CV = cardiovascular, T2DM = type 2 diabetes mellitus. 
 
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 will consist of 2 periods:  Treatment and Follow-up.  The 
Treatment Period will last for approximately 5 years with approximately 18 visits.  The first dose 
should be taken at Visit 2. (revised per Amendment 01).  The Follow-up Period extends from the 
end of treatment (EOT) visit to the EOS visit. Sponsor Notification of Study Completion will 
occur once, 1401 MACE+ events, 460 MACE events, and median treatment duration of 2.5 years 
occur. (revised per Amendment 02).  This is expected to occur on or before October 2018. 
Following this announcement (“Sponsor Notification of Study Completion”), sites will be 
instructed to bring subjects who remain on treatment for an EOT visit. An EOS visit will occur 
approximately 30 days later for subjects on treatment at Sponsor Notification of Study 
Completion. (revised per Amendment 01).  Subjects who are still being followed in the study but 
have already discontinued study medication ≥ 30 days before will return for an EOS visit.  
Subjects who are still being followed in the study but who discontinued study medication within 
the last 30 days will return for an EOS visit approximately 30 days after their last dose of study 
medication. 
 
Subjects will receive lorcaserin HCl 10 mg BID or placebo BID for approximately 5 years.  
Throughout the duration of the study, subjects will be provided with instructions regarding a 
reduced-calorie diet and increased physical activity program (see Appendix 4 of the protocol).  
Echocardiography will be performed on a subset of subjects at Baseline and at 6, 12, 18, and 24 
months, and yearly thereafter. Acquisition of new ECHO data in all subjects will cease when at 
least1000 subjects have completed the Month 36 echocardiographic assessment. 
 
 
All subjects will continue in the study until study completion, rather than for a prespecified 
number of visits.  Subjects who prematurely discontinue study drug will continue in the study for 
all subsequent study visits until study completion and are to complete visit procedures as 
indicated in Table 4 in the protocol.  It is preferred that these visits are in person.  However, if 
the subject is unable to attend a visit in person, a telephone visit may be performed.  The 


 
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outcome of the telephone visit must be clearly documented in the source record.  At a minimum, 
the site should attempt to have the subject return for an in-person visit at least once per year.  The 
study will terminate when 1401 MACE+ events have occurred and when there has been a 
median treatment duration of 2.5 years have accrued.  (revised per Amendment 02)  This is 
expected to occur on or before October 2018. 
 
When 460 adjudicated MACE events have occurred, an interim analysis will be conducted on 
MACE events (see Section 6). It will be conducted to establish whether the primary safety 
objective (MACE noninferiority) has been achieved. This analysis will be performed by an 
independent statistician and governed by an independent Data Monitoring Committee (DMC) 
and is anticipated to occur on or before (approximately) July 2017. If the primary safety 
objective has been achieved, the trial will continue for evaluation of additional endpoints as 
delineated in the objectives. 
 
An overview of the study design is presented in Figure 1. 
Figure 1 Study Design Schematic BID = twice daily; EOS = end of study; EOT = end of 
treatment; R = randomization. 
3.3.1 
Prerandomization Phase 
The Prerandomization Phase will last up to 30 days and consist of 1 visit during which subjects 
will be screened for eligibility and continue until randomization or exclusion.  The purpose of the 
Prerandomization Phase is to obtain informed consent and to establish protocol eligibility.  
Informed consent will be obtained after the study has been fully explained to each subject and 


 
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before the conduct of any screening procedures or assessments.  Procedures to be followed when 
obtaining informed consent are detailed in Section 5.3 of the protocol.  
Subjects must be overweight or obese with CV disease or other CV risk factors and must meet 
all inclusion and exclusion criteria.  The Screening Disposition case report form (CRF) page 
must be completed to indicate whether the subject is eligible to participate in the study and to 
provide reasons for screen failure, if applicable. 
3.3.2 
Randomization Phase 
The duration of the Randomization Phase will be approximately 56 months and will include 2 
periods:  Treatment and Follow-up.  Subjects whose screening assessments and evaluations are 
completed and reviewed by the investigator and who continue to meet all of the 
inclusion/exclusion criteria will enter the Randomization Phase.  Subjects will be randomized in 
a 1:1 ratio to receive lorcaserin HCl 10 mg BID or placebo. 
3.3.2.1 
Treatment Period 
The Treatment Period will last for approximately 5 years with approximately 18 visits. The first 
dose should be taken at the Randomization visit (Visit 2). (revised per Amendment 01) During 
the Treatment Period, subjects will continue treatment with the dose of lorcaserin HCl 10 mg or 
placebo BID in blinded fashion. 
3.3.2.2 
Follow-up Period 
For subjects who remain in the study through the Sponsor Notification of Study Completion, the 
Follow-up Period will begin immediately after the EOT assessments have been completed, and 
will consist of 1 EOS visit, occurring 30 days + 10 days after last dose of study drug for subjects 
who complete study treatment.  (revised per Amendments 01 and 02)   See Section 9.3.3 of the 
protocol for procedures for subjects who prematurely discontinue study drug. 
 
The scheduled of assessments are presented in Table 4 of the protocol. 
4 
DETERMINATION OF SAMPLE SIZE 
A sample size of 12,000 subjects should provide the required power for the primary endpoints 
and key secondary endpoint as follows: 
 
Primary Endpoints (revised per Amendment 02) 
 For 460 MACE events to have occurred by approximately 43 months from start of the 
trial, providing 95% power to exclude a noninferiority margin of 1.4, assuming an annual 
background rate of 1.5%, 15-month accrual period, 5% annual drop-out rate, α = 0.025, 
and a 1-sided test 
 For 1401 MACE+ events to have occurred by approximately 54 months from the start of 
the trial, providing  > 85% power to detect a 15% risk reduction with lorcaserin HCl, 
assuming an annual background rate of 3.5%, 15-month accrual period, 5% annual drop-
out rate, α = 0.05, and a 2-sided test 


 
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Key Secondary Endpoint (revised per Amendment 02) 
 For 457 events of conversion to T2DM in subjects who are prediabetic at the time of 
enrollment (~33%) to have occurred by approximately 54 months from the start of the 
study, providing 86% power to detect a 25% risk reduction with lorcaserin HCl, 
assuming an annual background rate of 4%, 15-month accrual period, 5% annual drop-
out rate, α = 0.05 and a 2-sided test.   
 
5 
STATISTICAL METHODS 
Statistical analyses will be performed by the sponsor or designee after the study is completed and 
the database is locked and released for unblinding. Statistical analyses will be performed using 
SAS software or other validated statistical software as required.  
 
All descriptive statistics for continuous variables will be reported using mean, standard deviation 
(SD), median, minimum and maximum.  Categorical variables will be summarized as number 
(percentage) of subjects. 
5.1 
STUDY ENDPOINTS 
Time from randomization to first occurrence of MACE will be the only endpoint to be 
analyzed at the Interim Analysis.  All other endpoints will be analyzed at Study Completion. 
5.1.1 
Primary Endpoints 
 Time from randomization to first occurrence of MACE (first occurrence of any of the 
following events:  MI, stroke, or CV death) at Interim Analysis only. 
 
 Time from randomization to first occurrence of MACE+ (first occurrence of any of 
the following events: MACE or hospitalization for unstable angina or HF, or any 
coronary revascularization) 
5.1.2 
Key Secondary Endpoint (revised per Amendment 02) 
 Time from randomization to conversion to T2DM, defined as first occurrence of 
any component of the 2013 ADA diagnostic criteria4 in subjects with prediabetes at 
Baseline.  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 subsequently confirmed on repeat laboratory testing: (revised per Amendments 01 
and 02): 
 
o HbA1c ≥ 6.5% 
o FPG ≥ 126 mg/dL (7.0 mmol/L) 
o 2-hour plasma glucose ≥200mg/dL (11.1 mmol/L) by an OGTT 
 


 
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Investigators should make every effort to obtain central lab confirmatory testing no later than 6 
weeks after meeting any of the above criteria. Abnormalities of any 1 of the above 3 criteria on 
repeat testing constitutes diagnostic confirmation of diabetes. Subjects who have been started on 
anti-diabetic medications following abnormalities in preliminary testing do not require 
confirmatory testing. (revised per Amendments 01 and 02). 
5.1.3 
Other Secondary Endpoints (revised per Amendment 02) 
 
MACE and MACE + Related: (revised per Amendment 02): 
 
 Time from randomization to first occurrence of each of the individual components of 
MACE+ 
 
 Time from randomization to first occurrence of all-cause mortality 
 
Diabetes and Prediabetes Related (revised per Amendment 02): 
 
 Time from randomization to conversion to normal glucose homeostasis (HbA1c ≤5.6% 
and fasting plasma glucose <100 mg/dL without any antidiabetic treatment) in subjects 
with prediabetes at Baseline  (revised per Amendments 01 and 02). ).  See Section 8.3.2 
for definition. 
 Time from randomization to conversion to T2DM in subjects without any type of 
diabetes at Baseline. (revised per Amendment 01).  See Section 8.3.1 for definition 
 Change from Baseline in HbA1c at 6 months in subjects with T2DM at Baseline 
 
Renal Related (revised per Amendment 02) 
 
 Time from randomization to first occurrence of 2 consecutive assessments within the 
same component of the composite endpoint or time to first occurrence of renal transplant 
or renal death, on scheduled or nonscheduled visits at least 30 days apart, indicative of 
new onset renal impairment or worsening of existing renal impairment (first occurrence 
of any of the following events: microalbuminuria, macroalbuminuria, worsening 
albuminuria, newly developed CKD or worsening of CKD, or doubling of serum 
creatinine, as defined above, or any of the following: ESRD, renal transplant, renal 
death) in all subjects. (revised per Amendment 02).  See Section 8.2.1 for definitions. 
 Time from randomization to first occurrence of 2 consecutive assessments within the 
same component of the composite endpoint or time to first occurrence of renal transplant 
or renal death, on scheduled or non-scheduled visits at least 30 days apart, indicative of 
new onset renal impairment or worsening of existing renal impairment (first occurrence 
of any of the following events:  microalbuminuria, macroalbuminuria, worsening 
albuminuria, newly developed CKD or worsening of CKD, or doubling of serum 
creatinine, as defined above, or any of the following:  ESRD, renal transplant, renal 
death) in subjects with prediabetes at Baseline (revised per Amendments 01 and 02). See 
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 Time from randomization to first occurrence of 2 consecutive assessments within the 
same component of the composite endpoint or time to first occurrence of renal transplant 
or renal death, on scheduled or nonscheduled visits at least 30 days apart, indicative of 
new onset renal impairment or worsening of existing renal impairment (first occurrence 
of any of the following events:  microalbuminuria, macroalbuminuria, worsening 
albuminuria, newly developed CKD or worsening of CKD, or doubling of serum 
creatinine, as defined above, or any of the following:  ESRD, renal transplant, renal 
death) in subjects with T2DM at Baseline (revised per Amendment 01). (revised per 
Amendment 02). See Section 8.2.1 for definitions 
 Time from randomization to first occurrence of 2 consecutive assessments, on scheduled 
or nonscheduled visits at least 30 days apart, indicative of improvement in renal function 
(first occurrence of regression of albuminuria or regression of CKD) in subjects with 
T2DM at Baseline. See Section 8.2.2 for definitions  
 
Secondary Endpoints Assessing Cardiac Valve Function and Pulmonary Arterial Pressure: 
(revised per Amendment 02)  
 Proportion of subjects without FDA-defined valvulopathy at Baseline who develop 
FDA-defined valvulopathy at 1 year (see Section 8.4 for definition) 
 Proportion of subjects with FDA-defined valvulopathy confirmed by documented 
objective assessments at Baseline who demonstrate worsened FDA-defined valvulopathy 
(see Section 8.4.1 for definition) at 1 year (revised per Amendment 01).  
 Change from Baseline in estimated pulmonary artery systolic pressure at 1 year 
5.1.4 
Exploratory Endpoints 
 
 Change from Baseline in CV risk factors at 1 year and yearly thereafter (e.g., 
body weight, dyslipidemia, insulin level, hypertension, and applicable biomarkers of 
CV risk and other end-organ diseases). For lipid parameters percent change from 
baseline will be used 
 
 Change from Baseline in eGFR and ACR at 1 year, yearly thereafter, and at the end 
of the study.  GFR will be estimated using creatinine, cystatin C and a combination of 
both (Section 8.1). 
 
