Clinical trial NCT03041792
Conditions: Obesity
Sponsor: Pfizer
Start date: 2017-02-20; Completion date: 2018-01-16
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This will be a randomized, double blind, placebo controlled, 2 arm, parallel group, methodology study to assess the effect of 6 weeks of liraglutide administration on food intake in obese subjects.

Detailed description:

Arms: arm 1: Liraglutide arm 2: Placebo comparator
Interventions: intervention 1: Liraglutide intervention 2: Placebo
Intervention descriptions: intervention 1: Liraglutide intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
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Final Protocol, 21 November 2016
Page 1
A 6-WEEK, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
TWO-ARM, PARALLEL METHODOLOGY STUDY TO ASSESS THE EFFECT OF 
LIRAGLUTIDE ON FOOD INTAKE IN OBESE SUBJECTS
Investigational Product Number:
Not Applicable (N/A)
Investigational Product Name:
Liraglutide
United States (US) Investigational New 
Drug (IND) Number:
N/A
European Clinical Trials Database 
(EudraCT) Number:
N/A
Protocol Number:
A9001498
Phase:
Methodology Study


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Document History
Document
Version Date
Summary of Changes and Rationale
Original protocol
21 November 2016
Not applicable (N/A)


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
LIST OF FIGURES ...................................................................................................................7
APPENDICES ...........................................................................................................................7
SCHEDULE OF ACTIVITIES..................................................................................................8
1. INTRODUCTION ...............................................................................................................12
1.1. Mechanism of Action/Indication.............................................................................12
1.2. Background .............................................................................................................12
1.3. Rationale..................................................................................................................13
1.3.1. Study Rationale...........................................................................................13
1.3.2. Dose Rationale............................................................................................15
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................16
3. STUDY DESIGN.................................................................................................................17
3.1. Study Overview.......................................................................................................17
3.2. Stopping Rules ........................................................................................................18
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................18
4.1. Inclusion Criteria.....................................................................................................18
4.2. Exclusion Criteria....................................................................................................19
4.3. Randomization Criteria ...........................................................................................22
4.4. Lifestyle Requirements ...........................................................................................22
4.4.1. Meals and Dietary Restrictions...................................................................22
4.4.2. Alcohol, Caffeine, and Tobacco .................................................................23
4.4.3. Activity .......................................................................................................23
4.4.4. Contraception..............................................................................................23
4.5. Sponsor’s Qualified Medical Personnel..................................................................24
5. STUDY TREATMENTS.....................................................................................................25
5.1. Allocation to Treatment ..........................................................................................25
5.2. Breaking the Blind ..................................................................................................26
5.3. Subject Compliance.................................................................................................26
5.4. Investigational Product Supplies.............................................................................26
5.4.1. Dosage Form and Packaging ......................................................................26
5.4.2. Preparation and Dispensing........................................................................26


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5.5. Administration.........................................................................................................27
5.5.1. Timing of Administration during Inpatient Visits (V3, V4, V5)................27
5.5.2. Timing of Home Administration (between V3 and V4, and between 
V4 and V5).......................................................................................................28
5.6. Investigational Product Storage ..............................................................................28
5.7. Investigational Product Accountability...................................................................28
5.7.1. Destruction of Investigational Product Supplies ........................................29
5.8. Concomitant Treatments .........................................................................................29
5.8.1. Anti-Hypertensive Medications..................................................................29
5.8.2. Lipid-Modifying Medications ....................................................................29
5.8.3. Other Acceptable Concomitant Medications..............................................29
6. STUDY PROCEDURES .....................................................................................................30
6.1. Chronology of Procedures.......................................................................................30
6.2. Screening (V1) ........................................................................................................31
6.3. Run In Visit (V2).....................................................................................................31
6.4. Dosing Period..........................................................................................................31
6.4.1. Inpatient Visits (V3, V4, V5) .....................................................................31
6.4.2. Daily Dosing from Days 2 to 19 and Days 23 to 40...................................31
6.5. Follow-Up (V6 and Phone Contact)........................................................................32
6.6. Subject Withdrawal.................................................................................................32
7. ASSESSMENTS..................................................................................................................33
7.1. Safety.......................................................................................................................34
7.1.1. Laboratory Tests .........................................................................................34
7.1.2. Pregnancy Testing ......................................................................................35
7.1.3. Physical Examinations................................................................................35
7.1.5. Blood Pressure and Pulse Rate ...................................................................37
7.1.6. Electrocardiogram.......................................................................................37
7.2. Pharmacokinetics ....................................................................................................38
7.2.1. Analysis of Acetaminophen Pharmacokinetics ..........................................38
7.3. Banked Biospecimens .............................................................................................39
7.3.1. Additional Research....................................................................................40
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7.4. Food Intake Assessment..........................................................................................40
7.5. Visual Analog Scale (VAS) Questionnaire.............................................................40
7.6. Gastric Emptying.....................................................................................................41
7.8. Blood Volume .........................................................................................................41
7.9. Assessment of Suicidal Ideation and Behavior.......................................................41
7.9.1. Columbia Suicide Severity Rating Scale (C-SSRS)...................................41
7.9.2. Patient Health Questionnaire-9 (PHQ-9)....................................................42
7.10. Rater Qualifications...............................................................................................42
8. ADVERSE EVENT REPORTING......................................................................................43
8.1. Requirements...........................................................................................................43
8.1.1. Additional Details on Recording Adverse Events on the CRF...................44
8.1.2. Eliciting Adverse Event Information..........................................................44
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal section)............................................................................44
8.1.4. Time Period for Collecting AE/SAE Information......................................44
8.1.5. Causality Assessment .................................................................................45
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................45
8.2. Definitions...............................................................................................................46
8.2.1. Adverse Events...........................................................................................46
8.2.2. Abnormal Test Findings .............................................................................46
8.2.3. Serious Adverse Events ..............................................................................47
8.2.4. Hospitalization............................................................................................48
8.3. Severity Assessment................................................................................................49
8.4. Special Situations ....................................................................................................49
8.4.1. Potential Cases of Drug-Induced Liver Injury............................................49
8.4.2. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................51
8.4.3. Medication Errors .......................................................................................53
8.5. Medical Device Complaint Reporting Requirements .............................................54
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................54
9.1. Sample Size Determination.....................................................................................54
9.2. Efficacy Analysis ....................................................................................................55
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9.2.1. Analysis of the Primary Endpoint...............................................................55
9.2.2. Analysis of Secondary Endpoints...............................................................55
9.3. Pharmacokinetic Analysis.......................................................................................56
9.3.1. Acetaminophen...........................................................................................56
9.4. Analysis of Other Endpoints ...................................................................................56
9.5. Safety Analysis........................................................................................................56
9.5.1. Electrocardiogram Analysis........................................................................57
9.6. Interim Analysis ......................................................................................................57
9.7. Data Monitoring Committee ...................................................................................57
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................58
11. DATA HANDLING AND RECORD KEEPING .............................................................58
11.1. Case Report Forms/Data Collection Tools/Electronic Data Record.....................58
11.2. Record Retention...................................................................................................59
12. ETHICS..............................................................................................................................59
12.1. Institutional Review Board/Ethics Committee......................................................59
12.2. Ethical Conduct of the Study ................................................................................59
12.3. Subject Information and Consent..........................................................................60
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................60
13. DEFINITION OF END OF TRIAL...................................................................................60
13.1. End of Trial in the United States...........................................................................60
14. SPONSOR DISCONTINUATION CRITERIA ................................................................61
15. PUBLICATION OF STUDY RESULTS..........................................................................61
15.1. Communication of Results by Pfizer ....................................................................61
15.2. Publications by Investigators ................................................................................62
16. REFERENCES ..................................................................................................................63
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LIST OF TABLES
Table 1.
Comprehensive Schedule of Activities...................................................................8
Table 2.
List of Procedures for Inpatient Visits (V3, V4, V5) ...........................................10
Table 3.
Liraglutide Dose Titration during Study...............................................................27
Table 4.
Clinical Laboratory Tests .....................................................................................34
LIST OF FIGURES
Figure 1.
Study Design.........................................................................................................17
APPENDICES
Appendix 1. Abbreviations......................................................................................................66


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. The investigator may schedule visits (unplanned visits) in addition to those listed in the schedule of activities table, in order 
to conduct evaluations or assessments required to protect the well-being of the subject.  For a list of abbreviations, refer to 
Appendix 1: Abbreviations.
Table 1.
Comprehensive Schedule of Activities
Protocol Activity
Screening
Run In
Double-Blind Randomized Dosing Period
Follow Up
Visit (V) Number
V1
V2
V3
V4
V5
V6a
Phone 
Contact
Days Relative to Dosing on Day 1
Day
-44 to -17
Day -16
Day -2
Day
-1 to 1
Day
2 to 18
Day 
19
Day
20 to 22
Day
23 to 39
Day 
40
Day
41 to 43
10 days 
post last 
dose
31 days 
post last 
dose
(3 days)
(3 days)
(3 days)
(3 days)
(3 days)
(3 days)
Outpatient visit 
X
X
Inpatient stay at study site
(See Table 2 For details)
Inpatient stay at study site
(See Table 2 For details)
Inpatient stay at study site
(See Table 2 For details)
X
Admission to CRU
X
X
X
Informed consent & demography
X
Serious and non-serious AE monitoring
X







X
Review inclusion/exclusion criteria
X
X
X
Medical history including alcohol, 
nicotine and drug use
X
Xb
Xb
Xb
Prior/concomitant treatments
X
X
Xb
Xb
Xb
X
Review lifestyle requirements
X
Xb
Xb
Xb
Review contraceptive method
X
X
Xb
Xb
Xb
X
X
C-SSRS and PHQ-9 questionnaires
X
Xb
Xb
Xb
X
Physical exam (height at V1 only)
Xc
Xd
Xc
Single supine 12-lead ECG
X
X
X
Single supine BP and PR 
X
X
X
Hematology, chemistry, lipid panel, UA 
X
X
Amylase, lipase, calcitonin
X
X
Serum -hCGg
X
X
X
FSH, TSH, HbA1c, HIV, HepBsAg, 
HepBcAb, HCVAb
X
Urine drug screen
X
X
X
X
X
Blinded IP administration
h
i
h
i
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a.
The procedures listed in this visit will also be performed if the subject is withdrawn from the study (See Follow-up section).
b.
Timing of specified procedures on day of admission (Day -2 [V3], Day 19 [V4], Day 40 [V5]) is flexible and may also take place on the morning Day -1 
[V3], Day 20 [V4], and Day 41 [V5], prior to fasting laboratory samples (V3-V5).  
c.
Full physical exam performed at V1 and V6 (See Physical Examinations section).
d.
Limited physical exam performed at V2 (See Physical Examinations section).
 
g.
At V1, serum -hCG will be obtained in all female subjects. At all other visits (V2-V6), Serum -hCG will be obtained in females of childbearing potential 
only.
h.
Blinded dosing of Investigational Product (IP)  will be administered on a daily basis from Day 2-18 and from Day 23-Day 39 by an unblinded administrator, 
either at subject’s home or via outpatient clinic visit as specified in Study Treatments section.
i.
For Day 19 and Day 40, blinded IP administration may occur at subject’s home or at inpatient CRU by an unblinded administrator, as long as time of 
administration of blinded IP adheres to guidelines in the Administration section.
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Table 2.
List of Procedures for Inpatient Visits (V3, V4, V5)
Study Day 
Day -1 (V3) 
Day 20 (V4) 
Day 41 (V5)
Day 0 (V3) 
Day 21 (V4) 
Day 42 (V5)
Day 1 (V3), 
Day 22 (V4)
Day 43 (V5)
Approx. Clock Time (24H)
6
7
7.5
8
8.5
9
10
12
12.5
13
14
18
6
7
8
10
12
12.5
13
14
18
22
6
7
Inpatient stay at CRU
























Serious and non-serious AE monitoring
X






















X
Limited physical exam
X
Single supine 12-lead ECG
X
Single supine BP and PR
X
X
X
X
X
X
X
X
X
Hematology, chemistry, lipid panel
Xa
Amylase, lipase, calcitonin
Xa
Serum -hCG
Xb
Prep D1 (V3 only) and Prep P2
Xa
Acetaminophen PK
Xa
X
X
X
X
X
Xc
Urinalysis
X
Breakfast (fixed kcal meal)e
X
X
X
Ad libitum mealse
X
X
X
X
Acetaminophen administration
Xf
Blinded IP administration
Xg
Xg
Xh
Food intake assessment
X
X
X
X
X
X
VAS questionnairei
X
X
X
X
X
X
X
X
X
X
X
X
 
j
X
Discharge from CRU
Xk
a.
Blood sampling performed before breakfast and administration of acetaminophen (V3, V4, V5) and prior to administration of IP on V4 and V5.  For Prep D1 collection: If 
not collected on the designated collection day, collect at the next available time point when biospecimens are being collected in conjunction with a subject 
visit. 
b.
Serum -hCG level for all female subjects of childbearing potential. Testing may also be completed on day of admission to CRU (Day -2 [V3], Day 19 [V4] and Day 40 [V5]. 
c.
Blood sampling performed before lunch.
e.
Meals served at approximate clock times during inpatient stay. 
f.
Acetaminophen administered with breakfast.
g.
Blinded IP administered at these time points on Days 20 (V4), Day 21 (V4), Day 41 (V5) and Day 42 (V5) only (not Day -1 [V3] and Day 0 [V3]).
h.
Blinded IP administered at this time point on Day 1 (V3) and Day 22 (V4) only (not Day 43 [V5]).
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i.
VAS questionnaires to be performed immediately prior to meals (breakfast and lunch on Days -1, 20, and 41 and lunch only on Days 0, 21, 42), then at 30, 60, and 
120 minutes following the start time of the meal.
 
