Effect of Tirzepatide on Energy Intake and Appetite-and Reward-Related Brain Areas in Overweight/Obese Subjects: A Placebo-Controlled 6-Week Study With Functional MRI
Phase: PHASE1
Conditions: Obesity, Overweight
Sponsor: Eli Lilly and Company

 
I8F-MC-GPHH(f) Clinical Pharmacology Protocol 
 
 
Eﬀect of TirzepaƟde on Energy Intake and AppeƟte-and Reward-Related Brain Areas in 
Overweight/Obese Subjects: A Placebo-Controlled 6-Week Study With FuncƟonal MRI 
 
 
NCT04311411 
 
 
Approval Date: 08-Oct-2021 

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Protocol I8F-MC-GPHH(f)
Effect of Tirzepatide on Energy Intake and Appetite- and 
Reward-Related Brain Areas in Overweight/Obese 
Subjects:  A Placebo-Controlled 6-Week Study with 
Functional MRI
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
tirzepatide (LY3298176), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.  
Tirzepatide (LY3298176)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly: 31 January
2020
Amendment (a) Electronically Signed and Approved by Lilly: 03 March 2020
Amendment (b) Electronically Signed and Approved by Lilly: 30 April 2020
Amendment (c) Electronically Signed and Approved by Lilly: 02 June 2020
Amendment (d) Electronically Signed and Approved by Lilly: 11 December 2020
Amendment (e) Electronically Signed and Approved by Lilly: 02 February 2021
Amendment (f) Electronically Signed and Approved by Lilly on approval date provided 
below.
Approval Date: 08-Oct-2021 GMT

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Table of Contents
Effect of Tirzepatide on Energy Intake and Appetite- and 
Reward-Related Brain Areas in Overweight/Obese Subjects:  
A Placebo-Controlled 6-Week Study with Functional MRI
Section
Page
Protocol I8F-MC-GPHH(f) Effect of Tirzepatide on Energy Intake and 
Appetite- and Reward-Related Brain Areas in Overweight/Obese 
Subjects:  A Placebo-Controlled 6-Week Study with Functional MRI .................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................18
3.1.
Study Rationale............................................................................................................18
3.2.
Background..................................................................................................................18
3.3.
Benefit/Risk Assessment..............................................................................................20
4.
Objectives and Endpoints..................................................................................................22
5.
Study Design.....................................................................................................................24
5.1.
Overall Design .............................................................................................................24
5.2.
Number of Participants.................................................................................................27
5.3.
End of Study Definition ...............................................................................................27
5.4.
Scientific Rationale for Study Design...........................................................................27
5.5.
Justification for Dose ...................................................................................................28
6.
Study Population...............................................................................................................30
6.1.
Inclusion Criteria..........................................................................................................30
6.2.
Exclusion Criteria ........................................................................................................33
6.3.
Lifestyle and Dietary Requirements..............................................................................37
6.3.1.
Meals and Dietary Restrictions.............................................................................37
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................37
6.3.3.
Activity................................................................................................................37
6.4.
Screen Failures.............................................................................................................37
7.
Treatment..........................................................................................................................38
7.1.
Treatment Administered...............................................................................................38
7.1.1.
Packaging and Labeling .......................................................................................39
7.2.
Method of Treatment Assignment ................................................................................39
7.2.1.
Selection and Timing of Doses.............................................................................39
7.3.
Blinding .......................................................................................................................40

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7.4.
Dose Modification........................................................................................................40
7.4.1.
Special Treatment Considerations ........................................................................40
7.4.1.1.
Management of Subjects with Gastrointestinal Symptoms ..............................40
7.5.
Preparation/Handling/Storage/Accountability...............................................................41
7.6.
Treatment Compliance .................................................................................................41
7.7.
Concomitant Therapy...................................................................................................41
7.8.
Treatment after the End of the Study............................................................................42
8.
Discontinuation Criteria ....................................................................................................43
8.1.
Discontinuation from Study Treatment.........................................................................43
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................43
8.1.2.
Discontinuation of Inadvertently Enrolled Subjects..............................................44
8.2.
Discontinuation from the Study....................................................................................44
8.3.
Subjects Lost to Follow-up...........................................................................................44
9.
Study Assessments and Procedures ...................................................................................45
9.1.
Efficacy Assessments...................................................................................................45
9.1.1.
Appetite and Eating Behavior Assessments..........................................................45
9.1.2.
Neuroimaging Assessments..................................................................................46
9.1.3.
Hormone and Metabolite Assessments .................................................................47
9.2.
Adverse Events ............................................................................................................47
9.2.1.
Serious Adverse Events........................................................................................48
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................49
9.2.2.
Adverse Events of Special Interest .......................................................................49
9.2.2.1.
Hypoglycemia ................................................................................................49
9.2.2.2.
Pancreatitis.....................................................................................................50
9.2.2.3.
Thyroid Malignancies and C-Cell Hyperplasia................................................51
9.2.2.4.
Hypersensitivity Events..................................................................................52
9.2.2.5.
Injection-Site Reactions..................................................................................52
9.2.2.6.
Hepatobiliary Disorders..................................................................................53
9.2.2.7.
Severe Gastrointestinal Adverse Events..........................................................53
9.2.2.8.
Acute Renal Events ........................................................................................53
9.2.3.
Complaint Handling.............................................................................................53
9.3.
Treatment of Overdose.................................................................................................53
9.4.
Safety...........................................................................................................................53
9.4.1.
Laboratory Tests ..................................................................................................53
9.4.2.
Vital Signs ...........................................................................................................54
9.4.3.
Body Weight and Waist Circumference................................................................54
9.4.4.
Electrocardiograms ..............................................................................................54
9.4.5.
Physical Examinations .........................................................................................55

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9.4.6.
Suicidal Ideation Assessment ...............................................................................55
9.4.7.
Safety Monitoring ................................................................................................55
9.4.7.1.
Hepatic Safety................................................................................................56
9.5.
Pharmacokinetics .........................................................................................................58
9.5.1.
Bioanalysis...........................................................................................................58
9.6.
Pharmacodynamics ......................................................................................................58
9.6.1.
Immunogenicity Assessments ..............................................................................58
9.7.
Genetics .......................................................................................................................59
9.8.
Biomarkers...................................................................................................................59
9.9.
Health Economics ........................................................................................................60
9.10. Passive Detection of Eating Activity ............................................................................60
10.
Statistical Considerations and Data Analysis.....................................................................61
10.1. Sample Size Determination ..........................................................................................61
10.2. Populations for Analyses..............................................................................................61
10.2.1.
Study Participant Disposition ...............................................................................61
10.2.2.
Study Participant Characteristics ..........................................................................61
10.2.3.
Treatment Compliance .........................................................................................61
10.3. Statistical Analyses ......................................................................................................61
10.3.1.
Safety Analyses....................................................................................................62
10.3.1.1.
Clinical Evaluation of Safety..........................................................................62
10.3.1.2.
Statistical Evaluation of Safety.......................................................................62
10.3.2.
Pharmacokinetic Analyses....................................................................................62
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................62
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................62
10.3.3.
Pharmacodynamic Analyses.................................................................................62
10.3.3.1.
Pharmacodynamic Parameter Estimation ........................................................62
10.3.3.2.
Pharmacodynamic Statistical Inference...........................................................63
10.3.4.
Evaluation of Immunogenicity .............................................................................63
10.3.5.
Interim Analyses..................................................................................................64
10.3.6.
Exploratory Analysis for Motion Sensor Modeling...............................................64
11.
References ........................................................................................................................65
12.
Appendices .......................................................................................................................70

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List of Tables
Table
Page
Table GPHH.1.
Objectives and Endpoints .......................................................................22
Table GPHH.2.
Study Treatments and Dose Escalation ...................................................38
Table GPHH.3.
Details of Buffet Meal............................................................................81

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List of Figures
Figure
Page
Figure GPHH.1.
Illustration of study design for Protocol I8F-MC-GPHH.........................26

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................71
Appendix 2.
Clinical Laboratory Tests........................................................................76
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................77
Appendix 4.
Blood Sampling Summary......................................................................80
Appendix 5.
Pharmacodynamic Assessments..............................................................81
Appendix 6.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............89
Appendix 7.
Pancreatic Monitoring ............................................................................91
Appendix 8.
Recommended Laboratory Testing for Hypersensitivity Events..............93
Appendix 9.
Protocol Amendment I8F-MC-GPHH(f) Summary - Effect of 
Tirzepatide on Energy Intake and Appetite- and Reward-Related 
Brain Areas in Overweight/Obese Subjects:  A Placebo-Controlled 
6-Week Study with Functional MRI .......................................................95

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1. Protocol Synopsis
Title of Study:
Effect of Tirzepatide on Energy Intake and Appetite- and Reward-Related Brain Areas in Overweight/Obese 
Subjects:  A Placebo-Controlled 6-Week Study with Functional MRI
Rationale:
Tirzepatide (LY3298176) is a long-acting, dual agonist that binds to the glucose-dependent insulinotropic 
polypeptide (GIP) receptor (GIPR) and the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R).  The available 
preclinical and clinical data indicate that simultaneous stimulation of these receptors may enhance insulin secretion, 
improve insulin sensitivity, and reduce body weight beyond the effect of selective GLP-1R stimulation.  
Study I8F-MC-GPHH (GPHH) is a Phase 1 study consisting of a 6-week treatment period, designed to examine the
effect of tirzepatide on energy intake, and central reward and appetite circuits compared with placebo to further 
understand the mechanisms involved in body weight reduction.
Objectives/Endpoints:  
Objectives
Endpoints
Primary
To compare the effect of 5-mg tirzepatide versus 
placebo, at Week 3 on energy intake in a clinical 
setting.

Change from baseline in energy intake (kcal) as 
assessed by ad libitum food intake test
Secondary
To compare the effect of 5-mg tirzepatide versus 
placebo, at Week 3 on:

Parameters of central reward and appetite circuits 
in the fasting state using BOLD fMRI

Change from baseline in BOLD fMRI activation 
to images of highly palatable food (high fat-high 
sugar and high fat-high carbohydrate) during the 
fasting state in the brain reward areas (insula, 
medial frontal gyrus, superior temporal gyrus, 
precentral gyrus, cingulate gyrus)

Parameters of behavioral appetite assessments

Change from baseline in fasting and postprandial 
appetite VAS, and fasting FCI, FCQ-S, Eating 
Inventory, Power of Food Scale questionnaires
Abbreviations:  BOLD = blood oxygenation level-dependent; FCI = Food Craving Inventory; FCQ-S = Food 
Craving Questionnaire-State; fMRI = functional magnetic resonance imaging; VAS = visual analog scale.
Summary of Study Design: 
Study I8F-MC-GPHH is a Phase 1, multicenter, randomized, partially blinded, placebo-controlled, parallel arm 
study, with a positive control, liraglutide, in overweight/obese subjects.  The primary objective of this study is to 
compare the effect of tirzepatide and placebo on energy intake, as assessed by ad libitum food intake test, after 
3 weeks of treatment at a therapeutic dose of 5 mg (Week 3).  Secondary objectives will compare these treatment 
groups for parameters of central reward and appetite circuits at Week 3.  Additional exploratory objectives will 
assess the effect of 10-mg tirzepatide versus placebo on energy intake and parameters of central reward and appetite 
at Week 6.  

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Further exploratory analysis will assess the effect of tirzepatide versus an approved GLP-1 receptor agonist,
liraglutide on energy intake and parameters of central reward and appetite signaling at Weeks 3 and/or 6.  
Liraglutide will also be used as a positive control for the neuroimaging assessments of appetite- and reward-related 
brain areas.  
Tirzepatide maintenance dose levels of 5, 10, and 15 mg are currently being evaluated in the Phase 3 program in 
T2DM and chronic weight management indication; both 5 and 10 mg doses are expected to result in weight loss. 
Tirzepatide 10 mg and liraglutide 3 mg will be attained via step-wise dose escalation to reduce the risk of 
gastrointestinal adverse events. Eligibility for this study will be assessed at screening (Visit 1) and confirmed at the 
beginning of the lead-in period (Visit 2).  
Treatment Arms and Planned Duration for an Individual Subject:
The study will consist of the following periods:  approximately 5-week screening period; 5-day lead-in period; 
6-week treatment period, and a 4-week safety follow-up period.  Subjects will be randomized in a 1:1:1 ratio to 
placebo, tirzepatide, or liraglutide.  Investigators and subjects will be blinded to tirzepatide and placebo treatment; 
however, liraglutide treatment will be open-label, therefore the study is considered partially blinded.  The 
randomization will be stratified by baseline BMI (27 to <30 kg/m2, 30 to <35 kg/m2, and 35 to 50 kg/m2).
Tirzepatide once-weekly (QW) dosing will start at 5 mg for 3 weeks followed by a dose escalation to 10 mg for 
3 weeks.  Subjects will return to the Clinical Research Unit (CRU) each week for the QW administration of 
tirzepatide or placebo.  
Liraglutide once-daily (QD) dosing will start at 0.6 mg for 1 week followed by weekly step-wise dose escalations to
1.2, 1.8, and 2.4 mg, until a 3 mg QD dose is reached.  The 3-mg dose of liraglutide will be maintained for 10 days.  
Subjects will self-administer liraglutide at home in the evening.
Number of Subjects:
Up to 111 subjects (37 subjects per treatment arm) are planned to be randomized so that approximately 93 subjects 
(31 subjects per treatment arm) complete the study, assuming 15% discontinuation rate.
Statistical Analysis:
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all protocol requirements.  
Safety parameters that will be assessed include safety lab parameters (including tirzepatide anti-drug antibodies), 
vital signs, treatment-emergent adverse events (TEAEs; including TEAEs of special interest), and serious adverse 
events (SAEs).  The parameters will be listed and summarized using standard descriptive statistics.
Pharmacodynamic (PD) analyses will be conducted on data from all subjects who receive at least 1 dose of the 
investigational product and have evaluable data. The primary PD parameter for analysis is energy (kcal) intake, 
which will be analyzed using an analysis of covariance (ANCOVA) to compare the effect of tirzepatide versus 
placebo at Week 3 with terms, treatment, baseline BMI stratum, and baseline energy (kcal) intake as a covariate in 
the model. The response variable in the model will be the change from baseline to Week 3 in energy (kcal) intake, 
as assessed by ad libitum food intake test. The primary analysis will show least squares means of energy (kcal) 
intake by treatment and the treatment difference of tirzepatide versus placebo as well as standard error and 95% 
confidence interval.  All tests will be done at the 2-sided 0.05 α level, unless otherwise specified.
Additional exploratory analyses of the data may be conducted as deemed appropriate.

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2. Schedule of Activities

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Study Schedule Protocol I8F-MC-GPHH:  Screening and Lead-in
Procedure
Screening
Lead-in
Comments
Week of Treatment
-5 to -2
-1
Visit
1
2
NA
NA
NA
3
Study Day
-35 to -5
-4
-3
-2
-1
1 
(predose)
Screening Procedures
Informed consent
X
Informed consent will be performed before any 
other screening procedures.
Lifestyle interview
X
Performed to ensure subjects understand what they 
will be doing and if they are capable of meeting
study demands.
Medical history, menstrual cycle 
assessment
X
Menstrual cycle assessment performed in females 
only.
Drug and alcohol screen
X
Procedures may be repeated throughout the study as 
deemed necessary by the investigator.
Physical examination/medical 
assessment
X
X
X
Full physical examination at screening.  After 
screening, medical assessment is performed to 
include medical review and targeted examination, 
as appropriate.
Height, weight, and BMI
X
X
X
Height and BMI at screening only.
Waist circumference
X
X
Vital signs (BP/PR/body temperature)
X
X
X
See Section 9.4.2 for details.  Vital sign 
measurements whose nominal times are not listed 
in the schedule should be taken before PK samples 
scheduled on the same day.  
ECGs (single for safety)
X
X
See Section 9.4.3 for details.  Electrocardiograms 
must be recorded before collecting any blood 
samples using equipment available at the study site.  
Confirm inclusion/exclusion criteria
X
X
C-SSRS (baseline/ screening form) + 
SHSF + SHFF
X
The SHFF is required only if triggered by the 
SHSF, per instructions in the form. 
PHQ-9
X
Clinical Procedures

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Procedure
Screening
Lead-in
Comments
Week of Treatment
-5 to -2
-1
Visit
1
2
NA
NA
NA
3
Study Day
-35 to -5
-4
-3
-2
-1
1 
(predose)
Outpatient visit at CRU
X
X
X
Lead-in outpatient visit can occur anytime between 
Day -4 and Day -1.
Training on signs/symptoms of 
hypoglycemia and self-treatment
X
Training can be completed anytime during the 
lead-in period prior to dosing.  
Training on self-administration of the 
subcutaneous liraglutide injection 
X
Training can be completed anytime during the 
lead-in period prior to dosing.
Concomitant medication review
X
X
X
Review of concomitant medication and adverse 
event can occur anytime between Day -4 and Day -
1.
Adverse event review
X
X
X
Randomization
X
Laboratory Tests
Safety laboratory tests
X
X
See Appendix 2 for details. Subjects will fast for at 
least 12 hours before all blood samples are
collected.
Pregnancy test
X
X
X
See Appendix 2 for details. Performed and results 
confirmed prior to MRI.
Hormones and metabolites for appetite 
and metabolism regulation in the 
fasting and postprandial states
X
Plasma or serum samples to be taken to measure 
ghrelin, glucagon, glucose, and triglycerides 
(fasting), insulin (fasting and postprandial), and 
PYY, active GIP, active GLP-1, pancreatic 
polypeptide, amylin, and leptin (postprandial).  
Postprandial samples will be taken within 
approximately 60 minutes of completing a test 
lunch meal.
Appetite and Eating Behavior
See Appendix 5 for details.

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Procedure
Screening
Lead-in
Comments
Week of Treatment
-5 to -2
-1
Visit
1
2
NA
NA
NA
3
Study Day
-35 to -5
-4
-3
-2
-1
1 
(predose)
Ad libitum food intake test at lunch 
(clinic-based), with appetite VAS
X
Appetite VAS will be completed before and after 
the lunch test meal. During Lead-in period, ad 
libitum food intake test at lunch can be done in 
between Day -4 and Day -1.
FCI, FCQ-S, Eating Inventory, BIS,
and Power of Food Scale 
questionnaires
X
During Lead-in period, questionnaires can be done 
in between Day -4 and Day -1 in a fasted state
shortly after arriving to the study site.
Retrospective appetite VAS
X
Neuroimaging
See Appendix 5 for details.
BOLD fMRI
X
During Lead-in period, fMRI can be done in 
between Day -4 and Day -1 in a fasted state.
Diagnostics
PK sample
X
PK sample not required for subjects randomized to 
liraglutide treatment.
Immunogenicity
X
Pharmacogenetic sample
X
Nonpharmacogenetic stored samples
X
Abbreviations:  BIS = Barratt Impulsiveness Scale; BMI = body mass index; BOLD = blood oxygenation level dependent; BP = blood pressure; CRU = clinical research unit; C-
SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; FCI = Food Craving Inventory; FCQ-S = Food Craving Questionnaire-State; fMRI = functional 
magnetic resonance imaging; GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagon-like peptide 1; MRI = magnetic resonance imaging; 
PD = pharmacodynamics; PHQ-9 = Patient Health Questionnaire-9; PK = pharmacokinetics; PR = pulse rate; PYY = peptide YY; SHFF = Self-Harm Follow-Up Form; SHSF 
= Self-Harm Supplementary Form; VAS = visual analog scale.