 Change from Baseline in LFTs (AST, ALT, alkaline phosphatase,  GGT, total and 
direct bilirubin) at 1 year and yearly thereafter 
 
 Proportion of subjects without FDA-defined valvulopathy at Baseline who develop 
FDA- defined valvulopathy at 2 years and yearly thereafter 
 
 Change from Baseline in estimated pulmonary artery systolic pressure at 2 years  
and yearly thereafter 
 Proportions of subjects with at least a 1-stage reduction in an obesity-related 
complication (prediabetes, metabolic syndrome, T2DM, hypertension, and 
hypertriglyceridemia/dyslipidemia) at 1 year and EOS; incidence of other obesity-related 
complications will be collected through AE reports, medical history, and use of 


 
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concomitant medications, based on 2014 Advanced Framework for a New Diagnosis of 
Obesity as a Chronic Disease (American Association of Clinical Endocrinologists 
[AACE] and American College of Endocrinology [ACE]). (revised per Amendment 01) 
 
 Change from Baseline in HbA1c, FPG, fasting insulin levels, and homeostatic model 
assessment insulin resistance (HOMA-IR) at 6 months in the following subpopulations of 
subjects with T2DM at Baseline:  (revised per Amendments 01 and 02) 
o Subjects with (HbA1c>7%) at Baseline 
o Subjects who have not been treated with antidiabetic agents at Baseline 
o Subjects who are on monotherapy with oral antidiabetic agent at Baseline 
o Subjects with early T2DM (duration of diagnosis of diabetes is less than 5 years) 
at Baseline 
 
 Proportion of subjects with reduction in the number of OAD medications or reduction in 
the dosage of OAD medications at 6 months in the following subpopulations of subjects 
with T2DM at Baseline: (revised per Amendment 01) 
o Subjects with (HbA1c >7%) at Baseline 
o Subjects who are on monotherapy with oral antidiabetic agent at Baseline 
o Subjects with early T2DM (duration of diagnosis of diabetes is less than 5 years) 
at Baseline 
 
 Proportions of subjects with prediabetes at Baseline who develop new diagnosis of 
diabetic retinopathy or new diagnosis of diabetic neuropathy by EOS (revised per 
Amendment 01) 
 
 Proportions of subjects with T2DM at Baseline who develop new diagnosis of diabetic 
retinopathy or new diagnosis of diabetic neuropathy by EOS (revised per Amendment 
01) 
 
5.2 
STUDY SUBJECTS 
5.2.1 
Definitions of Analysis Sets 
The number (percent) of subjects included in each analysis set will be presented by analysis set, 
treatment group and overall.  The description of the analysis data sets are: 
 The Safety Analysis Set: will be the group of subjects who received at least one dose 
of study drug and had at least one post dose safety assessment. 
 
 The Intent-to-Treat  (ITT) Set: will be the group of all randomized subjects regardless of 
whether they took study drug or not. This is the same as the Full Analysis Set. 
 
 Total Time Analysis Set:  Using the ITT, events are counted that occur while subjects 
are on and off treatment.   Subjects with no events will be censored at their last study 
contact or at the visit following Sponsor Notification of Study Completion, whichever 


 
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occurs first.  This analysis set will be used for the primary analysis.  See Section 8.5 for 
censoring algorithm. 
 
 On-Treatment plus 30 Days Analysis Set:  Using the ITT, events are counted that occur 
while subjects are “on treatment” and up to 30 days from their last dose.  Subjects with 
no events who discontinue early or complete the study will be censored at their last dose 
date plus 30 days.  See Section 8 for definition of “on treatment” and Section 8.5 for 
censoring algorithm. 
 
 On-Treatment Analysis Set:  Using the ITT, events are counted that occur while 
subjects are “on treatment”.  Subjects with no events who discontinue early or 
complete the study will be censored at their last dose date.  See Section 8 for 
definition of “on treatment” and Section 8.5 for censoring algorithm. 
 
 Prediabetes Analysis Set:  This set includes all subjects in the ITT set without a 
history of any type of diabetes and who are prediabetic at Baseline (defined in Section 
8). 
 Nondiabetes Analysis Set:  This set includes all subjects in the ITT set without a 
history of any type of diabetes at Baseline (defined in Section 8). 
 
 T2DM Analysis Set:  This set will be all subjects in the ITT who have T2DM at Baseline 
(defined in Section 8). 
 
 FDA-defined Valvulopathy Analysis Set:  This set will be all subjects in the ITT 
without FDA- defined valvulopathy at Baseline (defined in Section 8.4). The data from 
the ECHO sub-study will be pooled with the ECHO data from the 3 pivotal lorcaserin 
HCl studies (APD356-009, APD356-010, and APD356-011). 
 
 The PD Analysis Set will be the group of subjects who have both baseline and at 
least one post-baseline assessment of at least one PD parameter. 
 
Details of the censoring algorithms for time-to-event endpoints are presented in Section 8.5.  
 
5.2.2 
Subject Disposition 
The number of subjects screened and the number (percent) of subjects who failed screening and 
the reasons for screen failure will be summarized, based on data reported on the Screening 
Disposition CRF.  The distribution of the number of randomized subjects enrolled by each site 
will be summarized for each randomized treatment group.   The primary reasons for screen 
failures; did not meet inclusion/exclusion criteria, AE, lost to follow-up, withdrawal of consent, 
and other, will be presented. 
 
For study completion, the number (percent) of randomized subjects who completed the study 
(e.g. subject was in the study at the date of Final Sponsor Notification/Premature Study 
Discontinuation by Sponsor, whether subject is on or off treatment or death) and who 


 
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discontinued from the study will be summarized according to the primary reason for 
discontinuation based on data reported on the Final Study Disposition CRF. The number 
(percent) will be presented by treatment group and total for subjects; randomized, not treated, 
treated, who completed the study, and discontinued from the study.  For those who are 
considered to have discontinued from the study, the reasons for discontinuation from the study at 
Final Sponsor Notification/ Premature Study Discontinuation are captured in the Final Study 
Disposition CRF (Withdrawal of Consent, Lost to follow up, Study prematurely terminated by 
sponsor, and Other).  
 
Completion of Study Treatment:  the number (percent) of randomized and treated subjects who 
completed study treatment (e.g. subject was on study drug at the date of Final Sponsor 
Notification/Premature Study Discontinuation by Sponsor) and who discontinued from study 
treatment will be summarized according to the primary reason for discontinuation, based on data 
reported on both the Final Study Disposition CRF and Early Discontinuation from Study Drug 
CRF.  The number (percent) will be presented by treatment group and total for subjects; 
randomized, not treated, treated, who completed study on treatment, off treatment, and 
discontinued from study treatment.  The reasons for early discontinuation from study drug are: 
AE/SAE, Pregnancy/Breastfeeding, Subject choice unrelated to AE/SAE, Treatment Required 
with Prohibited Concomitant Medications, Other – study administrative reasons.  Subject choice 
will be further summarized as per the reasons captured in the Early Discontinuation from Study 
Drug CRF; Inadequate Therapeutic Effect, Logistical reason, and Other. 
 
 
5.2.3 
Protocol Deviations 
Major protocol deviations will be summarized, number (%), in addition a subject listing will be 
provided along with the description of the protocol deviation.  Protocol deviations will be 
identified prior to database lock. 
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized as outlined for the Safety 
Analysis Set and ITT in aggregate as well as stratified by CV strata, baseline glycemic status 
(e.g. normal glucose homeostasis, prediabetes, nondiabetes, and T2DM at baseline as defined in 
Section 8). 
 
Continuous demographic and baseline variables include age, height, weight, waist and hip 
circumference, duration of comorbid conditions (none, hypertension, dyslipidemia, sleep apnea, 
coronary artery disease (CAD)/CV disease), duration of T2DM, HbA1c, and BMI.   
 
Categorical variables include sex, age group (<65 years, ≥65 to < 75, , ≥75  years), race, 
ethnicity, HbA1c (prediabetes: 5.7% to <6.5%; normal glucose homeostasis: <5.7%), BMI (<30 
kg/m2, 30 to <35 kg/m2, ≥35 to  < 40 kg/m2  , ≥ 40 kg/m2), baseline body weight (by quartiles), 
presence of comorbid conditions (none, hypertension, dyslipidemia, sleep apnea, CAD/CV 
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<30μg/mg; microalbuminuria: ACR 30 to 299 μg/mg; macroalbuminuria: ACR ≥300 μg/mg), 
GFR (mL/min per 1.73 m2 BSA); kidney damage with normal or increased GFR ≥90; kidney 
damage with mildly decreased GFR 60 to 89; moderately decreased GFR 30 to 59; severely 
decreased GFR 15 to 29; kidney failure GFR <15 or dialysis; and type of diabetes medication 
used. 
 
5.2.5 
Medical History 
The medical history verbatim descriptions (investigator terms from the Other Medical history 
and Current Medical Condition CRF) will be classified into standardized medical terminology 
using the Medical Dictionary for Regulatory Activities (MedDRA).  Medical history will be 
coded to the MedDRA (Version 16.0 or higher) lower level term (LLT) closest to the verbatim 
term.  The linked MedDRA preferred term (PT) and primary system organ class (SOC) will also 
be captured in the database.  The number (percent) of subjects reporting a history of any medical 
condition will be summarized for each treatment group and overall. 
In addition, separate summary tables by treatment group and overall will be provided for; 
Diabetes History, Cardiovascular History, Malignancy History, Psychiatric History, and Sleep 
Apnea/NAFLD History.  
5.2.6 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD).  The number (percentage) of 
subjects who took prior and concomitant medications will be summarized on the Safety Analysis 
Set by treatment group, Anatomical Therapeutic Chemical (ATC) 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 any medications taken by the subject during the 30 
days before first dose administration of study drug and continued the concomitant medication 
during the double blind phase or started a concomitant medication during the double blind phase. 
All medications will be presented in subject data listing.   
5.2.7 
Treatment Compliance 
Overall  compliance rate will be determined  and defined as the difference in the tablets 
dispensed minus the number of tables returned, divided by the expected number of tablets to be 
taken, multiplied by 100.  Subjects will be considered compliant while they are on BID or QD 
dosing. Descriptive statistics (n, mean, standard deviation, median minimum, maximum) and 
number (%) of subjects in compliance categories (<50%, 50 to <80%, 80 to ≤120%, >120%) will 
be provided for the entire double-blind phase. The Safety Analysis Set will be used. See Section 
8.0 for derivation of compliance. 


