A Randomized, Placebo-Controlled, Parallel-Arm Study to Investigate the Effect of Once-Weekly Tirzepatide on Energy Expenditure and Food Intake in Obese Subjects
Phase: PHASE1
Conditions: Obesity
Sponsor: Eli Lilly and Company

Protocol I8F-MC-GPGU(f) 
A Randomized, Placebo-Controlled, Parallel-Arm Study to Investigate the Effect of 
Once-Weekly Tirzepatide on Energy Expenditure and Food Intake in Obese Subjects
NCT04081337   
Approval Date: 02-Aug-2021 

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Protocol I8F-MC-GPGU(f)
A Randomized, Placebo-Controlled, Parallel-Arm Study to 
Investigate the Effect of Once-Weekly Tirzepatide on 
Energy Expenditure and Food Intake in Obese Subjects
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: 23 July 
2019.
Amendment (a) Electronically Signed and Approved by Lilly: 11 September 2019
Amendment (b) Electronically Signed and Approved by Lilly: 22 October 2019
Amendment (c) Electronically Signed and Approved by Lilly:  31 January 2020
Amendment (d) Electronically Signed and Approved by Lilly:  24 February 2020
Amendment (e) Electronically Signed and Approved by Lilly: 03 August 2020
Amendment (f) Electronically Signed and Approved by Lilly on approval date provided 
below
Approval Date: 02-Aug-2021 GMT

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Table of Contents
A Randomized, Placebo-Controlled, Parallel-Arm Study to 
Investigate the Effect of Once-Weekly Tirzepatide on Energy 
Expenditure and Food Intake in Obese Subjects
Section
Page
Protocol I8F-MC-GPGU(f) A Randomized, Placebo-Controlled, Parallel-
Arm Study to Investigate the Effect of Once-Weekly Tirzepatide on 
Energy Expenditure and Food Intake in Obese Subjects......................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................20
3.1.
Study Rationale............................................................................................................20
3.2.
Background..................................................................................................................20
3.3.
Benefit/Risk Assessment..............................................................................................22
4.
Objectives and Endpoints..................................................................................................25
5.
Study Design.....................................................................................................................27
5.1.
Overall Design .............................................................................................................27
5.2.
Number of Participants.................................................................................................29
5.3.
End of Study Definition ...............................................................................................29
5.4.
Scientific Rationale for Study Design...........................................................................29
5.5.
Justification for Dose ...................................................................................................30
6.
Study Population...............................................................................................................32
6.1.
Inclusion Criteria..........................................................................................................32
6.2.
Exclusion Criteria ........................................................................................................35
6.3.
Lifestyle and Dietary Requirements..............................................................................38
6.3.1.
Meals and Dietary Restrictions.............................................................................39
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................39
6.3.3.
Activity................................................................................................................40
6.4.
Screen Failures.............................................................................................................40
7.
Treatment..........................................................................................................................41
7.1.
Treatment Administered...............................................................................................41
7.1.1.
Packaging and Labeling .......................................................................................41
7.2.
Method of Treatment Assignment ................................................................................42
7.2.1.
Selection and Timing of Doses.............................................................................42
7.3.
Blinding .......................................................................................................................42