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Study Schedule Protocol I8F-MC-GPHH:  Treatment Period
Procedure
Treatment
Week of Treatment
1
2
3
4
5
6
Visit
3
4
5
6
7
8
9
10
11
NA
Study Day
1 a
8
± 1
15
± 1
16
± 1
17 to 21g
22
± 1
29
± 1
36
± 1
37
± 1
38-39
± 1
Clinical Procedures
Outpatient visit at CRU
X
X
X
X
X
X
X
X
Weight
P
P
P
P
P
Waist circumference
P
P
Vital signs (BP/PR/body temperature)
P
P
P
P
P
P
P
P
ECGs (single safety)
Concomitant medication review
X
X
X
X
X
X
X
X
X
Adverse event review
X
X
X
X
X
X
X
X
X
Dose Administration
Tirzepatide/placebo b
X
X
X
X
X
X
Liraglutide c
Liraglutide will be self-administered every evening from Day 1 through Day 38
Laboratory tests
Safety laboratory tests
X
Pregnancy testh
X
X
Hormones and metabolites for appetite 
and metabolism regulation in the fasting 
and postprandial states d
X
X
Appetite and Eating Behavior
Ad libitum food intake test at lunch 
(clinic-based), with appetite VAS e
X
X
FCI, FCQ-S, Eating Inventory, BIS, and 
Power of Food Scale questionnaires
X
X
Retrospective appetite VAS
X
X
Neuroimaging
BOLD fMRI
X
X
Diagnostics
PK sample f
P
P
P

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Procedure
Treatment
Week of Treatment
1
2
3
4
5
6
Visit
3
4
5
6
7
8
9
10
11
NA
Study Day
1 a
8
± 1
15
± 1
16
± 1
17 to 21g
22
± 1
29
± 1
36
± 1
37
± 1
38-39
± 1
Immunogenicity
P
P
Nonpharmacogenetic stored samples
P
P
Abbreviations:  BIS = Barratt Impulsiveness Scale; BMI = body mass index; BOLD = blood oxygenation level-dependent; BP = blood pressure; CRU = clinical research unit; 
ECG = electrocardiogram; FCI = Food Craving Inventory; FCQ-S = Food Craving Questionnaire-State; fMRI = functional magnetic resonance imaging; 
GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagon-like peptide 1; MRI = magnetic resonance imaging; NA = not applicable; P = predose; 
PD = pharmacodynamics; PK = pharmacokinetics; PR = pulse rate; PYY = peptide YY; VAS = visual analog scale.
a  Predose assessments on Day 1 are shown in the Screening/Lead-in Schedule of Activities. 
b Tirzepatide or placebo will be administered in the CRU only by CRU staff, the morning after an overnight fast of at least 12 hours.  
c Liraglutide will be self-administered by the subject in the evenings while at home.  
d Plasma or serum samples to be taken to measure ghrelin, glucagon, glucose, and triglycerides (fasting), insulin (fasting and postprandial), and PYY, active GIP, 
active GLP-1, pancreatic polypeptide, amylin, and leptin (postprandial).  Postprandial samples will be taken within approximately 60 minutes of completing a 
test lunch meal.
e Appetite VAS will be completed before and after the test meal.
f PK sample not required to be collected for subjects randomized to liraglutide treatment.
g Adverse event and concomitant medication review may be remotely assessed any time between Days 17 and 21 if deemed necessary by the investigator.
h  Pregnancy test will be conducted prior to fMRI.

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Study Schedule Protocol I8F-MC-GPHH:  Follow-up Period
Procedure
Follow-up
Early 
Termination
Comments
Weeks Post-Final Dose
3
4
NA
Visit
12
NA
13
NA
Study Day
(Subjects Randomized to Tirzepatide/Placebo)
59 ± 1
60 - 63 ± 1
64 ± 1
NA
Study Day 
(Subjects Randomized to Liraglutide)
61 ± 1
62 - 65 ± 1
66 ± 1
NA
Clinical Procedures
Outpatient visit at CRU
X
X
X
At-home assessment
X
Weight and waist circumference
X
X
Vital signs (BP/PR/body temperature)
X
X
ECGs (single safety)
X
X
Concomitant medication review
X
X
X
Adverse event review
X
X
X
Physical examination
X
X
Laboratory tests
Safety laboratory tests
X
X
See Appendix 2 for details. Subjects will 
fast for at least 12 hours before all blood 
samples are collected.
Pregnancy test
X
X
Appetite and Eating Behavior
Training on use of RFPM and SmartIntake® app 
training
X
Ad libitum food intake test at lunch (clinic-based) 
X
X
See Appendix 5 for details.  Only test meal 
(lunch) is required to be completed on Visit 
13. Subjects must be wearing a
wrist-wearable device during the test meals.
Ad libitum food intake assessment (free-living) 
X
See Appendix 5 for details.  Measured with 
the RFPM and SmartIntake app.  Subjects 
will complete this assessment at home.

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Procedure
Follow-up
Early 
Termination
Comments
Weeks Post-Final Dose
3
4
NA
Visit
12
NA
13
NA
Study Day
(Subjects Randomized to Tirzepatide/Placebo)
59 ± 1
60 - 63 ± 1
64 ± 1
NA
Study Day 
(Subjects Randomized to Liraglutide)
61 ± 1
62 - 65 ± 1
66 ± 1
NA
Other Efficacy/PD Assessments
Provide subjects with wrist-wearable device and 
training on its use
X
See Section 9.10 for details.  
Passive eating activity data collection via 
wrist-wearable device
X
X
X
See Section 9.10 for details.  
Return wrist-wearable device to CRU staff
X
X
Diagnostics
PK sample
X
X
PK sample not required for subjects 
randomized to liraglutide treatment.
Immunogenicity
X
X
Abbreviations:  BP = blood pressure; CRU = clinical research unit; ECG = electrocardiogram; NA = not applicable; PD = pharmacodynamics; PK = pharmacokinetics; PR = pulse 
rate; RFPM = Remote Food Photography Method©.

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3. Introduction
3.1.
Study Rationale
Tirzepatide (LY3298176) is a long-acting, dual agonist that binds to the glucose-dependent 
insulinotropic polypeptide (GIP) receptor (GIPR) and the glucagon-like peptide-1 (GLP-1) 
receptor (GLP-1R).  The available preclinical and clinical data indicate that simultaneous 
stimulation of these receptors may enhance insulin secretion, improve insulin sensitivity, and 
reduce body weight beyond the effect of selective GLP-1R stimulation (Frias et al. 2018; 
Coskun et al. 2018).  Study I8F-MC-GPHH (GPHH) is a Phase 1 study consisting of a 6-week
treatment period, designed to examine the effect of tirzepatide on energy intake, and central 
reward and appetite circuits compared with placebo to further understand the mechanism 
involved in body weight reduction.
3.2.
Background
Glucagon-like peptide 1 is synthesized and secreted from enteroendocrine L cells in the small 
and large intestine and is a well-characterized incretin hormone that potentiates insulin and 
reduces glucagon secretion in a glucose-dependent manner after meal ingestion. GLP-1 exerts 
its insulinotropic action through distinct G-protein-coupled receptors highly expressed on islet 
cells and in some non-islet cells.  For example, GLP-1Rs are expressed throughout the brain, in 
regions that control glucose homeostasis, gut motility, energy intake, aversive signaling, and 
cardiovascular function (Campbell and Drucker 2013; Farr et al. 2016).  Currently, there are 
approved GLP-1 receptor agonists (GLP-1RAs) for the treatment of diabetes and obesity.  
Glucose-dependent insulinotropic polypeptide is synthesized and secreted by enteroendocrine K 
cells in the proximal intestine.  The GIPR is widely expressed in islets, gut, adipose tissue, and 
brain.  GIP secretion is primarily regulated by nutrients, especially fats.  GIP is responsible for 
the majority of the insulinotropic incretin effect in humans (Calanna et al. 2013; Nauck and 
Meier 2016; Nauck and Meier 2019). GIP has important additional functions that are distinct 
from GLP-1.  GIP promotes glucagon secretion at low blood glucose levels to augment 
endogenous glucose production.  It stimulates lipolysis and inhibits insulin-induced lipogenesis 
in human adipocytes.  Although GIP signaling on body weight regulation is neutral, 
co-administration of individual GIP and GLP-1 selective agonists as well as unimolecular 
co-agonists has shown profound weight-lowering benefits that exceed that of either agent alone 
(Finan et al. 2016).  Despite the observed effects of GIP, currently, no pharmaceutical agents that 
are based on its structure and function have been developed for treatment of metabolic 
conditions.  
Tirzepatide is a 39-amino-acid synthetic peptide with dual agonistic activity at both the GIP and 
GLP-1 receptors. Its structure is based on the GIP sequence and includes a C20 fatty di-acid 
moiety (Coskun et al. 2018). It is administered once weekly (QW) by subcutaneous (SC) 
injection.
Tirzepatide is being developed as a therapy to improve glycemic control in adults with type 2 
diabetes mellitus (T2DM), as an adjunct to diet and exercise.  Tirzepatide is also being 
investigated for chronic weight management and nonalcoholic steatohepatitis.

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In a Phase 1 study (Coskun et al. 2018) that included single- and multiple-ascending dose (SAD, 
MAD) parts, tirzepatide has been administered as a single SC dose up to 8 mg in healthy 
subjects.  In the MAD part, higher doses up to 10 mg were attained in healthy subjects via dose 
escalation.  In the same study, doses up to 15 mg were achieved in patients with T2DM via dose 
escalation.  In this study, gastrointestinal (GI) adverse events (AEs) (nausea, vomiting, diarrhea, 
abdominal distension) and decreased appetite were the most frequently reported events by both 
healthy subjects and patients with T2DM and were dose related.  Most AEs were mild in 
severity, a few were moderate, and none were reported as severe.  During the SAD study, the 
high incidence of GI AEs, notably vomiting, were considered to be dose limiting at the 8-mg 
dose; therefore, the 5-mg dose was considered the maximum tolerated dose (MTD) for a single 
dose.  A dose-dependent increase in heart rate was detected in both healthy subjects and patients 
with T2DM who received tirzepatide, similar to what was observed with selective GLP-1RAs.  
A few subjects experienced transient elevations in lipase and/or amylase levels, but these 
laboratory observations were not associated with any relevant clinical outcomes.
Once-weekly doses of 1, 5, 10, and 15 mg have been further investigated in a Phase 2 study 
(Frias et al. 2018).  Additionally, dose levels of 12 and 15 mg, attained using alternate 
dose-escalation schemes, were investigated in a 12-week Phase 2 study (Frias et al. 2020).  
Doses above 5 mg of tirzepatide were attained via stepwise dose escalation.  Results from the 
2 Phase 2 studies demonstrated that tirzepatide at doses between 5 and 15 mg provided clinically 
meaningful efficacy in lowering both glucose and body weight.  Gastrointestinal-related AEs 
(nausea, diarrhea, vomiting) were the most frequently reported AEs in Phase 2 studies.  The 
majority of the treatment-emergent adverse events (TEAEs) were mild or moderate in severity.  
Treatment with tirzepatide was associated with treatment-emergent anti-drug antibodies 
(TE-ADAs) in 40.7% in the 26-week Phase 2 study.  However, the presence of anti-drug 
antibodies (ADAs) appeared to have no effect on the pharmacokinetics (PK), safety, or efficacy 
of tirzepatide.  There were no other clinically relevant safety observations in the Phase 1 and 2 
studies.
Tirzepatide terminal half-life was estimated to be approximately 5 days, thus supporting a QW 
dosing regimen, with maximum observed drug concentration occurring 24 to 72 hours post-dose.
Glucagon-like peptide-1 receptor agonists have demonstrated efficacy in body weight reduction.  
Liraglutide (Saxenda®) is the first agent from this class that has been approved for the treatment 
of chronic weight management, at a dose of 3 mg/day.  The following dose escalation to a 3-mg 
dose is recommended to mitigate the risk of GI side effects; 1 week at 0.6 mg once-daily (QD), 
1 week at 1.2 mg QD, 1 week at 1.8 mg QD, 1 week at 2.4 mg QD, followed by 3.0 mg QD 
onwards (Saxenda package insert 2018). Commonly reported adverse reactions following 
liraglutide administration include GI disorders (e.g., nausea, diarrhea, constipation, vomiting), 
metabolism and nutrition disorders (hypoglycemia in patients with T2DM, decreased appetite), 
and nervous system disorders (e.g., headache) (Saxenda package insert 2018).  
Studies that investigated the mechanism of action of liraglutide have shown that liraglutide
induces weight loss by reducing appetite and energy intake, with no effect on energy expenditure
(van Can et al. 2014; Blundell et al. 2017).

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In Phase 1 and Phase 2 development, treatment with tirzepatide has shown clinically meaningful 
effect on body weight regulation by suppressing appetite and reducing energy intake, but no data 
are available regarding the effects of tirzepatide on brain activity related to different food cues.
In the literature, it is well demonstrated that GLP-1 affects central reward and appetite circuits of 
the brain in healthy lean and obese subjects as well as subjects with T2DM (van Bloemendaal et 
al. 2014; Farr et al. 2016; Hayes and Schmidt 2016).  
Compared with healthy lean subjects, obese patients with T2DM and non-diabetic obese subjects 
showed increased brain responses to visual food cues in appetite- and reward-related brain 
regions (insula and amygdala).  Intravenous treatment with a GLP-1 receptor agonist, exenatide, 
reduced these brain responses which correlated with reduction in food intake (van Bloemendaal 
et al. 2014). This effect was mediated by the GLP-1 receptor activation, as the 
exenatide-induced effects were inhibited by infusion of the GLP-1 receptor antagonist, exendin 
9-39 (van Bloemendaal et al. 2014). Similarly, treatment with liraglutide has been shown to 
reduce brain activation in response to highly desirable food images in the parietal cortex (Farr et 
al. 2016) as well as the insula and putamen (ten Kulve et al. 2016). Recent literature has 
proposed the reducing effect of liraglutide on brain activation may be short-term; at 5 weeks 
following dose escalation to 3 mg, treatment with liraglutide did not show differential activations 
in response to food cues, compared to placebo (Farr et al. 2019). These results warrant further 
investigations of how dual GIPR/GLP-1R agonism affects brain activation in response to visual 
food cues.
Study GPHH is designed to assess the effect of tirzepatide versus placebo on energy intake, 
assessed by ad libitum food intake test, as well as central reward and appetite circuits using 
functional magnetic resonance imaging (fMRI) under fasting condition.  The effect of liraglutide 
versus tirzepatide and placebo on energy intake will be assessed as an exploratory objective.  In 
addition, liraglutide treatment will be used in the current study as a positive control for 
neuroimaging assessments.  The study is expected to provide important, new information on 
feeding behavior associated with a dual GIP/GLP-1 receptor agonist treatment.
3.3.
Benefit/Risk Assessment
The most common safety issue with administration of tirzepatide was related to frequent 
reporting of decreased appetite and GI side effects, most commonly nausea, vomiting, and 
diarrhea.  These GI events were generally mild in severity, with few moderate, and no severe 
events reported in Phase 1 studies.  Tirzepatide triggered generation of ADAs in a subset of 
patients in Phase 2 trials.  The presence of tirzepatide ADA did not affect PK or 
pharmacodynamic (PD) parameters and was not associated with increased incidence of local or 
systemic hypersensitivity AEs in Phase 1 and Phase 2 studies up to 26 weeks of exposure.  Based 
on these results, tirzepatide ADA represents a low risk in exposed patients, but more data is 
needed for definitive conclusion on the frequency and severity of possible side effects.  No other 
clinically relevant safety concerns were identified in the dose range up to 15 mg, the highest dose 
investigated in Phase 1 and Phase 2 studies in T2DM patients, administered QW up to 26 weeks.
Findings to date indicate that the safety profile for a dual GIP/GLP-1 receptor agonist is similar 
to the safety profile of the selective GLP-1RAs.  Potential risks, such as GI effects, acute 

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pancreatitis, increases in heart rate, and hypoglycemic events are consistent with the risks 
associated with currently available GLP-1RAs, including liraglutide, the positive control in this 
trial.  To mitigate the risk of GI adverse events, the target tirzepatide 10 mg and liraglutide 3 mg 
doses will be attained via step-wise dose escalation.  Based on the results of Phase 2 study 
(Frias et al. 2018), tirzepatide doses of 5, 10, and 15 mg are expected to lead to meaningful body 
weight reduction.  While 5-mg tirzepatide can safely be administered as a first dose (i.e., the 
MTD in Study GPGA; Coskun et al. 2018), doses of 10 and 15 mg can be attained only via step 
wise dose escalation to minimize the potential for GI adverse events.
Details on the management of the potential risks are provided in Section 7.4.1.1 (Management of 
Subjects with Gastrointestinal Symptoms) and Section 9.2.2 (Adverse Events of Special 
Interest).  The monitoring plan for all AEs of special interest is included in this protocol, as well 
as treatment measures.
Since Study GPHH will enroll subjects without diabetes, no self-monitoring of plasma glucose
(PG) is planned.  Consistent with the mechanism of action of incretins, which are non-
secretagogues, severe hypoglycemia has not been reported in Phase 1 or Phase 2 trials that 
included healthy subjects or patients with T2DM.  However, to mitigate the risk, the subjects in 
this study will be trained on signs and symptoms of hypoglycemia and self-treatment measures.  
Section 9.2.2.1 (Hypoglycemia) describes definitions and criteria when diagnosing and 
categorizing an episode considered to be related to hypoglycemia, and provides detailed 
information concerning the management of hypoglycemia.  
There are several possible AEs associated with the planned procedures in the study.  A magnetic 
resonance imaging (MRI) scanner will be used to assess brain response patterns to food and 
control images (see Appendix 5 for more details).  Some level of claustrophobia or discomfort 
may be experienced from staying in the fMRI scanner.
Although there is a possibility of weight loss associated with tirzepatide treatment, subjects in 
Study GPHH are not expected to have direct health-related benefits due to the short duration of 
study treatment.  The potential risks described above, which are also similarly reported in 
liraglutide, are considered clinically detectable, transient, manageable, and associated with low 
long-term health risks.  The routine clinical safety monitoring procedures planned in this study is 
considered sufficient to mitigate the possible risks.
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated AEs of tirzepatide are to be found in the Investigator’s Brochure (IB).  
Information on AEs expected to be related to the investigational product (IP) can be found in 
Section 6 (Summary of Data, Development Core Safety Information) of the IB.  Information on 
SAEs that are expected in the study population independent of drug exposure will be assessed by 
the sponsor in aggregate, periodically during the course of the study, and can be found in 
Section 5 (Effects in Humans) of the IB.
More detailed information about the known and expected benefits and risks of liraglutide 
(Saxenda) may be found in the Package Insert or US Prescribing Information (USPI).