k.
Time of discharge is flexible but should occur after subject completes breakfast (V3, V4, V5) and receives IP (V3 and V4).
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1. INTRODUCTION
Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone that is predominantly 
released from the small intestine in response to food intake.1  GLP-1 activation of the GLP-1
receptor (GLP-1R) stimulates insulin release, inhibits glucagon secretion in a 
glucose-dependent manner, and delays gastric emptying.2,3 Several injectable peptidic 
GLP-1R agonists are approved for the treatment of Type 2 diabetes mellitus.  In addition, 
GLP-1 has been shown to increase satiety and suppress food intake, supporting the use of 
GLP-1R agonists for the treatment of obesity.4 Liraglutide is a peptide GLP-1R agonist that 
is approved both for the treatment of obesity (known as Saxenda®)5 and for the treatment of 
Type 2 diabetes (known as Victoza).6  
The primary purpose of this study is to assess the variability and operating characteristics of 
food (energy) intake in non-diabetic, obese subjects using liraglutide, an agent that has been 
demonstrated to result in decreased food intake.  This assessment will aid in determining if 
food intake is an appropriate decision-making endpoint 
1.1. Mechanism of Action/Indication
Liraglutide is a specific and potent GLP-1R agonist that is approved at doses up to 3.0 mg for 
the treatment of chronic weight management in adult subjects with body mass index (BMI) 
>30 kg/m2 (obese) or >27 kg/m2 body mass index (BMI) (overweight) with weight-related 
co-morbidities as adjunct with reduced calorie diet and increased physical activity,5 or at 
doses up to 1.8 mg to improve glycemic control in subjects with Type 2 diabetes mellitus.6
For this study, liraglutide is being used as a research tool to assess the performance 
characteristics of food intake as a primary endpoint in obese subjects.
1.2. Background 
Obesity is a chronic disease that is associated with serious co-morbidities including type 2 
diabetes mellitus, dyslipidemia, hypertension, atherosclerosis, obstructive sleep apnea and 
certain cancers.7  Obesity is also associated with increased all-cause mortality.8  The 
prevalence of obesity is estimated at greater than 35% of the United States (US) population 
and poses a major public health challenge.9  First line treatment for obesity is lifestyle 
intervention including diet, exercise and behavioral therapy.  While effective in many 
patients, lifestyle intervention is often not sustainable, and many patients regain weight after 
initial weight loss.10  Pharmacotherapy has been approved by the Food and Drug 
Administration (FDA) for long-term treatment of obesity and can be a useful adjunct to 
lifestyle intervention that helps augment and maintain weight loss.
GLP-1 is a hormone released from the gut post-prandially that improves appetite regulation 
and glucose metabolism.  The half-life of endogenous GLP-1 in vivo is exceptionally short at 
approximately 1 to 2 minutes, due to cleavage by dipeptidyl peptidase IV.11,12  Liraglutide is 
a long acting GLP-1 analog with 97% amino acid homology to native GLP-1 and a half-life 
of approximately 13 hours,13 making it suitable for once daily dosing.14  Liraglutide lowers 
blood glucose in a glucose-dependent manner by stimulating insulin secretion and inhibiting 
glucagon secretion from the pancreas via activation of GLP-1Rs.15 Liraglutide also delays 
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gastric emptying, reduces food intake, and suppresses appetite leading to weight loss.  This 
anorectic action is proposed to be mediated by activation of the GLP-1R in appetite centers 
of the brain.16,17,18
Liraglutide has been evaluated in many clinical trials, in both subjects with Type 2 diabetes 
and non-diabetic subjects with obesity.  The clinical development program for Saxenda
included 5 double-blind, placebo controlled trials in 3384 overweight or obese subjects for a 
mean treatment duration of 45.9 weeks (range 32 to 56 weeks duration).5
Two Phase 1 studies have evaluated the effect of liraglutide on food intake and appetite.16,17
In obese subjects treated with daily doses of liraglutide 3.0 mg for 5 weeks, food intake 
during a test meal (ad libitum lunch) was reduced by approximately 140 kcal.17  Liraglutide 
3.0 mg treated subjects also demonstrated delayed gastric emptying, reduced appetite, and 
increased nausea.  In subjects with Type 2 diabetes, daily doses of liraglutide 1.8 mg reduced 
food intake during an ad libitum lunch by approximately 200 kcal.16 In addition, the 
liraglutide 1.8 mg treated subjects demonstrated reduced hunger and higher fullness ratings.16
In clinical trials, the most common adverse events reported with Saxendawere nausea (in 
39% of subjects), diarrhea (in 21% of subjects), constipation (in 19% of subjects), and 
vomiting (in 16% of subjects).  The percentage of subjects reporting nausea declined as 
treatment continued, and most of the gastrointestinal adverse events were of mild or 
moderate intensity.  The most common adverse reactions leading to discontinuation were 
nausea (2.9% versus 0.2% for Saxendaand placebo, respectively), vomiting (1.7% versus 
less than 0.1%), and diarrhea (1.4% versus 0%).5
Additional information for liraglutide can be found in the Single Reference Safety Document 
(SRSD), which for this study is the Saxendalabel.5  The SRSD for the non-investigational 
medicinal product acetaminophen (administered as a challenge agent) will be its label.19
1.3. Rationale 
1.3.1. Study Rationale 
This study is designed to assess the performance characteristics of energy intake as a 
biomarker for anorexiant agents in obese subjects.  Study subjects will be randomized to
receive either liraglutide dosed up to 3.0 mg daily or placebo during 6 weeks of dosing.  
Additional goals of this study include:

To assess the variability and operating characteristics in study measures related to 
food intake, including gastric emptying, appetite, and satiety, with an agent that has 
been demonstrated to impact these endpoints.

To provide a mid-point assessment at 3 weeks that will assess food intake as an early 
signal of efficacy 
 
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
To create an internal database for energy intake and related assessments, such as 
tolerability, gastric emptying, appetite, satiety 
 
This study will enroll non-diabetic obese subjects who may be treated for co-existing 
conditions, such as hyperlipidemia or hypertension, but who are otherwise clinically stable.  
The study population is chosen in accordance with the Saxendaprescribing instructions,5
and the duration of dosing allows titration to the maximum dose of 3 mg daily for 2 weeks.  
In addition, to increase the comparability of the data from this methodology study to
published literature, inclusion criteria similar to a previously reported study, including BMI 
range, will be applied.17 Nicotine use is listed in the exclusion criteria, due to its possible 
confounding effect on appetite and food intake.  Furthermore, this study will enroll men and 
women who are not currently pregnant or breastfeeding and who have no intention of 
becoming pregnant during the study, in accordance with the Saxendaprescribing 
instructions.5
Subjects in this study will be randomized to receive either liraglutide (administered from 
Saxendapens) or placebo (0.9% normal saline administered subcutaneously) for 6 weeks.  
To ensure blinded status through the study, an unblinded pharmacist will manage study 
medication, and study medication will be administrated via an unblinded administrator.  
Imperfect blinding techniques are being utilized in this study, as neither the investigator site 
nor the Sponsor has access to a placebo device that matches Saxendapens.  Although an 
imperfect blinding approach is being utilized, blinding was deemed an essential component 
of the study design, as perception of appetite and satiety can be affected by external cues.  
Randomization will be stratified by baseline body weight to ensure that both treatment 
groups have similar baseline body weight, as subjects with lower baseline weight may 
demonstrate higher drug levels of liraglutide and greater degrees of weight loss than subjects 
with higher baseline body weight at the same dose of 3.0 mg daily.20
 
  To 
minimize the impact of the placebo effect on body weight and associated variability, subjects 
will complete a Run-in visit (V2) prior to the initial inpatient visit (V3) to stabilize food 
intake and body weight. 
In addition to assessing changes in energy intake and body weight with liraglutide, this study 
will generate an internal dataset of endpoints relevant to liraglutide-induced weight loss, 
including gastric emptying (measured by acetaminophen pharmacokinetic [PK]
concentrations after acetaminophen administration) and assessment of appetite and satiety
(measured by Visual Analog Scale [VAS] questionnaire).  
 
 
Energy intake will be measured over a period of 48 hours to assess day-to-day variability in 
food intake. 
 
 
 While published literature exists with liraglutide for many 
of these endpoints, gaps exist in the individual level data available in the literature, as 
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published studies were completed in separate, small study populations, with varying dose 
ranges of liraglutide explored.  This study seeks to fill those gaps by creating an internal 
dataset 
 
In addition to assessments of vital signs, electrocardiogram (ECG), standard safety labs and 
adverse events, amylase, lipase and calcitonin will be assessed at baseline and during the 
study in accordance with the Saxendaprescribing instructions.5  Assessment of Suicidal 
Ideation and Behavior (SIB) by Columbia Suicide Severity Rating Scale (C-SSRS)21 and
Patient Health Questionnaire-9 (PHQ-9)22 will also be performed in accordance with the 
Saxendaprescribing instructions.5 Furthermore, in light of a prior study demonstrating 
increases in diastolic blood pressure with short-term liraglutide administration,23 subjects will 
receive frequent blood pressure assessments at similar time points 
 
Banked biospecimens will be collected for the purpose of conducting research; specific uses 
are described in the Banked Biospecimens section.  Comparing the deoxyribonucleic acid 
(DNA), ribonucleic acid (RNA), protein, and metabolite variation patterns of subjects who 
respond well and those who respond poorly to treatment may help to better define the most 
appropriate group of subjects in which to target a given treatment.  Collecting biospecimens 
for exploratory pharmacogenomic/genomic/biomarker analyses and retaining them in the 
Biospecimen Banking System (BBS) make it possible to better understand the investigational 
product’s mechanism of action and to seek explanations for differences in, for example, 
exposure, tolerability, safety, and/or efficacy not anticipated prior to the beginning of the 
study. 
Banked biospecimens retained in the BBS may also be used in research on obesity. 
Providing these biospecimens is a required study activity for study sites and subjects, unless 
prohibited by local regulations or ethics committee (EC) decision. 
1.3.2. Dose Rationale
Liraglutide will be administrated subcutaneously in accordance with the Saxenda
prescribing instructions for a total of 6 weeks, with an initial dose of 0.6 mg per day and 
increasing by 0.6 mg in weekly intervals until a dose of 3.0 mg per day is reached.5 To 
ensure blinded status throughout the study, placebo (0.9% normal saline) will be 
administered subcutaneously via syringe in matching volume for 6 weeks. 
Additionally, the non-investigational medicinal product acetaminophen 1.5 g will be 
administered orally as a challenge agent to assess gastric emptying during inpatient visits.17
Following subcutaneous administration, maximum concentrations of liraglutide are achieved 
at approximately 11 hours post dosing with an elimination half-life of approximately 
13 hours, making liraglutide suitable for once daily administration.  Liraglutide exposure 
increases proportionally in the dose range of 0.6 mg to 3 mg and is considered similar among 
three subcutaneous injection sites (upper arm, abdomen, and thigh).  Liraglutide is 
extensively bound to plasma protein (greater than 98%), and is endogenously metabolized in 
a similar manner to large proteins without a specific organ as a major route of elimination.5
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2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective(s):
Primary Endpoint(s):

To assess the effect of liraglutide on 
food intake during 6 weeks of 
administration, compared to placebo.

Mean energy intake (in kcal) during ad 
libitum lunch meals.
Secondary Objective(s):
Secondary Endpoint(s):

To assess effects on safety measures and 
tolerability (including spontaneously 
reported nausea and vomiting) of 
liraglutide over 6 weeks of dosing.

To evaluate the effect of liraglutide on 
additional food intake endpoints during
6 weeks of administration, compared 
with placebo.

To assess the effect of liraglutide on 
appetite and satiety during 6 weeks of 
liraglutide administration, compared to 
placebo.

To assess the effect of liraglutide on 
gastric emptying during 6 weeks of 
liraglutide administration, compared 
with placebo.

Vital sign measurements, adverse event 
monitoring, changes in 12-lead ECGs, 
and clinical laboratory testing.

48-hour energy intake (in kcal).

Appetite and satiety scores, as assessed 
by VAS questionnaire.

Plasma area under the curve (AUC) of 
acetaminophen for 0-60 mins and 
0-300 minutes after acetaminophen 
administration.
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3. STUDY DESIGN
3.1. Study Overview
This will be a randomized, double-blind, placebo-controlled, 2-arm, parallel group, 
methodology study to assess the effect of 6 weeks of liraglutide administration on food intake 
in obese subjects.  Subjects will complete screening procedures to determine eligibility and 
once confirmed to meet all other criteria, will proceed to a Run in visit (V2) and then to 
randomization at V3. 
The study includes a total of six (6) visits to the site, including 3 outpatient visits (V1, V2
and V6) and 3 inpatient visits (V3, V4 and V5). Subjects will be randomized at V3 to
receive 1 of 2 blinded treatment regimens for a duration of 6 weeks: liraglutide (administered 
subcutaneously via pen injection and titrated per Saxendalabel5 to maximum dose of 
3.0 mg/day) or placebo (0.9% saline, administered subcutaneously via syringe in matching 
volume).  At V3, V4 and V5, subjects will be admitted for an inpatient stay and receive 
blinded investigation product (IP) from an unblinded administrator.  Each inpatient stay
consists of 4 days and 3 nights.  For the study duration between V3 and V4, and also between 
V4 and V5, subjects will be administered blinded IP on a daily basis via an unblinded 
administrator, either at home or at an outpatient visit. 
Total participation in the study for each subject, including Screening (V1) and investigator 
site Follow-up visits (V6) will be approximately 10 weeks (minimum) to 14 weeks 
(maximum).  In addition, there will be follow up contact with the subject via a phone call, at 
least 28 after last dose of IP (V5).  The overall study scheme is summarized in Figure 1.
Approximately 60 subjects (30 per arm) will be randomized at one or more study sites.  A 
minimum of 50 completed subjects (approximately 25 subjects per arm) are required for the 
study. The 60 randomized subjects account for a projected approximate premature 
withdrawal rate of 15% and reflects intent not to replace subjects prematurely withdrawn 
after first dose of IP.
Figure 1.
Study Design


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3.2. Stopping Rules 
Discontinuation of IP should be considered for a subject if any of the following conditions 
listed below occur.  This decision will be made after a discussion takes place between the 
sponsor study team and the investigator.  The sponsor study team may not overrule the 
investigator’s decision to discontinue IP in a particular subject.
1. Criteria for a potential Hy’s law case are met (see Potential Cases of Drug-Induced 
Liver Injury section); 
2. Subject becomes pregnant; 
3. Subject answers “yes” to question 4 or question 5 on the C-SSRS, indicating active 
suicidal ideation, with intent to act (see Assessment of Suicidal Ideation and Behavior
section).
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the 
study:
1. Female or male subjects who, at the time of screening, are between the ages of 18 and 
75 years, inclusive.
2. Male subjects able to father children and female subjects of childbearing potential and 
at risk for pregnancy must agree to use 2 highly effective methods of contraception 
throughout the study and for at least 28 days after the last dose of IP.  Female subjects 
of nonchildbearing potential must meet at least 1 of the following criteria:

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed with a serum follicle-stimulating 
hormone (FSH) level confirming the postmenopausal state;  

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure.
All other female subjects (including female subjects with tubal ligations) are 
considered to be of childbearing potential.
3. Body mass index (BMI) of 30.0 to 40.0 kg/m2 at the screening visit (V1).
4. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study. 