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7.4.
Dose Modification........................................................................................................42
7.4.1.
Special Treatment Considerations ........................................................................43
7.4.1.1.
Management of Hypoglycemia .......................................................................43
7.5.
Preparation/Handling/Storage/Accountability...............................................................43
7.6.
Treatment Compliance .................................................................................................43
7.7.
Concomitant Therapy...................................................................................................43
7.7.1.
Management of Subjects with Gastrointestinal Symptoms....................................44
7.8.
Treatment after the End of the Study............................................................................44
8.
Discontinuation Criteria ....................................................................................................45
8.1.
Discontinuation from Study Treatment.........................................................................45
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................45
8.1.2.
Temporary Interruption of Investigational Product ...............................................46
8.1.3.
Discontinuation of Inadvertently Enrolled Subjects..............................................46
8.2.
Discontinuation from the Study....................................................................................46
8.3.
Subjects Lost to Follow-up...........................................................................................47
9.
Study Assessments and Procedures ...................................................................................48
9.1.
Efficacy Assessments...................................................................................................48
9.1.1.
Primary Efficacy Assessment and Procedure........................................................48
9.1.2.
Secondary Efficacy Assessments and Procedures.................................................49
9.1.3.
Exploratory Efficacy Assessments and Procedures...............................................50
9.2.
Adverse Events ............................................................................................................51
9.2.1.
Serious Adverse Events........................................................................................52
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................52
9.2.2.
Adverse Events of Special Interest .......................................................................53
9.2.2.1.
Hypoglycemia ................................................................................................53
9.2.2.2.
Pancreatitis.....................................................................................................54
9.2.2.3.
Thyroid Malignancies and C-Cell Hyperplasia................................................55
9.2.2.4.
Major Adverse Cardiovascular Events............................................................56
9.2.2.5.
Supraventricular Arrhythmias and Cardiac Conduction 
Disorders........................................................................................................56
9.2.2.6.
Hypersensitivity Events..................................................................................56
9.2.2.7.
Injection-Site Reactions..................................................................................56
9.2.2.8.
Hepatobiliary Disorders..................................................................................57
9.2.2.9.
Severe Gastrointestinal Adverse Events..........................................................57
9.2.2.10.
Acute Renal Events ........................................................................................57
9.2.2.11.
Major Depressive Disorder/Suicidal Ideation Monitoring 
Using the C-SSRS and PHQ-9 Questionnaires................................................58
9.2.3.
Complaint Handling.............................................................................................58

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9.3.
Treatment of Overdose.................................................................................................58
9.4.
Safety...........................................................................................................................59
9.4.1.
Laboratory Tests ..................................................................................................59
9.4.2.
Vital Signs ...........................................................................................................59
9.4.3.
Electrocardiograms ..............................................................................................59
9.4.4.
Physical Examinations .........................................................................................60
9.4.5.
Safety Monitoring ................................................................................................60
9.4.5.1.
Hepatic Safety................................................................................................60
9.5.
Pharmacokinetics .........................................................................................................60
9.5.1.
Bioanalysis...........................................................................................................61
9.6.
Pharmacodynamics ......................................................................................................61
9.6.1.
Immunogenicity Assessments ..............................................................................61
9.6.2.
Body Weight and Waist Circumference................................................................62
9.7.
Genetics .......................................................................................................................62
9.8.
Biomarkers...................................................................................................................63
9.9.
Health Economics ........................................................................................................63
10.
Statistical Considerations and Data Analysis.....................................................................64
10.1. Sample Size Determination ..........................................................................................64
10.2. Populations for Analyses..............................................................................................64
10.2.1.
Study Participant Disposition ...............................................................................64
10.2.2.
Study Participant Characteristics ..........................................................................64
10.2.3.
Treatment Compliance .........................................................................................64
10.3. Statistical Analyses ......................................................................................................64
10.3.1.
Safety Analyses....................................................................................................64
10.3.1.1.
Clinical Evaluation of Safety..........................................................................64
10.3.1.2.
Statistical Evaluation of Safety.......................................................................65
10.3.2.
Pharmacokinetic Analyses....................................................................................65
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................65
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................65
10.3.3.
Pharmacodynamic Analyses.................................................................................65
10.3.3.1.
Pharmacodynamic Parameter Estimation ........................................................65
10.3.3.2.
Pharmacodynamic Statistical Inference...........................................................66
10.3.4.
Evaluation of Immunogenicity .............................................................................66
10.3.5.
Interim Analyses..................................................................................................67
11.
References ........................................................................................................................68
12.
Appendices .......................................................................................................................73

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List of Tables
Table
Page
Table GPGU.1.
Objectives and Endpoints .......................................................................25
Table GPGU.2.
Study Treatments and Dose Escalation ...................................................41
Table GPGU.3.
Whole-Room Calorimeter Respiratory Quotient Measurements..............95
Table GPGU.4.
Standardized Mixed-Meal Tolerance Test...............................................98

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List of Figures
Figure
Page
Figure GPGU.1.
Illustration of study design for Protocol I8F-MC-GPGU.........................28
Figure GPGU.2.
Illustration of clinical research unit procedures.......................................29

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................74
Appendix 2.
Clinical Laboratory Tests........................................................................80
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................82
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............85
Appendix 5.
Blood Sampling Summary......................................................................89
Appendix 6.
Efficacy Assessments .............................................................................91
Appendix 7.
Pancreatic Monitoring ..........................................................................100
Appendix 8.
Protocol Amendment I8F-MC-GPGU(f) Summary - A 
Randomized, Placebo-Controlled, Parallel-Arm Study to 
Investigate the Effect of Once-Weekly Tirzepatide on Energy 
Expenditure and Food Intake in Obese Subjects....................................103