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4. Objectives and Endpoints
Table GPHH.1 shows the objectives and endpoints of the study.
Table GPHH.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To compare the effect of 5-mg tirzepatide versus 
placebo, at Week 3, on energy intake in a clinical 
setting.

Change from baseline in energy intake (kcal) as 
assessed by ad libitum food intake test 
Secondary
To compare the effect of 5-mg tirzepatide versus 
placebo, at Week 3 on:

Parameters of central reward and appetite circuits 
in the fasting state using BOLD fMRI

Change from baseline in BOLD fMRI activation 
to images of highly palatable food (high fat-high 
sugar and high fat-high carbohydrate) during the 
fasting state in the brain reward areas (insula, 
medial frontal gyrus, superior temporal gyrus, 
precentral gyrus, cingulate gyrus)

Parameters of behavioral appetite assessments

Change from baseline in fasting and postprandial 
appetite VAS, and fasting FCI, FCQ-S, Eating 
Inventory, Power of Food Scale questionnaires
Exploratory
To compare the effect of 5- or 10-mg tirzepatide versus 
placebo at Week 3 and/or Week 6 on:

Parameters of central reward and appetite circuits 
in the fasting state using BOLD fMRI (Week 6/10 
mg)

Change from baseline in BOLD fMRI activation
to images of highly palatable food (high fat-high 
sugar and high fat-high carbohydrate) during the 
fasting state in the brain reward areas (insula, 
medial frontal gyrus, superior temporal gyrus, 
precentral gyrus, cingulate gyrus)

Parameters of behavioral appetite assessments
(Week 6/10 mg)

Change from baseline in fasting and postprandial
appetite VAS, and fasting FCI, FCQ-S, Eating 
Inventory, Power of Food Scale questionnaires

Energy intake in a clinical setting (Week 6/10 mg)

Change from baseline in energy intake (kcal) as 
assessed by ad libitum food intake test

Parameters of central reward and appetite circuits 
in the fasting state using BOLD fMRI (Week 3/5 
mg and Week 6/10 mg)

Change from baseline in BOLD fMRI activation 
to images of highly palatable food (high fat-high 
sugar and high fat-high carbohydrate) during
fasting state in the hippocampus, putamen, 
orbitofrontal cortex, and ventral striatum brain 
regions

Impulsivity (Week 3/5 mg and Week 6/10 mg)

Change from baseline in BIS questionnaire

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
Appetite and metabolism regulating hormones and 
metabolites (Week 3/5 mg and Week 6/10 mg)

Change from baseline in ghrelin, glucagon, 
glucose, and triglycerides (fasting), insulin (fasting 
and postprandial), and amylin, GIP, GLP-1, leptin, 
pancreatic polypeptide, and PYY (postprandial)
To compare the effect of 5- and 10-mg tirzepatide
versus liraglutide and liraglutide versus placebo at 
Week 3 and/or Week 6 on:

Energy intake in a clinical setting (Week 3/5 mg 
and Week 6/10 mg)

Changes from baseline in energy intake (kcal) as 
assessed by ad libitum food intake test 

Parameters of behavioral appetite assessments 
(Week 3/5 mg and Week 6/10 mg) 

Change from baseline in fasting and postprandial
appetite VAS, and fasting FCI, FCQ-S, Eating 
Inventory, Power of Food Scale questionnaires

Parameters of central reward and appetite circuits 
in the fasting state using BOLD fMRI (Week 3/5 
mg and Week 6/10 mg)

Change from baseline in BOLD fMRI activation
to images of highly palatable food (high fat-high 
sugar and high fat-high carbohydrate) during the 
fasting state in the brain reward areas (insula, 
medial frontal gyrus, superior temporal gyrus, 
precentral gyrus, cingulate gyrus, hippocampus, 
putamen, orbitofrontal cortex, and ventral 
striatum)

Appetite and metabolism regulating hormones and 
metabolites (Week 3/5 mg and Week 6/10 mg)

Change from baseline in ghrelin, glucagon, 
glucose, and triglycerides (fasting), insulin (fasting 
and postprandial), and amylin, GIP, GLP-1, leptin, 
pancreatic polypeptide, and PYY (postprandial)
To assess the safety and tolerability of tirzepatide.

Adverse events

Safety laboratory parameters

Frequency of treatment-emergent 
anti-tirzepatide antibodies
Abbreviations: BIS = Barratt Impulsiveness Scale; BOLD = blood oxygenation level-dependent; FCI = Food 
Craving Inventory; FCQ-S = Food Craving Questionnaire-State; fMRI = functional magnetic resonance imaging; 
GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagon-like peptide 1; PYY = peptide YY; VAS 
= visual analog scale.

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5. Study Design
5.1.
Overall Design
This is a Phase 1, multicenter, randomized, partially blinded, placebo-controlled, parallel-arm 
study, with a positive control, liraglutide in overweight/obese subjects.  The primary objective of 
this study is to compare the effect of tirzepatide and placebo on energy intake, as assessed by ad 
libitum food intake test, after 3 weeks of treatment at a therapeutic dose of 5 mg (Week 3). 
Secondary objectives will compare these treatment groups for parameters of central reward and 
appetite circuits at Week 3. Additional exploratory objectives will assess the effect of 10-mg 
tirzepatide versus placebo on energy intake and parameters of central reward and appetite at 
Week 6.  
Further exploratory analysis will assess the effect of tirzepatide versus liraglutide, and liraglutide
versus placebo on energy intake and parameters of central reward and appetite signaling at 
Weeks 3 and/or 6.  
Liraglutide will also be used as a positive control for the neuroimaging assessments of 
appetite- and reward-related brain areas.  
See Section 5.4 for details on study design rationale.  
The study will consist of 4 periods (see Section 2, Schedule of Activities):

approximately 5-week screening period (Visit 1; Days -35 to -5)

a 5-day lead-in period, including pre-dose assessments on Day 1 (Visits 2 to 3)
o
3 clinical research unit [CRU] outpatient visits

a 6-week treatment period (Visits 3 to 11)
o
9 CRU outpatient visits

a 4-week safety follow-up period (Visits 12 and 13)
o
2 CRU outpatient visits 
The subject will sign the informed consent form (ICF) before any study procedures are 
performed.  Eligibility will be assessed at screening (Visit 1) and confirmed during the lead-in 
period (Visit 2), when safety laboratory results will be available.  
Subjects will perform baseline assessments in the CRU prior to randomization, according to the 
Schedule of Activities (Section 2).  After the completion of all baseline procedures, subjects will 
be randomized in a 1:1:1 ratio to tirzepatide, placebo, or liraglutide. Investigators and subjects 
will be blinded to tirzepatide and placebo treatment; however, liraglutide treatment will be 
open-label, therefore the study is considered partially blinded (see Section 5.4).  The 
randomization will be stratified by baseline BMI (27 to <30 kg/m2, 30 to <35 kg/m2, and 35 to 
50 kg/m2).

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Tirzepatide QW dosing will start at 5 mg for 3 weeks followed by a dose escalation to 10 mg for 
3 weeks.  Subjects will return to the CRU each week for the QW administration of tirzepatide or 
placebo.
Liraglutide QD dosing will start at 0.6 mg for 1 week followed by weekly step-wise dose 
escalations to 1.2, 1.8, and 2.4 mg, until a 3 mg QD dose is reached.  The 3-mg dose of 
liraglutide will be maintained for 10 days.  Subjects will self-administer liraglutide at home in 
the evening.  
Section 2 (Schedule of Activities) details all planned visits and procedures for this study.  After 
completion of the 6-week treatment period, subjects will attend 2 follow-up outpatient visits at 
the CRU; approximately 3 and 4 weeks after the last dose of study drug. The final follow-up 
visit will assess subject safety, subjects will return the wearable device, and subsequently 
complete each subject’s participation.
All subjects will receive study diaries where they will be instructed to record relevant clinical 
information, when outside of the CRU (e.g., AEs, concomitant medications, details of drug 
dosing, hypoglycaemia symptoms).  
Figure GPHH.1 illustrates the study design.  Study governance considerations are described in 
detail in Appendix 3.

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Abbreviations: BOLD = blood oxygenation level-dependent; fMRI = functional MRI; QD = once daily; QW = once weekly.  
Figure GPHH.1.
Illustration of study design for Protocol I8F-MC-GPHH.

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5.2.
Number of Participants
Up to 111 subjects (37 subjects per treatment arm) may be enrolled to maximize the probability 
that approximately 93 subjects (31 subjects per treatment arm) complete the study.  For purposes 
of this study, a subject completes the study when all scheduled procedures shown in the Schedule 
of Activities have been finished.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
5.4.
Scientific Rationale for Study Design
Tirzepatide treatment is currently being investigated for chronic weight management, therefore 
overweight/obese subjects only will be enrolled as the target population.  In addition, 
overweight/obese subjects are expected to be more susceptible to a potential weight reduction 
effect by tirzepatide and liraglutide as compared to lean subjects.  Previous literature has 
confirmed obese subjects (body mass index [BMI] ≥30 kg/m2) had increased brain responses to 
food cues in central reward- and appetite-related brain regions, compared to lean subjects (BMI 
<25 kg/m2) (van Bloemendaal et al. 2014).  To avoid the confounding effect of changes in 
glucose regulation on energy intake, the study will enroll nondiabetic subjects only.
Study GPHH will employ a parallel-group design to avoid the confounding effects of the study 
treatments expected if a cross-over design is used.  
The primary study measure of the ad libitum food intake test was chosen as the most 
reproducible and clinically relevant measure of energy intake.  The secondary study measures, 
such as functional neuroimaging (blood oxygenation level-dependent [BOLD] MRI), parameters 
of appetite, and eating attitudes and behaviors, are expected to provide important additional data.  
All study measures and methods of assessment are well validated and fully established in the 
medical literature as the parameters and methods relevant for objectives of Study GPHH.  
Placebo has been chosen as the primary control treatment to assess whether any observed effects 
are treatment-related or simply reflect the study conditions.  Liraglutide (Saxenda) has been
chosen as a neuroimaging positive control for GLP-1 pharmacology.  Liraglutide (1.8 mg) has 
been shown to reduce brain activation in response to highly desirable food images in the parietal 
cortex (Farr et al. 2016) as well as the insula and putamen (ten Kulve et al. 2016).  The dose 
justification for tirzepatide and liraglutide is provided in Section 5.5 (Justification of Dose).
The timing of endpoint measurements (Week 3 and Week 6) was determined based on the effect 
of GLP-1 on brain centers and the time needed to escalate doses.  In addition, tirzepatide doses 
of 5-mg and 10-mg have shown to result in clinically meaningful body weight reduction (Frias et 
al. 2018).  Previous literature confirms liraglutide effects on central nervous system activation 
were observed following 10 to 17 days of treatment, where liraglutide dose was escalated weekly 
to 1.8 mg (Farr et al. 2016; ten Kulve et al. 2016), supporting efficacy assessments at Week 3 in 
the current study. Given the possibility that the effect of incretins on brain activation is short 

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term (Farr et al. 2019), the Week 3 efficacy assessment of 5-mg tirzepatide versus placebo will 
be the primary objective. The influence of higher tirzepatide doses, such as 10 mg, on brain 
activity is not yet understood, therefore efficacy assessments in the current study will occur at 
Week 6 (as exploratory endpoints), due to the need for dose escalation to attain a 10-mg 
tirzepatide dose.  
In addition, efficacy assessments at Week 6 was chosen to observe the effect of tirzepatide and 
liraglutide after the dose-escalation regimen to reach 10 mg and 3 mg, respectively. 
The dosing of tirzepatide will be double blinded and placebo-controlled in order to avoid bias in 
the collection and evaluation of data during its conduct.  Liraglutide dosing will be open label as 
blinding is not possible due to the QD dosing regimen.  In order to achieve the recommended 
liraglutide dose-escalation scheme, liraglutide doses must be self-administered daily in 
comparison to the weekly dosing of tirzepatide/placebo in the CRU.  
The rationale for the sample size is provided in Section 10.1 (Sample Size Determination).
5.5.
Justification for Dose
Tirzepatide maintenance dose levels of 5, 10, and 15 mg are currently being evaluated in the 
Phase 3 program for T2DM and chronic weight management indication. Results from a Phase 2 
study (Frias et al. 2020 have shown that in addition to the highest dose level of 15 mg, tirzepatide 
dose levels of 5 and 10 mg also result in clinically meaningful body weight reduction.  
Weekly doses of tirzepatide ranging from 0.25 to 8 mg have been studied in the single-ascending 
dose study, with MTD achieved at 5 mg when administered as a single dose. Dose levels of 
10 and 15 mg were tolerated when administered via step-wise dose escalation (Frias et al. 2018; 
Coskun et al. 2018).  Tirzepatide 15 mg is predicted to maintain an exposure multiple of 1.6 to 
2.4 to the no-observed-adverse-effect level doses in 6-month monkey and rat toxicology studies, 
respectively.  Additional information can be found in the IB.
Tirzepatide doses of 5 mg and 10 mg administered SC QW have been selected for investigation 
in this study based on current toxicology, and clinical data.  Doses of liraglutide QD for 17 days 
(dose escalated to 1.8-mg) reduced brain activation in response to highly desirable food images
(Farr et al. 2016; ten Kulve et al. 2016). However, following 5-weeks of dosing with liraglutide 
(dose escalated to 3-mg), differential brain activity in response to food cues, compared to 
placebo, was not observed (Farr et al. 2019).  Therefore, doses of 5- and 10-mg tirzepatide have 
been chosen in the current study as they can be attained in a reasonable duration, while providing 
an opportunity to observe brain activity signals up to 6 weeks.
The tirzepatide treatment period will consist of a step-wise dose escalation where dosing will 
start at 5 mg QW for the first 3 weeks followed by escalation to 10 mg QW at Week 4, followed 
by repeating administration of the 10-mg dose at Week 5 and Week 6. Dosing will be initiated at 
5 mg and administered for 3 weeks before escalating to a 10-mg dose. This stepwise increment 
was selected based on cumulative understanding of safety and GI tolerability from Phase 1 and 2 
studies.  It is expected to minimize GI tolerability concerns in this overweight/obese population 

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by permitting adequate time for development of tolerance to GI events. Near steady-state 
exposures are expected to be attained within 3 weeks of dosing at the 10-mg dose level.
The final liraglutide dose of 3 mg is selected because it is the highest dose approved for the 
treatment of chronic weight management. Additionally, the liraglutide dose of 1.8 mg at Week 3
should result in sufficient exposure to act as the positive control in the current study (Farr et al. 
2016).  The dose-escalation schedule of liraglutide to be used in the current trial is consistent 
with the recommended dosing of marketed liraglutide (Saxenda package insert 2018) and has 
been chosen to mitigate the risk of GI AEs.

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6. Study Population
Eligibility of subjects for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and electrocardiograms (ECGs).
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur within approximately 4 weeks prior to lead-in.  Eligible subjects will enter 
lead-in (Visit 2) approximately 4 days prior to randomization.  Subjects who are not enrolled 
within 6 weeks of screening may be subjected to additional medical assessment and/or clinical 
measurements to confirm their eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all the following criteria at 
screening:
Subject Characteristics
[1]
are overweight/obese (BMI of 27 kg/m2 to 50 kg/m2, inclusive, and can 
complete MRI scans (see Exclusion Criterion 8), and nondiabetic male or 
female subjects, as determined by medical history, physical examination, and 
laboratory assessments at screening;  
[2]
must be weight stable (no weight change of >4 kg) in the last 1 month;
[3]
have safety laboratory test results within normal reference range or with 
abnormalities deemed clinically insignificant by the investigator;
[4]
have venous access sufficient to allow for blood sampling as per the protocol;
[5]
male or female subjects between the ages of 18 to 65 years, inclusive;
[5a] male subjects:

men, regardless of their fertility status, with nonpregnant woman of 
childbearing potential (WOCBP) partners must agree to either remain 
abstinent (if this is their preferred and usual lifestyle) or use condoms 
plus 1 additional highly effective (less than 1% failure rate) method of 
contraception (such as combination oral contraceptives, implanted 
contraceptives, or intrauterine device) or effective method of 
contraception, (such as diaphragms with spermicide or cervical sponge) 
for the duration of the study and for 5 half-lives of study drug plus 
90 days, corresponding to 4 months after the last injection .  

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o
men and their partners may choose to use a double-barrier method 
of contraception.  (Barrier protection methods without concomitant 
use of a spermicide are not an effective or acceptable method of 
contraception.  Thus, each barrier method must include use of a 
spermicide.  It should be noted however that the use of male and 
female condoms as a double-barrier method is not considered 
acceptable due to the high failure rate when these barrier methods 
are combined.)
o
periodic abstinence (e.g., calendar, ovulation, symptothermal, 
postovulation methods), declaration of abstinence just for the 
duration of a study, and withdrawal are not acceptable methods of 
contraception.

men with pregnant partners should use condoms during intercourse for 
the duration of the study and until the end of estimated relevant potential 
exposure in WOCBP, which corresponds to 4 months following last 
injection.  

men must agree to refrain from sperm donation for the duration of the 
study and until their plasma concentrations are below the level that could 
result in a relevant potential exposure to a possible fetus, predicted to be 
4 months following last injection.

men who are in exclusively same-sex relationships (as their preferred 
and usual lifestyle) are not required to use contraception.
[5b] female subjects:

women of childbearing potential who are abstinent (if this is complete 
abstinence, as their preferred and usual lifestyle) or in a same-sex 
relationship (as part of their preferred and usual lifestyle) must agree to 
either remain abstinent or stay in a same-sex relationship without sexual 
relationships with males.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence just 
for the duration of a study, and withdrawal are not acceptable methods 
of contraception.

otherwise, WOCBP participating must agree to use effective 
contraception, where at least 1 form is highly effective (less than 1% 
failure rate), for the entirety of the study.  Contraception must continue 
following completion of IP administration for 30 days.
o
women of childbearing potential participating must test negative 
for pregnancy prior to initiation of treatment as indicated by a 
negative serum pregnancy test at the screening visit followed by a 
negative urine pregnancy test within 24 hours prior to exposure 
o
two forms of effective contraception, where at least 1 form is 
highly effective (less than 1% failure rate, such as combination 

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oral contraceptives, implanted contraceptives or intrauterine 
devices) will be used.  Effective contraception (such as male or 
female condoms with spermicide, diaphragms with spermicide or 
cervical sponges) may be used as the second therapy.  Barrier 
protection methods without concomitant use of a spermicide are 
not a reliable or acceptable method.  Thus, each barrier method 
must include use of a spermicide (that is, condom with spermicide, 
diaphragm with spermicide, female condom with spermicide).  It 
should be noted that the use of male and female condoms as a 
double barrier method is not considered acceptable due to the high 
failure rate when these methods are combined.
o
Not be breastfeeding

women who are not of childbearing potential may participate and 
include those who are:
o
infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as 
mullerian agenesis, or
o
postmenopausal – defined as either
i.
a woman at least 40 years of age with an intact uterus, not 
on hormone therapy, who has cessation of menses for at 
least 1 year without an alternative medical cause, AND a 
follicle-stimulating hormone (FSH) ≥40 mIU/mL; women 
in this category must test negative in pregnancy test prior to 
study entry
ii.
a woman 55 years or older not on hormone therapy, who 
has had at least 12 months of spontaneous amenorrhea; or
iii.
a woman 55 years or older with a diagnosis of menopause 
prior to starting hormone replacement therapy.
Informed Consent
[6]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures;
[7]
have given written informed consent approved by Lilly and the institutional 
review board (IRB) governing the site.