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5. Subjects who are willing and able to comply with all scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).  However, subjects treated for 
hypothyroidism, hypertension and/or hyperlipidemia are permitted in this study. 
2. Any condition possibly affecting drug absorption (eg, gastrectomy).
3. A positive urine drug test.
4. History of regular alcohol consumption exceeding 7 drinks/week for female subjects 
or 14 drinks/week for male subjects (1 drink = 5 ounces [150 mL] of wine or 
12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within 6 months 
before screening.
5. Treatment with an investigational drug within 30 days (or as determined by the local 
requirement) or 5 half-lives preceding the first dose of investigational product
(whichever is longer).
6. Screening supine blood pressure (BP) 150 mm Hg (systolic) or 90 mm Hg 
(diastolic), following at least 5 minutes of supine rest.  If BP is 150 mm Hg 
(systolic) or 90 mm Hg (diastolic), the BP should be repeated 2 more times and the 
average of the 3 BP values should be used to determine the subject’s eligibility.
7. Screening supine 12-lead ECG demonstrating a corrected QT (QTc) interval 
>450 msec or a QRS interval >120 msec.  If QTc exceeds 450 msec, or QRS exceeds 
120 msec, the ECG should be repeated 2 more times and the average of the 3 QTc or 
QRS values should be used to determine the subject’s eligibility.
8. Subjects with ANY of the following abnormalities in clinical laboratory tests at 
screening (V1), as assessed by the study-specific laboratory and confirmed by a 
single repeat test, if deemed necessary:

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level
2 × upper limit of normal (ULN);

Total bilirubin level 1.5 × ULN; subjects with a history of Gilbert's syndrome 
may have direct bilirubin measured and would be eligible for this study provided 
the direct bilirubin level is ULN;


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
Serum calcitonin 50 ng/L;

Amylase > ULN or lipase > ULN;

Thyroid stimulating hormone (TSH) outside of the laboratory reference range.
9. Pregnant or breastfeeding female subjects.
10. Use of prescription or nonprescription drugs and dietary supplements within 28 days 
prior to the first dose of investigational product, except as noted in the Concomitant 
Treatments section.
11. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
12. History of sensitivity to heparin or heparin-induced thrombocytopenia.
13. History of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C; positive 
testing for HIV, hepatitis B surface antigen (HepBsAg), hepatitis B core antibody 
(HepBcAb), or hepatitis C antibody (HCVAb).
14. Unwilling or unable to comply with the criteria in the Lifestyle Requirements section 
of this protocol.
15. Subjects who are investigator site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or subjects who are Pfizer employees, including their family members,
directly involved in the conduct of the study.
16. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.
17. Use of tobacco- or nicotine-containing products.
18. Personal or family history of medullary thyroid carcinoma (MTC) or multiple 
endocrine neoplasia syndrome type 2 (MEN2), or patients with suspected MTC per 
the investigator’s judgment.
19. Allergy or intolerance to liraglutide or other GLP-1R agonists.
20. Acute pancreatitis, history of chronic pancreatitis.
21. Acute gallbladder disease. 


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22. Renal impairment with a creatinine clearance <60 mL/min as determined by the 
Cockcroft-Gault equation at V1.
23. Patients with current or prior diagnosis of type 1 or type 2 diabetes mellitus.
24. Use of any insulin/anti-diabetic therapy during within 24 weeks prior to V1.
25. Glycosylated hemoglobin (HbA1c) 6.5% at V1.
26. Change in body weight 5 kg within 12 weeks prior to V1.
27. Use of GLP-1R agonists (including liraglutide, exenatide or other similar 
medications) within 24 weeks prior to V1.
28. Use of weight-modifying medications, including prescription or over-the-counter 
medications, herbal supplements, or marijuana within 12 weeks prior to V1.
29. Current or prior treatment with medications that may cause significant weight gain 
within 12 weeks prior to V1, including systemic corticosteroids (except for a short 
course of treatment, ie, <5 days), tricyclic antidepressants, atypical antipsychotic and 
mood stabilizers (eg, imipramine, amitriptyline, mirtazapine, paroxetine, phenelzine, 
chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid and its derivatives, 
and lithium).
30. Current or previous treatment within 12 weeks prior to V1 with any of the following 
medications that may affect glycemic measures: coumadin-type anticoagulants or 
other anticoagulants (eg, dabigatran, enoxaparin), anticonvulsants, antiarrhythmics, 
-blockers, thiazide diuretics >25 mg per day, and sympathomimetic agents.
31. Medical history or characteristics suggestive of genetic or syndromatic obesity or 
obesity induced by other endocrinologic disorders (eg, Cushing Syndrome).
32. History of major depressive disorder or history of other severe psychiatric disorders 
(eg, schizophrenia or bipolar disorder) within the last 2 years.
33. A Patient Health Questionnaire (PHQ-9) score 15 obtained at V1 (see Assessment of 
Suicidal Ideation and Behavior section).
34. Subjects with any lifetime history of a suicide attempt. 
35. Response of “yes” to question 1 of C-SSRS at V1, indicating a history of suicidal 
ideation (see Assessment of Suicidal Ideation and Behavior section).
36. Intolerance to acetaminophen use.
37. Intolerance or aversion to any components of the meals administered in the clinical 
research unit (CRU) for food intake and satiety assessments (eg, lactose intolerance, 
gluten intolerance or celiac disease).


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4.3. Randomization Criteria 
Subjects will be randomized into the study prior to dosing of IP on Day 1 (V3), provided they 
have satisfied all subject eligibility criteria outlined in the Inclusion Criteria and Exclusion 
Criteria sections of this protocol. 
Eligible subjects will be randomized prior to the first dose of IP to either liraglutide or 
placebo in a 1:1 ratio.  A computer-generated randomization schedule will be used to assign 
subjects to the treatment groups using the 1:1 allocation ratio stratified by body weight at 
V3 (100 kg or <100 kg). An attempt will be made to balance the number of subjects 
assigned to receive liraglutide and placebo within each stratum.
4.4. Lifestyle Requirements
4.4.1. Meals and Dietary Restrictions

Subjects must abstain from all food and drink (except water) at least 8, but preferably 
10 hours, prior to any fasting blood sample collections for clinical laboratory tests, 
glucose, and insulin assessments.

Water may be consumed as desired.
 
 

For the food intake assessment, the menus for each meal during the 48 hour period 
comprising the assessment will be identical across all assessments in the study. 

During inpatient visits, the total daily nutritional composition should be 
approximately 50% carbohydrate, 35% fat and 15% protein. 

During run in period (between V2 and V3) and home dosing (ie between V3 and V4
and between V4 and V5), subjects will be instructed to maintain usual dietary intake.
4.4.1.1. Breakfast (Fixed Kilocalorie) Meal
An identical fixed kcal breakfast (approximately 500 kcal) will be provided to study subjects 
at the time points listed in the Schedule of Activities.  The breakfast meal is standardized to 
minimize any variability in food intake assessment of the succeeding ad libitum lunch and 
dinner meals and 
.  Breakfast will be timed so that subjects start 
the meal at approximately 07:00 hours.  On study Days -1, 20 and 41, the breakfast meal will 
serve as the stimulus for 
 and the gastric emptying assessment.  Subjects will be 
instructed to complete the meal over a period of 20 minutes.  If a subject is unable to do so, 
this will be recorded as a protocol deviation.
4.4.1.2. Ad Libitum Meals
Ad libitum meals will be served to study subjects for lunch and dinner at the time points
listed in the Schedule of Activities.  Subjects will be instructed to consume their meals within 
30 minutes with a reminder notification at 25 minutes after initiation of meal ingestion.  
C
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Meals will be consumed until subjects reach satiety, stopping at will, without distractions 
such as reading materials, television, cell phones or computer.
4.4.2. Alcohol, Caffeine, and Tobacco

Intake of alcohol is permitted outside of inpatient study visits (V3, V4, V5) in 
moderation as defined in the Exclusion Criteria.

Subjects will abstain from alcohol for 24 hours prior to admission to the clinical 
research unit (CRU) and continue abstaining from alcohol until collection of the final 
PK sample of each inpatient stay.  Subjects may undergo an alcohol breath test or 
blood alcohol test at the discretion of the investigator.

Caffeine containing products will be permitted during the study with the following 
restrictions: caffeine containing products may not be consumed within 2 hours prior 
to measuring blood pressure, pulse rate, or ECGs.

Use of tobacco and nicotine-containing products is not permitted in this study.
4.4.3. Activity

Subjects will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests.  Walking at a normal pace will be permitted.

During run in period (between V2 and V3) and home dosing (ie, between V3 and V4 
and between V4 and V5), subjects will be instructed to maintain usual physical 
activity.
4.4.4. Contraception
In this study, fertile male subjects and female subjects who are of childbearing potential will 
receive placebo or liraglutide, which has been associated with demonstrated 
teratogenicity/fetotoxicity in nonclinical studies.5  Subjects who are, in the opinion of the 
investigator, sexually active and at risk for pregnancy with their partner(s) must agree to use
2 methods of highly effective contraception throughout the study and for at least 28 days
after the last dose of investigational product.  The investigator or his or her designee, in 
consultation with the subject, will confirm the subject has selected 2 appropriate methods of 
contraception for the individual subject and his or her partner(s) from the list of permitted 
contraception methods (see below) and will confirm that the subject has been instructed in 
their consistent and correct use.  At time points indicated in the Schedule of Activities, the 
investigator or designee will inform the subject of the need to use 2 highly effective methods 
of contraception consistently and correctly and document the conversation, and the subject’s 
affirmation, in the subject’s chart.  In addition, the investigator or designee will instruct the 
subject to call immediately if 1 or both of the selected contraception methods is discontinued 
or if pregnancy is known or suspected in the subject or partner. 


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Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the subject or 
male subject’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate. 
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
All sexually active male subjects must agree to prevent potential transfer to and exposure of 
partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 28 days after the last 
dose of investigational product.
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact number can also be used by investigator
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. For sites other than 
a Pfizer CRU, the contact number is not intended for use by the subject directly, and if a 
subject calls that number, he or she will be directed back to the investigator site.


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5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical study, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the investigational products are:

Liraglutide, administered subcutaneously via pen injection with dose titration to 
3.0 mg daily per Saxendaprescribing instructions;5

Placebo, 0.9% weight/volume (w/v) sodium chloride, United States Pharmacopeia 
(USP), administered subcutaneously via syringe injection with matching volume to 
liraglutide dose.
In addition, during each of the inpatient study visits (V3, V4, V5), a non-investigational 
medicinal product (acetaminophen 1.5 g) will be administered as a challenge agent for the 
assessment of gastric emptying (see Gastric Emptying section).
5.1. Allocation to Treatment
The investigator will assign subject numbers to the subjects as they are screened for the 
study.  Pfizer will provide a randomization schedule to the investigator and, in accordance 
with the randomization numbers, the subject will receive the study treatment regimen 
assigned to the corresponding randomization number. 
Subjects will be stratified into the study according to body weight at V3.  Once stratified, 
subjects will be randomized in a 1:1 ratio to receive liraglutide or placebo according to the 
randomization schedule generated by the sponsor.  With the exception of the study site 
pharmacist and the unblinded administrator(s), study site and sponsor personnel who are 
directly involved in the study conduct will be blinded to the randomization schedule.  The 
only exception will be in the event of an emerging safety issue which requires breaking the 
blind (see Breaking the Blind section).


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5.2. Breaking the Blind
At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind.  The method will be either a manual or an electronic process.  Blinding 
codes should be broken only in exceptional circumstances when knowledge of the actual 
treatment code is absolutely essential for further management of the subject.  Investigators 
are encouraged to discuss with a member of the study team if they believe that unblinding is 
necessary.  When the blinding code is broken, the reason must be fully documented and 
entered on the case report form (CRF).
5.3. Subject Compliance
Blinded IP will be administered by an unblinded administrator during all inpatient visits 
(V3, V4, and V5) and during dosing at home or via daily onsite visits for dosing (ie, dosing 
between V3 and V4 and between V4 and V5). 
5.4. Investigational Product Supplies
5.4.1. Dosage Form and Packaging
Liraglutide 6.0 mg/mL, 3 mL (Saxendapen) and accompanying 31 gauge pen needles will 
be provided by the study site.
The study site will also provide placebo, which is a 0.9% w/v sodium chloride, USP, and 
accompanying syringe and 31 gauge syringe needles for subcutaneous injection.
In addition, the study site will provide a dose of 1.5 g acetaminophen (45 mL of liquid form 
for oral administration with concentration of 500 mg/15 mL),19 which will be administered 
orally as a challenge agent to assess gastric emptying during inpatient visits.  Acetaminophen 
will be drawn into a syringe by the site pharmacist and dispensed to the inpatient CRU for 
administration to subject.
5.4.2. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the investigational product ready for administration or dispensing to the subject by qualified 
staff.  Dispensing is defined as the provision of investigational product, concomitant 
treatments, and accompanying information by qualified staff member(s) to a subject in 
accordance with this protocol.  Local health authority regulations or investigator site 
guidelines may use alternative terms for these activities.
Liraglutide and placebo will be prepared by qualified unblinded site personnel according to 
the IP manual and administered in blinded fashion to the subject.  IP should be prepared and 
dispensed by an appropriately qualified and experienced member of the study staff 
(eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy assistant/technician, 
or pharmacist) as allowed by local, state, and institutional guidance.
Doses of liraglutide will be dispensed from a pre-filled, multi-dose 6.0 mg/mL, 3 mL 
Saxendapen.  Placebo will be dispensed from a multi-dose vial of 0.9% w/v sodium 
chloride, USP.  Liraglutide pens, pen needles, placebo vial and accompanying syringes will 
be overseen by a qualified pharmacist who is unblinded in order to prepare the IP according 
to the randomization treatment assignments. 


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5.5. Administration
Designated and trained study staff administering blinded IP to subjects will be unblinded and 
will be separate from the study team who will be blinded.  Liraglutide will be administered 
from a 3 mL Saxendapen.24  Dosing with the Saxendapen is controlled by turning the 
dose selector until the dose indicator shows the relevant dose (10, 20, 30, 40, 50 clicks).  One 
click equals 0.06 mg.
Daily subcutaneous injections of placebo or liraglutide will be administered in the abdomen, 
thigh or upper arm by an unblinded administrator at home or via onsite daily visits (for 
dosing periods between V3 and V4 and between V4 and V5) and in the CRU during inpatient 
study visits (V3, V4 and V5, as detailed in the Schedule of Activities). For Day 19 and 
Day 40, blinded IP administration may occur at a subject’s home or at inpatient CRU by an 
unblinded administrator.  The site of subcutaneous injection may vary during the study but 
should be administered at one of the sites listed above and according to the Saxenda 
medication guide.24 A 31 gauge pen needle will be used with the Saxendapen, and a 
31 gauge insulin syringe will be used to administer placebo.24 The unblinded administrator 
will be instructed to perform an air shot before the first injection with the Saxendapen24 or 
placebo syringe and will prepare the dose of blinded IP in a separate location away from the 
subject. Subjects will be blindfolded during administration to maintain blinding to the IP.
As per the Saxendalabel,5 and in order to reduce the number of side effects, liraglutide will 
be initiated at a dose of 0.6 mg daily and escalated by 0.6 mg weekly up to a maximum of 
3 mg.  The dose titration schedule is shown in Table 3.  For subjects randomized to placebo 
injections, the volume of saline administered for a specific week of dosing will match the 
volume specified in the “Volume Administered” column in Table 3.  If a subject does not 
tolerate the next dose level during dose escalation, as determined by the Investigator, dose 
escalation to the next higher dose will be delayed by one week.  All subjects who are able to 
tolerate a minimum dose of liraglutide 1.8 mg daily for at least 2 weeks prior to Day 40 will 
progress to V5.
Table 3.
Liraglutide Dose Titration during Study
Week of Dosing
Daily Dose 
Administered
Number of Pen 
Clicks
Volume 
Administered
1
0.6 mg
10
0.1 mL
2
1.2 mg
20
0.2 mL
3
1.8 mg
30
0.3 mL
4
2.4 mg
40
0.4 mL
5
3.0 mg
50
0.5 mL
6
3.0 mg
50
0.5 mL
5.5.1. Timing of Administration during Inpatient Visits (V3, V4, V5)
During the inpatient visits to the CRU (V3, V4, and V5), subjects will receive IP at 
approximately 07:00 hours (plus or minus 60 minutes).  Designated unblinded investigator 
site personnel will administer IP and will be separate from the study team who will be 
blinded. 