 
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5.3 
DATA ANALYSIS GENERAL CONSIDERATIONS 
5.3.1 
Pooling of Centers  
This study is a multicenter, international study with 476 sites.  It is expected that due to the 
number of sites in this trial, sites will be pooled into regions, in order to have sufficient number 
of subjects per treatment group and CV disease strata.  The countries participating in this study 
are Australia, Bahamas, Canada, Chile, Mexico, New Zealand, Poland, and the USA.  The 
countries will be pooled into regions North America (USA, and Canada), and Rest of the World ( 
Bahamas, Chile, Mexico, Poland, Australia and New Zealand).  Region will be included as a 
covariate to explore region effects. 
5.3.2 
Assessment of Effect Modification 
In addition, to the primary and secondary analyses, outline in Sections 5.4.1 and 5.4.2 further 
exploratory analyses will be performed to assess for effect modification by a number of 
demographic and baseline variables outlined in Section 5.3.4 including: 
 Age treated as continuous and as categorical  
 Gender 
 Presence of T2DM 
 Race 
 Ethnicity 
 Region  
 BMI as continuous and categorical 
 eGFR as continuous and categorical 
A separate analysis will be performed for each covariate. 
5.3.3 
Multiple Comparisons/Multiplicity 
This study has two primary endpoints; MACE and MACE+.  The following closed sequential 
gatekeeping testing procedure (SGTP) will be used to control the family-wise error rate (FWER) 
at α = 0.05 (two-sided) in testing the two  primary endpoints (MACE and MACE+) and one key 
secondary endpoint, conversion to T2DM (revised per Amendment 02).   
Let H01 be the gatekeeping null hypothesis for non-inferiority testing of the MACE endpoint 
using a non-inferiority margin of 1.4 for the hazard ratio. 
Let H02, and H03 be the null hypotheses for superiority testing: MACE+ and conversion to 
T2DM, respectively. 
The SGTP testing hierarchy is presented below. 
 STEP1:  At the interim analysis, test the non-inferiority hypothesis for MACE, H01 (α 
= 0.025, one-sided).  If H01 is rejected, then proceed to STEP2, otherwise stop testing 
and the trial will be stopped.  This step will be performed as an interim analysis, see 
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 STEP2:  At study completion, the hypothesis H02 (α = 0.05, two-sided) is tested first. 
If the hypothesis is rejected then proceed to test H03 (α = 0.05, 2-sided).  If H02 is not 
rejected then testing stops at this point.. 
Figure 2 presents the SGTP (revised per Amendment 02) 
. 
Figure 2 Flowchart for SGTP  
MACE = major adverse cardiovascular events, MACE+ = MACE or hospitalization for unstable angina or heart 
failure, or any coronary revascularization;  Step 1 will be performed when 460 adjudicated MACE events occurred, 
at the Interim Analysis. Step 2 will be performed upon Sponsor Notification of Study Completion which will occur 
once 1401 MACE+ events, and 2.5 years median treatment duration..   
Analysis of other secondary endpoints will be used to support the results of primary analyses, 
thus no multiplicity adjustment will be performed. 
5.3.4 
Examination of Subgroups 
The primary endpoints will be analyzed for each of the demographic and baseline characteristics 
subgroups listed in Tables 2, and Baseline Cardiovascular Risk Level and Risk Factors, listed in 
Table 3.  For categorical parameters, categories with sparse number of subjects will be collapse.  
The final set of categories will be determined prior to database lock. 
 


 
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Table 2 
Subgroups of Demographic and Baseline Characteristics  
Characteristic 
Categories 
Age 
≤65,  65 to < 75,  75 years 
Gender 
Female, Male 
Race 
White 
Black or African American 
Other 
Asian 
American Indian or Alaska Native 
Native Hawaiian or Other Pacific Islander 
Other 
BMI 
 < 30 kg/m2 
≥ 30 to < 35 kg/m2 
≥ 35 to < 40 kg/m2 
≥ 40 kg/m2  
Waist circumference 
Women  
 <35 Inches (88cm)  
≥35 Inches (88cm) 
Men 
<40 Inches (102cm) 
≥40 Inches (102cm) 
Weight 
≤ 1st Quartile 
>1st Quartile to ≤ 2nd Quartile 
>2nd Quartile to ≤ 3rd Quartile 
> 3rd Quartile 
Duration of Type 2 Diabetes (years) 
< 5 years  
≥ 5 to < 10 years  
 10 to < 20 years  
≥  20 years  
HbA1C 
Non-diabetics (see Section 8) 
Normal (< 5.7%)  
Pre-diabetes (≥ 5.7% to < 6.5%) 
Diabetics (see Section 8 ) 
< 6.5% 
≥ 6.5% to  <7% 
≥ 7 to  < 8% 
≥ 8 to  < 9% 
 9% 


 
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Table 2 
Subgroups of Demographic and Baseline Characteristics  
Characteristic 
Categories 
FPG  
< 100 mg/dL 
 100 to < 126 mg/dL 
 126 to  < 150 mg/dL [≥ 7.0 mmol/L to  < 8.3 mmol/L] 
  150 to < 220 mg/dL [≥ 8.3 mmol/L to < 12.2 mmol/L] 
 220 to < 300 mg/dL [≥ 12.2 mmol/L to < 16.7 mmol/L]
 300 mg/dL [≥ 16.7 mmol/L] 
Blood Pressure 
Systolic BP (mmHg) 
 
<140 
≥140 
Diastolic BP (mmHg) 
<90 
≥90 
 
Renal Function (eGFR) 
> 60 mL/min 
 30 to ≤ 60 mL/min 
< 30 mL/min 
Albumin/creatinine ratio 
< 30 mg/g [< 3.4mg/mmol] 
≥ 30 to < 300 mg/g [≥ 3.4 mg/mmol - < 33.9 mg/mmol] 
≥ 300 mg/g [≥ 33.9 mg/mmol] 
Region and Country 
North America (US/Canada) 
Rest of World (ROW) 
Europe 
Central and South America 
Australia/NZ  
Baseline Diabetic  Medication use 
No medications/any insulin/oral meds without insulin 
GLP1 agonist/no GLP1 agonist 
SGLT2 inhibitor/no SGLT2 inhibitor 
SFU/no SF 
Metformin/no metformin 
SFU and Metformin/others 
Insulin/no insulin 
Insulin and SFU/others 
 
 
 


 
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Table 2 
Subgroups of Demographic and Baseline Characteristics  
Characteristic 
Categories 
Baseline Cardiovascular Medication Use
ASA 
Dual antiplatelet (ASA and P2Y12 receptor antagonist) 
Lipid Lowering Therapy 
Beta blocker 
ACEi/ARB/Aldosterone antagonist 
 
Table 3 
Subgroups of Baseline Cardiovascular Risk Level and Risk Factors 
Characteristic 
Categories 
CV Risk Level 
Primary prevention - Patients with multiple risk factors for CV 
events, but without established CV disease  
Secondary prevention - Patients with established CV disease 
 
Primary Prevention 
(Risk Factors as defined in 
protocol inclusion criteria) 
By risk factor:  
- Dyslipidemia 
- Hypertension  
- Renal impairment with either Calculated creatinine clearance ≥30 
to ≤60 mL/min per the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation or ACR≥30 μg/mg in spot urine 
- hsCRP > 3 mg/L 
By number of risk factors in addition to T2DM:  
1 additional risk factor (Dyslipidemia, hypertension, renal 
dysfunction or elevated hsCRP) 
2 additional risk factors 
3 additional risk factors  
4 additional risk factors 
Secondary Prevention (Established 
CV Disease as defined in the 
protocol inclusion) 
Coronary artery disease  
Peripheral vascular disease 
Cerebrovascular disease 
   Risk Scores( 0,1-2, and 3 or greater) See Section 8 for definition 
 
5.3.5 
Handling of Missing Data, Drop-outs, and Outliers 
Data will be monitored during the trial in order to minimize missing data. A detail retention plan 
in order to prevent missing data is found in Appendix 13.1.  The primary endpoints are time to 
event endpoints for MACE/MACE+.  Every effort will be made to find subjects who are lost to 
follow-up using patient finder services.  Once these subjects are found the sites will contact the 


 
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subject and will try to obtained vital status information on the subject.  Primary consideration is 
to establish if the subject is dead or alive. 
5.3.6 
Other Considerations 
Potential MACE/MACE+ events will be recorded throughout the study.  During this study, the 
endpoints of MACE and MACE+ will need to be reported in an expedited fashion by 
investigators to the Clinical Endpoint Committee (CEC) and to the Eisai Product Safety 
Department. MACE/MACE+ events will be recorded on the Adverse Event (AE) case report 
form, but these events will not be considered as AEs, nor will they be recorded as serious 
adverse events (SAEs) in the clinical trial safety database or be required to be reported to 
regulatory authorities in an expedited timeframe, with the exception of MACE or MACE+ events 
that are considered by the investigator to be at least possibly related to the study drug (i.e., where 
there is evidence to suggest a causal relationship).  
Details of which events to report, how to report, and the required supporting documentation will 
be detailed in a separate manual provided to the sites. 
Adjudication of Component Events for MACE/MACE+  
The component events of MACE; MI, or stroke, or CV death and the component events of 
MACE+; MI, or stroke, or CV death, or hospitalization for unstable angina or HF, or any 
coronary revascularization, will be adjudicated by the CEC, in order to reduce intra- and inter-
site variability. The CEC will centrally review each potential component event of MACE and 
MACE+ to ensure standardization of data collection and interpretation of such events reported 
throughout the study. The CEC will determine whether each potential component event meets 
criteria for MACE or MACE+. The CEC will remain blinded to treatment allocation and its 
activities and the criteria for classification of each component event of MACE/MACE+ will be 
documented in the CEC Charter, see Appendix 13.1.1. 
Adjudication of Conversion to Diabetes Events  
The conversion to diabetes events will be adjudicated by the CEC Diabetes Adjudication 
Charter, in order to reduce intra- and inter-site variability. The CEC will centrally review each 
potential event to ensure standardization of data collection and interpretation of such events 
reported throughout the study. The CEC will determine whether each potential event meets 
criteria for conversion to diabetes. The CEC will remain blinded to treatment allocation and its 
activities and the criteria for classification of each event will be documented in the charter, see 
Appendix 13.1.4. 
5.4 
EFFICACY ANALYSES 
The primary and key secondary endpoints, MACE, MACE+, and conversion to T2DM, will be 
analyzed using a Cox proportional hazards model that includes factors for treatment and 
stratification variable (presence of established CV disease or CV risk factors without established 
CV disease).  For other secondary and exploratory endpoints a two-sided α = 0.05 significance 
level will be used.  The primary safety analysis for MACE will be conducted when 460 


 
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adjudicated MACE events have been recorded at the interim analysis; the other analyses will be 
conducted when 1401 adjudicated MACE+ events have been recorded, and the study has 
completed. See Section 6 for Interim Analysis Plan. 
Secondary and exploratory time-to-event endpoints will be analyzed using a Cox proportional 
hazards model that includes factors for treatment and stratification variable (presence of 
established CV disease or CV risk factors without established CV disease), except for those 
endpoints that used the population with no T2DM at Baseline, the CV stratification variable will 
not be included in the model. 
For all time-to-event endpoints, plots of the Kaplan-Meier estimate of the survival function, 
cumulative hazard function, kernel-smoothed estimate of the hazard function, and median time 
estimates along with 100(1-α) % CI will be presented. In addition, parameter estimates, standard 
errors, hazard ratio and 100(1-α) % CI will presented.  In addition, event rates will be presented 
per 100 patient years where appropriate. 
Details of the censoring algorithms for time-to-event endpoints are presented in Section 8.5. 
 
5.4.1 
Primary Endpoint Analyses 
The primary safety analysis (Time to MACE using the Total Time Analysis Set) will be the only 
analysis performed at the interim analysis as outlined in Section 6.  All other analyses will be 
performed at Study Completion, see Section 8 for definition of Study Completion. 
Primary Safety Analyses 
 Time to MACE(Non-inferiority):  The estimate of the hazard ratio of lorcaserin HCl to 
placebo and the corresponding one-sided 97.5% confidence interval (CI) will be 
calculated.  Non-inferiority of lorcaserin HCl to placebo will be declared if the upper 
limit of the 97.5% CI is less than the non-inferiority margin of 1.4.  The Total Time 
Analysis Population  will be used as the primary  analysis at the time of the Interim 
Analysis. (revised per Amendment 02)   The On-Treatment Analysis Set and the On-
Treatment plus 30 Days Analysis Set will be used as a sensitivity analysis at Study 
Completion.  (revised per Amendment 02) 
Primary Efficacy Analyses 
 Time to MACE+ (Superiority):  The estimate of the hazard ratio of lorcaserin HCl to 
placebo and the corresponding two-sided 95% CI will be calculated.  The Total Time 
Analysis Population will be used as the primary analysis. (revised per Amendment 02)   
The On-Treatment Analysis Set and On-Treatment plus 30 Days Analysis Set will be 
used as a sensitivity analysis at Study Completion. (revised per Amendment 02) 
5.4.1.1 
Additional Sensitivity Analyses at Study Completion 
  


 
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 Time to MACE (Non-inferiority):  The primary safety analysis above, which will be 
conducted at the interim analysis, will be repeated at study completion as a sensitivity 
analysis. 
 