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6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening:
Medical Conditions - General
[8]
have a maximum body circumference >219 cm (i.e., at the widest point of the 
body) or a body weight >225 kg, in order to not exceed the body size 
limitations imposed by the MRI scanner machinery;
[9]
have a history or current cardiovascular (e.g., myocardial infarction, 
congestive heart failure, cerebrovascular accident, venous thromboembolism), 
respiratory, hepatic, renal, GI, endocrine, hematological (including history of 
thrombocytopenia), or neurological disorders capable of significantly altering 
the absorption, metabolism, or elimination of drugs; or constituting a risk 
when taking the IP; or may interfere with the interpretation of data;
[10] have obesity induced by other endocrinologic disorders (e.g., Cushing 
syndrome) or diagnosed monogenetic or syndromic forms of obesity (e.g., 
melanocortin 4 receptor deficiency or Prader-Willi syndrome)
[11] have acute or chronic pancreatitis or a history of acute idiopathic pancreatitis; 
or have other GI disorders (e.g., relevant esophageal reflux or gall bladder 
disease) that could be aggravated by GLP-1 analogs; 

Subjects who have had cholecystolithiasis (removal of gall stones) 
and/or cholecystectomy (removal of gall bladder) in the past, with no 
long-term complications, are eligible for participation;
[12] have a known clinically significant gastric emptying abnormality (e.g., severe 
diabetic gastroparesis or gastric outlet obstruction) or chronically take drugs 
that directly affect GI motility.
[13]
have or plan to have endoscopic and/or device-based therapy for obesity 
or have had device removal within the last 6 months (for example, mucosal 
ablation, gastric artery embolization, intragastric balloon and duodenal-jejunal 
bypass sleeve)
[14] have a prior or planned surgical treatment for obesity (excluding liposuction 
or abdominoplasty if performed >1 year prior to screening)
[15] have an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, 
calculated by Chronic Kidney Disease-Epidemiology at screening.
[16] have an intention to enter into a weight loss program during the study;
[17] have a personal or family history of medullary thyroid carcinoma (MTC), 
have multiple endocrine neoplasia syndrome type 2 (MEN 2), or calcitonin 
≥20 pg/mL at screening;
[18] are diagnosed with any form of diabetes prior to entry or have a hemoglobin 
A1c (HbA1c) value at screening of ≥6.5%;

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[19] have findings in the 12-lead ECG at screening that, in the opinion of the 
investigator, may increase the risks of potentially clinically relevant 
worsening associated with participation in the study;
[20] have blood pressure of ≥160/90 mmHg and/or pulse rate of <45 or >100 bpm 
(supine) at screening with or without stable doses [at least 1 month prior to 
screening] of anti-hypertension medications;
[21] have an active or untreated malignancy or have been in remission from a 
clinically significant malignancy (other than basal or squamous cell skin 
cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for <5 years
prior to screening;
[22] have evidence of human immunodeficiency virus (HIV) and/or positive HIV 
antibodies at screening;
[23] have evidence of hepatitis B or positive hepatitis B surface antigen and/or 
evidence of hepatitis C virus (HCV) or hepatitis C antibody at screening;

subjects with a previous diagnosis of HCV who have been treated with 
antiviral therapy and achieved a sustained virological response may be 
eligible for inclusion in the study, provided they have no detectable 
HCV RNA on the screening HCV polymerase chain reaction test.  A 
sustained virological response is defined as an undetectable HCV RNA 
level 24 weeks after completion of a full, documented course of an 
approved antiviral therapy for HCV.

subjects who have spontaneously cleared HCV infection, defined as (1):  
a positive HCV antibody test and (2):  a negative HCV RNA test, with 
no history of anti-HCV treatment, may be eligible for inclusion in the 
study, provided they have no detectable HCV RNA on screening for this 
study.
[24] have serum aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) >2.0× the upper limit of normal (ULN), total bilirubin (TBL) >1.5×
ULN (except for subjects with Gilbert’s syndrome, which can be enrolled with 
TBL <2.0× ULN), or alkaline phosphatase (ALP) >1.5× ULN; 

subjects with non-alcoholic fatty liver disease are eligible for 
participation;
[25] have had a blood donation of 450 mL or more in the last 3 months or any 
blood donation within the last month prior to screening;
[26] have a history of drug or alcohol abuse within the last 12 months prior to 
screening; or a positive drug or alcohol screen; and/or smoke >10 cigarettes 
per day or the equivalent;
[27] have a history of marijuana use within 3 months of enrollment and 
unwillingness to abstain from marijuana use during the trial.  Subjects should 
also refrain use of cannabidiol oil for the duration of the study.  

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[28] have had a blood transfusion or severe blood loss within the last 3 months, or 
have a hemoglobin value <11 g/dL (males) or <10 g/dL (females), 
[29] have an average weekly alcohol intake that exceeds 21 units per week (males) 
and 14 units per week (females) (1 unit = 12 oz or 360 mL of beer; 5 oz or 
150 mL of wine; 1.5 oz or 45 mL of distilled spirits), and/or are unwilling to 
stop alcohol consumption 12 hours before each CRU outpatient visit;
[30] have any lifetime history of a suicide attempt;
[31] Have a Patient Health Questionnaire-9 (PHQ-9) score of 15 or more at 
screening;
[32] On the Columbia-Suicide Severity Rating Scale (C-SSRS) at screening:
• a “yes” answer to either Question 4 (Active Suicidal Ideation with Some 
Intent to Act, Without Specific Plan) or
• a “yes” answer to Question 5 (Active Suicidal Ideation with Specific Plan and 
Intent) on the “Suicidal Ideation” portion of the C-SSRS, or
• a “yes” answer to any of the suicide-related behaviors (Actual Attempt, 
Interrupted Attempt, Aborted Attempt, Preparatory Act or Behavior) on the 
"Suicidal Behavior" portion of the C-SSRS, and
• the ideation or behavior occurred within the past month
[33] have a history of atopy or clinically significant multiple or severe drug 
allergies, or severe post-treatment hypersensitivity reactions (including, but 
not limited to, erythema multiforme major, linear immunoglobulin A 
dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis).
Prior/Concomitant Therapy - General
[34] have current or history of (within 6 months prior to screening or between 
screening and randomization) treatment with medications that may cause 
significant weight gain, including but not limited to:  tricyclic antidepressants, 
atypical antipsychotic mood stabilizers for example:
Tofranil® (imipramine), Elavil® (amitriptyline), Remeron® (mirtazapine), 
Paxil®/Seroxat® (paroxetine), Nardil® (phenelzine), Largactil®
(chlorpromazine), Mellaril® (thioridazine), Clozaril®/FazaClo®/Versacloz®
(clozapine), Zyprexa® (olanzapine), Depakote®/Convulex® (valproic acid)
and its derivatives, and/or Lithobid® (lithium)
Note:  selective serotonin reuptake inhibitors other than paroxetine are 
permitted.
Use of other medications not listed above, may result in subject exclusion at 
the discretion of the investigator in consultation with the Sponsor.  

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[35] have taken within 6 months prior to screening or between screening and 
randomization, medications (prescribed or over-the-counter) or alternative 
remedies intended to promote weight loss.  Examples include, but are not 
limited to:
Saxenda® (liraglutide 3.0 mg), Xenical®/Alli® (orlistat), Meridia®
(sibutramine), Acutrium® (phenylpropanolamine), Sanorex® (mazindol), 
Adipex® (phentermine), BELVIQ® (lorcaserin), Qsymia®
(phentermine/topiramate combination), and/or Contrave®
(naltrexone/bupropion).
Note:  Use of metformin or any other glucose-lowering medication, whether 
prescribed for polycystic ovary syndrome or diabetes prevention is not 
permitted.  
Use of other medications not listed above, may result in subject exclusion at 
the discretion of the investigator in consultation with the Sponsor.
[36] have received chronic (lasting >14 consecutive days) systemic glucocorticoid 
therapy (excluding topical, intra-articular, and inhaled preparations) within 
1 month before screening, or between screening and randomization;
[37] have been treated with any glucose-lowering agent during the last 3 months 
prior to screening or between screening and randomization;
[38] have received treatment with a drug that has not received regulatory approval 
for any indication within 3 months or 5 half-lives (whichever is longer) of 
screening.
Prior/Concurrent Clinical Trial Experience
[39] are persons who have previously completed or withdrawn from this study;
[40] have known allergies to tirzepatide or GLP-1 RAs;
[41] have previous exposure to tirzepatide or exposure to GLP-1 RA in the 
previous 6 months prior to screening and between screening and 
randomization;
[42] are currently enrolled in a clinical study involving an IP or any other type of 
medical research judged not to be scientifically or medically compatible with 
this study.
Other Exclusions
[43] female subjects who are breastfeeding;
[44] suffer from claustrophobia sufficiently severe that it may preclude completion 
of MRI scanning;
[45] have contraindications such as cardiac pacemakers, aneurysm clips, or other 
metallic implants considered unsafe for MRI scanning;

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[46] are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted;
[47] are Eli Lilly and Company employees;
[48] are deemed unsuitable by the investigator for any other reason.
6.3.
Lifestyle and Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.
6.3.1. Meals and Dietary Restrictions
Subjects shall fast for at least 12 hours overnight prior to each outpatient visit where fasting 
samples are drawn.  Subjects will fast for at least 12 hours prior to tirzepatide/placebo dosing, 
after which subjects will receive a meal.  Liraglutide will be dosed without regard to timing of 
meals.  Water can be consumed freely.  
Subjects will only consume lunch test meal provided by the CRU during outpatient visits.  
Further details regarding dietary requirements for the planned assessments in the CRU at 
baseline, Week 3, and Week 6 of the treatment period, and 3 and 4 weeks post final dose of the 
follow-up period are described in Appendix 5.  
6.3.2. Caffeine, Alcohol, and Tobacco 
Regular caffeine drinkers are required to maintain their usual amount of caffeine intake 
throughout the study including on CRU outpatient visit days.  
No alcohol will be allowed at least 12 hours before each CRU outpatient visit.  Between CRU 
outpatient visits, weekly alcohol should not exceed 21 units per week for males and 14 units per 
week for females (a unit is defined in Section 6.2 Exclusion Criteria).  
Subjects will not be allowed to use tobacco products in the CRU.
6.3.3. Activity
Subjects will be advised to maintain their regular levels of physical activity/exercise during the 
study.  No intense physical activity will be allowed for at least 48 hours before each CRU 
outpatient visit.  When certain study procedures are in progress at the CRU, subjects may be 
required to remain recumbent or sitting.  
6.4.
Screen Failures
Screening tests such as clinical laboratory tests and vital signs/ECGs may be repeated at the 
discretion of the investigator.  Individuals who do not meet the criteria for participation in this 
study (screen failure) may be re-screened up to 1 time.  The interval between re-screenings 
should be at least 2 weeks.  Each time re-screening is performed, the individual must sign a new 
ICF and will be assigned a new site screening number.  Subject numbers/enrollment numbers are 
assigned on the morning of Day 1.

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7. Treatment
7.1.
Treatment Administered
Subjects will receive tirzepatide or placebo administered SC QW for 6 doses or liraglutide 
administered SC QD for 38 days.  Table GPHH.2 shows the treatment regimens.
Table GPHH.2.
Study Treatments and Dose Escalation
Dosing Schemes
Treatment
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Tirzepatide
1 × 5-mg PFS 
(Day 1)
1 × 5-mg PFS 
(Day 8)
1 × 5-mg PFS 
(Day 15)
1 × 10-mg 
PFS (Day 22)
1 × 10-mg 
PFS (Day 29)
1 × 10-mg 
PFS (Day 36)
Placebo
1 × PFS 
(Day 1)
1 × PFS 
(Day 8)
1 × PFS 
(Day 15)
1 × PFS 
(Day 22)
1 × PFS 
(Day 29)
1 × PFS 
(Day 36)
Liraglutide
0.6 mg QD
(Days 1-7)
1.2 mg QD
(Days 8-14)
1.8 mg QD
(Days 15-21)
2.4 mg QD
(Days 22-28)
3 mg QD
(Days 29-35)
3 mg QD
(Days 36-38)
Abbreviations:  PFS = prefilled syringe; QD = once daily.
Tirzepatide or placebo will be administered QW at the CRU in a blinded fashion.  
Liraglutide will be administered QD in an open-label manner and will be self-administered in the 
evening by the subject at home.  Subjects will receive adequate training for liraglutide 
self-administration from site personnel.  
All injections will be administered into the SC tissue of the abdominal wall.  Injection sites will 
be alternated weekly for tirzepatide/placebo and daily for liraglutide, between 4 sites (right and 
left lower quadrants and right and left upper quadrants) of the abdominal wall.
Dosing will occur at approximately the same time of day in all groups and on the same day for 
the QW groups.  The actual time of dosing will be recorded in the subject’s electronic case report 
form (eCRF).  
Whenever possible, IP administration at the CRU should be carried out by the same personnel.  
Additional details are provided in Section 7.3 (Blinding).  The personnel who administer study 
drugs will be unblinded to liraglutide, but they will remain blinded to subjects receiving 
tirzepatide or placebo.  
The investigator or designee is responsible for:

explaining the correct use of the IP to the site personnel 

verifying that instructions are followed properly

maintaining accurate records of IP dispensing and collection

and returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials.  

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The site will be instructed to discard used medications according to local regulations.
7.1.1. Packaging and Labeling
Tirzepatide and matching placebo will be supplied by Lilly.  Tirzepatide will be provided as 
prefilled syringes (PFS) containing 0.5 mL solution and provided in individual cartons to be 
dispensed.  Placebo will be provided as matching 0.5-mL PFS.  
Liraglutide will be the positive control and the commercially available formulation (Saxenda®)
will also be supplied by Lilly.
The IP will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Subjects who meet all criteria for enrollment will be randomized in a 1:1:1 ratio to receive 
tirzepatide, liraglutide, or placebo.  Assignment to treatment will be determined by a 
randomization table with treatment codes.  The randomization will be stratified by baseline BMI 
(27 to <30 kg/m2, 30 to <35 kg/m2, and 35 to 50 kg/m2).  
7.2.1. Selection and Timing of Doses
The doses will be administered QW (tirzepatide or placebo) or QD (liraglutide) according to the 
randomization schedule, on the same day of the week (QW doses) and at approximately the same 
time of the day.  The actual time of all dose administrations will be recorded in the subject’s 
eCRF.
Tirzepatide and placebo will be administered in the morning of each dosing day following an 
overnight fast of at least 12 hours.  Liraglutide will be administered in the evening of each dosing 
day without regard to timing of meals.  
A visit window (±1 day) may be used for dosing of tirzepatide or placebo only when the subject 
is unable to visit the CRU on the scheduled day.  If a subject is not able to receive his/her
tirzepatide or placebo dose on the scheduled day (±1 day), the dose should be administered as 
soon as possible and at least 72 hours prior to the next scheduled dose.  If the remaining time to 
the next scheduled dose is less than 72 hours, the dose will not be administered and will be 
considered a missed dose.  
Investigator site staff will take reasonable steps to educate and inform study subjects randomized 
to liraglutide to be compliant to their treatment (e.g., written instructions, reminder calls, verbal 
reinforcement during clinic visits).  If a subject misses their daily dose of liraglutide, the subject 
will be instructed to administer the missed dose as soon as they remember, then administer the 
next daily dose as usual on the following day.  The subject will be instructed not to administer an 
extra dose or increase their dose on the following day to make up for the missed dose. If a 
subject misses their daily dose of liraglutide for 2 days or more, they will be instructed to contact 
staff at the CRU.  

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7.3.
Blinding
The sponsor, investigators, and subjects will be blinded to tirzepatide and placebo treatment 
assignments; however, liraglutide will be administered in an open-label manner.  Therefore, the 
study will be considered partially blinded.
Blinding between tirzepatide and placebo will be maintained throughout the conduct of the study 
as described in the separate Blinding and Unblinding Plan.  To preserve the blinding of 
tirzepatide and placebo allocation, all study site personnel, except those who dispense and 
administer tirzepatide and placebo, will be blinded to treatment allocation.  Tirzepatide, placebo, 
and liraglutide will be dispensed by the site pharmacy in accordance to the randomization table.  
The site staff will take the necessary steps to ensure that subjects will remain blinded to 
tirzepatide and placebo administration.  
If a subject’s study treatment assignment is unblinded (tirzepatide or placebo only), the subject 
must be discontinued from the study, unless the investigator obtains specific approval from a 
Lilly clinical pharmacologist (CP) or clinical research physician (CRP) for the subject to 
continue in the study.  During the study, emergency unblinding should occur only by accessing 
the subject’s emergency code.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment (tirzepatide or placebo only) is warranted for medical 
management of the event. The subject’s safety must always be the first consideration in making 
such a determination.  If the investigator decides that unblinding is warranted, it is the 
responsibility of the investigator to promptly document the decision and rationale and notify 
Lilly as soon as possible.
Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dose Modification
The subject should follow the planned dosing regimen.  In the case of poor tolerability during the 
study, dosing may need to be terminated following the guidance provided in Section 8.1.1
(Permanent Discontinuation from Study Treatment).
Deviations from the planned tirzepatide dose escalation are generally not permitted; however, at 
the discretion of the investigator, subjects may dose escalate to 10 mg tirzepatide 1 week later
than planned if expected to improve tolerability. A delay in dose escalation of tirzepatide will 
not impact the planned total treatment duration. Deviations from the planned liraglutide dose 
escalation are not permitted. 
7.4.1. Special Treatment Considerations
7.4.1.1.
Management of Subjects with Gastrointestinal Symptoms
The tirzepatide and liraglutide dose-escalation schemes have been designed to minimize the 
development of intolerable GI symptoms.  The dose-escalation period for tirzepatide is 
considered to be 3 weeks to reach the 10-mg dose.  The dose-escalation period for liraglutide is 
considered to be 4 weeks to reach the 3-mg maintenance dose.  During the dose-escalation 

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period, every effort should be made by the investigator to be able to escalate and maintain 
subjects on the corresponding study drug dosage.  
To mitigate GI symptoms and manage subjects with poorly tolerated GI AEs, the investigator 
should:

Advise subjects to eat smaller meals, for example, splitting 3 daily meals into 4 or more 
smaller meals, and to stop eating when they feel full.