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5.5.2. Timing of Home Administration (between V3 and V4, and between V4 and V5)
To allow for additional flexibility in the timing of IP administration at home between V3 and 
V4 and between V4 and V5, the time chosen for daily administration of IP may be 
determined by the subject and designated unblinded administrator.  Once this time is chosen, 
doses of IP should be administered by a designated unblinded administrator at approximately 
the same time each day (plus or minus 2 hours) without regard to the timing of meals. 
5.6. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature-monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product-label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site. 
5.7. Investigational Product Accountability
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
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5.7.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.8. Concomitant Treatments
Subjects in this study will be allowed to take certain concomitant medications to treat 
coexisting conditions such as hyperlipidemia and hypertension.  Attempts must be made not
to alter the doses and regimens of chronic background medications after randomization and 
for the duration of participation in this study.  All concomitant treatments taken during the 
study must be recorded with indication, daily dose, and start and stop dates of administration.  
All subjects will be questioned about concomitant treatments at each study visit, and any 
changes must be captured in the CRF.
Treatments taken within 28 days before the first dose of IP will be documented as a prior 
treatment.  Treatments taken after the first dose of IP will be documented as concomitant 
treatments.
5.8.1. Anti-Hypertensive Medications
Use of background antihypertensive agent(s) is permitted (unless noted in Exclusion 
Criteria).  Doses of antihypertensive agents should be stable for at least 4 weeks prior to V2.  
Changes to therapy or doses during the duration of the study should be avoided, if possible.
5.8.2. Lipid-Modifying Medications
Use of lipid-modifying agent(s) is permitted (unless noted below in Exclusion Criteria).  
Doses of lipid-modifying agents should be stable for at least 4 weeks prior to V2.  Changes to 
therapy or doses should be avoided during the study, if possible. 
5.8.3. Other Acceptable Concomitant Medications
Subjects on the following list of medications must be on stable doses (ie, at least 4 weeks 
prior to V2) and for the duration of participation in the study through V6:

Inhaled and topical corticosteroids.

Thyroid replacement therapy.

Hormonal contraception, including oral contraceptive pills (OCPs), transdermal 
contraceptive patches and intrauterine devices.

Postmenopausal hormone therapy. 


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Limited use of nonprescription medications that are not believed to affect subject safety or 
the overall results of the study may be permitted on a case-by-case basis following approval 
by the sponsor.

Acetaminophen may be used at doses of 2 g/day.  Acetaminophen should not be 
taken for 12 hours prior to and 12 hours after acetaminophen administration at 
07:00 hours on Day -1 (V3), Day 20 (V4), and Day 41 (V5) (see Schedule of 
Activities).
6. STUDY PROCEDURES
6.1. Chronology of Procedures
During the inpatient visits (V3, V4, and V5), for the procedures described below, where 
multiple procedures are scheduled at the same time point(s) relative to dosing, the following 
chronology of events should be adhered to, where possible:

12-lead ECG: obtain prior to vital sign measurements and as close as possible to the 
scheduled time, but prior to blood specimen collection (refer to Electrocardiogram
section);

Blood pressure and pulse rate: obtain as close as possible to the scheduled time, but 
prior to blood specimen collection (refer to Blood Pressure and Pulse Rate section);

If an intravenous catheter is placed for serial blood sample collections, ECGs and 
vital sign (pulse rate, BP) assessments should be collected either prior to the insertion 
of the catheter or after sufficient rest period after catheter insertion to minimize
impact of catheter placement on these assessments;

Fasting blood samples for clinical laboratory tests: after assessment of 12-lead ECG 
and blood pressure and pulse rate but prior to start of meal and/or dosing of IP (refer 
to Laboratory Tests section);

Fasting sample for acetaminophen PK should occur prior to start of meal, dosing of 
acetaminophen and dosing of IP;

If the blood collection nominal time coincides with the nominal time of a meal, these 
blood samples should be collected prior to start of the meal.

Dosing (refer to Administration section): should occur as close as possible to the
scheduled nominal time with or without a meal;

Other procedures: obtain all other procedures as close as possible to the scheduled 
time, but may be obtained before or after blood specimen collection.
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6.2. Screening (V1)
Refer to Schedule of Activities Table 1 for the study procedures to be completed at the 
Screening visit.
Subjects will be screened within 28 days prior to V2 to confirm that they meet the subject 
selection criteria for the study.  The investigator (or an appropriate delegate at the 
investigator site) will obtain informed consent from each subject in accordance with the 
procedures described in the Subject Information and Consent section.  If the time between 
screening and V2 exceeds 28 days as a result of unexpected delays, then subjects do not 
require rescreening if the Day -1 (V3) laboratory results meet the eligibility criteria.
To prepare for study participation, subjects will be instructed on the information in the
Lifestyle Requirements and Concomitant Treatments sections of this protocol.
6.3. Run In Visit (V2)
Refer to the Schedule of Activities Table 1 for the study procedures to be completed at V2.  
 
6.4. Dosing Period
6.4.1. Inpatient Visits (V3, V4, V5)
Refer to Schedule of Activities Table 1 and Table 2 for the study procedures to be completed
at V3, V4 and V5. At V3 only, collect a genomic banked biospecimen.  If missed, collect at 
the next available time point when biospecimens are being collected in conjunction with a 
subject visit.
If a subject has any clinically significant, study-related abnormalities at the conclusion of a 
scheduled inpatient portion of the study, the Pfizer medical monitor (or designated 
representative) should be notified and the subject may be asked to remain in the Clinical 
Research Unit until such abnormalities are deemed not clinically significant, or it is safe for 
outpatient Follow-up.  If the subject is unable or unwilling to remain in the CRU and/or when 
outpatient Follow-up is deemed appropriate, the Pfizer medical monitor (or designated 
representative) should be so notified, and the investigator should make every effort to arrange 
Follow-up evaluations at appropriate intervals to document the course of the abnormalities.
6.4.2. Daily Dosing from Days 2 to 19 and Days 23 to 40

Refer to Schedule of Activities Table 1 for the study procedures to be completed from 
Days 2 to 19 and Day 23 to 40. Blinded IP will be administered on a daily basis by an 
unblinded administrator either at the subject’s home or at an outpatient visit per dose 
titration schedule listed in the Administration section. 
 
 
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6.5. Follow-Up (V6 and Phone Contact)
In this study, there are two Follow-up visits, as follows: 

The first is an on-site visit where the subjects will return to the investigator site
10 3 days following the last dose of investigational product;

The second is a telephone contact to occur 31 3 days following the last dose of 
investigational product;

Refer to Schedule of Activities Table 1 for the study procedures to be completed at 
each of the two Follow-up visits.
6.6. Subject Withdrawal
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events section) or behavioral reasons, or the 
inability of the subject to comply with the protocol-required schedule of study visits or 
procedures at a given investigator site.  The early termination visit applies only to subjects 
who are randomized, receive at least one dose of IP and then are prematurely withdrawn 
from the study.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  The investigator or site staff should attempt to contact the subject twice.  After 
2 attempts, CRU staff may send a registered letter.  If no response is received from the 
subject, the subject will be considered lost to follow-up.  All attempts to contact the subject 
and information received during contact attempts must be documented in the subject’s 
medical record.  In any circumstance, every effort should be made to document subject 
outcome, if possible.  The investigator should inquire about the reason for withdrawal, 
request that the subject return for a final visit, if applicable, and follow up with the subject 
regarding any unresolved adverse events (AEs).
It may be appropriate for the subject to return to the clinic for final safety assessments to be 
scheduled as early as practically feasible following the decision to withdraw from the study.  
Subjects should be questioned regarding their reason for withdrawal.  At the early withdrawal 
visit, every effort must be made to complete the assessments to be performed at the onsite 
Follow up visit (see Table 1 of Schedule of Activities).
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the subject’s safety was preserved.
If the subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
Subjects who withdraw from the study may be replaced at the discretion of the investigator 
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Withdrawal of Consent: 
Subjects who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol-specified follow-up procedures.  The only 
exception to this is when a subject specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the subject to provide this information.  
Subjects should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible.  The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or post treatment 
study follow-up, and entered on the appropriate CRF page.  In the event that vital status 
(whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
Lost to Follow-up: 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the subject as noted above.  All 
attempts should be documented in the subject’s medical records.  If it is determined that the 
subject has died, the site will use locally permissible methods to obtain the date and cause of 
death.  If the investigator’s use of a third-party representative to assist in the follow-up 
portion of the study has been included in the subject’s informed consent, then the investigator 
may use a sponsor-retained third-party representative to assist site staff with obtaining the 
subject’s contact information or other public vital status data necessary to complete the 
follow-up portion of the study.  The site staff and representative will consult publicly 
available sources, such as public health registries and databases, in order to obtain updated 
contact information.  If, after all attempts, the subject remains lost to follow-up, then the 
last-known-alive date as determined by the investigator should be reported and documented 
in the subject’s medical records.
7. ASSESSMENTS
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and
well-being of the subject.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
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7.1. Safety
7.1.1. Laboratory Tests
The following clinical laboratory tests will be performed at times defined in the Schedule of 
Activities section of this protocol and will be performed by the study site laboratory.  
Additional laboratory results may be reported on these samples as a result of the method of 
analysis or the type of analyzer used by the clinical laboratory; or as derived from calculated 
values.  These additional tests would not require additional collection of blood.  Unscheduled 
clinical laboratory measurements may be obtained at any time during the study to assess any 
perceived safety concerns.
Table 4.
Clinical Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
Blood Urea Nitrogen (BUN)
Creatinine
Glucose 
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
Aspartate aminotransferase 
(AST)
Alanine aminotransferase 
(ALT)
Total bilirubin
Alkaline phosphatase
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
Serum -hCGb
Lipid panel: total 
cholesterol, HDL-C, 
LDL-C, triglycerides
Amylase
Lipase
Calcitonin
Urine drug screen
At V1, only:
FSH
TSH
HbA1c
Human Immunodeficiency 
Virus (HIV)
Hepatitis Panel:  HepBsAg, 
HepBcAb, HCVAb
Additional Tests
(Needed for Hy’s Law)
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug and/or 
protein adduct levels
a. Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b. Serum -hCG for all female subjects at V1.  At V2-V6, serum -hCG for women of childbearing potential only.

The minimum requirement for drug screening includes cocaine, tetrahydrocannabinol
(THC), opiates/opioids, benzodiazepines, and amphetamines.
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
Subjects will complete urine drug testing during each inpatient stay per the Schedule 
of Activities.  Additional unscheduled urine drug testing may be performed at the 
discretion of the investigator.  Drug testing conducted prior to dosing must be 
negative during each inpatient stay for subjects to continue dosing with
investigational product. 

Blood samples 
 
at the pre-specified nominal 
time points outlined in Table 2 of the Schedule of Activities and analyzed at the study 
site. Samples obtained within 10% of the nominal time (eg, within 6 minutes of a 60 
minute sample) relative to baseline laboratory samples will not be captured as a 
protocol deviation, as long as the exact time of the sample collection is noted on the 
source document and data collection tool (eg, CRF/DCT).
Any remaining serum/plasma from samples collected for clinical laboratory measurements at 
baseline and at all times after dose administration may be retained and stored for the duration 
of the study.  Upon completion of the study, these retained safety samples may be used for 
the assessment of exploratory safety biomarkers or unexpected safety findings.  These data 
will not be included in the clinical study report (CSR).  Samples to be used for this purpose 
will be shipped to either a Pfizer-approved Biospecimen Banking System (BBS) facility or 
other designated laboratory and retained for up to 1 year following the completion of the 
study.
7.1.2. Pregnancy Testing
All serum pregnancy tests used in this study must have a sensitivity of at least 25 mIU/mL 
and must be performed by a certified laboratory.  For female subjects of childbearing 
potential, 2 negative pregnancy tests are required before receiving investigational product
(1 negative pregnancy test at screening [V1] and 1 at the baseline visit immediately before 
investigational product administration [V3]).  Following a negative pregnancy test result at 
screening, appropriate contraception must be commenced and the second negative pregnancy 
test result will then be required at the baseline visit and within 5 days after the first day of the 
menstrual period (counting the first day of the menstrual period as Day 1) before the subject 
may receive the investigational product.  In the absence of regular menstrual bleeding, the 
study candidate should have used 2 forms of contraception for at least 1 month before the 
second pregnancy test.  Pregnancy tests will also be performed at V2, V3, V4, V5 and at the 
end of the study (V6) to confirm that the subject has not become pregnant during the study.  
Pregnancy tests will also be done whenever 1 menstrual cycle is missed and when potential
pregnancy is otherwise suspected, and may be repeated if requested by institutional review
boards (IRBs)/ethics committees (ECs) or if required by local regulations. In the case of a 
positive confirmed pregnancy, the subject will be withdrawn from administration of IP and 
from the study. 
7.1.3. Physical Examinations
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation.  A full physical examination 
will include head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, 
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and gastrointestinal, musculoskeletal, and neurological systems.  The limited or abbreviated 
physical examination will be focused on general appearance, the respiratory and 
cardiovascular systems, and subject-reported symptoms.
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
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7.1.5. Blood Pressure and Pulse Rate
BP and PR will be measured at times specified in the Schedule of Activities section of this
protocol.  Additional collection times, or changes to collection times, of BP and PR will be 
permitted, as necessary, to ensure appropriate collection of safety data.
Supine BP will be measured with the subject’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest.  The same arm 
(preferably the dominant arm) will be used throughout the study. If an intravenous catheter 
is used for blood collection, BP should not be taken from the arm with an intravenous 
catheter.  Subjects should be instructed not to speak during measurements.
The same properly sized and calibrated BP cuff will be used to measure BP each time.  The 
use of an automated device for measuring BP and PR is acceptable; however, when done 
manually, PR will be measured in the brachial/radial artery for at least 30 seconds.  When the 
timing of these measurements coincides with a blood collection, BP and PR should be 
obtained prior to the nominal time of the blood collection.
7.1.6. Electrocardiogram 
12-Lead ECGs should be collected at times specified in the Schedule of Activities section of 
this protocol.
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position. 
To ensure safety of the subjects, a qualified individual at the investigator site will make 
comparisons to baseline measurements.  If the QTc interval is increased by 45 msec from 
the baseline, or an absolute QTc value is 500 msec for any scheduled ECG, then 
2 additional ECGs will be collected, approximately 2 to 4 minutes apart, to confirm the 
original measurement.  If either of the QTc values from these repeated ECGs remains above 
the threshold value (ie, is 45 msec from the baseline, or is 500 msec), then a single ECG 
must be repeated at least hourly until QTc values from 2 successive ECGs fall below the 
threshold value that triggered the repeat measurement.
If QTc values remain 500 msec (or 45 msec from the baseline) for greater than 4 hours (or 
sooner, at the discretion of the investigator), or QTc intervals get progressively longer, the 
subject should undergo continuous ECG monitoring.  A cardiologist should be consulted if 
QTc intervals do not return to less than 500 msec (or to <45 msec above the baseline) after 
8 hours of monitoring (or sooner, at the discretion of the investigator).
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In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTc values are in the 
acceptable range.
7.2. Pharmacokinetics 
The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the PK samples at the exact nominal time relative to dosing.  
However, samples obtained within 10% of the nominal time (eg, within 6 minutes of a 
60-minute sample) from dosing will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and data collection tool 
(eg, CRF). 
Samples will be analyzed using a validated analytical method in compliance with vendor 
standard operating procedures (SOPs).
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.  Any deviation from the specified sample handling 
procedure resulting in compromised sample integrity will be considered a protocol deviation.
PK samples may be used for metabolite identification and/or evaluation of the bioanalytical 
method, as well as for any other internal exploratory purposes.  These data will not be 
included in the CSR.
7.2.1. Analysis of Acetaminophen Pharmacokinetics
During all study periods, blood samples (4 mL) to provide approximately 1.5 mL plasma for 
pharmacokinetic (PK) analysis of acetaminophen will be collected into appropriately labeled 
tubes containing K2EDTA at times specified in the Schedule of Activities section of the 
protocol. 
 