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1. Protocol Synopsis
Title of Study:
A Randomized, Placebo-Controlled, Parallel-Arm Study to Investigate the Effect of Once-Weekly Tirzepatide on 
Energy Expenditure and Food Intake in Obese Subjects
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 co-stimulation of these receptors may enhance insulin secretion, improve 
insulin sensitivity, and reduce body weight (BW) beyond the effect of selective GLP-1R stimulation.  
Study I8F-MC-GPGU is an 18-week treatment (±1 week), 4-week post treatment follow-up, Phase 1 study designed 
to examine the effect of tirzepatide compared with placebo on energy expenditure (EE) and food intake in obese 
subjects to provide mechanistic insight to BW reduction attributable to dual GIP/GLP-1 receptor agonism.
Objectives/Endpoints:  
Objectives
Endpoints
Primary
To assess the effect of tirzepatide versus placebo on
SMR after 18 weeks (±1 week) of treatment 

The change from baseline to Week 18 in SMR, as 
measured in the respiratory chamber (whole-room 
calorimetry)
Secondary
To assess the effect of tirzepatide versus placebo after
18 weeks (±1 week) of treatment:

Appetite and food intake

The change from baseline to Week 18 in appetite 
VAS

The change from baseline to Week 18 in food 
intake as assessed by ad libitum meal test

Energy expenditure 

The change from baseline to Week 18 in 24-hour 
EE

Substrate oxidation rates

The change from baseline to Week 18 in 24-hour 
RQ

The change from baseline to Week 18 in sleep RQ 

The change from baseline to Week 18 in duration 
of periods with RQ<0.80

The change from baseline to Week 18 in fat, 
protein, and carbohydrate oxidation

Body weight and body composition

The change from baseline to Week 18 in BW

The change from baseline to Week 18 in body fat 
free mass

The change from baseline to Week 18 in body fat 
mass

The change from baseline to Week 18 in the 
percentage of body fat mass

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Objectives
Endpoints
Secondary (continued)

Lipid metabolism

The change from baseline to Week 18 in 
triglycerides, cholesterol, LDL, VLDL, and HDL 
cholesterol, FFA, glycerol, 3-hydroxybutyrate, and 
acylcarnitines assessed during sMMTT

The change from baseline to Week 18 in 
ApoB-48, ApoB-100, ApoC-III, and LPL during 
sMMTT

The change from baseline to Week 18 in fasting 
concentration of leptin, adiponectin, IGFBP 1 and 
2

Insulin sensitivity

The change from baseline to Week 18 in fasting 
insulin resistance (as measured by the HOMA2 
method [HOMA2-IR]) and postprandial insulin 
sensitivity indices (Matsuda, OGIS, and Stumvoll) 
assessed during sMMTT

Glucose control

The change from baseline to Week 18 in fasting 
and postmeal glucose during sMMTT

The change from baseline to Week 18 in 
hemoglobin A1c
Abbreviations: ApoB-48 = apolipoprotein B-48; ApoB-100 = apolipoprotein B-100; ApoC-III = apolipoprotein 
C-III; BW = body weight; EE = energy expenditure; FFA = free fatty acid; HDL = high-density lipoprotein; 
HOMA2 = Homeostatic Model Assessment of Insulin Resistance; HOMA2-IR = insulin resistance as measured 
by the HOMA2 method; IGFBP = insulin-like growth factor binding protein; LDL = low-density lipoprotein; 
LPL =  lipoprotein lipase; OGIS = Oral Glucose Insulin Sensitivity; RQ = respiratory quotient; 
sMMTT = standardized mixed-meal tolerance test; SMR = sleep metabolic rate; VAS = visual analog scale; 
VLDL = very low-density lipoprotein.
Summary of Study Design:  
Study I8F-MC-GPGU is a Phase 1, single-center, randomized, sponsor (study team members directly involved in 
study management)-, investigator- and subject-blind, placebo-controlled, parallel-arm study in obese subjects. This 
study is designed to assess differences in the mechanisms of action with respect to energy balance, lipid and 
carbohydrate metabolism, and insulin sensitivity between tirzepatide and placebo, both in combination with a 
low-calorie diet in non-diabetic, obese subjects.
Eligibility for this study will be assessed at screening (Visit 1) and confirmed at lead-in (Visit 2).  Tirzepatide 15 mg 
will be attained via step-wise dose escalation to reduce the risk of gastrointestinal adverse events.
Treatment Arms and Planned Duration for an Individual Subject:  
The study will consist of the following periods: 4-week screening period, 2-week lead-in period, 18-week (±1 week)
treatment period, and a 4-week safety follow-up period.  Subjects will be screened within 4 weeks prior to lead-in.
Eligible subjects will enter lead-in (Visit 2) within 2 weeks prior to randomization.  Subjects will be randomized in a 
1:1 ratio to tirzepatide or placebo. Tirzepatide dosing will start at a dose of 2.5 mg once weekly (QW) for 2 weeks, 
followed by step-wise dose escalation to 5 mg QW for 2 weeks, and 10 mg QW for 4 weeks, until the 15-mg QW 
dose is reached and maintained for the remainder of the treatment period (10 weeks ±1 week). Study participants 
will target BW reduction of 10% (±2%) after approximately 14 weeks of treatment, followed by BW maintenance 
until the final on-treatment visit (Visit 20).