Prescribe symptomatic medication (for example, anti-emetic or anti-diarrheal medication) 
per local country availability and individual subject needs.

Discontinuation from study treatment as per guidance provided in Section 8.1.1
(Permanent Discontinuation from Study Treatment).
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by sponsor, during transit for all IP received and any discrepancies 
are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive IP or study materials, and only authorized 
site staff may supply or administer IP while in the CRU. Subjects will receive training from only 
authorized site staff on how to self-administer liraglutide at home.  
All IP should be stored in an environmentally controlled and monitored (manual or automated) 
area in accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
Tirzepatide and placebo will be administered at the study site and documentation of treatment 
administration will occur at the site.  Liraglutide will be self-administered at home and 
compliance will be assessed at each visit by direct questioning and subject diaries.  Deviations 
from the prescribed dosing regimen should be recorded in the eCRF.  
Subjects randomized to receive liraglutide who are repeatedly (2 or more episodes) noncompliant 
with dosing will be reviewed by the investigator and sponsor to determine if the subject should 
continue treatment or be discontinued from the study.
7.7.
Concomitant Therapy
Section 6.2 (Exclusion Criteria) provides a list of excluded medications in this study prior to 
randomization (e.g., weight-modifying agents, systemic glucocorticoids, glucose-lowering 
agents).  These medications are also not allowed during the treatment period.  

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Subjects on stable concomitant medication at the time of study entry, other than those that are 
prohibited, should continue their regular, unchanged dose throughout the study.  
In general, concomitant medication should be avoided; however, acetaminophen (1g, maximum 
3 g/24 hours) may be administered at the discretion of the investigator for treatment of headaches 
etc.  If the need for concomitant medication (other than acetaminophen) arises, inclusion or 
continuation of the subject may be at the discretion of the investigator after consultation with a 
Lilly CP or CRP.  
Any medication used during the course of the study must be documented in source documents 
and entered into the eCRF.  
7.8.
Treatment after the End of the Study
Not applicable.  Tirzepatide and liraglutide will not be made available to subjects after 
completion of the study.

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8. Discontinuation Criteria
Subjects discontinuing from the treatment prematurely for any reason should complete an early 
termination visit and safety follow-up visit procedures per Section 2 (Schedule of Activities) of 
this protocol.
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of IP:

The subject requests to discontinue IP

If a subject is inadvertently enrolled and it is determined that continued treatment with IP 
would not be medically appropriate (Section 8.1.2 Discontinuation of Inadvertently 
Enrolled Subjects)

If a subject is diagnosed with acute or chronic pancreatitis after randomization

If a subject is confirmed to have developed T2DM after randomization

If a subject is diagnosed with MTC after randomization

If a subject is diagnosed with an active or untreated malignancy (other than basal or
squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer)
after randomization

If the investigator, after consultation with the sponsor-designated medical monitor, 
determines that a systemic hypersensitivity reaction has occurred related to study drug 
administration

If a subject is diagnosed with any other TEAE, SAE, or clinically significant laboratory
value for which the investigator believes that permanent IP discontinuation is the 
appropriate measure to be taken

If female subject becomes pregnant
Discontinuation of the IP for abnormal liver tests should be considered by the investigator when 
a subject meets 1 of the following conditions after consultation with the Lilly-designated medical 
monitor:

ALT or AST >8× ULN 

ALT or AST >5× ULN sustained for more than 2 weeks

ALT or AST >3× ULN and (TBL >2× ULN or international normalized ratio >1.5)

ALT or AST >3× ULN, with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

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Subjects who discontinue IP early will be also discontinued from the study after performing the 
early termination (ET) visit and safety follow-up visit procedures, as specified in Section 2
(Schedule of Activities).
8.1.2. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CP/CRP and the investigator to 
determine if the subject may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CP/CRP to allow the 
inadvertently enrolled subject to continue in the study with or without continued treatment with 
IP.  
8.2.
Discontinuation from the Study
In addition to the situations that result in IP discontinuation described in Section 8.1.1
(Permanent Discontinuation from Study Treatment), subjects will be discontinued in the 
following circumstances:

Enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study
o
if the subject, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

Subject Decision
o
the subject, or legal representative, requests to be withdrawn from the study.
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.

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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 4 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
Appendix 5 details the procedures for efficacy assessments.  
The specifications in this protocol for the timings of safety and sample collections are given as 
targets to be achieved within reasonable limits.  Modifications may be made to the time points 
based upon emerging clinical information.  The scheduled time points may be subject to minor 
alterations; however, the actual time must be recorded correctly in the eCRF.  Failure or delays 
(i.e., outside stipulated time allowances) in performing procedures or obtaining samples due to 
legitimate clinical issues (e.g., equipment technical problems, venous access difficulty, or subject 
defaulting or turning up late on an agreed scheduled procedure) will not be considered as 
protocol deviations but the CRU will still be required to notify the sponsor in writing via a file 
note.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
In this study, the measures used to assess mechanisms of action of study treatments with respect 
to energy intake, and central reward and appetite circuits are considered efficacy measures.  The 
planned assessments will be performed at baseline, Week 3, and Week 6.  Food intake tests will 
also be completed 3 and 4 weeks following the final dose of study drug in the follow-up period.  
All parameter calculations, when applicable, and analyses are described in Section 10.3
(Statistical Analyses) or in the statistical analysis plan (SAP).
9.1.1. Appetite and Eating Behavior Assessments
To characterize the treatment effect on energy intake, clinic-based food intake test will be 
completed at the time points specified in the Schedule of Activities (Section 2).  Energy intake 
(kcal) will be the primary endpoint.  
The treatment effect on attitude towards food will be assessed with the use of several 
food-related questionnaires, completed at the time points specified in the Schedule of Activities 
(Section 2).  The following questionnaires will be applied: 

appetite visual analog scale (VAS) for hunger, fullness, satiety, prospective food 
consumption, desire for specified foods, and overall appetite score 

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
Food Craving Inventory (FCI)

Food Craving Questionnaire-State (FCQ-S)

Eating Inventory

Power of Food Scale
A full description of all appetite and eating behavior assessment methods are detailed in 
Appendix 5.  
9.1.2. Neuroimaging Assessments
To characterize the treatment effect on central reward and appetite circuits in the brain, fMRI 
scans will be completed at the time points specified in the Schedule of Activities (Section 2).  

BOLD fMRI: Day -4 to Day -1 (baseline), Day 16 (Week 3, Visit 6), and Day 37 (Week 
6, Visit 11) 
On each day, BOLD fMRI scan will be completed in the fasting state and subjects will perform a 
food image task during each scan.  
The principal brain reward areas to be examined will be the:

insula

medial frontal gyrus

superior temporal gyrus

precentral gyrus

cingulate gyrus
In addition, exploratory brain reward areas to be examined will be the:

hippocampus

putamen

orbitofrontal cortex

ventral striatum 
The change from baseline to Week 3 in BOLD fMRI brain activation in response to images of 
highly palatable foods versus non-food objects during fasting state will be considered as a 
secondary endpoint in the current study.  All other data collected from functional neuroimaging 
will be considered exploratory.  
A full description of the MRI assessment method, including the food image task, is detailed in 
Appendix 5.  
Impulsivity assessments are described in Appendix 5.

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9.1.3. Hormone and Metabolite Assessments
To explore potential effects of study treatment on hormones and metabolites related to appetite 
and the regulation of nutrient metabolism, plasma or serum samples will be collected at the time 
points provided in the Schedule of Activities (Section 2).  
The changes from baseline to Week 3 and Week 6 of the following hormones and metabolites
will be considered exploratory endpoints:

amylin

ghrelin

GIP

GLP-1

leptin

pancreatic polypeptide

peptide YY

insulin

glucagon
In addition to safety monitoring, fasting plasma glucose and triglycerides will be measured as 
efficacy endpoints at baseline, Week 3 and Week 6.  
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the subject to discontinue the investigational product before 
completing the study.  The subject should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
The investigator will record all relevant AE and SAE information in the eCRF.  After the ICF is 
signed, study site personnel will record, via eCRF, the occurrence and nature of each subject’s 
preexisting conditions.  Additionally, site personnel will record any change in the condition(s) 
and the occurrence and nature of any AEs.  

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The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, or a study procedure, concomitant treatment or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the investigational product, study device and/or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
If a subject’s IP is discontinued as a result of an AE, study site personnel must report this to Lilly 
or its designee via eCRF.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above

when a condition related to the PFS necessitates medical or surgical intervention to 
preclude either permanent impairment of a body function or permanent damage to a body 
structure, the serious outcome of “required intervention” will be assigned.
Study site personnel must alert the Lilly CP/CRP, or its designee, of any SAE as soon as 
practically possible.
Additionally, study site personnel must alert Lilly Global Patient Safety, or its designee, of any 
SAE within 24 hours of investigator awareness of the event via a sponsor-approved method.  If 
alerts are issued via telephone, they are to be immediately followed with official notification on 
study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.  

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Pregnancy (maternal or paternal exposure to IP) does not meet the definition of an AE.  
However, to fulfill regulatory requirements any pregnancy should be reported following the SAE 
process to collect data on the outcome for both mother and fetus.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator reports as related to IP or procedure.  Lilly has procedures that 
will be followed for the recording and expedited reporting of SUSARs that are consistent with 
global regulations and the associated detailed guidance.
9.2.2. Adverse Events of Special Interest
9.2.2.1.
Hypoglycemia
Tirzepatide is an incretin which acts on the pancreatic β cell as a non-secretagogue; therefore, the 
risk of hypoglycemia is very low.  Similarly, the risk of hypoglycemia is considered low with 
liraglutide.  
If hypoglycemia occurs, each episode should be treated according to the standards of care by the 
investigator and additional monitoring of glucose levels may be requested at the investigator’s 
discretion. As a general safety precaution, subjects will be trained during the lead-in period
about signs and symptoms of hypoglycemia, how to treat hypoglycemia, and how to collect 
appropriate information for each episode of hypoglycemia.
Hypoglycemia may be identified by spontaneous reporting of symptoms from participants
(whether confirmed or unconfirmed by simultaneous glucose values) or by blood glucose 
samples collected during study visits.
Subjects may, at the investigator’s discretion, be given glucometers to assist in the evaluation of 
reported symptoms consistent with hypoglycemia.  Subjects receiving glucometers will record 
relevant information (for example, glucose values, symptoms) in a diary.
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the PG values in this section refer to values 
determined by a laboratory or International Federation of Clinical Chemistry and Laboratory 
Medicine plasma-equivalent glucose meters and strips) (American Diabetes Association 2019):
Glucose Alert Value (Level 1):

Documented symptomatic hypoglycemia is defined as any time a subject feels
that he or she is experiencing symptoms and/or signs associated with 
hypoglycemia, and has a PG level of ≤70 mg/dL (≤3.9 mmol/L)

Documented asymptomatic hypoglycemia is defined as any event not 
accompanied by typical symptoms of hypoglycemia, but with a measured PG 
≤70 mg/dL (≤3.9 mmol/L)

Documented unspecified hypoglycemia is defined as any event with no 
information about symptoms of hypoglycemia available, but with a measured PG 
≤70 mg/dL (≤3.9 mmol/L)

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Clinically Significant Hypoglycemia (Level 2):

Documented symptomatic hypoglycemia is defined as any time a subject feels 
that he/she is experiencing symptoms and/or signs associated with hypoglycemia, 
and has a PG level of <54 mg/dL (<3.0 mmol/L)

Documented asymptomatic hypoglycemia is defined as any event not 
accompanied by typical symptoms of hypoglycemia, but with a measured PG 
<54 mg/dL (<3.0 mmol/L)

Documented unspecified hypoglycemia is defined as any event with no 
information about symptoms of hypoglycemia available, but with a measured PG 
<54 mg/dL (<3.0 mmol/L)
Severe Hypoglycemia (Level 3):

Severe hypoglycemia is defined as an episode with severe cognitive impairment 
requiring the assistance of another person to actively administer carbohydrate, 
glucagon, or other resuscitative actions.  These episodes may be associated with 
sufficient neuroglycopenia to induce seizure or coma.  Blood glucose 
measurements may not be available during such an event, but neurological 
recovery attributable to the restoration of blood glucose to normal is considered 
sufficient evidence that the event was induced by a low blood glucose
concentration.  
Other Hypoglycemia Categories:

Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs 
between bedtime and waking
If a hypoglycemic event meets the criteria of severe, the investigator must record the event as 
serious on the AE eCRF and report it to Lilly as an SAE.
To avoid duplicate reporting, all consecutive blood glucose values ≤70 mg/dL (3.9 mmol/L) 
occurring within a 1-hour period may be considered to be a single hypoglycemic event (Weinberg 
et al. 2010; Danne et al. 2013).
In each case of suspected or confirmed hypoglycemia, it is important that the event be properly 
categorized, the effect of the intervention be assessed, and the frequency of hypoglycemia be 
evaluated.  The role of dietary changes and physical exercise (or any other contributing factor) in 
the development of an event should be established.  The subject should receive additional 
education, if deemed appropriate.
9.2.2.2.
Pancreatitis
Glucagon-like peptide-1 receptor agonists have been associated with a possible risk of acute 
pancreatitis.  Acute pancreatitis is defined as an AE of interest in all studies with tirzepatide 
including this study.  Acute pancreatitis is an acute inflammatory process of the pancreas that 
may also involve peripancreatic tissues and/or remote organ systems (Banks and Freeman 2006).  
The diagnosis of acute pancreatitis requires 2 of the following 3 features:

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
abdominal pain, characteristic of acute pancreatitis (generally located in the 
epigastrium and radiates to the back in approximately half the cases [Banks and 
Freeman 2006; Koizumi et al. 2006]; the pain is often associated with nausea 
and vomiting)

serum amylase (total and/or pancreatic) and/or lipase ≥3× ULN

characteristic findings of acute pancreatitis on computed tomography (CT) scan or 
MRI
If acute pancreatitis is suspected, appropriate laboratory tests (including levels of pancreatic 
amylase and lipase) should be obtained via the local laboratory.  Imaging studies, such as 
abdominal CT scan with or without contrast, MRI, or gallbladder ultrasound, should be 
performed.  If laboratory values and/or abdominal imaging support the diagnosis of acute 
pancreatitis, the subject must discontinue IP, and will be discontinued from the study after 
completing all ET and follow-up procedures.  A review of the subject’s medical data, including 
concomitant medications, should be conducted to assess potential causes of pancreatitis.
Each case of AE of pancreatitis must be reported.  If typical signs and/or symptoms of 
pancreatitis are present and confirmed by laboratory values (lipase or amylase [total and/or 
pancreatic]) and imaging studies, the event must be reported as an SAE.  For a potential case that 
does not meet all of these criteria, it is up to the investigator to determine the seriousness of the 
case (AE or SAE) and the relatedness of the event to IP.
Each subject will have measurements of amylase and lipase, which are part of the safety 
laboratory tests as shown in Section 2 (Schedule of Activities) to assess the effects of study 
treatment on pancreatic enzyme levels.  Serial measures of pancreatic enzymes have limited 
clinical value for predicting episodes of acute pancreatitis in asymptomatic subjects (Nauck et al. 
2017; Steinberg et al. 2017a; Steinberg et al. 2017b).  Thus, further diagnostic follow-up of cases 
of asymptomatic pancreatic hyperenzymemia (lipase and/or pancreatic amylase ≥3× ULN) is not 
mandated but may be performed based on the investigator’s clinical judgment and assessment of 
the subject’s overall clinical condition.  If further diagnostic assessment due to asymptomatic 
hyperenzymemia is warranted, it should follow Lilly standard algorithm for the monitoring of 
pancreatic enzymes (Appendix 7).
9.2.2.3.
Thyroid Malignancies and C-Cell Hyperplasia
Individuals with personal or family history of MTC and/or MEN 2 will be excluded from the 
study, as well as those with calcitonin ≥20 pg/mL at screening. Participants who are diagnosed 
with MTC and/or MEN-2 during the study will have study drug stopped and should continue 
follow-up with an endocrinologist.
The assessment of thyroid safety during the study will include reporting of any case of thyroid 
malignancy, including MTC and papillary carcinoma, and measurements of calcitonin at 
screening.  This data will be captured in the specific section of the eCRFs.

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9.2.2.4.
Hypersensitivity Events
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data describing each symptom should be provided
to the sponsor in the eCRF. 
The sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study drug. It is recommended that participants
who experience a systemic hypersensitivity reaction be treated per the local standard of care.  
In the case of generalized urticaria or anaphylaxis, additional blood samples should be collected 
as described in Appendix 8 (Recommended Laboratory Testing for Hypersensitivity Events).  
Laboratory results are provided to the sponsor via the central laboratory.  
IP should be temporarily interrupted in any individual suspected of having a severe or serious 
allergic reaction to IP.  IP may be restarted when/if it is safe to do so, in the opinion of the 
investigator.  If IP is permanently discontinued, the subject will be discontinued from the study 
(Section 8.1.1 Permanent Discontinuation from Study Treatment).
9.2.2.5.
Injection-Site Reactions
Injection-site assessments for local tolerability will be conducted, when reported as:

an AE from a subject, or

a clinical observation from an investigator.
Reported injection-site reactions will be characterized within the following categories:

edema

erythema

induration

itching

pain
Injection-site reactions will be collected on the eCRF created for these events.  At the time of AE 
occurrence, unscheduled samples may be collected for measurement of tirzepatide ADA and 
tirzepatide concentration if the event is suspected to be immune related by the investigator.
All injection-site reactions reported as AEs will be closely monitored until resolution.  The report 
of a clinically significant AE of injection-site reaction may prompt notification of the sponsor, 
clinical photography, and referral for dermatologic evaluation and consideration of a skin biopsy 
and laboratory evaluations (ALT, AST, complete blood count with percent eosinophils, and 
additional immunogenicity testing).
Site staff will be provided with separate instructions/training on how to evaluate injection-site 
reactions and their severity in a consistent manner.  Photographs of injection-site reactions may 
be taken in a standardized manner for record-keeping purposes; however, the photographs will 
not be used to evaluate the severity of injection-site reaction.