 
 
 
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7.3. Banked Biospecimens
Banked biospecimens will be collected from subjects for exploratory research relating to the 
drug response and disease/condition under study.  These collections are not typically 
associated with a planned assessment described in the protocol.  They will be handled in a 
manner that protects each subject’s privacy and confidentiality.  Banked biospecimens will 
be assigned the subject’s study identification code (ID) at the site.  The data generated from 
these banked biospecimens will also be indexed by this ID.  Biospecimens will be kept until 
destruction in facilities with access limited to authorized personnel, and biospecimen-derived 
data will be stored on password-protected computer systems.  The key between the subject’s 
ID and the subject’s direct personally identifying information (eg, name, address) will be 
held at the study site.  Biospecimens will be used only for the purposes described in the 
protocol and informed consent document; any other uses require additional ethical approval.  
Unless a time limitation is required by local regulations or ethical requirements, 
biospecimens will be stored for many years (no time limit) to allow for research in the future, 
including research conducted during the lengthy drug-development process and also 
post-marketing research.  Subjects may withdraw their consent for the use of their banked 
biospecimens at any time by making a request to the investigator; in this case, any remaining 
biospecimens will be destroyed, but data already generated from the biospecimens will 
continue to be available to protect the integrity of existing analyses. 
Unless prohibited by local regulations or ethics committee decision, a 4-mL blood genomic 
banked biospecimen Prep D1 (dipotassium edetic acid [ethylenediaminetetraacetic acid] 
[K2EDTA] whole-blood collection optimized for DNA analysis) will be collected at the 
time specified in the Schedule of Activities section of the protocol to be retained for potential 
pharmacogenomic/genomic/biomarker analyses related to drug response and 
disease/condition under study.  For example, putative safety biomarkers, drug-metabolizing 
enzyme genes, drug-transport protein genes, or genes thought to be related to the mechanism 
of drug action may be examined.  The primary purpose is to examine DNA; however, the 
biospecimen may also be used to study other molecules (eg, RNA, proteins, and metabolites).
 
 
 
The banked biospecimens will be collected from all subjects unless prohibited by local 
regulations or IRB/EC decision. 
It is possible that the use of these biospecimens may result in commercially viable products.  
Subjects will be advised in the informed consent document that they will not be compensated 
in this event.
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7.3.1. Additional Research 
Unless prohibited by local regulations or IRB/EC decision, subjects will be asked to indicate 
on the consent form whether they will allow banked biospecimens to also be used to design 
and conduct research in order to gain a further understanding of other diseases and to 
advance science, including development of other medicines for patients.
Subjects need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in the Banked Biospecimens section will be used.  Subjects may still 
participate in the study if they elect not to allow their banked biospecimens to be used for the 
additional purposes described in this section.
7.4. Food Intake Assessment
Food intake will be assessed at the times listed in Table 2 of the Schedule of Activities.
All meals will be prepared at the study site while the subject is inpatient.  For every ad 
libitum meal, each portion will be weighed and recorded before and after each meal. The 
following parameters will be measured: total kcal consumed per day, total kcal of each 
macronutrient consumed per day, total kcal consumed per meal and total kcal of each 
macronutrient consumed per meal.  The total daily nutritional composition offered in the 
inpatient meals will be approximately 50% carbohydrates, 35% fat and 15% protein.
Observed food intake will be measured as the total number of calories consumed during the 
specified time period, calculated (to the nearest 50 kcal) as the difference of the total number 
of calories provided minus the total number of calories remaining after meals.
7.5. Visual Analog Scale (VAS) Questionnaire
Appetite, satiety, fullness, hunger, and prospective consumption will be measured at the 
study site using a validated VAS questionnaire.25 The VAS questionnaire will be completed 
by the subject at each of 4 time points: immediately prior to administration of the meal, 
30, 60 and 120 minutes after start time of the specified meals, per the Schedule of Activities. 
The VAS is an assessment in which subjects place a vertical line across a 100 millimeter 
(mm) line to rank their response to various questions.  The 100 mm line is anchored by 
responses such as “Not At All Full” and “Totally Full” at either end.  Scoring will consist of 
measuring the distance of the vertical line from the response at the left end and will be used 
to explore the relationships between subjective reports of appetite and other VAS measures 
immediately prior to and following administration of the meal.
Questionnaires will be provided to the subjects showing one question at a time (eg, one 
question on each page).  Study staff will instruct the subjects to complete their responses to 
all VAS questions by placing a mark at the point on the 100 mm line which corresponds to 
how the subjects are feeling.  Subjects will be instructed not to discuss or compare their 
ratings with other subjects during this assessment.  Subjects will not be able to refer to their 
previous ratings when marking the VAS at each time point.  The measurement will be scored 
by study staff who will measure, in millimeters, the distance from the left end of the line to 
the mark made by subjects using a standardized ruler.  This value in millimeters will be 
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Deviations in collection time for VAS questionnaires of 5 minutes of the nominal time 
pre- and post-test meal collection time will be recorded as a protocol deviation.
The volume of water consumed with the meal and for the entire 1.5 hour VAS assessment 
period following the meal will be measured and recorded in the CRF. 
7.6. Gastric Emptying
Gastric emptying will be assessed using plasma acetaminophen concentrations over 5 hours
as indicated in Table 2 of the Schedule of Activities.  After fasting blood sampling on Day -1, 
Day 20 and Day 41, subjects will receive liquid oral acetaminophen 1.5 g with a fixed 
breakfast meal consisting of approximately 500 kcal, which must be consumed within 
20 minutes.  The blood sampling for determining acetaminophen concentrations will be 
performed at each of the pre-defined 7 nominal time points outlined in the Schedule of 
Activities: prior to breakfast and at 30, 60, 90, 120, 180 and 300 minutes after intake of the 
acetaminophen with breakfast.  The last blood sampling at 300 minutes should be completed 
before the ad libitum lunch.  Deviations in blood sampling time for gastric emptying 
>10% of the nominal time (eg, more than 6 minutes of a 60-minute sample) will be recorded 
as a protocol deviation.
7.8. Blood Volume
The total blood sampling volume for individual subjects in this study is approximately 
530 mL.  The actual collection times of blood sampling may change.  Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days.
7.9. Assessment of Suicidal Ideation and Behavior
7.9.1. Columbia Suicide Severity Rating Scale (C-SSRS)
The Columbia Suicide Severity Rating Scale (C-SSRS) is an interview based rating scale to 
systematically assess suicidal ideation and suicidal behavior.21 The “baseline/lifetime” 
version of the C-SSRS will be administered at the Screening visit (V1).  Subjects who 
respond “yes” to Question 1 will not be permitted in the study (see Exclusion Criteria).  The 
“since last evaluation” version of the C-SSRS will be administered on V3, V4, V5 and V6 as 
listed in Table 1 of the Schedule of Activities.  The C-SSRS will be administered by study 
site staff who have completed training in its administration.
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7.9.2. Patient Health Questionnaire-9 (PHQ-9)
The Patient Health Questionnaire-9 Items (PHQ-9) is a 9-item self-report scale for the 
assessment of depressive symptoms.22  The PHQ-9 will be completed by subjects and 
reviewed by appropriately trained site staff at the pre-defined time points outlined in the 
Schedule of Activities. A PHQ-9 score of 15 at V1 indicates clinically significant 
depression and serves as an exclusion criterion for this study (see Exclusion Criteria). 
The study site will ensure access to and evaluation by a qualified mental health professional 
(MHP) for any subjects demonstrating suicidal ideation and behavior.  A qualified MHP 
should have one of the following backgrounds:

Psychiatry (board certified or board eligible);

Clinical psychology (PsyD or PhD degree);

Licensed clinical social worker (LCSW) with master’s level training;

Psychiatric nurse practitioner (PNP).
7.10. Rater Qualifications
For specific rating assessments (C-SSRS), only qualified raters will be allowed to evaluate 
and/or rate subjects in this study.  The minimum qualifications a rater must meet for each 
study rating assessment will be outlined in a guidance document provided to each 
participating site.  The level of experience with the target population (or equivalent), specific 
scale experience (or equivalent), and certification required (if applicable) will be listed and 
used to determine whether a rater is approved for a given assessment.  Proposed raters who 
do not meet specific criteria but who may be qualified based on unique circumstances may be 
individually reviewed by the study clinical team to determine whether or not a waiver may be 
issued. The rater must become certified to perform selected study assessments before he or 
she can participate in the conduct of the study.  For specifically defined assessments, rater 
training and standardization exercises may be conducted, and written and signed 
documentation will be provided by the site for each rater’s certification.  In return, each site 
will be provided written and signed documentation outlining each rater’s certification for 
specific study assessments.  Recertification may be required at periodic intervals during the 
study.  The raters who administer specific study assessments will be documented in a 
centralized location, and all site staff who administer ratings will be verified in the site study 
documentation during the conduct of the study.


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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product under 
study during pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 


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subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously
reported by the study subject.  In addition, each study subject will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days after the last administration of the investigational product.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.


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8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.


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8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or


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
Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
Medical device complaints may meet the SAE reporting requirement criteria (see the Medical 
Device Complaint Reporting Requirements section).  An incident is any malfunction (ie, the 
failure of a device to meet its performance specifications or to perform as intended; 
performance specifications include all claims made in the labeling for the device) that, 
directly or indirectly, might lead to or might have led to the death of a subject, or user, or of 
other persons, or to a serious deterioration in their state of health. 


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A serious injury that can cause a serious deterioration in state of health can include:

A life-threatening illness, even if temporary in nature;

A permanent impairment of a body function or permanent damage to a body 
structure; 

A condition necessitating medical or surgical intervention to prevent the above 2 
bulleted items;
Examples: clinically relevant increase in the duration of a surgical procedure; a 
condition that requires hospitalization or significant prolongation of existing 
hospitalization;

Any indirect harm as a consequence of an incorrect diagnostic or in vitro diagnostic 
device test results when used within the manufacturer’s instructions for use;

Fetal distress, fetal death, or any congenital abnormality or birth defects.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);


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
Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 


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(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.


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In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.2. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.2.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).


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
A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.


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8.4.2.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.2.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.3. Medication Errors 
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE) 
Only if associated with an 
SAE 
8.4.3.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength.
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.


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Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.5. Medical Device Complaint Reporting Requirements 
All medical device complaints, regardless of whether the medical device complaint is 
associated with an AE, will be recorded on the applicable pages within the CRF.  This 
includes potential incidents or malfunctions associated with the use of a medical device 
product.  An incident or malfunction is an event that might have led to death or serious 
deterioration in health, or if it occurred again might lead to death or serious deterioration in 
health.
Pfizer is to be notified of all medical device complaints within 24 hours of the investigator’s 
awareness of the event.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their
analyses will also be reflected in a protocol amendment.
9.1. Sample Size Determination
The sample size is based on the primary endpoint, change in mean energy intake from 
baseline to Week 6 (in kcal) for ad libitum lunch meals.  The standard deviation (SD) for the 
change from baseline in energy intake (EI) for an ad libitum lunch meal was estimated to be 
approximately 261 kcal.  The standard deviation of mean change from baseline in EI was 
estimated from literature sources26,27 which were randomized, double-blind,
placebo-controlled studies with endpoints and experimental conditions similar to the current 
protocol. 
The null hypothesis to be tested is that the difference between liraglutide and placebo is 
greater than or equal to 0 after 6 weeks of dosing vs. the alternative hypothesis that the 
difference between liraglutide and placebo is less than 0 after 6 weeks of dosing.  Using a 
between-group comparison at Week 6, 25 completers in each arm provides approximately 
85% power to detect a true mean change from baseline in energy intake equal to 200 kcal.  
This assumes a type 1 error equal to 5% (one-sided).  Keeping remaining assumptions the 
same, for a higher estimated SD of approximately 283 kcal, the power would reduce to 79%.  
This estimate is for a test conducted at a one-sided level of significance of 5%.  Assuming a 
15% average drop-out in the study, the sample size would be approximately 30 randomized 
subjects per arm for a total sample size of 60 randomized subjects, yielding 50 completers.


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9.2. Efficacy Analysis
All subjects who meet all of the following criteria will be included in the efficacy analysis:

Completed baseline assessment of food intake;

Received at least one dose of randomized, blinded IP; AND

Completed at least one post-baseline measurement (after taking randomized IP).
Subjects who withdraw prior to tolerating liraglutide 1.8 mg daily for 2 weeks will not be 
included in the efficacy analysis.
9.2.1. Analysis of the Primary Endpoint 
The primary endpoint is change from baseline in mean energy intake, measured in Kcal, 
during ad libitum lunch test meals.  Mean energy intake will be calculated from ad libitum 
lunch test meals on Day -1 and Day 0 for V3, Day 20 and Day 21 for V4, and Day 41 and 
Day 42 for V5.  Mean change from baseline will be calculated using V3 as baseline.  The 
data from V4 and V5 will be incorporated in the same statistical model.  This longitudinal 
modelling technique provides robust estimates and allows assessment of the effect at 
Weeks 3 and 6 in the same model.  The primary time point for calculation of mean change 
from baseline at V3 is Week 6 (V5).  All other collection time points will be considered 
secondary.
 
 
 
  
 
 
Supplemental analyses of the primary variable will be performed to support the robustness of 
the conclusions drawn from the primary analysis described above such as, verifying
assumptions of normality.  Details of these supplemental analyses will be included in the 
SAP.
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) will be 
provided for the baseline and change from baseline values by treatment group and visit.
9.2.2. Analysis of Secondary Endpoints
The secondary efficacy endpoint for food intake is change from baseline in 48-hour energy 
intake.  The analysis method will be similar to the analysis method for the primary endpoint. 
CCI


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Detailed description of analyses for other secondary endpoints will be outlined in the SAP.  
Continuous and discrete modelling techniques will be applied whenever applicable. 
9.3. Pharmacokinetic Analysis
9.3.1. Acetaminophen 
The acetaminophen concentration population is defined as all enrolled subjects who received 
at least one dose of acetaminophen at the in-patient visit and in whom at least one 
concentration value is reported.
Similar to previously published studies,17,28 the following parameters will be assessed: 
maximum acetaminophen concentration (Cmax); time to maximum acetaminophen
concentration (Tmax); area under acetaminophen concentration curve from 0 to 60 minutes
(AUC0–60 min); area under acetaminophen concentration curve from 0 to 300 minutes
(AUC0-300 min) and relative acetaminophen exposure during the first postprandial hour
(AUC0-60 min/AUC0–300 min).  PK concentrations will be summarized and presented with 
summary statistics and data permitting, additional pharmacokinetic parameters may be 
estimated. 
 