 Time to MACE (Superiority):  The estimate of the hazard ratio of lorcaserin HCl to 
placebo and the corresponding one-sided 97.5% confidence interval (CI) will be 
calculated.  Superiority lorcaserin HCl to placebo will be declared if the upper limit of the 
97.5% CI is less than 1.  The Total Time Analysis Set, the On-Treatment Analysis Set, 
and the On-Treatment plus 30 Days Analysis Sets will be used.  
 
 The incidence rate difference and the incidence rate ratio between lorcaserin and placebo 
will also be analyzed as supportive analysis for each of the primary endpoints above. The 
adjusted risk difference (incidence rate difference) and relative risk (incidence rate ratio) 
along with their respective 95% CI will be estimated using a Poisson regression model 
(using PROC GENMOD in SAS) with a robust error variance (sandwich error 
estimator)1,2.  The model will include factors for treatment and stratification variable 
(presence of established CV disease or CV risk factors without established CV disease).  
The Total Time Analysis Set, the On-Treatment Analysis Set, and the On-Treatment plus 
30 Days Analysis Sets will be used. 
 
 Subjects that start another weight reduction medication or had bariatric 
procedure: For MACE and MACE+ endpoints using the Total Time Analysis Set.  In 
this sensitivity analysis subjects will be censored when the subject starts another 
weight reduction medication or undergoes a bariatric procedure. 
 Subjects who permanently down titrate from BID dosing to QD dosing:  For MACE 
and MACE+ endpoints using the On-treatment and On-treatment plus 30 days Analyses 
Sets.  In this sensitivity analysis events will be not counted when the subject is on QD 
dosing. 
 Subjects who prematurely discontinued: For the MACE (Superiority) and MACE+ 
endpoints, multiple imputation will be used to impute censored data for those subjects 
who are lost to follow-up.  The Total Time Analysis Set will be used. 
5.4.2 
Key Secondary Analysis (revised per Amendment 02) 
 Time to conversion to T2DM (Superiority).  The estimate of the hazard ratio of 
lorcaserin HCl to placebo and the corresponding two-sided 95% CI will be calculated.  
The Prediabetes and Total Time Analyses Sets will be used as the primary analysis. The 
Prediabetes along with the On-Treatment Analysis Set and the On-Treatment plus 30 
Days Analysis Set will be used as a sensitivity analysis at Study Completion (revised per 
Amendment 02). 
 
5.4.3 
Secondary Endpoint Analyses 
For the following endpoints, a Cox proportional hazards model with factors for treatment and 
stratification variable (presence of established CV disease or CV risk factors without established 
CV disease) will be used.  The estimate of the hazard ratio of lorcaserin HCl to placebo and the 
corresponding 2-sided 95% CI will be calculated. See Section 8.5 for details on censoring 
algorithms for the time-to-event endpoints. 


 
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The secondary endpoints are considered as supportive analysis to the primary endpoints and key 
secondary endpoint, therefore no correction for Type I error rate will be performed. 
 
 
o The time-to-event of each component of MACE+. The Total Time Analysis Set 
will be used as the primary analysis.  The On-Treatment Analysis Set and the 
On-Treatment plus 30 Days Analysis Set will be used as sensitivity analyses. 
o Time-to-event of all-cause mortality. The Total Time Analysis Set will be used as 
the primary analysis.  The On-Treatment Analysis Set and the On-Treatment plus 
30 Days Analysis Set will be used as sensitivity analyses. 
o Time-to-event of new onset renal impairment or worsening existing renal 
impairment in all subjects.  The ITT Analysis Set will be used for this analysis.  
(revised per Amendment 02) 
o Time-to-event of new onset renal impairment or worsening existing renal 
impairment in subjects with T2DM at Baseline.  The T2DM Analysis Set will be 
used for this analysis.   
o Time-to-event of new onset renal impairment or worsening existing renal 
impairment in subjects with prediabetes at Baseline.  The Prediabetes Analysis 
Set will be used for this analysis.  (revised per Amendment 01) 
o Time-to-event of improvement in renal function.  The T2DM Analysis Set will be 
used for this analysis. 
o Time-to conversion to T2DM in subjects without any type of diabetes at Baseline.  
The Nondiabetes Analysis Set will be used for this analysis.  (revised per 
Amendment 01) 
o Time to conversion to normal glucose homeostasis (HbA1c ≤5.6% and fasting 
plasma glucose <100 mg/dL without any antidiabetic treatment).  The Prediabetes 
Analysis Set will be used for this analysis.  (revised per Amendments 01 and 02) 
 Change from Baseline in HbA1c at 6 months in subjects with T2DM at Baseline will be 
analyzed using an analysis of covariance (ANCOVA) model with treatment and 
stratification variable (presence of established CV disease or CV risk factors without 
established CV disease) as factors, and baseline HbA1c, as a covariate.  Comparison 
between lorcaserin HCl and placebo will be made at 6 months.  The estimated treatment 
difference between lorcaserin HCl and placebo and the 2-sided 95% CI will be 
calculated.  The T2DM Analysis Set will be used for this analysis.  (revised per 
Amendment 01) 
 
In addition to the analysis of the ECHO data from this study, the following analyses will be 
repeated by pooling the ECHO data from this study with the data from the 3 pivotal lorcaserin 


 
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HCl studies (APD356-009, -010, and -011) with terms added for study and treatment by study 
interaction term in the model in order to account for the variability of the different studies. 
 The proportion of subjects who meet FDA-defined valvulopathy in echocardiographically 
determined heart valve changes will be analyzed using logistic regression including 
treatment as a factor and baseline BMI as a covariate.  Comparison between lorcaserin 
HCl and placebo will be made at 1 year.  The FDA-defined Valvulopathy Analysis Set 
will be used for this analysis. 
 The proportion of subjects with FDA-defined valvulopathy at Baseline who demonstrate 
worsened FDA-defined valvulopathy will be analyzed using logistic regression including 
treatment as a factor and baseline BMI as a covariate.  A comparison between lorcaserin 
HCl and placebo will be made at 1 year.  The ITT analysis set in subjects with 
FDA-defined valvulopathy at Baseline will be used for this analysis.  (revised per 
Amendment 01) 
 The change from Baseline in echocardiographically-determined pulmonary arterial 
systolic pressure will be analyzed using a mixed-effects model with repeated measures 
with treatment as a factor and baseline BMI as a covariate.  Comparison between 
lorcaserin HCl and placebo will be made at 1 year and the corresponding 2-sided 95% CI 
will be calculated.  (revised per Amendment 01)  The ITT will be used for this analysis.   
5.4.4 
Other Efficacy Analyses 
The associations between the presence of FDA-defined valvulopathy and Change from Baseline 
in body weight or BMI, at 1 year, will be analyzed using logistic regression including 
stratification variable (presence of established CV disease or CV risk factors without 
established CV disease), baseline weight (or BMI), age, and Week 52 weight change (or BMI 
change) as independent variables in the model.  The model will be run for each treatment group 
separately and for all patients (with their treatment group not included in the model).  The odds 
ratio, p-value and 2-sided 95% CI will be calculated, along with the regression coefficients, 
standard errors and 95%CIs.  The ITT analysis set in subjects with FDA-defined Valvulopathy 
at Baseline will be used for this analysis. 
5.5 
PHARMACOKINETIC, PHARMACODYNAMIC AND PHARMACOGENOMIC / 
PHARMACOGENETIC  
5.5.1 
Pharmacokinetic Analyses 
Not applicable. 
5.5.2 
Pharmacodynamic Analyses 
A PD analysis plan will be defined and reported separately.   
5.5.3 
Biomarker Analyses 
A biomarker analysis plan will be defined and reported separately 


 
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5.5.4 
Pharmacogenomic/Pharmacogenetic Analyses 
A pharmacogenomic analysis plan will be defined and reported separately. 
5.6 
SAFETY ANALYSES 
All safety analyses will be performed on the Safety Analysis Set.  The incidence of AEs 
(including changes from baseline in physical examination), out-of-normal-range laboratory 
safety test variables, abnormal ECG findings, along with change from Baseline in laboratory 
safety test variables, ECGs, and vital sign measurements summarized yearly by treatment group 
using descriptive statistics. 
5.6.1 
Extent of Exposure 
Cumulative exposure to study drug will be summarized by the number and percentage of 
subjects (remaining in study) exposed to study drug in days or other time units by treatment 
group.  In addition, the number of days or other time units of exposure will be summarized 
descriptively as a continuous variable.  The average dose and relative dose intensity (actual dose 
administered divided by planned dose) will be summarized by month and overall study and by 
treatment group. 
5.6.2 
Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA - Version 16.0 or higher).  AEs will be coded to the MedDRA lower level term (LLT) 
closest to the verbatim term.  The linked MedDRA preferred term (PT) and primary system 
organ class (SOC) are also captured in the database. 
All AEs observed during the study will be reported on the CRF. All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the subject 
signs the study ICF through the end of the study and for a minimum of 30 days after the last 
dose. Serious AEs will be collected through the end of study, and for a minimum of 30 days after 
the last dose. 
A treatment-emergent AE (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 (including CEC adjudicated events) will be 
included in summary tables.  All AEs, treatment emergent or otherwise, will be presented in 
subject data listings. 


 
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TEAEs will be summarized by treatment group on the Safety Analysis Set.  The incidence of 
TEAEs will be reported as the number (percentage) of subjects with TEAEs by SOC and PT 
(these summaries will be done with and without CEC adjudicated events).  A subject will be 
counted only once within a SOC and PT, even if the subject experienced more than one TEAE 
within a specific SOC and PT.  The number (percentage) of subjects with TEAEs will also be 
summarized by maximum severity (mild, moderate, or severe).  The number (percentage) of 
subjects with TEAEs will also be summarized by relationship to study drug (Yes = related, and 
No = Not related). 
AEs will be summarized by the following subgroups:  age (< 65 years, ≥ 65 years to <75years, 
≥75 years), sex (male, female), race (white, black, other), presence of established CV disease or 
CV risk factors without established CV disease, pre-diabetes at Baseline, and T2DM at Baseline 
(with and without).  
 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 SAEs will be summarized 
by MedDRA SOC and PT for each treatment group.  A subject data listing of all SAEs 
will be provided. 
 The number (percentage) of subjects with TEAEs leading to discontinuation from study 
drug will be summarized by MedDRA SOC and PT for each treatment group.  A subject 
data listing of all AEs leading to discontinuation from study drug will be provided. 
 The incidence of AEs of interest (Study Specific Events, see Section 9.5.4.4 of the 
protocol) will be summarized separately. In addition, for each AE of interest, Kaplan-
Meier curves and median time to first event and 95% CI will be presented. The Safety 
Analysis Set will be used for this analysis. 
 