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Number of Subjects:
Up to 56 subjects may be enrolled (randomized) to maximize the probability that approximately 46 subjects 
complete the study assuming a 15% discontinuation rate.
Statistical Analysis:
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. 
Safety analyses will be conducted for all randomized subjects, whether or not they completed all protocol 
requirements.
Additional exploratory analyses of the data may be conducted as deemed appropriate.
The primary PD parameter for analysis is sleep metabolic rate (SMR) measured using whole-room indirect 
calorimetry (respiratory chamber), which will be analyzed using an analysis of covariance model (ANCOVA) to 
compare the effect of tirzepatide versus placebo.  The dependent variable to be used in the model will be the change 
from baseline to 18 weeks in SMR.  The independent variables will include treatment as a factor, baseline SMR and 
body composition parameter(s) as covariates. The primary analysis will be performed in all randomized subjects 
with evaluable data (modified intent-to-treat [mITT] population). Similar analysis will also be performed in subjects
who reach the BW target range of -10% (±2%) at Week 18 as a sensitivity analysis.
Other PD parameters that are scheduled to be measured only once postbaseline will be analyzed using a similar 
ANCOVA model with baseline measurement and treatment group as covariates. For parameters that are measured 
in the respiratory chamber, an adjustment for body composition parameter(s) as covariates may be applied if deemed 
appropriate. If the response is positive for all subjects and highly skewed, a log-transformation may be considered.  
Other parameters that are positive and skewed may be log-transformed.
The PD parameters that are scheduled to be measured at least twice postbaseline will be analyzed using a 
mixed-model repeated-measure method with restricted maximum likelihood estimation.  The model will include the 
treatment, visit, and treatment-by-visit interaction as fixed effects, baseline value of the dependent variable as a 
covariate, and subject as a random effect.  An unstructured variance-covariance matrix will be used to model the 
within-subject effects.
All PD analyses will performed in the mITT population and selected analyses also in on-BW-target population. All 
analyses will show least squares means of each treatment and the treatment difference in the original scale 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.

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2. Schedule of Activities

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Study Schedule Protocol I8F-MC-GPGU:  Screening and Lead-In
Procedure
Screening
Lead-In
Comments
Visit
1*
2
Week of Treatment
-6 to -2
-2 to -1
Week of treatment should be established versus the day 
of randomization (end of lead-in).
Study Day
-42 to -14
Any time from Day -14 to Day-1
-5
-4
-3
-2
-1
Screening Procedures
Informed consent
X
Medical history
X
Lifestyle interview
X
Performed to ensure subjects understand what they will 
be doing and if they are capable of meeting study 
demands. 
Drug and alcohol screen
X
Procedures may be repeated throughout the study as 
deemed necessary by the investigator.
Physical examination/
medical assessment
X
X
Full physical examination at screening. After 
screening, medical assessment is performed to include 
medical review and targeted examination, as
appropriate.
Height
X
Weight
X
X
See Section 9.6.2 for details.
Waist circumference
X
Vital signs (BP/PR/body temperature)
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
X
X
See Section 9.4.3 for details.
Concomitant medications
X
X
C-SSRS (baseline/ screening form) + 
SHSF + SHFF
X
X
The SHFF is required only if triggered by the SHSF, 
per instructions in the form. Day-5 C-SSRS assessment 
may be performed any time from Day -5 to before the 
first dose.
PHQ-9
X
Review/confirm inclusion/exclusion 
X