9.4. Analysis of Other Endpoints 
Pharmacogenomic data (Prep D1.5 samples),
 
  When these samples are 
analyzed, the results will be reported separately and not part of the clinical study report. 
9.5. Safety Analysis
AEs, ECGs, BP, PR, and safety laboratory data will be reviewed and summarized, and any 
clinical laboratory, ECG, BP, and PR abnormalities of potential clinical concern will be 
presented in tabular and/or graphical format and summarized descriptively, where 
appropriate.
Medical history and physical examination information, as applicable, collected during the 
course of the study will be considered source data and will not be required to be reported, 
unless otherwise noted.  However, any untoward findings identified on physical 
CCI
CCI
CCI


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examinations conducted during the active collection period will be captured as AEs, if those 
findings meet the definition of an AE. Data collected at screening that are used for 
inclusion/exclusion criteria, such as laboratory data, ECGs, and vital signs, will be 
considered source data, and will not be required to be reported, unless otherwise noted.  
Demographic data collected at screening will be reported.
The safety analysis set will include all subjects who have received at least one dose of 
blinded IP.  Safety data will be presented in tabular and/or graphical format and summarized
descriptively, where appropriate.  All safety endpoints will be listed and summarized in 
accordance with Pfizer Data Standards.  Categorical outcomes (eg, AEs) will be summarized 
by subject counts and percentage.  Continuous outcome (eg, BP, heart rate, etc) will be 
summarized using N, mean, median, standard deviation, etc.  Change from baseline in 
laboratory data, ECGs and vital signs will also be summarized.  Subject listings will be 
produced for these safety endpoints accordingly.
Data relevant to the assessment of suicidality will be mapped to the Columbia-Classification 
Algorithm of Suicide Assessment (C-CASA) codes.  Baseline and post-baseline C-SSRS data 
(mapped to C-CASA scores) will be summarized descriptively by treatment group at baseline 
and each post-baseline visit.
The safety analyses will be carried out in the safety population, detailed analyses will be 
described in the SAP. 
9.5.1. Electrocardiogram Analysis
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval, and QRS interval will be summarized by treatment and time.
The number (%) of subjects with maximum post dose QTc values and maximum increases 
from baseline in the following categories will be tabulated by treatment: 
Safety QTc Assessment
Borderline (msec)
Prolonged (msec)
Absolute value
450 - <480
480
Absolute change
30-<60
60
In addition, the number of subjects with corrected and uncorrected QT values 500 msec will 
be summarized.
9.6. Interim Analysis 
This study will not be utilizing an interim analysis.
9.7. Data Monitoring Committee 
This study will not use a data monitoring committee.


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10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct for studies 
conducted at non-Pfizer investigator sites, to ensure that the protocol and Good Clinical 
Practices (GCPs) are being followed.  The monitors may review source documents to 
confirm that the data recorded on CRFs[data collection tool (DCTs)] are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection. The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject’s medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
For studies conducted at non-Pfizer investigator sites, it is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Data Collection Tools/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.


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In most cases source documents are the hospital or the physician's chart.  In these cases, data 
collected on the CRFs must match those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.


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12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by laws. 
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study subjects. The investigator 
site will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC
before use, and available for inspection.
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed.  The investigator 
will retain the original of each subject's signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in the United States
Last subject last visit (LSLV) is defined as the date the investigator reviews the last subject’s 
final safety data and determines that no further evaluation is required for the subject to 
complete the trial.


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14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer. 
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 7 days.  As directed by Pfizer, all study materials must be collected and 
all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual patients have been removed) on www.pfizer.com for Pfizer-sponsored 
interventional studies at the same time the US Basic Results document is posted to 
www.clinicaltrials.gov.


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15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”)
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship,
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
1.
Ørskov C, Holst JJ, Knuhtsen S,et al. Glucagon-like peptides GLP-1 and GLP-2, 
predicted products of the glucagon gene, are secreted separately from pig small intestine 
but not pancreas. Endocrinology. 1986; 119(4):1467-75.
2.
Kreymann B, Williams G, Ghatei MA, et al. Glucagon-like peptide-1 7-36: a 
physiological incretin in man. Lancet. 1987; 2(8571):1300-4.
3.
Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of 
gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol. 
1997; 273(5):E981-8.
4.
Flint A, Raben A, Astrup A, et al. Glucagon-like peptide 1 promotes satiety and 
suppresses energy intake in humans. J Clin Invest. 1998; 101(3):515-20.
5.
SAXENDA[Package insert], Drugs@FDA. 2016 Sep., Available:  
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206321s003lbl.pdf
<Assessed Oct 26, 2016>.
6.
VICTOZA[Package insert], Drugs@FDA. 2016 Apr., Available: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022341s025lbl.pdf 
<Assessed Oct 26, 2016>.
7.
Guh DP, Zhang W, Bansback N, et al. The incidence of co-morbidities related to 
obesity and overweight: a systematic review and meta-analysis. BMC Public Health. 
2009; 9:88.
8.
Flegal KM, Kit BK, Orpana H, et al. Association of all-cause mortality with overweight 
and obesity using standard body mass index categories: a systematic review and meta-
analysis. JAMA. 2013; 309(1):71-82.
9.
Ogden CL, Carroll MD, Kit BK, et al. Prevalence of childhood and adult obesity in the 
United States, 2011-2012. JAMA. 2014; 311(8):806-14.
10.
Anderson JW, Konz EC, Frederich RC, et al. Long-term weight-loss maintenance: a 
meta-analysis of US studies. Am J Clin Nutr. 2001; 74(5):579-84.
11.
Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1 by human 
plasma in vitro yields an N-terminally truncated peptide that is a major endogenous 
metabolite in vivo. J Clin Endocrinol Metab. 1995; 80(3):952-7.
12.
Deacon CF, Pridal L, Klarskov L, et al. Glucagon-like peptide 1 undergoes differential 
tissue-specific metabolism in the anesthetized pig. Am J Physiol. 1996; 271(3):E458-64.
13.
Knudsen LB, Nielsen PF, Huusfeldt PO, et al. Potent derivatives of glucagon-like 
peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med 
Chem. 2000; 43(9):1664-9.


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14.
Agersø H, Jensen LB, Elbrønd B, et al. The pharmacokinetics, pharmacodynamics, 
safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. 
Diabetologia. 2002; 45(2):195-202.
15.
Juhl CB, Hollingdal M, Sturis J, et al. Bedtime administration of NN2211, a long-acting 
GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 
diabetes. Diabetes. 2002; 51(2):424-9.
16.
Flint A, Kapitza C, Zdravkovic M. The once-daily human GLP-1 analogue liraglutide 
impacts appetite and energy intake in patients with type 2 diabetes after short-term 
treatment. Diabetes Obes Metab. 2013; 15(10):958-62.
17.
van Can J, Sloth B, Jensen CB, et al. Effects of the once-daily GLP-1 analog liraglutide 
on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, 
non-diabetic adults. Int J Obes (Lond). 2014; 38(6):784-93.
18.
Secher A, Jelsing J, Baquero AF, et al. The arcuate nucleus mediates GLP-1 receptor 
agonist liraglutide-dependent weight loss. J Clin Invest. 2014; 124(10):4473-88.
19.
EXTRA STRENGTH ACETAMINOHPEN ADULT RAPID BURST CHERRY-
acetaminophen liquid [Drug information], dailymed.nlm.nih.gov. 2016 Jan., Available:  
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9e7543d9-6249-45b5-b67d-
c1b439423b9c <Assessed Oct 26, 2016>.
20.
Wilding JP, Overgaard RV, Jacobsen LV, et al. Exposure-response analyses of 
liraglutide 3.0 mg for weight management. Diabetes Obes Metab. 2016; 18(5):491-9.
21.
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: 
initial validity and internal consistency findings from three multisite studies with
adolescents and adults. Am J Psychiatry. 2011; 168(12):1266-77.
22.
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity 
measure. J Gen Intern Med. 2001; 16(9):606-13.
23.
Lovshin JA, Barnie A, DeAlmeida A, et al. Liraglutide promotes natriuresis but does 
not increase circulating levels of atrial natriuretic peptide in hypertensive subjects with 
type 2 diabetes. Diabetes Care. 2015; 38(1):132-9.
24.
SAXENDA(liraglutide [rDNA origin]) Injection [Medication Guide], Available: 
http://www.novo-pi.com/saxenda_med.pdf <Assessed Oct 26, 2016>.
25.
Flint A, Raben A, Blundell JE, et al. Reproducibility, power and validity of visual 
analogue scales in assessment of appetite sensations in single test meal studies. Int J 
Obes Relat Metab Disord. 2000; 24(1):38-48.
26.
Savastano DM, Hodge RJ, Nunez DJ, et al. Effect of two dietary fibers on satiety and 
glycemic parameters: a randomized, double-blind, placebo-controlled, exploratory 
study. Nutr J. 2014; 13:45.


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27.
Harrold JA, Hughes GM, O'Shiel K, et al. Acute effects of a herb extract formulation 
and inulin fibre on appetite, energy intake and food choice. Appetite. 2013; 62:84-90.
28.
Horowitz M, Flint A, Jones KL, et al. Effect of the once-daily human GLP-1 analogue 
liraglutide on appetite, energy intake, energy expenditure and gastric emptying in type 2 
diabetes. Diabetes Res Clin Pract. 2012; 97(2):258-66.


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Appendix 1. Abbreviations 
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
ABP
ambulatory blood pressure
ABPM
ambulatory blood pressure monitoring
AE
adverse event
ALT
alanine aminotransferase
AUC0–60 min
area under acetaminophen concentration curve from T = 0 - 1 h
AUC0–300 min
area under acetaminophen concentration curve from T = 0 - 5 h
AUC0–60 min
/AUC 0–300 min
relative acetaminophen exposure during the first postprandial hour
AST
aspartate aminotransferase
β-hCG
beta human chorionic gonadotropin 
BBS
Biospecimen Banking System 
BMI
body mass index 
BP
blood pressure
BUN
blood urea nitrogen
C-CASA
Columbia Classification Algorithm of Suicide Assessment 
C-SSRS
Columbia Suicide Severity Rating Scale 
CK
creatine kinase
Cmax
maximum acetaminophen concentration
CO2
carbon dioxide
CRF
case report form
CRU
clinical research unit
CSA
clinical study agreement
CSR
clinical study report
CT
clinical trial
DCT
data collection tool
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
electrocardiogram
EDP
exposure during pregnancy
EI
energy intake
EIA
enzyme immunoassay 
EU
European Union
EudraCT
European Clinical Trials Database
f/u
follow up
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
CCI


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Abbreviation
Term
GIP
glucose-dependent insulinotropic polypeptide  
GLP-1
glucagon-like peptide-1 
GLP-1R
GLP-1 receptor
HbA1c
glycosylated hemoglobin
hCG
human chorionic gonadotropin
HCl
hydrochloric acid
HCVAb
hepatitis C antibody
HDL-C
High-density lipoprotein cholesterol
HepBcAb
hepatitis B core antibody
HepBsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
ICD
informed consent document
ICH
International Conference on Harmonisation
ICF
informed consent form
ID
identification code
IND
investigational new drug
INR
international normalized ratio
IP
Investigational product
IRB
institutional review board
IUD
intrauterine device
IV
intravenous
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LCSW
licensed clinical social worker
LDL-C
low-density lipoprotein cholesterol
LFT
Liver function test
LSLV
last subject last visit
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MEN2
multiple endocrine neoplasia syndrome type 2 
MHP
mental health professional
 
MRI
magnetic resonance spectroscopy
MTC
medullary thyroid carcinoma
N/A
not applicable
OCPs
oral contraceptive pills
PCD
Primary completion date
PHQ-9
Patient Health Questionnaire-9
PI
principal investigator
PK 
Pharmacokinetics
PGx
pharmacogenomics
PNP
psychiatric nurse practitioner
PR
pulse rate
PT
prothrombin time
CCI


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Abbreviation
Term
PYY
pancreatic peptide YY3-36
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SIB
Suicidal Ideation and Behavior
SOP
standard operating procedures
SPA
spontaneous physical activity
SRSD
single reference safety document
TA
therapeutic area
TBili
total bilirubin
THC
tetrahydrocannabinol
Tmax
time to maximum paracetamol concentration
TSH
thyroid stimulating hormone 
UA
urinalysis
ULN
upper limit of normal
US
United States
USP
United States Pharmacopeia
V
visit
VAS
visual analog scale
WBC
white blood cell
CCI


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Appendix 2. Questions Listed in the Visual Analog Scale (VAS)
I am not
hungry at all
How hungry do you feel?
I have never
been more hungry
I am completely 
empty
How satisfied do you feel?
I can not eat another 
bite
Not at all full
How full do you feel?
Totally full
Nothing at all
How much do you think you can eat?
A lot
Yes, very much
Would you like to eat something sweet?
No, not at all
Yes, very much
Would you like to eat something salty?
No, not at all
Yes, very much
Would you like to eat something savoury?
No, not at all
Yes, very much
Would you like to eat something fatty?
No, not at all

SAP_001.pdf: 
Protocol A9001498 (Liraglutide) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 1
TMF Doc ID: 98.03
Protocol A9001498
A 6-WEEK, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
TWO-ARM, PARALLEL METHODOLOGY STUDY TO ASSESS THE EFFECT OF 
LIRAGLUTIDE ON FOOD INTAKE IN OBESE SUBJECTS
Statistical Analysis Plan 
(SAP)
Version:
Final
Date:
16-FEB-2017