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9.2.2.6.
Hepatobiliary Disorders
All events of treatment-emergent biliary colic, cholecystitis, or other suspected events related to 
gallbladder disease should be evaluated and additional diagnostic tests performed, as needed.  In 
cases of elevated liver markers, hepatic monitoring should be initiated as outlined in 
Section 9.4.7.1 (Hepatic Safety) and Appendix 6 (Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality.
9.2.2.7.
Severe Gastrointestinal Adverse Events
Tirzepatide or liraglutide may cause severe GI AEs, such as nausea, vomiting, and diarrhea.  
Information about severe GI AEs as well as antiemetic/antidiarrheal use will be collected in the 
AE form of the eCRF.  For detailed information concerning the management of GI AEs, refer to 
Section 7.4.1.1 (Management of Subjects with Gastrointestinal Symptoms).
9.2.2.8.
Acute Renal Events
Renal safety will be assessed based on laboratory renal functional assessment as well as 
assessment of AEs suggestive of acute renal failure or worsening of chronic renal failure.  
Subjects with GI AEs, including nausea, diarrhea, and vomiting are at increased risk of 
developing dehydration.  Dehydration may cause a deterioration in renal function, including 
acute renal failure.  Subjects should be advised to notify investigators in case of severe nausea, 
frequent vomiting, or symptoms of dehydration.
9.2.3. Complaint Handling
Lilly collects product complaints on IPs and drug delivery systems used in clinical trials in order 
to ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements.
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product or drug delivery system so that the 
situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of tirzepatide or liraglutide is considered any dose 
higher than the dose assigned through randomization.
For patients with suspected or confirmed overdose with tirzepatide or liraglutide, there is no 
specific antidote.  The patient should be watched for GI symptoms and hypoglycemia.  
Treatment is supportive, depending on the subject’s symptoms.  For detailed information, refer to 
the IB for tirzepatide and package insert for liraglutide.  
9.4.
Safety
9.4.1. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).  

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With the exception of safety laboratory test results that may unblind the study, Lilly or its 
designee will provide the investigator with the results of laboratory tests analyzed by a central 
vendor, if a central vendor is used for the study.
9.4.2. Vital Signs
Vital sign measurements should be taken before obtaining an ECG tracing, at visits where 
required (see Section 2, Schedule of Activities), and before collection of blood samples for 
laboratory testing. For each parameter, 2 measurements will be taken using the same arm. An 
appropriately sized cuff (cuff bladder encircling at least 80% of the arm) should be used to 
ensure the accuracy of blood pressure measurements.  The arm used for the blood pressure
measurement should be supported at the heart level. The recordings should be taken at least 1 
minute apart. Each measurement of sitting heart rate and blood pressure needs to be recorded in 
the eCRF. Any AE related to changes in blood pressure and heart rate should be reported, per 
requirements provided in Section 9.2.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted.
9.4.3. Body Weight and Waist Circumference
Weight and waist circumference will be measured according to the schedule provided in the 
Schedule of Activities (Section 2).  
Subjects will be weighed at approximately the same time in the morning, before dosing and after
an overnight fast and evacuation of the bowel and bladder, if possible. Weight will be measured 
twice on each scheduled occasion, with the subject stepping off the scale between measurements.  
A third measurement will be made if the first 2 measurements are >0.5 kg apart. The 2 closest 
measurements will be recorded. Wherever possible, the same scale will be used for all weight
measurements throughout the study, and the scale will not be moved or recalibrated. Subjects 
will be weighed in light clothing.  Weight measurements will be recorded in the source document 
and the eCRF.
Waist circumference will be measured at the midpoint between the inferior border of the rib cage 
and the superior aspect of the iliac crest.  The subject will stand in a straight, upright position 
with feet together and arms at the side. The area measured will be cleared of all clothing other 
than undergarments. The measurement should be taken at the end of normal expiration. Two 
separate measures will be taken and steps are repeated until 2 measurements are obtained within 
0.5 cm of each other.
9.4.4. Electrocardiograms
For each subject, single 12-lead ECGs should be collected according to the Schedule of 
Activities (Section 2).  
Electrocardiograms must be recorded before collecting any blood samples.  Subjects must be 
supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake 

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during ECG collection.  Electrocardiograms may be obtained at additional times, when deemed 
clinically necessary.  All ECGs recorded should be stored at the investigational site.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings be 
identified.  
If a clinically significant finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the subject can 
continue in the study.  The investigator, or qualified designee, is responsible for determining if 
any change in subject management is needed and must document his/her review of the ECG 
printed at the time of collection.  Any clinically significant findings from ECGs that result in a 
diagnosis and that occur after the subject receives first dose of the IP should be reported to Lilly, 
or its designee, as an AE via eCRF.
9.4.5. Physical Examinations
Physical examinations and routine medical assessments will be conducted as specified in the 
Schedule of Activities (Section 2) and as clinically indicated.
9.4.6. Suicidal Ideation Assessment
Overweight and obese patients are at an increased risk of depression (Luppino et al. 2010).  
Depression can increase the risk of suicidal ideation and behavior.  Therefore, study subjects will 
be screened at trial entry for depression, suicidal ideation and behavior using the C-SSRS and 
PHQ-9 as specified in the Schedule of Activities (Section 2). Subjects of higher risk of severe 
depression and/ or suicidality will be excluded (refer to EC 28-30, Section 6.2)
The C-SSRS (Columbia Lighthouse Project [WWW]) is a scale that captures the occurrence, 
severity, and frequency of suicidal ideation and/or behavior during the assessment period.  The 
scale includes suggested questions to solicit the type of information needed to determine if 
suicidal ideation and/or behavior occurred.  The tool was developed by the National Institute of 
Mental Health trial group for the purpose of being a counterpart to the Columbia Classification 
Algorithm of Suicide Assessment categorization of suicidal events.  For this study, the C-SSRS 
is adapted for the assessment of the ideation and behavior categories only.  The Intensity of 
Ideation and Lethality of Behavior sections are removed
The PHQ-9 is a validated self-report screening tool that assesses the presence and intensity of 
depressive symptoms.  The PHQ-9, which incorporates the 9 Diagnostic and Statistical Manual-
IV depression criteria as “0” (not at all) to “3” (nearly every day), was developed for use in 
primary care settings (Kroenke et al. 2001).
9.4.7. Safety Monitoring
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study.

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Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CP or 
CRP will periodically review the following data:

trends in safety data

laboratory analytes including glucose, amylase, and lipase

serious and nonserious AEs, including AEs of interest (see Section 9.2.2)
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
9.4.7.1.
Hepatic Safety
Close hepatic monitoring
Laboratory tests (Appendix 6), including ALT, AST, ALP, TBL, direct bilirubin, 
gamma-glutamyl transferase (GGT), and creatine kinase (CK), should be repeated within 48 to 
72 hours to confirm the abnormality and to determine if it is increasing or decreasing, if 1 or 
more of these conditions occur:
If a participant with baseline results of ... 
develops the following elevations:
ALT or AST <1.5× upper limit of normal (ULN)
ALT or AST ≥3× ULN
ALP <1.5× ULN
ALP ≥2× ULN
TBL <1.5× ULN
TBL ≥2× ULN (except for patients with Gilbert’s syndrome)
ALT or AST ≥1.5× ULN
ALT or AST ≥2× baseline
ALP ≥1.5× ULN
ALP ≥2× baseline
TBL ≥1.5× ULN
TBL ≥1.5× baseline (except for patients with Gilbert’s 
syndrome)
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated CP/CRP.  At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, history of alcohol 
drinking and other substance abuse.
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests.  
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and lab results stabilize.  Monitoring of ALT, AST, ALP, and 
TBL should continue until levels normalize or return to approximate baseline levels.
Comprehensive hepatic evaluation  
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions occur:

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If a participant with baseline results of...  
develops the following elevations:
ALT or AST <1.5× ULN
ALT or AST ≥3× ULN with hepatic signs/symptoms*, or
ALT or AST ≥5× ULN
ALP <1.5× ULN
ALP ≥3× ULN
TBL <1.5× ULN
TBL ≥2× ULN (except for patients with Gilbert’s syndrome)
ALT or AST ≥1.5× ULN
ALT or AST ≥2× baseline with hepatic signs/symptoms*, or
ALT or AST ≥3× baseline
ALP ≥1.5× ULN
ALP ≥2× baseline
TBL ≥1.5× ULN
TBL ≥1.5× baseline (except for patients with Gilbert’s syndrome) 
* Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, and/or 
eosinophilia >5%.
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for prothrombin time-international normalized ratio 
(PT-INR); tests for viral hepatitis A, B, C, or E; tests for autoimmune hepatitis; and an 
abdominal imaging study (for example, ultrasound or CT scan).  
Based on the patient’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus 
(HDV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), acetaminophen levels, 
acetaminophen protein adducts, urine toxicology screen, Wilson’s disease, blood alcohol levels, 
urinary ethyl glucuronide, and blood phosphatidylethanol. Based on the circumstances and the 
investigator’s assessment of the participant’s clinical condition, the investigator should consider 
referring the participant for a hepatologist or gastroenterologist consultation, magnetic resonance 
cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), 
cardiac echocardiogram, or a liver biopsy.  
Additional safety data collection in hepatic safety eCRF should be performed in study 
participants who meet 1 or more of the following conditions: 

Elevation of serum ALT to ≥5× ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5× ULN)
o
In participants with baseline ALT ≥1.5× ULN, the threshold is ALT ≥3× baseline 
on 2 or more consecutive tests

Elevated serum TBL to ≥2× ULN (except for cases of known Gilbert’s syndrome)
o
In participants with baseline TBL ≥1.5× ULN, the threshold should be TBL ≥2×
baseline

Elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests 
o
In participants with baseline ALP ≥1.5× ULN, the threshold is ALP ≥2× baseline 
on 2 or more consecutive blood tests

Hepatic event considered to be a SAE

Discontinuation of study drug due to a hepatic event.

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Note: the interval between the 2 consecutive blood tests should be at least 2 days.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities, venous blood samples of 
approximately 3 mL each will be collected to determine the plasma concentrations of tirzepatide.  
A maximum of 3 samples may be collected at additional time points during the study if 
warranted and agreed upon between both the investigator and sponsor.  Instructions for the 
collection and handling of blood samples will be provided by the sponsor.  The actual date and 
24-hour clock time of each sampling will be recorded.
Drug concentration information that may unblind the study will not be reported to investigative 
site or blinded personnel until the study has been unblinded.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of tirzepatide will be assayed using a validated liquid chromatography mass 
spectrometry method.  Analyses of samples collected from placebo-treated subjects are not 
planned.
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
1 year following last subject visit for the study.  During this time, samples remaining after the 
bioanalyses may be used for exploratory analyses such as metabolism work, protein binding, 
and/or bioanalytical method cross-validation.
9.6.
Pharmacodynamics
Briefly, PD assessments will include parameters of food intake, and central reward and appetite 
circuits.  A detailed description of PD efficacy measures is provided in Section 9.1 (Efficacy 
Assessments).  A description of procedures for obtaining the PD parameters is detailed in 
Appendix 5 and the analyses of these parameters is detailed in the SAP.
9.6.1. Immunogenicity Assessments 
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected to determine antibody production against tirzepatide.  To interpret the results of 
immunogenicity, a venous blood sample will be collected at the same time points to determine 
the plasma concentrations of tirzepatide.
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of tirzepatide at a laboratory approved by the sponsor.  Antibodies may be further characterized 
and/or evaluated for their ability to neutralize the activity of tirzepatide on GIP and GLP-1 
receptors.  Positive tirzepatide ADA samples may also be tested for cross-reactivity against 
native GIP and GLP-1, and, if positive, may then be tested for neutralizing antibodies against 
native GIP and/or GLP-1.  

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All subjects will have an ADA sample measured at ET and at the safety follow-up visit.  A 
risk-based approach will be used to monitor subjects who develop TE-ADA, defined in 
Section 10.3.4 (Evaluation of Immunogenicity).
Every attempt should be made to contact subjects for the follow-up immunogenicity assessment; 
however, if subjects are unwilling or unable to return for the visit, this is not considered a 
protocol violation.
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and IRBs allow, at a facility selected by the sponsor.  The duration 
allows the sponsor to respond to future regulatory requests related to tirzepatide.  Any samples 
remaining after 15 years will be destroyed.  
9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities, where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
tirzepatide and to investigate genetic variants thought to play a role in T2DM, obesity, and/or 
diabetic complications.  Assessment of variable response may include evaluation of AEs or 
differences in efficacy.  
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or IRBs impose shorter time limits, for the study at a facility 
selected by Lilly or its designee. This retention period enables use of new technologies, response 
to regulatory questions, and investigation of variable response that may not be observed until 
later in the development of tirzepatide or after tirzepatide is commercially available.  
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section.  
9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, mechanism of action, variability of subject response (including 
safety), and clinical outcome.  Sample collection is incorporated into clinical studies to enable 
examination of these questions through measurement of biomolecules including DNA, RNA, 
proteins, lipids, and other cellular elements.  

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Serum and plasma samples for non-pharmacogenetic biomarker research will be collected at the 
times specified in the Schedule of Activities (Section 2) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
tirzepatide, pathways associated with T2DM, obesity, and/or diabetic complications, mechanism 
of action of tirzepatide, and/or research method, or for validating diagnostic tools or assay(s) 
related to T2DM, obesity, and/or diabetic complications.
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or IRBs impose shorter time limits, at a facility selected by Lilly 
or its designee.  This retention period enables use of new technologies, response to regulatory 
questions, and investigation of variable response that may not be observed until later in the 
development of tirzepatide or after tirzepatide is commercially available.  
9.9.
Health Economics
This section is not applicable for this study.
9.10. Passive Detection of Eating Activity
To evaluate and refine an eating activity pattern recognition model, motion sensor data will be 
collected passively via a wrist-wearable device during the last week of the follow-up period of 
the study (Section 2; Schedule of Activities).
At Visit 12 (approximately 3 weeks following the last dose of study drug), subjects will visit the 
CRU on an outpatient basis, where they will be provided with a wrist-wearable device to be 
worn on their dominant arm.  The device will be worn during an ad libitum food intake test and 
subjects will then continue to wear the device for a further 4 days at home.  The device should 
always be worn on dominant hand/wrist (24/7) on the days specified.  
On all days the subject is wearing the device at home (approximately 4 days), eating events will 
be detected (food and corresponding utensils, if applicable) in free-living conditions using the 
Remote Food Photography Method© (RFPM) and SmartIntake® app (Appendix 5).  Energy and 
gram intake will not be calculated with the RFPM/SmartIntake® app, rather, the date and 
timestamp of the eating events will be evaluated in relation to data from the wrist-worn motion 
sensor.
At Visit 13 (approximately 4 weeks following the last dose of study drug), subjects will again 
return to the CRU on an outpatient basis.  While the device is still being worn, subjects will 
complete an ad libitum food intake test.  Subjects will then be required to return the 
wrist-wearable device to the CRU staff.  
The start and end time of each ad libitum food intake test during the follow-up period should be 
recorded in the eCRF.

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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
The sample size is derived such that the primary endpoint shall be met. In particular, that is to 
compare the change from baseline treatment difference in ad libitum calorie intake during lunch.
The foundation for making a reasonable assumption for effect size and variability is based on 
both unblinded data from I8F-MC-GPGC (Study GPGC) and blinded data from I8F-MC-GPGT
(Study GPGT). Study GPGC is a Phase 1 study to investigate safety, tolerability, PK, and PD of 
tirzepatide subcutaneously administered once weekly to Japanese patients with T2DM. Study 
GPGT is a 28-week Phase 1 study designed to examine α and β cell function, insulin sensitivity, 
glucose and lipid metabolism, food intake (ad libitum calorie intake during lunch), and energy 
expenditure in patients with T2DM treated with tirzepatide.
Combining the results from Study GPGC and blinded data from Study GPGT, the estimated 
variability (standard deviation) is 289 kcal and the estimated treatment difference between 
placebo and tirzepatide is 212 kcal. Therefore, at least 80% power can be achieved based on 2 
sample t-test using 2-sided test at alpha level of 0.05 with a sample size of 31 completers per
arm. Assuming 15% discontinuation rate, approximately 111 subjects (37 subjects per treatment 
arm) are planned to be randomly assigned.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study. All 
subjects who discontinue from the study will be identified, and the extent of their participation in 
the study will be reported.  If known, a reason for their discontinuation from study will be given.
10.2.2. Study Participant Characteristics
Demographic and baseline characteristics will be summarized by treatment group.  These data 
will be summarized using standard descriptive statistics.
10.2.3. Treatment Compliance 
Treatment compliance will be listed and summarized using standard descriptive statistics.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacodynamic analyses will be conducted on data from all subjects who receive at least 
1 dose of tirzepatide, placebo, or liraglutide and have evaluable PD data.  Sensitivity analyses 
may be performed as deemed necessary.  
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.

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Additional exploratory analyses of the data may be conducted as deemed appropriate.  
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
The incidence of AEs for each treatment will be presented by severity and by association with IP 
as perceived by the investigator.  Adverse events reported to occur prior to study entry will be 
distinguished from those reported as new or increased in severity during the study.  Each AE will 
be classified by the most suitable term from the medical regulatory dictionary.
All AEs and SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety lab parameters (including tirzepatide 
ADA), vital signs, TEAEs (including TEAEs of special interest), and SAEs.  
Summary statistics will be presented by treatment for the safety measures.  Additionally,
statistical analysis may be performed if warranted upon review of the data.
The analysis details will be provided in the SAP.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Sparse PK samples will be collected across the 6-week treatment duration according to Section 2
(Schedule of Activities).  Tirzepatide concentrations will be determined to support an 
understanding of tirzepatide exposure over the treatment duration and compare with expected 
tirzepatide PK.
10.3.2.2. Pharmacokinetic Statistical Inference
No summaries or analyses of PK parameters are planned.  Tirzepatide concentrations may be 
summarized by week.  
10.3.3. Pharmacodynamic Analyses
10.3.3.1. Pharmacodynamic Parameter Estimation
Pharmacodynamic parameters will be measured at baseline, Week 3, and Week 6, to assess the 
effect of study treatments on energy intake and central reward and appetite circuits in the brain.  
Parameters are provided in Section 9.1 and additional considerations are described below.  
Measures of Appetite and Food Intake 

Energy intake assessed by ad libitum food intake test: The primary endpoint is energy 
intake (kcal) during lunch in a clinical setting. The lunch consists of a buffet meal, where 
subjects can eat as much or as little as they wish. Other food intake variables such as
grams of carbohydrate, protein, and fat (saturated and unsaturated) consumed, as well as 
the percent of energy intake (kcal) from carbohydrate, protein, and fat (saturated and 
unsaturated) may also be computed if deemed necessary.  