5.6.3 
Laboratory Values 
Central Laboratory results will be summarized using Système International (SI) units, as 
appropriate.  For all quantitative parameters listed in protocol Section 9.5.1.5 Safety Assessments 
(Laboratory Measurements), the actual value and the change from baseline to each postbaseline 
visit and to the EOT (defined as the last on-treatment value) will be summarized by visit and 
treatment group using descriptive statistics.  Qualitative parameters listed in protocol 
Section 9.5.1.5 will be summarized using frequencies (number and percentage of subjects), and 
changes from baseline to each postbaseline visit and to EOT 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 
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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 EOT.  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 13.1 (Sponsor’s Grading for Laboratory Values) 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. 
5.6.4 
Vital Signs 
Descriptive statistics for vital signs parameters (i.e., diastolic and systolic BP, pulse, weight) 
and changes from Baseline will be presented by visit and treatment group.  Descriptive 
statistics and changes from Baseline will also be presented by visit and treatment group for 
waist and hip circumference.  In addition, systolic and diastolic blood pressure will be 
summarized by clinically notable changes (see Section 8). 
5.6.5 
Electrocardiograms 
Abnormal ECG findings will be presented as shifts from baseline (normal/abnormal clinically 
significant/abnormal not clinically significant) to post baseline (normal/abnormal clinically 
significant/abnormal not clinically significant) visits. The number and percent of subjects will be 
presented. 
5.7 
OTHER ANALYSES 
No other analyses are planned. 
5.8 
EXPLORATORY ENDPOINT ANALYSES 
 
 The change from Baseline in CV risk factors (body weight, BMI, waist and hip 
circumference, dyslipidemia, insulin level, hypertension, inflammatory biomarkers) will 
be analyzed using a mixed-effects model with repeated measures with treatment, month, 
month by treatment interaction and stratification variable (presence of established CV 
disease or CV risk factors without established CV disease) as factors and Baseline value 
as a covariate. Comparison between lorcaserin HCl and placebo will be made at 1year.  
The estimated treatment difference in the LSM between lorcaserin HCl and placebo, p-
value, and the two-sided 95% CI will be calculated.  The ITT will be used for this 
analysis.  SAS PROC MIXED will be used using an unstructured covariance matrix 
(TYPE=UN).  If the model fails to converge then other covariance structures such as; 
Heterogeneous Toeplitz covariance structure (TYPE= TOEPH), heterogeneous 
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 For subjects with NAFLD at Baseline, the change from Baseline in liver function tests 
(AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin) will be analyzed 
using a mixed-effects model with repeated measures with treatment, month, month by 
treatment interaction and stratification variable (presence of established CV disease or 
CV risk factors without established CV disease) as factors and Baseline value as a 
covariate. Comparison between lorcaserin HCl and placebo will be made at 1 year.  The 
estimated treatment difference in the LSM between lorcaserin HCl and placebo, p-
value, and the two-sided 95% CI will be calculated.  The ITT will be used for this 
analysis.  SAS PROC MIXED will be used using an unstructured covariance matrix 
(TYPE=UN).  If the model fails to converge then a Heterogeneous Toeplitz covariance 
structure (TYPE= TOEPH) will be used. 
 The proportion of subjects who meet FDA-defined valvulopathy in 
echocardiographically determined heart valve changes will be analyzed using a logistic 
GLMM for repeated measures including treatment, month, month by treatment 
interaction as factors and baseline BMI as a covariate. Comparison between lorcaserin 
HCl and placebo will be made at 2 years and yearly thereafter. The odds ratio, p-value 
and 2-sided 95% CI will be calculated.  The FDA-defined Valvulopathy Analysis Set 
will be used for this analysis. 
 The change from baseline in eGFR and ACR will be analyzed using a mixed-effects 
model with repeated measures with treatment, month and month by treatment interaction 
as a factor and baseline value as a covariate. Comparison of the trajectories for lorcaserin 
HCl and placebo will be made at 1 year, yearly thereafter, and at EOS. The estimated 
treatment difference in the LSM between lorcaserin HCl and placebo, p-value, and the 
two-sided 95% CI will be calculated.  The ITT will be used for this analysis.  SAS 
PROC MIXED will be used using an unstructured covariance matrix (TYPE=UN).  If 
the model fails to converge then a Heterogeneous Toeplitz covariance structure (TYPE= 
TOEPH) will be used. 
 The change from Baseline in echocardiographically-determined pulmonary arterial 
systolic pressure will be analyzed using a mixed-effects model with repeated measures 
with treatment, month, month by treatment interaction as factors and baseline pulmonary   
arterial systolic pressure and baseline BMI as covariates. Comparison between lorcaserin 
HCl and placebo will be made at 2 years and yearly thereafter. The estimated treatment 
difference in the LSM between lorcaserin HCl and placebo, p-value, and the two-sided 
95% CI will be calculated.  The ITT will be used for this analysis. SAS PROC MIXED 
will be used using an unstructured covariance matrix (TYPE=UN).  If the model fails to 
converge then a Heterogeneous Toeplitz covariance structure (TYPE= TOEPH) will be 
used. 
 Change from Baseline in HbA1c, FPG, fasting insulin levels, and homeostatic model 
assessment insulin resistance (HOMA-IR),  at 6 months in subjects with T2DM at 
Baseline will be analyzed using an ANCOVA model with treatment and stratification 
variable (presence of established CV disease or CV risk factors without established CV 


 
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disease) as factors, and baseline HbA1c, as a covariate. Comparison between lorcaserin 
HCl and placebo will be made at 6 months. The estimated treatment difference in the 
LSM between lorcaserin HCl and placebo, p-value, and the two-sided 95% CI will be 
calculated.  The T2DM Analysis Set will be used for this analysis, in the following 
subpopulations. 
o Subjects with (HbA1c>7%) at Baseline 
o Subjects who have not been treated with antidiabetic agents at Baseline 
o Subjects who are on monotherapy with oral antidiabetic agent at Baseline 
o Subjects with early T2DM (duration of diagnosis of diabetes is less than 5 years) 
at Baseline. 
 Proportion of subjects with reduction in the number of OAD medications or reduction in 
the dosage of OAD medications in the following subpopulations of subjects with T2DM 
at Baseline will be analyzed using logistic regression including treatment as factor. 
Comparison between lorcaserin HCl and placebo will be made at 6 months. The odds 
ratio, p-value and 2-sided 95% CI will be calculated.  The T2DM Analysis Set will be 
used for this analysis, in the following subpopulations:  
o Subjects with (HbA1c >7%) at Baseline 
o Subjects who are on monotherapy with oral antidiabetic agent at Baseline 
o Subjects with early T2DM (duration of diagnosis of diabetes is less than 5 years) 
at Baseline. 
 Proportions of subjects with at least a 1-stage reduction in an obesity-related 
complication (prediabetes, metabolic syndrome, T2DM, hypertension, and 
hypertriglyceridemia/dyslipidemia), incidence of other obesity-related complications will 
be collected through AE reports, medical history, and use of concomitant medications, 
will be analyzed using logistic regression including treatment as factor. Comparison 
between lorcaserin HCl and placebo will be made at 1 year and EOS. The odds ratio, p-
value and 2-sided 95% CI will be calculated.  The ITT Analysis Set will be used for this 
analysis. 
 
Logistic regression including treatment as factor will be used for the following endpoints.  
Comparison between lorcaserin HCl and placebo will be made at EOS.  The odds ratio, p-value 
and 2-sided 95% CI will be calculated. 
 
The Prediabetes Analysis Set will be used for the following analyses: (revised per Amendment 
01) 
 Proportions of subjects with prediabetes at Baseline who develop new diagnosis of 
diabetic retinopathy at EOS. 
 Proportions of subjects with prediabetes at Baseline who develop new diagnosis of 
diabetic neuropathy at EOS. 
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 Proportions of subjects with T2DM at Baseline who develop new diagnosis of diabetic 
retinopathy at EOS. 
 Proportions of subjects with T2DM at Baseline who develop new diagnosis of diabetic 
neuropathy at EOS. 
6 
INTERIM ANALYSES  
There will be one interim analysis; when 460 adjudicated MACE events have occurred, 
the primary analysis for MACE will be conducted.  This will be the analysis to rule out a 
hazard ratio of 1.4.  If the non-inferiority margin is met, the study will continue to accrue 
events until the required number of MACE+ and diabetes conversion events have occurred.    
 
The interim analysis for MACE endpoint will be performed by an independent statistician 
and governed by an independent DMC and is anticipated to occur on or before 
(approximately) July 2017.  The interim analysis will be conducted according to a DMC 
Charter to establish whether the MACE primary objective has been achieved. 
 
To maintain the integrity and credibility of the trial, procedures will be implemented to 
ensure the DMC and independent statistician have sole access to evolving information from 
the clinical trial regarding comparative efficacy and safety data aggregated by treatment group.  
Full details of the DMC procedures including primary responsibilities of the DMC, its 
relationship with other trial components, its membership, and the purpose and timing of 
its meetings will be documented in the DMC Charter.  These details will also include 
procedures to ensure confidentiality and proper communication, the safety and statistical 
monitoring guidelines to be implemented by the DMC, and an outline of the content of the 
closed reports and open reports that will be provided to the DMC. See Appendix 13.1.2 for the 
DMC charter.  In addition, the Study Integrity Charter in Appendix 13.1.2, describes the 
membership, responsibilities, data access, and firewalls, when 460 adjudicated MACE events 
are achieved and the IA is conducted. 
 
At the interim analysis for MACE, the estimate of the hazard ratio of lorcaserin HCl to 
placebo and the corresponding one-sided 97.5% CI will be calculated.  Non-inferiority 
between lorcaserin HCl and placebo  will  be  declared  if  the  upper  limit  of  the  97.5%  CI  
is  less  than  the non-inferiority margin of 1.4. Otherwise, lorcaserin HCl will be declared as 
not noninferior to placebo and the trial will stop. 
 
If non-inferiority between lorcaserin HCl and placebo is confirmed when 460 adjudicated 
MACE events are observed at approximately 43 months from the start of the study, then the 
study will be continued to observe 1401 adjudicated MACE+ events at approximately 54 
months from the start of the study, and 2.5 years median treatment duration.  
6.1 
INTERIM ANALYSIS STATISTICAL ANALYSIS PLAN  
At the interim analysis; when 460 adjudicated MACE events have occurred, the following 
analysis will be performed using a Cox proportional hazards model that includes factors for 
treatment and stratification variable (presence of established CV disease or CV risk factors 
without established CV disease).   


 
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Details of the censoring algorithm for the MACE endpoint is presented in Section 8.5.1. 
 
6.1.1 
Primary Endpoint Analysis for time to MACE 
Primary endpoint analysis for time to MACE for Non-inferiority:  The estimate of the hazard 
ratio of lorcaserin HCl to placebo and the corresponding one-sided 97.5% CI will be calculated.  
Non-inferiority of lorcaserin HCl to placebo will be declared if the upper limit of the 97.5% CI is 
less than the non-inferiority margin of 1.4.  The Total Time Analysis Population will be used.   
7 
CHANGES IN THE PLANNED ANALYSES 
The following exploratory endpoints were not analyzed. 
 Proportion of subjects with reduction in the number of OAD medications or reduction in 
the dosage of OAD medications in the following subpopulations of subjects with T2DM 
at Baseline will be analyzed using logistic regression including treatment as factor. 
Comparison between lorcaserin HCl and placebo will be made at 6 months. The odds 
ratio, p-value and 2-sided 95% CI will be calculated.  The T2DM Analysis Set will be 
used for this analysis, in the following subpopulations:  
o Subjects with (HbA1c >7%) at Baseline 
o Subjects who are on monotherapy with oral antidiabetic agent at Baseline 
o Subjects with early T2DM (duration of diagnosis of diabetes is less than 5 years) 
at Baseline. 
 
Reason: Difficulty in defining reduction or change in dosage OAD medications and 
interpretation of results. 
 Proportions of subjects with at least a 1-stage reduction in an obesity-related 
complication (prediabetes, metabolic syndrome, T2DM, hypertension, and 
hypertriglyceridemia/dyslipidemia), incidence of other obesity-related complications will 
be collected through AE reports, medical history, and use of concomitant medications, 
will be analyzed using logistic regression including treatment as factor. Comparison 
between lorcaserin HCl and placebo will be made at 1 year and EOS. The odds ratio, p-
value and 2-sided 95% CI will be calculated.  The ITT Analysis Set will be used for this 
analysis. 
Reason:  It was determined that this population will show no change in Obesity Staging  
 


 
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8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
The baseline value for efficacy and safety will be defined as the most recent value reported prior 
to or at randomization.  Adverse events with missing severity will be assigned the highest 
severity.  Adverse events with missing relationship will be assigned as related, as part of a 
sensitivity analysis. Adverse events and Concomitant Medications with partial dates will be 
imputed according the algorithm defined in the SDTM specifications, also included in Appendix 
13.6. 
DEFINITIONS 
 
 Clinically Notable Changes in Blood Pressure: 
 
 
Systolic blood pressure 
 
Increase from baseline of ≥ 20 mm Hg 
 
Post-baseline value > 160mm Hg 
 
Post-baseline value > 160mm and Increase ≥ 20 mm Hg 
 
Decrease from Baseline of ≥ 20 mm Hg 
 
Post-baseline value <60 mm Hg 
 
Post-baseline value < 60mm and Decrease ≥ 20 mm Hg 
 
 
Diastolic blood pressure 
 
Increase from baseline of ≥ 20mm Hg 
 
Post-baseline value > 100mm Hg 
 
Post-baseline value > 100mm Hg and Increase ≥ 20mm Hg 
 
Decrease from Baseline of ≥ 10 mm Hg 
 
Post-baseline value < 50 mm Hg 
Post-baseline value < 50 mm Hg and Decrease ≥ 10 mm Hg 
 Treatment Compliance: Treatment compliance will be determined for the entire double blind 
phase.  Subjects taking BID or QD dosing will be considered as been compliant.  The total 
tablets taken = total tablets dispensed – total tablets returned. 
 