Protocol A9001498 (Liraglutide) Statistical Analysis Plan
DMB02-GSOP-RF02 3.0 STATISTICAL ANALYSIS PLAN TEMPLATE 30-Jun-2015
Page 2
TMF Doc ID: 98.03
TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives .......................................................................................................5
2.2. Study Design .............................................................................................................7
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................8
3.1. Primary Efficacy Endpoint(s)....................................................................................8
3.2. Secondary Efficacy Endpoint(s)................................................................................8
3.2.1. 48-hour Energy Intake..................................................................................8
3.2.2. Appetite, Satiety, Fullness, Hunger and Prospective Consumption 
VAS....................................................................................................................8
3.3. Other Efficacy Endpoints..........................................................................................9
3.4. Baseline Variables...................................................................................................10
3.5. Pharmacokinetic Endpoints.....................................................................................10
3.6. Safety Endpoints .....................................................................................................11
3.6.1. Adverse Events...........................................................................................11
3.6.2. Suicidality Assessment...............................................................................11
3.6.3. Laboratory Data..........................................................................................11
3.6.4. Vital Signs ..................................................................................................12
3.6.5. ECGs...........................................................................................................12
4. ANALYSIS SETS ...............................................................................................................13
4.1. Full Analysis Set .....................................................................................................13
4.2. Safety Analysis Set..................................................................................................13
4.3. Other Analysis Sets .................................................................................................13
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................13
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5.1. Hypotheses and Decision Rules..............................................................................13
6. GENERAL METHODS.......................................................................................................14
6.1. Analyses for Binary Data ........................................................................................14
6.2. Analyses for Continuous Data.................................................................................14
6.3. Analyses for Categorical Data.................................................................................14
6.4. Analyses for Time to Event Data ............................................................................14
6.5. Methods to Manage Missing Data ..........................................................................14
7. ANALYSES AND SUMMARIES ......................................................................................15
7.1. Primary Endpoint(s) ................................................................................................15
7.1.1. Mean energy intake (in Kcal) during ad libitum lunch meals ....................15
7.1.1.1. Primary Analysis.......................................................................15
7.1.2. Sensitivity/Robustness Analyses ................................................................15
7.2. Secondary Endpoint(s) ............................................................................................15
7.2.1. 48-hour Energy Intake................................................................................15
7.2.2. Appetite and Satiety Scores........................................................................16
7.4. Other Endpoint(s)....................................................................................................19
7.4.1. Pharmacokinetics........................................................................................19
7.6. Baseline and Other Summaries and Analyses.........................................................22
7.6.1. Baseline Summaries....................................................................................22
7.6.2. Study Conduct and Subject Disposition .....................................................22
7.6.3. Study Treatment Exposure .........................................................................22
7.6.4. Concomitant Medications and Non-Drug Treatments................................22
7.7. Safety Summaries and Analyses .............................................................................22
7.7.1. Adverse Events...........................................................................................22
7.7.2. Suicidality Assessment...............................................................................23
7.7.3. Laboratory Data..........................................................................................23
7.7.4. Vital Signs ..................................................................................................23
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7.7.5. Electrocardiogram.......................................................................................23
7.7.6. Physical Examination .................................................................................23
8. INTERIM ANALYSES.......................................................................................................23
9. REFERENCES ....................................................................................................................24
10. APPENDICES ...................................................................................................................25
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments................................................5
Table 2.
Clinical Laboratory Tests .....................................................................................12
Table 3.
C-CASA Suicidality Events and Codes................................................................28
Table 4.
C-SSRS Mapped to C-CASA (Suicidality Events and Codes) ............................28
LIST OF FIGURES
Figure 1.
Study Design...........................................................................................................7
APPENDICES
Appendix 1. Summary of Efficacy Analyses...........................................................................25
Appendix 2. Example SAS code for primary analysis ............................................................26
Appendix 3. Categorical Classes for ECG and Vital Signs.....................................................27
Appendix 4. C-SSRS Mapped to C-CASA..............................................................................28


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1. VERSION HISTORY
This  Statistical Analysis Plan (SAP) for Study A9001498 is based on the protocol dated 
21 November 2016.  
Table 1.
Summary of Major Changes in SAP Amendments
SAP Version
Change
Rationale
1
Not Applicable
Not Applicable
2. INTRODUCTION
Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone that is predominantly 
released from the small intestine in response to food intake.  GLP-1 activation of the GLP-1
receptor (GLP-1R) stimulates insulin release, inhibits glucagon secretion in a glucose 
dependent manner, and delays gastric emptying. In addition, GLP-1 has been shown to 
increase satiety and suppress food intake, supporting the use of GLP-1R agonists for the 
treatment of obesity.  Several injectable peptidic GLP-1R agonists are approved for the 
treatment of Type 2 diabetes mellitus.  Liraglutide is a peptide GLP-1R agonist that is 
approved both for the treatment of obesity (known as Saxenda) and for the treatment of 
Type 2 diabetes (known as Victoza). 
The primary purpose of this study is to assess the effect of liraglutide on food (energy) intake 
in non-diabetic, obese subjects, an agent that has been demonstrated to result in decreased 
food intake.  This assessment will aid in determining if food intake is an appropriate 
decision-making endpoint for 
 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study A9001498.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
2.1. Study Objectives
Primary Objective(s):
Primary Endpoint(s):

To assess the effect of liraglutide on 
food intake during 6 weeks of 
administration, compared to placebo.

Mean energy intake (in kcal) during ad 
libitum lunch meals.
Secondary Objective(s):
Secondary Endpoint(s):

To assess effects on safety measures and 
tolerability (including spontaneously 

Vital sign measurements, adverse event 
monitoring, changes in 12-lead ECGs, 
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reported nausea and vomiting) of 
liraglutide over 6 weeks of dosing. 

To evaluate the effect of liraglutide on 
additional food intake endpoints during 
6 weeks of administration, compared 
with placebo.

To assess the effect of liraglutide on 
appetite and satiety during 6 weeks of 
liraglutide administration, compared to 
placebo.

To assess the effect of liraglutide on 
gastric emptying during 6 weeks of 
liraglutide administration, compared 
with placebo.
and clinical laboratory testing.

48-hour energy intake (in kcal). 

Appetite and satiety scores, as assessed 
by Visual Analog scale (VAS)
questionnaire. 

Plasma area under the curve (AUC) of 
acetaminophen for 0-60 mins and 
0-300 minutes after acetaminophen 
administration. 
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2.2. Study Design
This will be a randomized, double-blind, placebo-controlled, 2-arm, parallel group, 
methodology study to assess the effect of 6 weeks of liraglutide administration on food intake 
in obese subjects.  Subjects will complete screening procedures to determine eligibility and 
once confirmed to meet all other criteria, will proceed to a Run in visit (V2) and then to 
randomization at V3. 
The study includes a total of six (6) visits to the site, including 3 outpatient visits (V1, V2
and V6) and 3 inpatient visits (V3, V4 and V5).  Subjects will be randomized at V3 to 
receive 1 of 2 blinded treatment regimens for a duration of 6 weeks: liraglutide (administered 
subcutaneously via pen injection and titrated per Saxendalabel to maximum dose of 
3.0 mg/day) or placebo (0.9% saline, administered subcutaneously via syringe in matching 
volume).  At V3, V4 and V5, subjects will be admitted for an inpatient stay and receive 
blinded investigation product (IP) from an unblinded administrator.  Each inpatient stay
consists of 4 days and 3 nights.  For the study duration between V3 and V4, and also between 
V4 and V5, subjects will be administered blinded IP on a daily basis via an unblinded 
administrator, either at home or at an outpatient visit. The study is double-blind, however the 
site pharmacist will be unblinded to administer the drug because there is not a perfect match 
placebo.
Total participation in the study for each subject, including Screening (V1) and investigator 
site follow-up visits (V6) will be approximately 10 weeks (minimum) to 14 weeks 
(maximum).  In addition, there will be follow up contact with the subject via a phone call, at 
least 28 after last dose of IP (V5).  The overall study scheme is summarized in Figure 1. 
Approximately 60 subjects (30 per arm) will be randomized at one or more study sites.  A 
minimum of 50 completed subjects (approximately 25 subjects per arm) are required for the 
study.  The 60 randomized subjects account for a projected approximate premature 
discontinuation rate of 15% and reflects intent not to replace subjects prematurely 
discontinued after first dose of IP.
Figure 1.
Study Design


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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Efficacy Endpoint(s)
Food intake will be assessed at the times listed in the Schedule of Activities (SoA) in the 
protocol. 
All meals will be prepared at the study site during inpatient visits.  For every ad libitum meal, 
each portion will be weighed and recorded before and after each meal. The following 
parameters will be measured: total kcal consumed per day, total kcal of each macronutrient 
(carbohydrate, fat or protein) consumed per day, total kcal consumed per meal and total kcal 
of each macronutrient consumed per meal.  The total daily nutritional composition offered in 
the inpatient meals will be approximately 50% carbohydrates, 35% fat and 15% protein.
Observed food intake will be measured as the total number of calories consumed during the 
specified time period, calculated (to the nearest 50 kcal) as the difference of the total number 
of calories provided minus the total number of calories remaining after meals.
The change from baseline in mean energy intake (in kcal) during ad libitum lunch meals will 
be the primary endpoint. Baseline is defined as the mean of the measurements at Visit V3 
(Day -1 and 0). Change from baseline will be calculated as the measurement at follow-up 
minus the measurement at Visit V3. 
3.2. Secondary Efficacy Endpoint(s)
3.2.1. 48-hour Energy Intake
A secondary efficacy endpoint for food intake is change from baseline in 48-hour energy 
intake.  It will be calculated similar to the primary endpoint.  Baseline is defined as the 
48-hour period at Visit V3.  Change from baseline will be calculated as the measurement at 
V4 or V5 minus the measurement at Visit V3.
3.2.2. Appetite, Satiety, Fullness, Hunger and Prospective Consumption VAS
An additional secondary endpoint of appetite, satiety, fullness, hunger, and prospective 
consumption will be measured at the study site using a validated VAS questionnaire.  The 
VAS questionnaire will be completed by the subject at each of 4 time points: immediately 
prior to administration of the meal, 30, 60 and 120 minutes after start time of the specified 
meals, per the SoA in the protocol.
The VAS is an assessment in which subjects place a vertical line across a validated 
100 millimeter (mm) line to rank their response to various questions.  The line is anchored by 
responses such as “Not At All Full” and “Totally Full” at either end.  Scoring will consist of 
measuring the distance in mm of the vertical line from the response at the left end and will be 
used to explore the relationships between subjective reports of appetite and other VAS 
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The overall appetite score will be calculated as the average of the four individual scores 
[satiety+fullness+(100−prospective food consumption)+(100−hunger)] divided by 4. In 
addition to the overall appetite score the individual scores (for satiety, fullness, nausea, 
100−prospective food consumption, 100−hunger) will also be analyzed to estimate the 
treatment effect. For each of these subscores the parameters to be assessed will be fasting 
rating (i.e. effect at time point 0 for VAS, i.e. the measure collected prior to administration of 
the meal), mean rating AUC (30-120) min, maximum rating (maximum for a given meal) and 
30 min postprandial rating (i.e. 30 minutes after start time of the specified meals).
Baseline VAS will be the VAS collected at Visit V3 (Day -1 and 0).  The baseline value will 
be the mean of the VAS scores at Day -1 and 0. Moreover the baseline for the fasting rating 
will be the mean baseline rating at time point 0, baseline for mean rating AUC30-285/255 min 
will be the mean rating AUC30-285/255 min for Day -1 and 0 (mean of  Day -1 and 0), 
baseline for maximum rating will be mean of maximum rating for Day -1 and maximum 
rating for Day 0, baseline for 30 min postprandial rating will be mean of 30 min postprandial 
rating on Day -1 and Day 0.
Change from baseline will be defined as the VAS at the current visit minus VAS at the 
baseline visit.
3.3. Other Efficacy Endpoints
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3.4. Baseline Variables
The baseline visit will occur at Visit V3.  Medical history will be collected at baseline.  
3.5. Pharmacokinetic Endpoints
PK samples for acetaminophen will be collected at Visits V3, V4 and V5 at the time points 
specified in the SoA.  
Data permiting the following pharmacokinetic endpoints will be calculated.
Parameter
Definition
Method of Determination
Single Dose 
Cmax
Maximum plasma concentration
Observed directly from data
Tmax
Time at which Cmax  occurred
Observed directly from data as time of first 
occurrence
AUC0-60 min
Area under the concentration-time 
profile from time zero to 60 minutes
Linear/Log trapezoidal method
AUC0-300 min
Area under the concentration-time 
profile from time zero to 300 minutes
Linear/Log trapezoidal method
Relative 
acetaminophen 
exposure (0-1)
Relative acetaminophen exposure during 
the first postpandrial hour
(AUC0-60 min/AUC0–300 min)
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3.6. Safety Endpoints
3.6.1. Adverse Events
An adverse event is considered treatment emergent relative to a given treatment if:

the event occurs for the first time during the effective duration of treatment and was 
not seen prior to the start of treatment (for example, during the baseline or run-in 
period), or

the event was seen prior to the start of treatment but increased in severity during 
treatment.
3.6.2. Suicidality Assessment
The C-SSRS is a validated tool to evaluate suicidal ideation and behavior. At Screening 
Visit, if there is a “yes” to question 1 of the C-SSRS, the subject will not be included in the 
study. Data relevant to the assessment of suicidality will be mapped to the Columbia-
Classification Algorithm of Suicide Assessment (C-CASA) codes (Appendix 4).
3.6.3. Laboratory Data
The following clinical laboratory tests will be performed at times defined in the SoA of this 
protocol and will be performed by the study site laboratory.  Additional laboratory results 
may be reported on these samples as a result of the method of analysis or the type of analyzer 
used by the clinical laboratory; or as derived from calculated values.  These additional tests 
would not require additional collection of blood.  Unscheduled clinical laboratory 
measurements may be obtained at any time during the study to assess any perceived safety 
concerns.
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Table 2.
Clinical Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
Blood Urea Nitrogen (BUN)
Creatinine
Glucose 
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
Aspartate aminotransferase 
(AST)
Alanine aminotransferase 
(ALT)
Total bilirubin
Alkaline phosphatase
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
Serum -hCGb
Lipid panel: total 
cholesterol, HDL-C, 
LDL-C, triglycerides
Amylase
Lipase
Calcitonin
Urine drug screen
At V1, only:
FSH
TSH
HbA1c
Human Immunodeficiency 
Virus (HIV)
Hepatitis Panel:  HepBsAg, 
HepBcAb, HCVAb
Additional Tests 
(Needed for Hy’s Law)
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug and/or 
protein adduct levels
a. Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b. Serum -hCG for all female subjects at V1.  At V2-V6, serum -hCG for women of childbearing potential only.
The baseline laboratory measurement will be the one taken at Visit V3.  Change from 
baseline will be at V4 or V5 measurement minus baseline.
3.6.4. Vital Signs
BP and PR will be measured at times specified in the SoA of this protocol.  Additional 
collection times, or changes to collection times, of BP and PR will be permitted, as 
necessary, to ensure appropriate collection of safety data. Baseline will be the measurement 
taken prior to administration of study treatment at Visit V3 (Day 1). Change from baseline 
will be the measurement at follow-up minus the measurement at baseline.
3.6.5. ECGs
12-Lead ECGs should be collected at times specified in the SoA.
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Baseline will be the measurement taken prior to administration of study treatment at Visit V3
(Day -1). For change from baseline assessment, it will be the measurement at follow-up 
minus the measurement at baseline.
4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to unblinding and releasing the database and classifications 
will be documented per standard operating procedures.
4.1. Full Analysis Set
All subjects who meet the  criteria stated below will be included in the Full analysis set 
(FAS:

Completed baseline assessment of food intake;

Received at least one dose of randomized, blinded IP; AND 

Completed at least one post-baseline measurement (after taking randomized IP).
This also implies that subjects who withdraw prior to tolerating liraglutide 1.8 mg daily will 
not be included in the efficacy analysis (per protocol Section 9.2). Subjects who only 
complete V4 (or week 3 visit) will be included in the efficacy analysis.
4.2. Safety Analysis Set
All subjects who receive at least one dose of study medication classified according to the 
actual study treatment received. The safety analysis set is the primary population for 
treatment administration/compliance and safety. A randomized but not treated subject will be 
excluded from the safety analyses.  A treated but not randomized subject will be reported 
under the treatment actually received. 
4.3. Other Analysis Sets
The acetaminophen PK analysis set will consist of all subjects who received at least one dose 
of acetaminophen and has one quantifiable acetaminophen concentration.
 