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
Appetite VAS:  The VAS scales will be analyzed as continuous variables on the 
0-100 scale for individual components.  Overall appetite score is calculated as the 
average of the 4 individual scores (satiety + fullness + [100-prospective food 
consumption] + [100-hunger]/4) (Flint et al. 2000; van Can et al. 2014). The higher 
overall appetite score indicates less appetite and the lower score indicates more appetite.
Measures of Central Reward and Appetite Circuits

BOLD fMRI: Mean percent BOLD signal differences between views of highly palatable 
food (HF-HS and HF-HCCHO) versus non-food objects (e.g. office supplies, furniture) 
will be calculated within 5 principal food reward-related regions of interest; distinct 
locations within the insula, medial frontal gyrus, superior temporal gyrus, precentral 
gyrus, and cingulate gyrus.  Additional analysis will examine the BOLD signal 
differences in 4 exploratory food reward-related regions of interest; the hippocampus, 
putamen, orbitofrontal cortex, and ventral striatum.  
Additional analyses using other functional contrasts (e.g., Highly Palatable foods versus Not 
Highly Palatable Foods, not highly palatable foods versus nonfood objects) may be conducted as 
necessary. Other PD measures and exploratory measures will be described in the SAP.  
10.3.3.2. Pharmacodynamic Statistical Inference
The primary endpoint will be analyzed using an analysis of covariance (ANCOVA) to compare 
the effect of tirzepatide versus placebo at Week 3 on energy intake with terms, treatment, 
baseline BMI stratum, and baseline energy (kcal) intake as a covariate in the model.  The 
response variable will be the change from baseline to Week 3 in energy (kcal) intake, as assessed 
by ad libitum food intake test.  
The primary analysis will show least squares means of energy (kcal) intake by treatment and the 
treatment difference of tirzepatide versus placebo as well as standard error and 95% confidence 
interval.  All tests will be done at the 2-sided 0.05 α level, unless otherwise specified.
Analyses for secondary and exploratory endpoints will be specified in SAP.  
10.3.4. Evaluation of Immunogenicity
The frequency and percentage of subjects with preexisting ADA and with TE-ADA+ to 
tirzepatide may be tabulated. Treatment-emergent ADAs are defined as those with a titer 2-fold 
(1 dilution) greater than the minimum required dilution if no ADAs were detected at baseline 
(treatment-induced ADA) or those with a 4-fold (2 dilutions) increase in titer compared to 
baseline if ADAs were detected at baseline (treatment-boosted ADA). For the TE-ADA+ 
patients the distribution of maximum titers may be described.  The frequency of neutralizing 
antibodies may also be tabulated in TE-ADA+ patients.
The relationship between the presence of antibodies and the PK parameters and PD response 
including safety and efficacy to tirzepatide may be assessed.

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10.3.5. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly CP, CRP/investigator, or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol.
10.3.6. Exploratory Analysis for Motion Sensor Modeling
An existing model for eating activity recognition based on data from wrist-wearable device 
motion sensors (accelerometer and gyroscope) will be applied to classify time segments as 
involving eating or not.  Classification accuracy of this model will be evaluated relative to the 
ground truth labels collected in this study.  Ground truth labels are defined as the meal times 
obtained by the CRU staff during the follow-up period days, on which ad libitum food intake 
tests will be performed; a time when the food is weighed before and after the meal will be used 
as the time of meal start and end, respectively.  Ground truth will also be obtained on the days 
when subjects use the RFPM and SmartIntake® app in free-living conditions, where the 
timestamps associated with food photographs before and after the meal will be used as the time 
of meal start and end, respectively.  
Classification accuracy will be characterized using sensitivity, specificity, precision, and area 
under the curve.  
The existing model will be refined by re-training it with additional data from this study.  Data 
collected in this study will be split into training, validation, and test datasets to ensure that data 
used in model re-training will not be used in the assessment of the re-trained model accuracy.  
Re-trained model accuracy will be assessed using the same metrics as described above.  
The analyses specified in this section will be detailed in the digital biomarker analysis plan.

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11.
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Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity 
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12.
Appendices

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Appendix 1.
Abbreviations and Definitions

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Term
Definition
ADA
anti-drug antibody
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BAT
basophil activation test
BIS
Barratt Impulsiveness Scale
blinding
A procedure in which one or more parties to the study are kept unaware of the treatment 
assignments.  Unless otherwise specified, blinding will remain in effect until final database 
lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the subject is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the subject are not.  A double-blind study is one in 
which neither the subject nor any of the investigator or sponsor staff who are involved in 
the treatment or clinical evaluation of the subjects are aware of the treatment received
BMI
body mass index
BOLD
blood oxygenation level dependent
CAT
computer adaptive test
CBF 
cerebral blood flow
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CP
Clinical Pharmacologist

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CRP
Clinical Research Physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician or other medical officer.
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale
CT
computed tomography
ECG
electrocardiogram
eCRF
electronic case report form
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
ET
early termination
FCI
Food Craving Inventory
FCQ-S
Food Craving Questionnaire-State
fMRI
functional magnetic resonance imaging
GCP
good clinical practice
GI
gastrointestinal
GIP
glucose-dependent insulinotropic
GIPR
glucose-dependent insulinotropic receptor
GLP-1
glucagon-like peptide 1 
GLP-1R
glucagon-like peptide1 receptor
GLP-1RA
glucagon-like peptide 1 receptor agonist
HCV
hepatitis C virus
HCCHO
high carbohydrate
HF
high fat
HIV
human immunodeficiency virus
HP
high protein
HS
high sugar
IB
Investigator’s Brochure

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informed 
consent/informed 
consent form (ICF)
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the subject’s decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form.  
ICH
International Council for Harmonisation
Ig
immunoglobulin
IP
investigational product:  A pharmaceutical form of an active ingredient or placebo being 
tested or used as a reference in a clinical study, including products already on the market 
when used or assembled (formulated or packaged) in a way different from the authorized 
form, or marketed products used for an unauthorized indication, or marketed products used 
to gain further information about the authorized form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
IRB
institutional review board
Legal 
Representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective subject, to the subject’s participation in the clinical study.
LCCHO
low carbohydrate
LF
low fat
LP
low protein
MAD
multiple ascending dose
MEN 2
multiple endocrine neoplasia syndrome type 2
MRI
magnetic resonance imaging
MTC
medullary thyroid carcinoma
NPAL
not highly palatable
open label
A study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study participant are aware of the drug therapy received during the 
study.
PAL
Highly palatable
PD
pharmacodynamic
PHQ-9
Patient Health Questionnaire-9
PFS
pre-filled syringe
PG
plasma glucose

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PK
pharmacokinetic
QD
once daily
QW
once weekly
randomize
the process of assigning subjects/patients to an experimental group on a random basis
RFPM
Remote Food Photography Method©
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous(ly)
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
TBL
total bilirubin
TE-ADA
treatment-emergent anti-drug antibody
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment 
ULN
upper limit of normal
VAS
visual analog scale
WOCBP
women of childbearing potential

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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Phosphorus
Leukocytes (WBC)
Glucose (fasting)a
Absolute counts of
Blood urea nitrogen
Neutrophils
Uric acid
Lymphocytes
Total protein
Monocytes
Albumin
Eosinophils
Total bilirubin
Basophils
Alkaline phosphatase
Platelets
Alanine aminotransferase
Aspartate aminotransferase
Urinalysis
Creatinine
Specific gravity
Lipase (fasting)
pH
Amylase
Protein
Triglycerides (fasting)a
Glucose
Total cholesterol (fasting)
Ketones
Low-density lipoprotein (fasting)
Bilirubin
High-density lipoprotein (fasting)
Urobilinogen
Hemoglobin A1c
Blood
Leukocytes
Serologye
Microscopyb
Hepatitis B surface antigen
Hepatitis C antibody, hepatitis C RNA
HIV antibody
Endocrine
FSHb, c
Pregnancy test (urine, serum)f
Calcitonind
Drug and alcohol screeng
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
a
At timepoints when glucose and triglyceride efficacy assessments coincide with safety laboratory tests, glucose 
and triglycerides will only be analyzed once.  
b
If clinically indicated, as per investigator’s discretion.
c
Female subjects only.
d
At screening only
e
At screening only (unless previously performed within the last 6 months with reports available for review).  See 
exclusion criteria (Section 6.2) for further details.  
f
Performed for women of childbearing potential only.  Serum pregnancy test is done at screening and follow-up 
and urine pregnancy test is performed on Days -4, 1, 15, and 36.
g
Performed at screening.  Procedures may be repeated throughout the study as deemed necessary by the 
investigator.

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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the subject understands the nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each subject or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of investigational 
product.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the subject or the subject’s legal representative and 
retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.  Study-specific recruitment 
material should be approved by Lilly.
Ethical Review
The investigator must give assurance that the institutional review board (IRB) was properly 
constituted and convened as required by ICH guidelines and other applicable laws and 
regulations.
Documentation of IRB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site.  Lilly or its representatives must approve the ICF 
before it is used at the investigative site.  All ICFs must be compliant with the ICH guideline on 
GCP.
The study site’s IRB should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae

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Regulatory Considerations
This study will be conducted in accordance with the protocol and with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party organization.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, the principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study site, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the eCRFs, and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

review and evaluate eCRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.

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In addition, Lilly or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site.  The study may be audited by Lilly and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable IRBs with direct access to the original source 
documents.
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.  
The purpose and use of subject personal information collected will be provided in a written
document to the subject by the sponsor.
Study and Site Closure
Discontinuation of Study Site
Study site participation may be discontinued if Lilly or its designee, the investigator, or the IRB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.

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Appendix 4.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and estimated blood volumes 
for all blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol I8F-MC-GPHH Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa,b
24
1
24
Safety laboratory testsa,b
22.5
4
90
Tirzepatide PK
3
5 (+3)
24
Pharmacodynamics
Ghrelin (fasting)c
2
3
6
Glucagon (fasting)c
2
3
6
Glucose (fasting) – Weeks 3 and 6c
2
2
4
Triglycerides (fasting) – Weeks 3 and 6c
2.5
2
5
Insulin (fasting)c
2.5
3
7.5
Insulin (postprandial)c
2.5
3
7.5
Peptide YY (postprandial)c
5
3
15
Pancreatic polypeptide (postprandial)c
5
3
15
Leptin (postprandial)c
4
3
12
Active GIP and GLP-1 (postprandial)c
2
3
6
Amylin (postprandial)c
5
3
15
Immunogenicity
10
4 (+3)
70
Pharmacogenetics
10
1
10
Nonpharmacogenetic stored samplec (fasted)
11
3
33
Total
350
Total for clinical purposes [rounded up to nearest 10 mL] 
350
Abbreviations: GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagon-like peptide 1; 
PK = pharmacokinetics.
a
additional samples may be drawn if needed for safety purposes.
b
performed on site or in a local laboratory.
c
performed at a central or referral laboratory, including for storage.

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Appendix 5.
Pharmacodynamic Assessments
5.1.
Ad Libitum Food Intake Test
Food intake will be quantified in a clinical setting.  
5.1.1.
Clinic-Based Food Intake Test
Food intake will be quantified via test meals conducted in the CRU at lunch during the 6-week 
treatment period (Baseline, Day -4 to Day -1), Day 16 [Week 3, Visit 6], and Day 37 [Week 6, 
Visit 11]), and during the third and fourth weeks of the follow-up period i.e. [Visit 12] and [Visit 
13], respectively. The start time of the lunch test meals will be consistent within subjects across 
testing occasions.  Start and end times of the test meals will be recorded.  
Subjects will complete a test lunch that begins between approximately 11:30 AM and 12:30 PM.  
Lunch will consist of buffet meal (Table GPHH.3).
Table GPHH.3.
Details of Buffet Meal
baked potato chips
grilled chicken bites
barbeque sauce
baked tortilla chips
popcorn chicken bites
sweet and sour sauce
corn chips
cheddar cheese
M&M’S®
pretzel twists
swiss cheese
crème-filled chocolate cake rolls
buttered popcorn
salsa
raisins
mixed nuts with salt
fat-free ranch dressing
fruit punch
baby carrots
cheese dip
water
Subjects will be instructed that they can eat as much or as little as they wish during the test meals 
and that they should alert a staff member when they are finished eating, at which time the 
subjects will leave the test meal. Staff members will check on the subjects after 25 minutes and 
terminate the session after 40 minutes if the subject does not end the session.
Food intake will be quantified by precisely weighing foods before and after the test meals, as 
close to the beginning and end of the meal as possible.  During the follow-up period, the time the 
food is weighed before and after the test meals will be recorded.  Energy and nutrient intake will 
be calculated by linking each food to a match in the United States Department of Agriculture 
(USDA) Food and Nutrient Database for Dietary Studies (FNDDS) Studies (USDA 2018) or 
data from the food producer/manufacturer.  
5.1.2.
Free-Living Food Intake
The time of meals will be assessed for approximately 4 days during the last week of follow-up 
period (beginning approximately 3 weeks post-final dose of study drug). During the follow-up 
period, energy and gram intake will not be calculated, rather, the start and stop times of the meal 
will be quantified based on the timestamps of the food images. These data will be collected with 
the Remote Food Photography Method© (RFPM) (Martin et al. 2009, 2013) and SmartIntake®

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smartphone application (or app). The RFPM and SmartIntake® app were developed by Corby 
Martin, Ph.D., H. Raymond Allen, Ph.D., and colleagues at the Pennington Biomedical Research 
Center. RFPM data are collected with the SmartIntake® app, which is used to streamline data 
collection and minimize subject burden. 
Self-report methods, such as pen-and-paper and dietary recall, rely on the ability of the subject to 
accurately recall the types and portion sizes of foods consumed, and the accuracy of these 
methods have been questioned (Beaton et al. 1997; Tran et al. 2000; Schoeller et al. 1990; 
Bandini et al. 1990). Importantly, ~50% of the error in self-report methods is due to subjects’
inability to accurately estimate portion size (Beasley et al. 2005), a limitation that is avoided 
when using the RFPM and SmartIntake® app.  
The RFPM and SmartIntake® app also result in the collection of data in real-time with food 
image data which can be evaluated via a password protected website for quality and 
completeness; thus, providing a platform to reduce missing data and facilitate data quality.
When using the SmartIntake® app, subjects place a reference card next to their food and capture 
images of their food selection and plate waste. The user identifies foods that are not easily 
identified by wrappers or containers by typing a food description into a text box. Drop-down 
boxes also allow the user to indicate what meal or snack is being consumed, and also where the 
food was obtained (e.g., home prepared, restaurant) and where it is being eaten. These data and 
food images are automatically and wirelessly sent by the app to the server-based Food 
Photography Application©, which is used to manage the data collection process and analyze the 
food images to estimate energy and nutrient intake.  
To facilitate data quality and completeness, the SmartIntake® app includes Ecological 
Momentary Assessment (EMA) methodology (Stone et al. 1994) to remind subjects to capture 
images of the foods and beverages that they consume. These reminders are text messages that 
are scheduled for delivery at the personalized meal-times of the subjects. The responses to 
EMAs are tracked in near real time, which allows the research team to quickly identify when 
data collection problems occur. In such cases, a back-up method is used (e.g., a food record or 
food recall conducted by phone). The content of the text reminders can be customized by the 
researcher or clinician.  
The SmartIntake® app sends subjects’ food images and accompanying food descriptions to a 
Pennington server where the Pennington team analyzes the images to estimate food intake if 
needed. The analysis process relies on the Food Photography Application©, which allows the 
operator to identify a match for each food from the Food and Nutrient Database for Dietary 
Studies (USDA 2018) and other sources, such as manufacturer’s information and Nutrition Fact 
Panels, to calculate energy and nutrient intake. Additionally, the operator uses the program to 
estimate portion size by visually comparing subjects’ food images to images of foods with a 
known portion size (i.e., standard portion images). This process relies on existing and validated 
methodology (Martin et al. 2012, Martin et al. 2009, Williamson et al. 2004; Williamson et al. 
2003) to estimate food selected and plate waste, which is used to calculate food intake by 
difference. The RFPM has been found to accurately measure the energy and nutrient intake of 

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adults, with error of 3.7% over 6 days in free-living conditions compared to the gold standard, 
doubly labeled water.
During the current study, subjects will be trained how to use the RFPM and SmartIntake® app 
during their visit to the center to capture imaging data on Day 59.    All food consumption during 
the observation period should be recorded and subjects will receive regular reminders and 
extensive review of their data in near real time to foster data quality and completeness. These 
procedures will facilitate data collection as a formal run-in is not being conducted before data 
collection begins.  Subjects will be instructed to photograph their food as closely as possible to 
the actual meal start and end.  
5.2
Magnetic Resonance Imaging
Functional neuroimaging, in the forms of BOLD fMRI will be used to assess brain response 
patterns to food and non-food images. The MRI scanning will occur on different scanners such 
as a 3T General Electric Discovery 750W with 32-channel head coil, a 3T General Electric 
Discovery 750 with 32-channel head coil, a 3T Siemens Prisma with a 64-channel head coil, or a 
3T Philips Achieva with a 32-channel head coil. Functional neuroimaging session will be 
conducted after participants fast overnight for at least 8 hours (ten Kulve et al. 2016).  
Subjects will be required to complete the food image task during the BOLD fMRI scan.  The 
food image task was developed using images from the Food-pic database (Blechert et al. 2014).
Briefly, 90 food images across sweet and savory tastes, high- and low-energy density, and varied 
macronutrient composition, were included along with 15 images of non-food objects (e.g.
everyday household objects). This results in 105 images in total. Macronutrient categories 
(Geiselman et al. 1998) were made by categorizing each food as:

low versus high fat (LF vs HF, <30% vs >30%)

low versus high sugar (LS vs. HS, <30% vs. >30%) 

low versus high carbohydrate (LCCHO vs HCCHO, <30% vs >30%)

low versus high protein (LP vs HP, <13% vs >13%)  
This resulted in 6 food categories with 15 photos in each: 
1. HF/HS
2. HF/HCCHO
3. HF/LCCHO/HP
4. HS/LF
5. LF/HCCHO
6. LF/LCCHO/HP
Each 600 × 450 color photo shows 1 food on a white background.

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Among the 6 food categories, HF-HS and HF-HCCHO will be called highly palatable (PAL) 
food and LF-LCCHO-HP will be called not highly palatable (NPAL) food.
In each trial of the task, 1 food photo is displayed for 5 seconds followed by 0.5 seconds of a 
fixation crosshair. Next, the same image scaled to 80% of the original size is shown with the 
words “How much do you want to eat this?” for 2.5 seconds. A slider bar with “Not at all” and 
“Want very much” on the left and right ends appears. The subject moves a joystick to select a 
slider bar position and clicks a joystick button to respond. A fixation crosshair displays for a 
minimum of 1.5 seconds before the next trial. There are 15 trials (i.e. 15 photos) per block and 
14 inter-trial intervals per block: an average of 150 s/block. This is followed by a 30 s inter-
block interval before the next block. total of 7 blocks and 6 inter-block intervals: 20.5 minutes of 
recorded data. Prior to the beginning of the task, subjects will be given time to practice the task 
in the scanner. Additionally, a high-resolution structural scan will be acquired. The total duration 
of each MRI session will be around 40 minutes.
For the purposes of evaluating inter-scanner variability to ensure that the fMRI data from all sites 
can be analyzed collectively at the end of the study, subjects will be required to complete a 
bilateral hand squeeze motor task during the BOLD fMRI scan, consisting of 4 blocks after the 
food image task. Each block will consist of 30 seconds of bilateral hand squeezing followed by 
30 seconds of rest (around 3 minutes total run time). 
To model respiratory and cardiac effects on the BOLD signals, participants will be fitted with a 
lap belt and pulse oximeter.  The respiratory cycle signal and cardiac cycle signal will be 
regressed out of all time series data.  
BOLD fMRI Data Processing
The BOLD fMRI acquisition parameters include repetition time of 3000 ms, echo time of 30 ms, 
flip angle of 90°, slice thickness of 3.5 mm, and 64×64 image matrix.  
As in prior work (King et al. 2018), a T1-weighted magnetization-prepared 180° radio-frequency 
pulses and rapid gradient-echo (MP RAGE) will be collected as an anatomical reference for 
functional data.  
Preprocessing of fMRI data will be done by an external imaging laboratory services provider.
For the hand squeezing fMRI task, BOLD contrasts of hand squeezing versus resting within 
bilateral somatomotor ROIs will be calculated. For the food image fMRI task, highly palatable 
food (HF-HS, HF-HCCHO), not highly palatable foods (LF-LCCHO-HP), and non-food object 
blocks will be modeled. To assess brain activation related to viewing food pictures, the contrast 
between highly palatable foods and non-food objects will be computed. Additionally, the 
contrast between highly palatable foods and not highly palatable foods as well as the contrast 
between not highly palatable foods and non-food objects may be computed. Contrasts between 
each specific food category and non-food objects may also be computed if deemed necessary. 
Average BOLD contrast in each of 9 areas associated to brain reward will be reported (insula, 
medial frontal gyrus, superior temporal gyrus, precentral gyrus, cingulate gyrus, hippocampus, 
putamen, orbitofrontal cortex, and ventral striatum). 