Compliance = 100 x Total tablets taken / Total tablets Expect 
 Secondary Prevention Risk Scores 
The Risk score is calculated by totaling the number of risk factors a subject has at baseline 
and categorizing the total score into 0, 1-2, or ≥3.  See table below. 


 
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Risk Factor 
Points 
Congestive heart failure 
1 
Hypertension 
1 
Age ≥ 75 years 
1 
Diabetes mellitus 
1 
Prior stroke 
1 
Prior CABG 
1 
Peripheral arterial disease 
1 
Renal dysfunction (eGFR <60 mL/min 1.73 m-2
1 
Current smoker 
1 
Prior MI 
1 
 
 
 On treatment:  This definition applies to the “On-Treatment” and “On-Treatment plus 30 
Days” Analyses Sets described in Section 5.2.1.  A subject is considered to be “on treatment” 
while the subject is on study drug.   If a subject permanently discontinues study drug, the 
subject is considered to be “off treatment”.  If a subject is taking BID dosing or QD dosing, 
or stops and restart study drug then the subject is still considered to be “on treatment” 
 Subject who Completed the Study on Study Drug :  A subject is considered to have 
completed the study on study drug, if  the last dose date for the subject falls 1 day prior or 
on/after the date of Sponsor notification of Study Completion and “Subject Status at Final 
Sponsor Notification Visit/Premature Study Discontinuation or  “Subject Status at Final 30-
Day Follow-up Visit” = “Completed”, “Death”.  
 Subject who Completed the Study :  A subject is considered to have completed the study , if 
in the Final Study Disposition CRF, “Subject Status at Final Sponsor Notification 
Visit/Premature Study Discontinuation Visit” = “Completed” , “Death”, or “Subject Status at 
Final 30 Day Follow-up Visit” = “Completed” or “Death”.  For these subjects the EOT is the 
same as the EOS visit. 


 
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 Study Completion:  Sponsor Notification of Study Completion will occurred once 1401 
MACE+ adjudicated events, and 2.5 years median treatment duration. 
 Subjects without Any Type of Diabetes at Baseline:  Subject must meet  the following 
conditions; 
o On the Diabetes History Form “Clinical diagnosis of diabetes?” = “No” and 
o Not initiated any diabetes treatment prior to or at Baseline and 
o None of the following where available 
o HbA1c ≥ 6.5% in all central or local labs assessments prior to or at Baseline and 
o FPG ≥ 126 mg/dL (7.0 mmol/L) in all central or local labs assessments prior to or 
at Baseline and 
o 2-hour plasma glucose ≥ 200 mg/dL(11.1mmol/L) by an OGTT test prior to or at 
Baseline and 
o random plasma glucose > or = 200 with  associated symptoms of hyperglycemia 
prior to or at Baseline  
 Subject who are Pre-diabetic at Baseline: Subject must meet all the following conditions; 
o On the Diabetes History Form “Clinical diagnosis of diabetes?” = “No” and 
o Not initiated any diabetes treatment prior to or at Baseline and 
o At least one of the following:  
o HbA1c 5.7% to <6.5% or  
o FPG 100 to 125 mg/dL (5.55 to 6.94 mmol/L) between Screen and Baseline 
and 
o None of the following where available 
o HbA1c ≥ 6.5% in all central or local labs assessments prior to or at Baseline 
and 
o FPG ≥ 126 mg/dL (7.0 mmol/L) in all central or local labs assessments prior 
to or at Baseline and 
o random plasma glucose > or = 200 with  associated symptom of 
hyperglycemia prior to or at Baseline and 
o 2-hour plasma glucose ≥ 200 mg/dL(11.1mmol/L) by an OGTT test prior to or 
at Baseline and 
 Subject who are Normoglycemic at Baseline: 
 Subject must meet the following conditions; 
o On the Diabetes History Form “Clinical diagnosis of diabetes?” = “No” AND 
o Not initiated any diabetes treatment prior to or at Baseline AND 
o None of the following where available:  
o HbA1c ≥ 5.7% in all central or local labs assessments prior to or at Baseline  


 
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o FPG ≥ 100 mg/dL (5.55 mmol/L) in all central or local labs assessments prior 
to or at Baseline  
o 2-hour plasma glucose ≥ 200 mg/dL(11.1mmol/L) by an OGTT test prior to or 
at Baseline  
o Random glucose > or = 200 with associated symptoms of hyperglycemia prior 
to or at Baseline 
o Subject is not otherwise defined as ‘pre-diabetic’ at baseline 
 
 
 Subjects who are T2DM at Baseline: Subject must meet at least one  of the following 
conditions.  
o On the Diabetes History Form “Clinical diagnosis of diabetes?” = “Yes” and Type of 
Diabetes = 2 on Diabetic History CRF or 
o HbA1c ≥ 6.5% prior to or at Baseline in either central or local labs or 
o FPG ≥ 126 mg/dL (7.0 mmol/L) prior to or at Baseline in either central or local labs 
or 
o 2-hour plasma glucose ≥ 200 mg/dL(11.1mmol/L) by an OGTT test or 
o Random plasma glucose > or = 200 with  associated symptoms of hyperglycemia 
prior to or at Baseline 
o Any diabetes treatment prior to or at Baseline  
 Subjects who are T1DM at Baseline: Subject must meet the following conditions.  
o On the Diabetes History Form “Clinical diagnosis of diabetes?” = “Yes” and Type of 
Diabetes = 1 on Diabetic History CRF 
 Subjects who are DM at Baseline:  
o Subjects who meet criteria for T1DM or T2DM above 
8.1 
CALCULATION OF GFR 
The following equations5 will be used to estimate GFR. 
Cystatin C Equation 
GFR = 133 x min (scys/0.8, 1)-0.499 x max (scys/0.8, 1)-1.328 x 0.966age x [0.932 (if female)] 
Creatinine-Cystatin C Equation 


 
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GFR = 135 x min (scr/k, 1)α  x max (scr/k, 1)-0.601 x min (scys/0.8, 1)-0.375 x  
            max (scys/0.8, 1)-0.711 x  0.995age x [0.969x (if female)] x [1.08(if black)] 
Where, k and α are defined by gender below,  scr = serum creatinine,  scys = serum cystatin, min 
(a, 1) = indicates the minimum of a or 1,  max (a, 1) = indicates the maximum of a or 1, and (if 
condition) = 1 if true or 0 if false. 
 
Female 
Male 
k 
0.7 
0.9 
α 
-0.248 
-0.207 
 
8.2 
DETERMINATION OF RENAL IMPAIRMENT OR IMPROVEMENT  
8.2.1 
Determination of new onset or worsening of Renal Impairment  
Time from randomization to first occurrence of 2 consecutive assessments within the same 
component of the composite endpoint or time to first occurrence of renal transplant or renal 
death, on scheduled or nonscheduled visits at least 30 days apart, indicative of new onset renal 
impairment or worsening of existing renal impairment (first occurrence of any of the following 
events:  microalbuminuria, macroalbuminuria, worsening albuminuria, newly developed CKD 
or worsening of CKD, or doubling of serum creatinine, or any of the following:  ESRD, 
renal transplant, renal death).  Table 4 presents the definitions for each of these events and 
Appendix 13.2 presents the definition of Chronic Kidney Disease (CKD) stages.  


 
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Table 4 Definitions of newly develop or worsening of renal impairment events 
Renal Impairment Event 
Definition 
Newly Developed 
Albuminuria 
For subjects without any microalbuminuria (ACR ≥ 30 μg/mg in spot 
urine), or macroalbuminuria(ACR ≥ 300 μg/mg in spot urine) at 
baseline or subject shows first evidence of; 
 
 
microalbuminuria (ACR ≥ 30 μg/mg in spot urine) with an ACR 
value increased  ≥ 30% from Baseline 
or 
 
macroalbuminuria(ACR ≥ 300 μg/mg in spot urine) with an ACR 
value increased  ≥ 30% from Baseline 
 
 
Worsening albuminuria  
microalbuminuria present at Baseline and develops macroalbuminuria, 
and ACR value increases ≥30% from baseline  assessment during 
treatment 
Newly develop CKD  
eGFR ≥ 90 mL/min per 1.73 body surface area (BSA) and without 
kidney damage at Baseline changes to CKD Stage 1 or higher 
classified by the 2002 National Kidney Foundation (NKF) guidelines, 
where kidney damage referred to in the guideline is defined as the 
emergence of microalbuminuria as defined above, during treatment 
Worsening of CKD  
CKD Stage 1 or higher defined by NKF guidelines worsens to higher 
CKD stages (eGFR ≥ 90 with albuminuria at Baseline decreases to < 
90, or eGFR 60 to 89 at Baseline becomes <60, or eGFR 30 to 59 at 
Baseline becomes < 30 mL/min per 1.73 BSA) during treatment 
Doubling of serum creatinine 
creatinine value is at least 2 times the Baseline value and ≥ 1.5mg/dL 
during treatment 
ESRD 
eGFR < 15 mL/min per 1.73 body surface area (BSA) or renal dialysis 
(captured as an SAE) 
renal transplant 
Captured as an SAE 
renal death 
 Adjudicated death event by SAE 
 
8.2.2 
Determination of Improvement of Renal function  
Time  from  randomization  to  first  occurrence  of  2  consecutive  assessments,  on scheduled 
or nonscheduled visits at least 30 days apart, indicative of improvement in renal function (first 
occurrence of regression of albuminuria or regression of CKD), see Appendix 13.2 for 
definitions CKD stages. The renal improvement events are defined as; 
 
Regression of albuminuria: defined as when subjects with macroalbuminuria at Baseline 
develop microalbuminuria or non-albuminuria (ACR < 30 μg/mg in spot urine), or subjects with 
microalbuminuria at Baseline become non-albuminuric, and ACR value decreases ≥ 30% from 
previous assessment during treatment. 
 
Regression of CKD: defined as when a subject with CKD Stage 1 or higher at Baseline 
improves to normal or lower stages by NKF guideline (eGFR   ≥ 90 with albuminuria at 


 
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Baseline improves to eGFR   ≥ 90 without albuminuria (ACR < 30 μg/mg in spot urine), or 
eGFR 60 to 89 at Baseline becomes eGFR   ≥ 90 with or without albuminuria, or eGFR between 
30 to 59 at Baseline improves to > 60 mL/min per 1.73 BSA) during treatment. 
 
8.3 
DETERMINATION OF CONVERSION TO T2DM OR TO NORMAL GLUCOSE HOMEOSTASIS  
8.3.1 
Determination of conversion to T2DM  
For the following 2 cohorts, subjects without any type diabetes at Baseline and subjects who are 
prediabetic at Baseline, as per the definitions in Section 8 above, the time from randomization 
to conversion to T2DM will be adjudicated as per  the CEC Diabetes Adjudication Charter, see 
Appendix 13.1.4.  
 
For subjects who did not experienced any event, the censoring algorithm is described in Section 
8.5.2.2.   
 