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Procedure
Screening
Lead-In
Comments
Visit
1*
2
Week of Treatment
-6 to -2
-2 to -1
Week of treatment should be established versus the day 
of randomization (end of lead-in).
Study Day
-42 to -14
Any time from Day -14 to Day-1
-5
-4
-3
-2
-1
criteria
Clinical Procedures
CRU admission
X
Training on signs/symptoms of 
hypoglycemia and self-treatment
X
Training can be completed anytime during the lead-in 
period (prior to discharge).
AEs
X
X
X
X
X
Randomization
X
Performed after all baseline assessments.
Laboratory Tests
Safety laboratory tests (including 
hemoglobin A1c and calcitonin)
X
X
See Appendix 2 for details. Subjects will fast for at 
least 10 hours before all blood samples are collected.
As fasting glucose is collected as part of the sMMTT 
procedure, glucose need not be included here.
Insulin, leptin, adiponectin, IGFBP 1, 
IGFBP 2
X
See Appendix 6, Table GPGU.4 for sampling details.
Glucose
X
See Appendix 6, Table GPGU.4 for sampling details.
Lipid panel:
Triglycerides, total cholesterol
LDL-C, VLDL-C, HDL-C
ApoB-48, ApoB-100, ApoC-III
LPL
FFA, glycerol, 3-hydroxybutyrate, 
acylcarnitine 
X
See Appendix 6, Table GPGU.4 for sampling details.
OGTT
X
To determine subject eligibility per requirements listed 
in Section 6.1 (Inclusion Criteria), OGTT will be 
performed (see Appendix 6 for details).
Pregnancy test 
X
X
For women of childbearing potential, a serum 
pregnancy test will be performed at screening.  Urine 
pregnancy test will be performed on Day -4.
Investigative Tests

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Procedure
Screening
Lead-In
Comments
Visit
1*
2
Week of Treatment
-6 to -2
-2 to -1
Week of treatment should be established versus the day 
of randomization (end of lead-in).
Study Day
-42 to -14
Any time from Day -14 to Day-1
-5
-4
-3
-2
-1
Appetite (VAS), ad libitum food intake 
test
X
See Appendix 6 for details.
Retrospective VAS
X
See Appendix 6 for details.
Food craving inventory and food 
preference questionnaire
X
See Appendix 6 for details.
Adipose tissue biopsy (abdominal)
X
Sample will be collected outside of the respiratory 
chamber. See Appendix 6 for details.
Respiratory chamber
X
X
X
Approximately 2 × 23 hours from Day -3 to Day -1.
See Appendix 6 for details.
sMMTT
X
See Appendix 6 for details of the procedure and 
sampling schedule.
DXA scan
X
See Appendix 6 for details. The predose DXA scan may 
be scheduled any time from Day -5 to Day -1.
*Screening activities on Visit 1 may be performed over more than 1 day if necessary to fit subject and site scheduling.

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Study Schedule Protocol I8F-MC-GPGU: Treatment Period
Procedure
Treatment
Comments
Visit
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Week of Treatment
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Study Day
1
8
±1
15
±1
22
±1
29
±1
36
±1
43
±1
50
±1
57
±1
64
±1
71
±1
78
±1
85
±1
92
±1
99
±1
Clinical Procedures
Weight
P
P
P
P
P
P
P
P
P
P
P
P
P
P
Refer to screening and lead-in table.
Vital signs (BP/PR/body 
temperature)
P
P
P
P
P
P
P
Refer to screening and lead-in table.
ECGs
X
Refer to screening and lead-in table.
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination/
medical assessment
X
Refer to screening and lead-in table.
CRU discharge
X
CRU discharge will be ± 1 day.
C-SSRS (Since Last Visit 
Version) + SHSF + SHFF
X
X
X
The SHFF is required only if 
triggered by the SHSF, per 
instructions in the form. The C-
SSRS since last visit version here 
refers to when last C-SSRS 
assessment was performed.
PHQ-9
X
Outpatient
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Investigational Product
Investigational product
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Tests
Safety laboratory tests
(including hemoglobin A1c 
and calcitonin)
X
Glucose
X
Fasting sample. 
Insulin, leptin, adiponectin, 
IGFBP 1, IGFBP 2
X
X
Fasting samples.