 
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
The null hypothesis to be tested is that the difference between liraglutide and placebo is 
greater than or equal to 0 after 6 weeks of dosing vs. the alternative hypothesis that the 
difference between liraglutide and placebo is less than 0 after 6 weeks of dosing.  Liraglutide
will be considered superior to placebo with respect to mean energy intake during ad libitum 
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lunch meals if the difference is less than 0 and is statistically significant at the one-sided 0.05 
level.
6. GENERAL METHODS 
6.1. Analyses for Binary Data
Not applicable.
6.2. Analyses for Continuous Data
A linear mixed-effect repeated measures model with fixed effects for treatment, time (visit), 
a treatment by time interaction, baseline value of energy intake, and a random effect for 
subject, will be used to analyze the change from baseline in energy intake (this will be 
denoted as the primary analysis). A sensitivity analysis will conducted that will also include 
effects for baseline value of energy intake by treatment interaction and baseline body weight
and gender in the model.  The estimation method used will be restricted maximum
likelihood. Due to the unknown nature of the longitudinal data, different covariance
structures among repeated measures will be examined based on model diagnostics.  Different 
covariance structures such as unstructured, compound symmetric and AR1, and so on will be 
tested.  The model resulting in the lowest Aikaike Information Criteria (AIC) will be used.  
Using this model, 95% confidence intervals comparing the mean change from baseline in EI 
estimates at Week 6 for liraglutide vs. placebo will be computed.
6.3. Analyses for Categorical Data
Not applicable.
6.4. Analyses for Time to Event Data
Not applicable.
6.5. Methods to Manage Missing Data
No adjustments for missing data will be made except for PK data.
In all PK data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.)
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
A concentration has been collected as ND (ie, not done) or NS (ie, no sample),
A deviation in sampling time is of sufficient concern or a concentration has been flagged 
anomalous by the pharmacokineticist.


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Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
7. ANALYSES AND SUMMARIES
7.1. Primary Endpoint(s)
7.1.1. Mean energy intake (in Kcal) during ad libitum lunch meals
7.1.1.1. Primary Analysis
Endpoints: Change from baseline in energy intake during ad libitum lunches

Analysis time points: Visit V4 and Visit V5 (primary endpoint)

Analysis population: FAS

Analysis methodology: MMRM model (specified in Section 6.2).  
Reporting results:
Raw data: The available sample size (ie, sample size available for this endpoint), mean, 
standard deviation, median, minimum and maximum at baseline and post-baseline will be 
presented for each treatment arm.

Change from baseline: The sample size, mean, standard deviation, median, minimum 
and maximum will be presented for each treatment arm. The LS means, 95% 
confidence interval for the LS means, difference between the LS means and the 
corresponding 95% confidence interval will be presented.  
Figures
Line plot of LS means andplacebo-adjusted LS means and 95% confidence interval at
Visit V4 and Visit V5.
7.1.2. Sensitivity/Robustness Analyses
The primary endpoint analysis will be repeated adding a treatment by baseline energy intake 
interaction, baseline body weight and gender to the model.
7.2. Secondary Endpoint(s)
The secondary endpoints of 48-hour energy intake, appetite and satiety scores, 
 
 will be analyzed using the same methods as the primary 
endpoint.
7.2.1. 48-hour Energy Intake
Endpoints: Change from baseline in 48-hour energy intake 
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
Analysis time points: Visit V4 and Visit V5

Analysis population: FAS

Analysis methodology: MMRM model (specified in Section 6.2).  
Reporting results:
Raw data: The available sample size, mean, standard deviation, median, minimum and 
maximum at baseline and post-baseline will be presented for each treatment arm.

Change from baseline: The sample size, mean, standard deviation, median, minimum 
and maximum will be presented for each treatment arm. The LS means, 95% 
confidence interval for the LS means, difference between the LS means and the 
corresponding 95% confidence interval will be presented.  
Figures
Line plot of LS means and placebo-adjusted LS means and 95% confidence interval 
at Visit V4 and Visit V5.
7.2.2. Appetite and Satiety Scores
Endpoints: Change from baseline in appetite and satiety scores

Analysis time points: all post-baseline visits

Analysis population: FAS

Analysis methodology: MMRM model (specified in Section 6.2).  
Reporting results:
Raw data: The available sample size, mean, standard deviation, median, minimum and 
maximum at baseline and post-baseline will be presented for each treatment arm.

Change from baseline: The sample size, mean, standard deviation, median, minimum 
and maximum will be presented for each treatment arm. The LS means, 95% 
confidence interval for the LS means, difference between the LS means and the 
corresponding 95% confidence interval will be presented.  
Figures
Line plot of LS means and placebo-adjusted LS means and 95% confidence interval 
at Visit V4 and Visit V5.


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7.4. Other Endpoint(s)
7.4.1. Pharmacokinetics
Actual PK sampling times will be used in the derivation of PK parameters.
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If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (ie not calculated). (Note that NC values will not be generated beyond the 
day that a subject discontinues.)
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular dose with 3 evaluable measurements.
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the compound is adequately absorbed in the 
body), this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics or statistical analyses.
Each acetaminophen PK parameter will be summarized by visit (V3, V4 and V5) and will 
include the set of summary statistics as specified in the table below:
Single Dose
AUC0-60, AUC0-300, AUC0-60/AUC0-300,Cmax,
N, arithmetic mean, median, cv%, standard 
deviation, minimum, maximum, geometric 
mean and geometric cv%.
Tmax
N, median, minimum, maximum
Presentations for acetaminophen concentrations will include:

A listing of all concentrations sorted by subject ID, treatment arm (active vs. placebo)
and nominal time post acteminophen dose.  The concentration listing will also include the 
actual times.  Deviations from the nominal time will be given in a separate listing. The 
listing will also capture for active arms what liraglutide dose the subject was on when the 
acetaminophen measurement was taken.

A summary of concentrations by treatment arm and nominal time post-acetaminophen 
dose, where the set of statistics will include n, mean, median, standard deviation, 
coefficient of variation (cv), minimum, maximum and the number of concentrations 
above the lower limit of quantification.

Median concentrations time plots (on both linear and semi-log scales) against nominal 
time post-dose by treatment (active vs. placebo) and visit (all treatments on the same plot 
per scale, based on the summary of concentrations).

Mean concentrations time plots (on both linear and semi-log scales) against nominal time 
post-dose by treatment (active vs. placebo) and visit (all treatments on the same plot per 
scale, based on the summary of concentrations).

Individual concentration time plots by treatment and visit (on both linear and semi-log 
scales) against actual time post-dose.


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
Individual concentration time plots by subject (on both linear and semi-log scales) against 
actual time post-dose.
The length of time used for the x-axes of these plots will be decided on review of the data, 
and will depend on how long acetaminophen concentration is quantifiable in the matrix.
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual subject plots by time, the actual PK sampling time will be 
used.
There will be 1 summary table presenting all acetaminmophenacetaminophen PK parameters.  
This will include data from both treatment groups and will be paged by visit.  The treatment 
subheading will include the treatment details (active vs. placebo) and visit information.  
A listing of the liragultide steady state concentrations may be reported.
Endpoints: Absolute and change from baseline in plasma area under the curve (AUC) of 
acetaminophen for 0-60 mins and 0-300 minutes after acetaminophen administration

Analysis time points: visits V4 and V5

Analysis population: FAS

Analysis methodology: MMRM model (specified in Section 6.2).  
Reporting results:
Raw data: The sample size, mean, standard deviation, median, minimum and maximum at 
baseline and post-baseline will be presented for each treatment arm.

Change from baseline: The sample size, mean, standard deviation, median, minimum 
and maximum will be presented for each treatment arm. The LS means, 95% 
confidence interval for the LS means, difference between the LS means and the 
corresponding 95% confidence interval will be presented.  
Figures

Mean concentration curves by treatment group and visit.

Line plot of LS means and 95% confidence interval at Visit V4 and Visit V5.

Line plot of descriptive means for area under the curve (0-300 mins) and 95% 
confidence interval at Visit V4 and Visit V5.
Endpoints: Tmax and Cmax after acetaminophen administration

Analysis time points: Visits V3, V4 and V5


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
Analysis population: FAS

Analysis methodology: Summary Statistics  
Reporting results:
Raw data: The sample size, mean, standard deviation, median, minimum and maximum at 
baseline and post-baseline will be presented for each treatment arm.
Change from baseline: For Cmax the sample size, mean, standard deviation, 95% confidence 
interval median, minimum and maximum will be presented for each treatment arm. 
7.6. Baseline and Other Summaries and Analyses
7.6.1. Baseline Summaries
Demographics and medical history variables will be summarized by treatment group using 
the FAS.
7.6.2. Study Conduct and Subject Disposition
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed in the full analysis set and as well as for safety.  Frequency counts 
will be supplied for subject discontinuations by treatment.
Data will be reported in accordance with reporting standards.
7.6.3. Study Treatment Exposure
A summary of the number of doses received as well as the median total dose by visit and 
treatment group will be provided.  
7.6.4. Concomitant Medications and Non-Drug Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
7.7. Safety Summaries and Analyses
7.7.1. Adverse Events
Adverse events will be tabulated and reported by treatment and time, according to sponsor 
reporting standards.
CCI


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7.7.2. Suicidality Assessment
Baseline for CSSRS is defined as the measure on Visit V3 (Day -2). Data relevant to the 
assessment of suicidality will be mapped to the Columbia-Classification Algorithm of 
Suicide Assessment (C-CASA) codes as given in Appendix 4. Baseline and post-baseline 
CSSRS data (mapped to C-CASA scores) will be summarized categorically by treatment 
group at baseline and each post-baseline visit. Categorical summaries of the PHQ-9 will be 
presented by treatment group at baseline and post-baseline visits.
7.7.3. Laboratory Data
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards.  Baseline is as defined in Section 3.6.2.
7.7.4. Vital Signs
Absolute values and changes from baseline in systolic and diastolic blood pressure, pulse rate 
will be summarized by treatment and time post-dose, according to sponsor reporting 
standards.  Baseline is as defined in Section 3.6.3.
7.7.5. Electrocardiogram
Categorical summary tables will be summarized by treatment and time post-dose using 
sponsor reporting standards. Baseline is as defined in Section 3.6.4. Potential effects of 
Liraglutide on ECG parameters will be assessed using the following:

Descriptive statistics for PR, QRS, QT, QTcF, QTcB, and HR, and change from 
baseline in those parameters summarized by treatment and time postdose.

Categorical comparisons of maximum individual increase from baseline and 
post-dose QTcF and QTcB intervals by treatment group. The categories are included 
in Appendix 3. The number and percentage of subjects in each category will be 
tabulated by treatment group.
Standard algorithms and reporting formats will be applied. A listing of ECG comments on
findings and normal/abnormal results will be provided.
7.7.6. Physical Examination
All physical exam data will be provided in the listings.
8. INTERIM ANALYSES
Not applicable.


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9. REFERENCES 
1.
A9001498 Protocol 21st November, 2016.
2.
Flint A, Kapitza C, Zdravkovic M. The once-daily human GLP-1 analogue liraglutide
impacts appetite and energy intake in patients with type 2 diabetes after short-term
treatment. Diabetes Obes Metab. 2013; 15(10):958-62.
3.
Van Can J, Sloth B, Jensen CB, et al. Effects of the once-daily GLP-1 analog liraglutide 
on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, 
non-diabetic adults. Int J Obes (Lond). 2014; 38(6):784-93.


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10. APPENDICES
Appendix 1. Summary of Efficacy Analyses
Endpoint
Analysis 
Set
Statistical 
Method
Model
Missing 
Data
Interpretation
Change from 
baseline in energy 
intake during lunch
FAS
MMRM
Treatment, Visit, Treatment 
by Visit, baseline energy 
intake
None
Primary
Change from 
baseline in energy 
intake during lunch
FAS
MMRM
Treatment, visit, Treatment 
by Visit, baseline energy 
intake, treatment by baseline 
energy intake, baseline 
weight, gender
None
Sensitivity
Change from 
baseline in 48-hour 
intake
FAS
MMRM
Treatment, Visit, Treatment 
by Visit, baseline energy 
intake
None
Secondary
Change from 
baseline in appetite
and satiety scores
FAS
MMRM
Treatment, Visit, Treatment 
by Visit, baseline energy 
intake
None
Secondary
CCI
CCI


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Appendix 2. Example SAS code for primary analysis 
PROC MIXED data=new covtest;
CLASS subjid treatmnt xvisit;
MODEL FI_CHG=treatmnt xvisit treatmnt*xvisit baseline /alpha=0.05 cl ddfm=kr;
REPEATED xvisit/TYPE=un SUBJECT=subjid;
lsmeans treatmnt*xvisit/cl pdiff alpha=0.05;
run;


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Appendix 3. Categorical Classes for ECG and Vital Signs 
Categories for QTcF
QTcF (ms)
450max. <480
480max.<500
max. 500
QTcF (ms) 
increase from 
baseline
30max. <60
max. 60
Categories for PR and QRS
PR (ms)
max. 300
PR (ms) increase 
from baseline
Baseline >200 
and max. 
25% increase
Baseline 200 and 
max. 50% 
increase
QRS (ms)
max. 200
QRS (ms) 
increase from 
baseline
Baseline >100 
and max. 
25% increase
Baseline 100 and 
max. 50% 
increase
Categories for Vital Signs
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) 
change from baseline
max. decrease 30
max. increase 30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) 
change from baseline
max. decrease 20
max. increase 20
Supine pulse rate (bpm)
min. <40
max. >120
Standing pulse rate (bpm)
min. <40
max. >120


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Appendix 4. C-SSRS Mapped to C-CASA
Table 3.
C-CASA Suicidality Events and Codes
Event 
Code
Event
1
Completed suicide
2
Suicide attempt
3
Preparatory acts towards imminent suicidal behavior
4
Suicidal ideation
5
Self-injurious behavior, intent unknown
6
Not enough information, fatal
7
Self-injurious behavior, no suicidal intent
8
Other, accident, psychiatric; mental 
9
Not enough information, non fatal
* Note: Event Codes 5, 6, 8 and 9 are not applicable to prospectively collected 
data
Table 4.
C-SSRS Mapped to C-CASA (Suicidality Events and Codes)
C-CASA 
Event Code
C-CASA Event
C-SSRS Response
1
Completed suicide
As captured in the safety database
2
Suicide attempt
“Yes” on “Actual Attempt”
3
Preparatory acts towards imminent 
suicidal behavior
“Yes” on any of the following:
”Aborted attempt”, or 
“Interrupted attempt”, or 
“Preparatory Acts or Behavior”
4
Suicidal ideation
“Yes” on any of the following:
“Wish to be dead”, or
“Non-Specific Active Suicidal Thoughts”, or 
“Active Suicidal Ideation with Any Methods (Not Plan) 
without Intent to Act”, or 
“Active Suicidal Ideation with Some Intent to Act, 
without Specific Plan”, or 
“Active Suicidal Ideation with Specific Plan and Intent”
7
Self-injurious behavior, no suicidal 
intent
“Yes” on “Has subject engaged in Non-suicidal Self-
Injurious Behavior?”