8.3.2 
Determination of conversion to normal glucose homeostasis  
For subjects with prediabetes at Baseline the time from randomization to conversion to normal 
glucose homeostasis (HbA1c ≤5.6% and fasting plasma glucose <100 mg/dL without any 
antidiabetic treatment . The primary analysis will be based on conversion to normal glucose 
homeostasis that is achieved and maintained through the duration of the study.  Sensitivity 
analyses will include an assessment of 1) any conversion to normal glucose homeostasis at one 
or more time points during the study and 2) sustained for 2 consecutive measurements separated 
by 30 days.  For subjects who did not experienced any event, the censoring algorithm is 
described is in Table 7. 
 
8.4 
FDA DEFINED VALVULOPATHY AND PULMONARY ARTERIAL PRESSURE 
The aortic and mitral valve regurgitation will be categorized as absent, trace, mild, moderate or 
severe.  FDA-defined valvulopathy, or simply “FDA valvulopathy,” stipulate that significant 
valvular regurgitation comprises mild or greater aortic valve regurgitation and/or moderate 
or greater mitral valve regurgitation. The ECHO sub-study data presents the mitral and aortic 
valve severity as 5 categories; ABSENT, TRACE, MILD, MODERATE, and SEVERE. 
 
 
For each subject and visit a dichotomous variable will be created, where; 
 
 1 = mild or greater aortic valve regurgitation and/or moderate or greater mitral valve 
regurgitation 
 
 0 = aortic valve regurgitation is absent or trace and mitral valve regurgitation is mild or 
less. 
 


 
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For the secondary endpoints assessing cardiac valve function and pulmonary arterial pressure 
listed in Section 5.1.2 the ECHO sub-study data from this study will be pooled with studies 
ADP356-009, -010, and -011. 
8.4.1 
Worsened FDA-defined valvulopathy 
For subjects with FDA-defined valvulopathy at Baseline, worsened FDA-defined valvulopathy is 
define as any increase in valvular regurgitation from Baseline in either the aortic or mitral valve. 
8.5 
CENSORING 
The individual EOS date will be defined as the time of the last visit or study contact for each 
individual patient. If no event occurs for an endpoint, the earlier of the last study contact, the 
visit following Sponsor Notification of Study Completion or death will be treated as the 
censoring date.   
 
MACE, MACE+ and conversion to T2DM events will be handled in the following manner 
according to their timing with respect to study milestones: 
 Events that are recorded as beginning prior to the date of randomization will not be 
counted in the event analyses.  The subject will be included in the analysis as not 
experienced the event.  These events that are recorded as beginning prior to the date of 
randomization they will be included in a listing. 
 Events that occur at any time after randomization and up to and including the first of the 
last visit/contact or visit following Sponsor Notification of Study Completion and 
reported before database lock will be adjudicated and included in all efficacy and safety 
analyses. 
 Events that occur at any time after randomization and up to and including the last 
visit/contact and reported after database lock will be not be adjudicated and will not be 
included in the primary efficacy and safety analysis. They will be recorded in a tabular 
fashion as part of the final study report and may be included in sensitivity analyses. 
 Events that occur after last visit/contact will not be included in the primary efficacy and 
safety analyses but may be included in the safety database if they fulfill safety reporting 
criteria. 
Events in subjects who withdraw consent for clinical follow-up: 
 All events that occur before withdraw of consent are included in analyses.  
 Events that occur after withdraw of consent will be included in the primary analyses if 
they were found through vital status search prior to database lock.  
Events in subjects who stop and re-start study medication. 
 For the Total Time Analysis Set all events are counted regardless of whether the subject 
is on or off treatment. 


 
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 For the On-treatment Analysis Set events are counted only when the subject in “on-
treatment”.  See Section 8, for definition of “on-treatment”. 
 For the On-treatment plus 30 days Analysis Set events are counted when the subject is 
“on-treatment” and up to 30 days from their last dose.  See Section 8, for definition of 
“on-treatment”. 
For ITT subjects who were not treated the censoring time will be determined from the 
randomization date to the date of final disposition. 
8.5.1 
Censoring at Interim Analysis for MACE 
There will be one interim analysis; when 460 adjudicated MACE events have occurred, the 
primary analysis for MACE will be conducted. The censoring algorithm is found in the Table 5 
and see Appendix 13.2 for diagrams of censoring algorithms.  See Section 6 for details on 
interim analysis. 
 
For subjects who experienced an event, their time-to-event will be determined from the 
randomization date to the date of the event, for the Total Time Analysis. The censoring variable 
will be, CENSORED=0.  For subjects who do not experienced an event, the censoring time will 
be determined from the randomization date  to the date of the data extraction for those continuing 
in the study or according to the details below for subjects who are not continuing in the study at 
the time of the interim analysis.  For these subjects, the censoring variable will be, 
CENSORED=1. 
 
Table 5  Censoring Date For subjects who did not experienced an event at the Interim Analysis 
Analysis 
Seta 
Ongoing 
Withdrawal From Study Follow-up 
Total Time 
on Study 
Date of the adjudicated CEC 
database lock will be used for all 
ongoing subjects  
In the Final Study Disposition Form use the date from, 
Date of Final Sponsor Notification/Premature Study 
Discontinuation  
and 
status for discontinuation equals any of the following; 
 
Withdrew Consent 
 
Non- CV Death 
 
Other 
a See Section 5.2.1 for definitions of Analysis Sets and Appendix 13.5.1 for diagrams of censoring 
algorithms 
 
8.5.2 
Censoring at Study Completion 
8.5.2.1 
Censoring for MACE, MACE+, each Component of MACE, and All-Cause Mortality 
If non-inferiority between lorcaserin HCl and placebo is confirmed at the interim analysis, 
then the study will be continued to observe; 1401MACE+ events at approximately 54 months 
from the start of the study and 2.5 years median treatment duration. 


 
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MACE non-inferiority and superiority, each component of MACE, and All-cause mortality will 
analyzed at study completion as part of additional sensitivity analyses.  The censoring algorithm 
is the same for these endpoints but differs by Analysis Set as described in the Table 6, and see 
Appendix 13.2 for diagrams of censoring algorithms. 
 
For subjects who experienced an event, their time-to-event will be determined from the 
randomization date (for the Total Time Analysis) and the start date of study drug (for the On-
Treatment and On-Treatment + 30-Days Analyses), to the date of the event.  The censoring 
variable will be, CENSORED=0.  For subjects who do not experienced an event, the censoring 
time will be determined from the randomization date (for the Total Time Analysis) and the start 
date of study drug (for the On-Treatment and On-Treatment + 30-Days Analyses),  to the date 
described in Table 6, along with a matching censoring variable, CENSORED=1. 
 
 
Table 6     Censoring Date For subjects who did not experienced an event at Study Completion 
Analysis 
Seta 
Completed the Study 
Withdrawal From Study Follow-up 
Total Time 
on Study 
In the Final Study Disposition Form use 
the date from , Date of Final Sponsor 
Notification/Premature Study 
Discontinuation  
and  status is equal to completed 
 
In the Final Study Disposition Form use the 
date from , Date of Final Sponsor 
Notification/Premature Study Discontinuation  
 and 
status for discontinuation equals any of the 
following; 
 
Withdrew Consent 
 
Lost to Follow up 
 
Study Terminated by Sponsor 
 
death (except for All Cause-mortality) 
 
Other 
On-
Treatment + 
30 Days  
Date of  last dose from Study 
Medication Form + 30 Days 
 
 
Date of last dose from Study Medication Form 
+ 30 Days 
On-
Treatment   
Date of last dose from Study Medication 
Form  
Date of last dose from Study Medication Form  
a See Section 5.2.1 for definitions of Analysis Sets  and Appendix 13.5.2 for diagrams of censoring 
algorithms 
 
8.5.2.2 
Censoring for Conversion to T2DM 
For subjects who experienced an event, their time-to-event will be determined from the 
randomization date to the date of first abnormal laboratory test as per the Diabetes CEC Diabetes 
Adjudication Charter, Appendix 13.1.4.  The censoring variable will be, CENSORED=0.  For 
subjects who do not experienced an event, the censoring time will be determined from the 
randomization date to the date described in the Table 6, using the Total Time on Study Analysis 
Set, along with a matching censoring variable, CENSORED=1.  The above censoring algorithm 


 
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will be applied to both cohorts 1) subjects without any type diabetes at Baseline and 2) subjects 
with prediabetis at Baseline. 
8.5.2.3 
Censoring for Secondary Time-to-Event Endpoints 
The censoring algorithm is the same for all secondary time-to-event endpoints and across the 
different Analysis Sets.  Since all the Analyses Sets used the ITT population for these secondary 
endpoints, then for subjects who experienced an event, their time-to-event will be determined 
from the randomization date to the date of the event.  The censoring variable will be, 
CENSORED=0.  For subjects who do not experienced an event, the censoring time will be 
determined from the randomization date to the date described in Table7, along with a matching 
censoring variable, CENSORED=1. 
 
Table 7    Censoring Date for Subjects who did not Experience an Event at Study Completion for 
Secondary Renal and Glucose Homeostasis Endpoints 
Time-to-Event Endpoint 
Analysis 
Seta 
Completed the Study 
Withdrawal From Study Follow-
up 
New onset of renal 
impairment or 
worsening of existing 
renal impairment in 
subjects with T2DM at 
Baseline 
T2DM  
 
In the Final Study 
Disposition Form use the 
date from ;  
Date of Final Sponsor 
Notification/Premature 
Study Discontinuation  
and  status is equal to 
completed 
 
In the Final Study Disposition 
Form use the date from, Date of 
Final Sponsor 
Notification/Premature Study 
Discontinuation  
and 
status for discontinuation equals 
any of the following; 
• 
Withdrew Consent 
• 
Lost to Follow up 
• 
Study Terminated by Sponsor 
• 
Death 
• 
Other 
New onset of renal 
impairment or 
worsening of existing 
renal impairment in all 
subjects enrolled in the 
study 
Total Time 
 
Improvement in renal 
function 
 
T2DM  
 
New onset of renal 
impairment or 
worsening of existing 
renal impairment in 
subjects with 
prediabetes at Baseline 
Prediabetes 
 
Conversion  to  normal  
glucose  homeostasis 
Prediabetes 
a See Section 5.2.1 for definitions of Analysis Sets  
 


 
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8.5.2.4 
Censoring for Sensitivity Analysis Time-to-Event Endpoints 
Subjects that start another weight reduction medication or has a bariatric procedure:  
MACE and MACE+ endpoints will be analyzed using the Total Time Analysis Set.   
 
For subjects who experienced an event and did not start on another weight reduction medication 
or did not have bariatric surgery, their time-to-event will be determined from the randomization 
date to the date of the event.  The censoring variable will be, CENSORED=0. 
 
For subjects who experienced an event and started on another weight reduction medication or 
undergoes bariatric surgery,  the censoring variable will be , CENSORED=0, if date of event is 
either prior to date of starting a weight reduction medication or having bariatric surgery  or the 
event occurred after having stopped taking a weight reduction medication.  Their time-to-event 
time will be determined from randomization date to date of the event.   The censoring variable 
will be, CENSORED=1, if the date of event is equal to or greater than date of having bariatric 
surgery or the event date occurred while on a weight reduction medication.   The censoring time 
will be determined from the randomization date to the earliest date of starting another weight 
reduction medication and/or having bariatric surgery.  If date of starting another weight reduction 
medication or having bariatric surgery is prior to the randomization date, then censoring time 
will be set to the randomization date. 
 
 
 For subjects who do not experience an event and did not start on another weight reduction 
medication or did not have bariatric surgery, the censoring time will be determined from the 
randomization date to the date described in the Table 6 using the Total Time on Study Analysis 
Set, along with a matching censoring variable, CENSORED=1. 
 
For subjects who do not experience an event and start on another weight reduction medication or 
undergoes bariatric surgery, the censoring time will be determined from the randomization date 
to the date of starting a weight reduction medication or the date of the bariatric surgery, along 
with a matching censoring variable, CENSORED=1.  If date of starting another weight reduction 
medication or having bariatric surgery is prior to the randomization date, then censoring time 
will be set to the randomization date. 
8.6 
DEFINITION OF VISIT WINDOWS 
Table 4 of the protocol presents the schedule of procedures/Assessments.  Some 
procedures/assessments are performed at 3 months, 6 months or yearly intervals. Table 8 
presents the protocol specified visits/months and corresponding time windows used for visit-wise 
analyses are presented in terms of days relative to the first dose.  For subjects that are 
randomized, the last available assessment on or before the randomization date will be used as the 
Baseline-Day 1.  If more than one measurement is included in a visit window, the measurement 
collected closest to the scheduled date will be used in the analysis. In the case where two 
measurements were collected an equal number of days before and after the Scheduled Day the 
later of the two measurements will be used for analysis.  