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Procedure
Treatment
Comments
Visit
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Week of Treatment
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Study Day
1
8
±1
15
±1
22
±1
29
±1
36
±1
43
±1
50
±1
57
±1
64
±1
71
±1
78
±1
85
±1
92
±1
99
±1
Lipid panel:
Triglycerides, total 
cholesterol
LDL-C, VLDL-C, HDL-C
ApoB-48, ApoB-100, 
ApoC-III
LPL
FFA, glycerol, acylcarnitine
3-hydroxybutyrate 
P
P
Fasting samples.
Investigative Tests
Retrospective VAS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Food craving inventory and 
food preference questionnaire
X
Diagnostics
PK sample
P
P
P
All samples for PK and 
immunogenicity must be taken 
predose, and time-matched as much 
as possible.
Immunogenicity 
P
P
P
Nonpharmacogenetic stored 
samples
P
P
P
Fasting samples.
Pharmacogenetic sample
P

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Study Schedule Protocol I8F-MC-GPGU:  Treatment Period Continued and Follow-up/Early Termination
Procedure
Treatment
Follow-up/ET
Comments
Visit
18
19
20
20
20
20
20
20
21
Week of Treatment
16
17
18
18
18
18
18
18
22
Study Day
106
±1
113
±1
120
±7
121
122
123
124
125
Within 4 weeks 
after last dose
Clinical Procedures
Weight
P
P
P
X
X
X
X
Refer to screening and lead-in table
Vital signs (BP/PR/body 
temperature)
P
X
X
X
X
Refer to screening and lead-in table.
ECGs
X
Refer to screening and lead-in table.
Concomitant medications
X
X
X
X
X
AEs
X
X
X
X
X
X
X
X
X
Physical examination/
medical assessment
X
X
Refer to screening and lead-in table.
Outpatient visit
X
X
X
C-SSRS (Since Last Visit 
Version) + SHSF + SHFF
X
X
The SHFF is required only if triggered by the 
SHSF, per instructions in the form. The C-
SSRS since last visit version here refers to when 
the last C-SSRS assessment was performed.
PHQ-9
X
X
CRU admission
X
CRU discharge
X
Investigational Product
Investigational Product
administration
X
X
X
Laboratory Tests
Safety laboratory tests (including 
hemoglobin A1c and calcitonin)
X
X
Fasting sample. As fasting glucose is collected 
as part of the sMMTT procedure, glucose need 
not be included here.
Glucose
X
See Appendix 6, Table GPGU.4 for sampling 
details.

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Procedure
Treatment
Follow-up/ET
Comments
Visit
18
19
20
20
20
20
20
20
21
Week of Treatment
16
17
18
18
18
18
18
18
22
Study Day
106
±1
113
±1
120
±7
121
122
123
124
125
Within 4 weeks 
after last dose
Insulin, leptin, adiponectin, 
IGFBP 1, IGFBP 2
X
See Appendix 6, Table GPGU.4 for sampling 
details.
Lipid panel:
Triglycerides, total cholesterol
LDL-C, VLDL-C, HDL-C
ApoB-48, ApoB-100, ApoC-III
LPL
FFA, glycerol, 3-hydroxybutyrate, 
acylcarnitine 
X
See Appendix 6, Table GPGU.4 for sampling 
details.
Pregnancy test 
X
X
For women of childbearing potential, a urine 
pregnancy test will be performed on Day 122. 
Serum pregnancy test at follow-up.
Investigative Tests
Appetite (VAS), ad libitum food 
intake test
X
Retrospective VAS
X
Food craving inventory and food 
preference questionnaire
X
Adipose tissue biopsy 
(abdominal)
X
Respiratory chamber
X
X
X
Approximately 2 × 23 hours from Days 123
to 125.  See Appendix 6 for details.
sMMTT
X
See Appendix 6 for details on the procedures 
and sampling schedule.
DXA scan
X
See Appendix 6 for details. The postdose DXA 
scan may be scheduled any time from Day 123
to 125.
Diagnostics