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5.3.
Appetite Visual Analog Scales
The aim of the appetite visual analog scale (VAS) is to determine the effects of study treatments 
on appetite sensations and desire for specific foods.  Two types of VAS will be used to assess 
subjective ratings of appetite and affect; laboratory-based and retrospective.
5.3.1.
Appetite Visual Analog Scale
During the laboratory-based test meals on (Baseline, Day -4 to Day -1), Day 16 [Week 3, Visit 
6], and Day 37 [Week 6, Visit 11]), subjects will complete VAS ratings immediately before and
after the test lunch.  
Subjects will be asked to rate their feelings of hunger, satiety, fullness, prospective food 
consumption, and desire for specific foods on a 10-cm (100-mm) line, or a 100-unit line 
represented on a piece of paper; anchored by verbal descriptors, usually “not at all” and 
“extremely.”  The ratings will include the following 8 questions (Flint et al. 2000):

How hungry do you feel right now?

How satisfied do you feel right now?

How full do you feel right now?

How much food do you think you could eat right now?

Would you like to eat something sweet?

Would you like to eat something salty?

Would you like to eat something savory?

Would you like to eat something fatty?
Pen-and-paper VAS will be used and will include a 10-cm line.  Subjects will record their rating 
on the respective lines, ranging from 0 (“not at all”) to 100 (“extremely”).  Only provided or 
printed (not copied) paper VAS can be used, as copying them alters the length line.  
Overall appetite score is calculated as described in Section 10.3.3.1 (Pharmacodynamic 
Parameter Estimation).
5.3.2.
Retrospective Appetite Visual Analog Scale
Visual analog score will be used to measure average ratings of appetite that subjects experienced 
over the past week.  These ratings will occur on Baseline, Day -4 to Day -1, Day 16 [Week 3, 
Visit 6], and Day 37 [Week 6, Visit 11]).
The retrospective method of collecting VAS data has been found to be consistent with daily 
assessments of satiety (Womble et al. 2003).  These VAS items will assess 4 appetite-related 
metrics and the instructions to the subjects will be modified, as detailed here: 

How hungry did you feel over the past week?

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
How satisfied did you feel over the past week?

How full did you feel over the past week?

How much food did you think you could eat over the past week?
In addition to the 4 appetite metrics noted above, retrospective VAS will also be used to quantify 
feelings of nausea, malaise, and gastrointestinal distress over the previous week.  Specifically, 
the following items will be administered:

How much nausea did you have over the past week?

How much malaise did you have over the past week?

How much gastrointestinal distress did you have over the past week?
These 3 items will be anchored with verbal descriptors ranging from “none at all” to “an extreme 
amount”.  
5.4.
Food Intake-Related Questionnaires
Subjects’ attitudes towards food will be evaluated with the Food Craving Inventory (FCI), Food 
Craving Questionnaire-State (FCQ-S), Eating Inventory, and Power of Food Scale.  These food-
related questionnaires will be administered at Day -4 to Day -1 [baseline], Day 16 [Week 3, Visit 
6], and Day 37 [Week 6, Visit 11]).  Attempts will be made for questionnaires to be completed in 
a fasted state shortly after arriving to the study site.   
5.4.1.
Food Craving Inventory
The 33-item FCI (White et al. 2002) will be used to measure cravings for specific food groups. 
The measure consists of 5 empirically derived factors: 

high fats

sweets

carbohydrates/starches

fast food fats

and fruits and vegetables
The FCI is scaled in a frequency format assessing the frequency of cravings for particular foods 
over the past month. All items are scored in the following manner: Never = 1, Rarely = 2, 
Sometimes = 3, Often = 4, Always = 5. 
The instructions for the FCI will be altered for Days 16 and 37 (Week 3, Visit 6 and Week 6, 
Visit 11) to include the following time frame: “Since the last time you completed this 
questionnaire, how often have you experienced a craving for the food?”.  This differs from the 
original instructions which denotes a 1-month time frame.  All other instructions on the FCI will 
remain the same as the original. 

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5.4.2.
Food Craving Questionnaire-State
The FCQ-S is a 15-item measure that assesses the strength of state food cravings at the moment
of administration.  The FCQ-S has demonstrated good validity and internal consistency in 
non-clinical populations at the moment of provision (Cepeda-Benito et al. 2000; Moreno et al. 
2008).  
Desire, anticipation positive, anticipation negative, lack of control, and hunger scores are 
measured.  Greater scores for each sub-scale denote higher levels of craving.
5.4.3.
Eating Inventory
The Eating Inventory is a 51-item validated questionnaire that assesses 3 eating-related 
constructs: 

dietary restraint 

disinhibition 

perceived hunger (Stunkard and Messick. 1985; Sunkard and Messick 1988) 
Dietary restraint refers to the intent and ability to restrict food intake, disinhibition measures the 
tendency to overeat, and hunger measures susceptibility to feelings of hunger. Scores for 
restraint, disinhibition, and hunger range from 0 to 21, 0 to 18, and 0 to 14, respectively, and a 
greater number indicates greater levels of each respective eating component.
5.4.4.
Power of Food Scale
The Power of Food Scale measures appetite for palatable foods in the environment at the 
following 3 levels of food proximity: food available, food present, and food tasted.  The Power 
of Food Scale has adequate internal consistency and test-retest reliability (Lowe et al. 2009).
5.5.
Impulsivity
Impulsivity will be measured with the Barratt Impulsiveness Scale (BIS) on Day -4 to Day -1 
[baseline], Day 16 [Week 3, Visit 6], and Day 37 [Week 6, Visit 11]). Attempts will be made for 
BIS questionnaire to be completed in a fasted state shortly after arriving to the study site.
5.5.1.
Barratt Impulsiveness Scale
The BIS is a 30-item self-report measure describing impulsive or non-impulsive behaviors and 
preferences. The scale consists of 6 first order factors as follows: 

attention

cognitive stability

motor

perseverance

self-control

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
cognitive complexity
The scale also consists of 3 second-order factors:  attentional, motor, and non-planning. 
The items are rated on a 4-point scale with responses ranging from 1 = rarely/never to 4 = almost 
always/always. The measure assesses the personality/behavioral construct of impulsiveness and 
has demonstrated good psychometric properties in multiple populations (Patton et al. 1995; Reid 
et al. 2014).

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Appendix 6.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Evaluation of subjects with treatment-emergent abnormal hepatic biochemical tests during a 
clinical trial.  Extent and type of work-up may vary by subject’s history, severity of liver injury, 
underlying disease, and geography.  
Recommended Evaluation
Competing Causes of Abnormal Liver Tests
1st Line Testing
ALT, AST, ALP, TBL, direct bilirubin, GGT, CK
Routine follow up 
Thorough history of symptoms, co-existing medical 
conditions, concomitant medications, dietary and 
nutritional supplements, excessive exercise or muscle 
injury, alcohol consumption, illicit substances.  
Systemic infection/ sepsis; ischemic/ congestive 
hepatic injury; gallstone disease; alcoholic liver 
disease; muscle injury/ rhabdomyolysis; 
acetaminophen toxicity; DILI due to another drug, 
herbal or dietary supplement.  
Serum CK
Muscle injury/rhabdomyolysisa
Anti-HAV (IgM)
Acute HAV infection
HBsAg
Anti-HBc IgG, IgM
Acute hepatitis B; exacerbation of chronic hepatitis B
Anti-HCV 
HCV RNA (PCR)b
Acute hepatitis Cc; exacerbation of chronic hepatitis C
Anti-HEV (IgG, IgM), HEV RNAd
Acute hepatitis E
ANA, ASMA, quantitative immunoglobulins 
(IgG, IgM, IgA)
Autoimmune hepatitise
Hepatobiliary imaging 
(ultrasonography, CT scan, MRI, MRCP)f
Biliary obstruction; pancreatitis; gallstones; 
portal-vein/ hepatic vein thrombosis; hepatic 
metastasis 
2nd Line Testing
PT-INR
For patients with elevated TBL or suspected liver 
failure 
Serological tests for EBV, CMV, HSV 
May need to obtain acute and convalescent serological 
tests
Hepatic injury caused by CMV, EBV, HSV
EBV-DNA, CMV- DNA, HSV-DNA by PCR.  
Liver biopsy needed to confirm HSV
Hepatic injury caused by CMV, EBV, HSV
Additional Testsg
Bone specific ALP (ALP fractionation)
Differentiate bone from liver origin 
LKM-1 antibody
Autoimmune hepatitis
Urinary ethylglucuronideh, 
blood phosphatidylethanoli
Alcoholic liver disease
Serum acetaminophen level; 
acetaminophen protein adducts
Acetaminophen toxicity
Review of blood pressure, pulse, electrocardiogram, 
echocardiogram, cardiology consult
Ischemic or congestive hepatic injury 

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Urine toxicology screen
Hepatotoxicity due to cocaine, opiates and other illicit 
substances
Anti-HDV
Hepatitis D 
Blood or urine cultures 
Systemic infection, sepsis
Serum ceruloplasmin, serum copper Slit lamp eyes 
examination for Kayser-Fleischer rings, genetic testing
Wilson’s disease
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANA = antinuclear antibody; 
anti- = antibody; ASMA = anti-smooth muscle antibody; AST = aspartate aminotransferase; CK = creatinine 
kinase; CMV = cytomegalovirus; CT = computed tomography; DILI = drug-induced liver injury; EBV = Epstein 
Bar Virus; GGT = gamma-glutamyl transferase; HAV = hepatitis A virus; HBc = hepatitis B core; 
HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis D 
virus; HEV = hepatitis E virus; HSV = herpes simplex virus; Ig = immunoglobulin; INR = international 
normalized ratio; LKM-1 = liver kidney microsomal type 1; MRCP = magnetic resonance 
cholangiopancreatography; MRI = magnetic resonance imaging; PCR = polymerase chain reaction; 
PT-INR = prothrombin time-international normalized ratio; RNA = ribonucleic acid; TBL = total bilirubin.
a
Serum AST typically (although not always) is higher than ALT
b
If anti-HCV positive, HCV RNA is required to confirm HCV infection
c
Acute hepatitis C may be anti-HCV negative but HCV RNA positive 
d
If anti-HEV IgM positive, consider confirmation with HEV RNA by nested PCR
e
A liver biopsy is needed to confirm a diagnosis of autoimmune hepatitis 
f
If cholestatic injury, MRCP may be recommended
g
Based on medical history and clinical judgment
h
Alcohol consumption in past 3 to 5 days 
i
Alcohol consumption in past 3 weeks

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Appendix 7.
Pancreatic Monitoring
Abbreviations:  CT = computed tomography; L/A = lipase and/or amylase; MRI = magnetic resonance imaging; 
ULN = upper limit of normal.

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Subjects diagnosed with pancreatitis will be discontinued from the study.  Investigators will be 
responsible for following, through an appropriate healthcare option, these pancreatitis AEs until 
the events resolve or are explained.  Adverse events that meet the diagnostic criteria of acute 
pancreatitis will be captured as serious adverse events (SAEs).  For all other pancreatic AEs 
(such as idiopathic or asymptomatic pancreatic enzyme abnormalities), the investigator will be 
responsible for determining the seriousness of the event (AE or SAE) and the relatedness of the 
event to investigational product.

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Appendix 8.
Recommended Laboratory Testing for 
Hypersensitivity Events
Lab testing should be performed at the time of a Systemic Hypersensitivity Event. Important 
information about why, when, and what to test for are provided below. The management of the 
adverse event may warrant lab testing beyond that described below and should be performed as 
clinically indicated.
Laboratory testing during a Systemic Hypersensitivity Event is not performed for diagnostic 
purposes. Its intent is several fold:

To help characterize and classify systemic hypersensitivity reactions

To meet regulatory expectations

To improve subsequent clinical management by helping to distinguish between the 
various mechanistic bases of anaphylaxis
When Should Labs Be Obtained?

In the presence of generalized urticaria or if anaphylaxis is suspected

After the subject has been stabilized, obtain a sample within 1 to 2 hours of the event; 
however, samples may be obtained as late as 12 hours after the event as analytes can 
remain altered for an extended period of time. Record the time at which the sample was 
collected.

Obtain a follow-up sample at the next regularly scheduled visit or after 4 weeks, 
whichever is later.
What Labs* Should Be Obtained?

Tryptase**

ADA and tirzepatide concentration (PK)
o
ADA testing should include drug-specific immunoglobulin (Ig)E or the basophil 
activation test (BAT)#. These tests are not routinely available and need to be 
developed for individual molecules based on their evolving safety profile.  
Samples are collected, and testing conducted once the assay is available, as 
appropriate. Please consult an immunologist within GPS for further guidance.

Complement
o
C3a and C5a

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
Cytokines
o
IL‐6, IL‐1β, IL‐10 (or any cytokine panel that includes these 3 cytokines)
*
These labs are bundled in the Clinical Laboratory Operations Hypersensitivity Lab Testing 
Kit.  
** If a tryptase sample is obtained more than 2 hours after the event (i.e., within 2 to 12 hours), 
or is not obtained because more than 12 hours have lapsed since the event, obtain urine for 
N-methylhistamine (NMH) testing.  Note that for tryptase serum samples obtained within 
2 to 12 hours of the event, urine NMH testing is performed in addition to tryptase testing.  
Collect the first void urine following the event.  Obtain a follow-up urine for NMH testing 
at the next regularly scheduled visit or after 4 weeks, whichever is later.
# 
The BAT is an in vitro cell based assay that only requires a serum sample.  It is a surrogate 
assay for drug specific IgE but is not specific for IgE.

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Appendix 9.
Protocol Amendment I8F-MC-GPHH(f) 
Summary - Effect of Tirzepatide on Energy Intake and 
Appetite- and Reward-Related Brain Areas in 
Overweight/Obese Subjects:  A Placebo-Controlled 
6-Week Study with Functional MRI
Overview
Protocol I8F-MC-GPHH, Effect of Tirzepatide on Energy Intake and Appetite- and 
Reward-Related Brain Areas in Overweight/Obese Subjects:  A Placebo-Controlled 6-Week 
Study with Functional MRI, has been amended.  The new protocol is indicated by Amendment 
(f) and will be used to conduct the study in place of any preceding version of the protocol.
This amendment is considered a nonsubstantial protocol amendment.
The overall changes and rationale for the changes made to this protocol are as follows:

Appendix 5 was updated to include language on 
o
the types of scanners on which MRI scanning will occur to specify the different 
scanners used across the different study sites and,
o
the hand squeezing task following the food image task to evaluate inter-scanner 
variability across the different scanners. The hand squeezing task produces 
consistent patterns of motor cortex activation in the brain, independent of scanner
type.

The hand squeezing task will be used to ensure that the fMRI data from all 
sites can be analyzed collectively at the end of the study.
o
The description of preprocessing of fMRI data was deleted because it will be 
performed by an external imaging laboratory services provider.

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Revised Protocol Sections
Note: All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.

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Appendix 5
5.2
Magnetic Resonance Imaging
Functional neuroimaging, in the forms of BOLD fMRI will be used to assess brain response 
patterns to food and non-food images. The MRI scanning will occur on different scanners such 
as a 3T General Electric Discovery 750W with 32-channel head coil, a 3T General Electric 
Discovery 750 with 32-channel head coil, a 3T Siemens Prisma with a 64-channel head coil, or a 
3T Philips Achieva with a 32-channel head coil. Functional neuroimaging session will be 
conducted after participants fast overnight for at least 8 hours (ten Kulve et al. 2016).  
Subjects will be required to complete the food image task during the BOLD fMRI scan.  The 
food image task was developed using images from the Food-pic database (Blechert et al. 2014).
Briefly, 90 food images across sweet and savory tastes, high- and low-energy density, and varied 
macronutrient composition, were included along with 15 images of non-food objects (e.g.
everyday household objects). This results in 105 images in total.
For the purposes of evaluating inter-scanner variability to ensure that the fMRI data from all sites 
can be analyzed collectively at the end of the study, subjects will be required to complete a 
bilateral hand squeeze motor task during the BOLD fMRI scan, consisting of 4 blocks after the 
food image task. Each block will consist of 30 seconds of bilateral hand squeezing followed by 
30 seconds of rest (around 3 minutes total run time).
BOLD fMRI Data Processing
The BOLD fMRI acquisition parameters include repetition time of 3000 ms, echo time of 30 ms, 
flip angle of 90°, slice thickness of 3.5 mm, and 64×64 image matrix.  
As in prior work (King et al. 2018), a T1-weighted magnetization-prepared 180° radio-frequency 
pulses and rapid gradient-echo (MP RAGE) will be collected as an anatomical reference for 
functional data.  
Preprocessing of fMRI data will be done by an external imaging laboratory services provider. in 
SPM8 includes slice-timing correction, head-motion correction, smoothing, and warping to a 
standard coordinate frame.  Time points with head rotation greater than 2or translation greater 
than 2 mm will be removed.  Data will be entered into a first-level voxel-wise analysis with each 
trial modeled as a boxcar function that covers the period of time when the large image is viewed.  
The boxcar function is convolved with the canonical hemodynamic response function. 
Functional scans will be analyzed in the context of the general linear model. 
For the hand squeezing fMRI task, BOLD contrasts of hand squeezing versus resting within 
bilateral somatomotor ROIs will be calculated.  For the food image fMRI task, hHighly palatable 
food (HF-HS, HF-HCCHO), not highly palatable foods (low fat-low carbohydrate-high 
proteinLF-LCCHO-HP), and non-food object blocks will be modeled. To assess brain activation 
related to viewing food pictures, the contrast between highly palatable foods and non-food 
objects will be computed. Additionally, the contrast between highly palatable foods and not 
highly palatable foods as well as the contrast between not highly palatable foods and non-food 
objects may be computed. Contrasts between each specific food category and non-food objects 

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may also be computed if deemed necessary. Average BOLD contrast in each of 9 areas 
associated to brain reward will be reported (insula, medial frontal gyrus, superior temporal gyrus, 
precentral gyrus, cingulate gyrus, hippocampus, putamen, orbitofrontal cortex, and ventral 
striatum).

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