 
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For ECHO and PAH assessments when assessing a new or worsened event then the most severe 
assessment will be selected if 2 or more assessments fall within a visit window. 
 
Table 8  Visit Windows Measurements 
Scheduled 
Visit 
Scheduled 
Month 
Scheduled 
Day 
Time Window 
(Days) 
Time Window 
(Days) For 6 
Month 
Interval 
Assessments 
Time Window 
(Days) For 
Yearly 
Interval 
Assessments 
1 
Screening 
-30 
-1 
 
 
 
 
2 
Baseline/ 
Randomization 
1 
1 
1 
1 
 
3 
3 
90 
2 
135 
 
 
4 
6 
180 
136 
225 
2 
270 
 
 
5 
9 
270 
226 
315 
 
 
6 
12 
360 
316 
405 
271 
450 
2 
540 
7 
15 
450 
406 
495 
 
 
8 
18 
540 
496 
585 
451 
630 
 
 
9 
21 
630 
586 
675 
 
 
10 
24 
720 
676 
780 
631 
810 
541 
900 
11 
28 
840 
781 
900 
 
 
12 
32 
960 
901 
1020 
 
 
 
 
13 
36 
1080 
1021 
1140 
 
 
901 
1260 
14 
40 
1200 
1141 
1260 
 
 
 
 
15 
44 
1320 
1261 
1380 
 
 
16 
48 
1440 
1381 
1500 
 
 
1261 
1620 
17 
52 
1560 
1501 
1620 
 
 
EOT 
56 
1680 
1621 
1710 
  
  
EOS 
58 
1740 
1711 
Open 
 
 
 
 
8.7 
PROTOCOL DEVIATIONS 
Protocol Deviations will be collected in the eCRF and included in the database.  These protocol 
deviations will be review and monitored during the course of the study by the study team.  
Protocol deviations will rated as “Major” or “Minor” and finalized prior to data base lock.  


 
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9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
10 
STATISTICAL SOFTWARE 
All statistical analyses will be performed by Eisai Inc. or designee, using SAS Version 9.2 or 
later.   
11 
MOCK TABLES, LISTINGS AND GRAPHS (TLGS) 
The study TLG shells will be provided in a separate document, which will show the content and 
format of all tables, listings, and graphs in detail. 


 
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12 
REFERENCES 
1. Zou, G.  A Modified Poisson Regression Approach to Prospective Studies with Binary Data. 
Am. J. Epidemiol., 2004; 159:702-706. 
2. Spiegelman, D. and Hertzmark, Easy Calculations for Risk or Prevalence Ratios and 
Differences.  Am. J. Epidemiol., 2005; 162:199-200. 
3. American Diabetes Association Position Statement: Standards of Medical Care – 2013. 
Diabetes Care, Volume 36, Supplement 1, January 2013. 
4. Inker, L.A. et. al. Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin 
C. N Engl. J. Med., 2012;367:20-29. 


 
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13 
APPENDICES 
13.1 
Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results  
The following table of Sponsor’s Grading for Laboratory Values is copied from the protocol, Appendix 5.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 x 109/L 
< LLN – 3000/mm3  
< 3.0 – 2.0 x 109/L 
< 3000 – 2000/mm3 
< 2.0 – 1.0 x 109/L 
< 2000 – 1000/mm3  
< 1.0 x 109/L 
< 1000/mm3  
Lymphocytes  
< LLN – 800/mm3  
< LLN – 0.8 x 109/L
< 800 – 500/mm3 
< 0.8 – 0.5 x 109/L 
< 500 – 200/mm3  
< 0.5 – 0.2 x 109/L 
< 200/mm3
< 0.2 x 109/L 
Neutrophils  
< LLN – 1.5 x 109/L 
< LLN – 1500/mm3  
< 1.5 – 1.0 x 109/L 
< 1500 – 1000/mm3 
< 1.0 – 0.5 x 109/L 
< 1000 – 500/mm3  
< 0.5 x 109/L 
< 500/mm3  
Platelets 
< LLN – 75.0 x 
109/L 
< LLN – 
75,000/mm3  
< 75.0 – 50.0 x 109/L
< 75,000 – 
50,000/mm3  
< 50.0 – 25.0 x 109/L 
< 50,000 – 
25,000/mm3 
< 25.0 x 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 x ULN > 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x ULN 
ALT 
> ULN – 3.0 x ULN > 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x ULN 
AST 
> ULN – 3.0 x ULN > 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x ULN 
Bicarbonate, serum-low  
< LLN – 16 mmol/L
< 16 – 11 mmol/L 
<11 – 8 mmol/L 
< 8 mmol/L  
Bilirubin (hyperbilirubinemia) 
> ULN – 1.5 x ULN > 1.5 – 3.0 x ULN 
> 3.0 – 10.0 x ULN  
> 10.0 x 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 x ULN > 1.5 – 3.0 x ULN 
> 3.0 – 6.0 x ULN 
> 6.0 x ULN 
GGT (γ-Glutamyl transpeptidase)  > ULN – 3.0 x ULN > 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x 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 
(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 


 
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The following table of Sponsor’s Grading for Laboratory Values is copied from the protocol, Appendix 5.Sponsor’s Grading 
for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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, LLN = lower limit of normal, N/A = not applicable, ULN = 
upper limit of normal, WBC = white blood cell. 
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 
14, 2010). 
 


 
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13.2 
Classification of Chronic Kidney Disease  
Chronic Kidney Disease: A Clinical Action Plan 
Stage 
Description 
GFR (mL/min/1.73m2)
Action* 
  
At increased risk 
≥90 
(with CKD risk factors) 
Screening 
CKD risk reduction 
1 
Kidney damage with normal or 
GFR 
≥90 
Diagnosis and treatment: 
Treatment of comorbid conditions,
slowing progression, CVD risk 
reduction 
2 
Kidney damage with mild GFR 
60-89 
Estimating progression 
3 
Moderate GFR 
30-59 
Evaluating and treating complications 
4 
Severe GFR 
15-29 
Preparation for kidney replacement 
therapy 
5 
Kidney Failure 
<15 
(or dialysis) 
Replacement (if uremia present) 
Shaded area identifies patients who have chronic kidney disease; unshaded area designates individuals who are at 
increased risk for developing chronic kidney disease. Chronic kidney disease is defined as either kidney damage or 
GFR <60 mL/min/1.73 m2 for   3 months. Kidney damage is defined as pathologic abnormalities or markers of 
damage, including abnormalities in blood or urine tests or imaging studies. 
* Includes actions from preceding stages. 
Abbreviations: GFR, glomerular filtration rate; CKD, chronic kidney disease; CVD, cardiovascular disease. 


 
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13.1 
 CHARTERS AND RETENTION PLAN TO PREVENT MISSING DATA 
13.1.1 
CEC Charter  
Final CEC Charter 
 
13.1.2 
DMC Charter and Integrity Charter 
Final DMC Charter and Integrity Charter 
 
13.1.3 
Retention Plan to prevent missing data 
Final Retention Plan to Prevent Missing Data 
 
13.1.4 
Conversion to Type II Diabetes Adjudication Charter 
Final Clinical Events Committee Diabetes Adjudication Charter 


 
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13.2 
 DIAGRAMS OF CENSORING ALGORITHMS 
13.2.1 
Censoring at Interim Analysis 
 
13.2.2 
Censoring at Study Completion 
 


 
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13.3 
ADVERSE EVENT START AND END DATE IMPUTATION ALGORITHM 
Description of Incomplete 
End Date  
   Imputed  date 
Day missing (YearMonth only) and Date of Death is not missing  
  
YearMonth earlier than 
YearMonth of Date of Death 
Impute to the last day of the month 
  
YearMonth equals YearMonth 
of Date of Death 
Date of Death 
Month missing (Year) and Date of Death is not missing  
  
Year earlier than Year of Date 
of Death 
Impute to the last day of the year 
  
Year equals Year of Date of 
Death 
Date of Death 
ALL is missing and Date of Death is not missing  
     
Date of Death 
Day missing (YearMonth) and Date of Death is missing  
   YearMonth 
Impute to the last day of the month 
Month missing (Year) and Date of Death is missing  
   Year 
Impute to the last day of the year 
ALL is missing and Date of Death is missing  
     
No imputation 
Description of Incomplete 
Start Date  
   Imputed  date 
Day missing (YearMonth 
Only) 
  
  
  
YearMonth earlier than 
YearMonth of First Dose Date 
Impute to first of the month 
  
YearMonth equal YearMonth 
of First Dose Date 
Impute to First Dose Date or AE End Date, whichever is earlier 
  
YearMonth greater than 
YearMonth of First Dose Date 
Impute to first of the month 
Month missing (Year)  
     
  
Year earlier than Year of First 
Dose Date 
Impute to first of the year 
  
Year equal Year of First Dose 
Date 
Impute to First Dose Date or AE End Date, whichever is earlier 
   Year greater than Year of First 
Impute to first of the year 


 
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Dose Date 
ALL is missing 
     

Impute to First Dose Date ( or randomization date for subjects who did 
take study treatment) or AE End Date, whichever is earlier 
 
 
13.4 
CONCOMITANT MEDICATION START AND END DATE IMPUTATION ALGORITHM 
There is clear evidence the drug was STOPPED BEFORE the Screening Visit (from Prior Meds 
page) 
Description of Incomplete End Date  
  
Imputed  date 
Day missing (YearMonth) and Date of Screening is not missing  
  
YearMonth earlier than YearMonth of Date of 
Screening 
Impute to the last day of the month 
   YearMonth equals YearMonth of Date of Screening 
Date of Screening 
Month missing (Year) and Date of Screeningis not missing  
   Year earlier than Year of Date of Screening 
Impute to the last day of the year 
   Year equals Year of Date of Screening 
Date of Screening 
ALL is missing and Date of Screening is not missing  
     
Date of Screening 
There is NO clear evidence the drug was STOPPED BEFORE the Screening Visit 
Description of Incomplete End Date  
  
Imputed  date 
Day missing (YearMonth only) and Date of Death is not missing  
  
YearMonth earlier than YearMonth of Date of 
Death 
Impute to the last day of the month 
   YearMonth equals YearMonth of Date of Death 
Date of Death 
Month missing (Year) and Date of Death is not missing  
   Year earlier than Year of Date of Death 
Impute to the last day of the year 
   Year equals Year of Date of Death 
Date of Death 
ALL is missing and Date of Death is not missing  
     
Date of Death 
Day missing (YearMonth) and Date of Death is missing  
   YearMonth 
Impute to the last day of the month 
Month missing (Year) and Date of Death is missing  
   Year 
Impute to the last day of the year 
ALL is missing and Date of Death is missing  
     
No imputation 


 
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Description of Incomplete 
Start Date  
   Imputed  date 
Day missing (YearMonth 
Only) 
  
  
  
YearMonth earlier than 
YearMonth of First Dose Date 
Impute to first of the month 
  
YearMonth equal YearMonth 
of First Dose Date 
Impute to First Dose Date or Med End Date, whichever is earlier 
  
YearMonth greater than 
YearMonth of First Dose Date 
Impute to first of the month 
Month missing (Year)  
     
  
Year earlier than Year of First 
Dose Date 
Impute to first of the year 
  
Year equal Year of First Dose 
Date 

Impute to First Dose Date(or randomization date for subjects who did 
take study treatment) or Med End Date, whichever is earlier 
  
Year greater than Year of First 
Dose Date 
Impute to first of the year 
ALL is missing 
     
Impute to First Dose Date or Med End Date, whichever is earlier