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Procedure
Treatment
Follow-up/ET
Comments
Visit
18
19
20
20
20
20
20
20
21
Week of Treatment
16
17
18
18
18
18
18
18
22
Study Day
106
±1
113
±1
120
±7
121
122
123
124
125
Within 4 weeks 
after last dose
PK samples
P
X
Immunogenicity / PK sampling times must be 
time-matched as much as possible.
Immunogenicity 
P
X
Nonpharmacogenetic stored 
samples
P
X
Fasting samples.
Abbreviations:  AEs = adverse events; ApoB-48 = apolipoprotein B-48; ApoB-100 = apolipoprotein B-100; ApoC-III = apolipoprotein C-III; BP = blood pressure; CRU = clinical 
research unit; C-SSRS = Columbia-Suicide Severity Rating Scale; DXA = dual energy X-ray absorptiometry; ECG = electrocardiogram; ET = early termination; FFA = free 
fatty acid; HDL-C = high-density lipoprotein cholesterol; IGFBP = insulin-like growth factor binding protein; LDL-C = low-density lipoprotein cholesterol; LPL =  lipoprotein 
lipase; OGTT = oral glucose tolerance test; P = predose; PD = pharmacodynamics; PHQ-9 = Patient Health Questionnaire-9; PK = pharmacokinetics; PR = pulse rate; SHFF = 
Self-Harm Follow-Up Form; SHSF = Self-Harm Supplementary Form; sMMTT = standard mixed-meal tolerance test; VAS = visual analog scale; VLDL-C = very low-density 
lipoprotein cholesterol.
Note:  If multiple procedures take place at the same time point, the following order of assessments should be used: Vital signs, ECG, PD, PK, immunogenicity, safety laboratory, 
storage samples.

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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 co-stimulation of 
these receptors may enhance insulin secretion, improve insulin sensitivity, and reduce body 
weight (BW) beyond the effect of selective GLP-1R stimulation (Frias et al. 2018; Coskun et al. 
2018).  Study I8F-MC-GPGU (GPGU) is an 18-week treatment (±1 week), 4-week post 
treatment follow-up, Phase 1 study designed to examine the effect of tirzepatide compared with 
placebo on energy expenditure (EE) and food intake in obese subjects to provide mechanistic 
insight to BW reduction attributable to dual GIP/GLP-1 receptor agonism (GIPRA/GLP-1RA).
3.2.
Background
GLP-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, food intake, aversive signaling, and cardiovascular 
(CV) function (Campbell and Drucker 2013). Currently, there are several approved GLP-1 
receptor agonists (GLP-1RAs) for the treatment of diabetes and obesity. The dosing of 
GLP-1RAs in humans is limited by gastrointestinal (GI) adverse effects, such as nausea and 
vomiting.
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. GIP has important additional 
functions that are distinct from GLP-1. GIP promotes glucagon secretion at low blood glucose 
(BG) levels to augment endogenous glucose production.  It stimulates lipolysis and inhibits
insulin-induced lipogenesis in human adipocytes.  In preclinical models, the effect of selective 
GIP signaling on BW regulation is neutral. However, recent preclinical reports have
demonstrated that, under certain conditions, GIPR agonism improves energy homeostasis, in 
addition to glucose-lowering effects. 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, a dual GIPRA/GLP-1RA, is a 39-amino acid synthetic peptide. Its structure is based 
on the GIP sequence and includes a C20 fatty di-acid moiety which facilitates albumin binding.  
It has a chemical structure and pharmacologic profile that is distinct from the GLP-1RAs due to 

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the additional GIP activity.  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. Phase 3 studies are also planned 
for chronic weight management in obese adults and a Phase 2 study is planned for nonalcoholic 
steatohepatitis.
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, 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.  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 episodes 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).  An additional dose level of 12 mg and alternate dose escalation schemes 
were investigated in a 12-week Phase 2 study.  Doses above 5 mg of tirzepatide were attained via 
step-wise dose escalation.  Results from the 2 Phase 2 studies demonstrated that tirzepatide at 
doses between 5 and 15 mg provided clinically meaningful efficacy in both glucose- and 
BW-lowering.  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 largest and longest 
Phase 2 study. However, the presence of anti-drug antibodies (ADAs) appeared to have no 
effect on pharmacokinetic (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 postdose.
The prevalence of obesity has increased worldwide resulting in an increased risk of its common 
comorbidities including T2DM, fatty liver disease, hypertension, and dyslipidemia as well as 
increased CV risk. The available obesity prevention and treatment strategies have limited 
success due to the complex regulation of energy homeostasis, which is the balance between 
energy intake and energy expenditure (EE). Diet and life-style modification are the first-line 
treatment in the management of obesity but these often fail to provide sustainable weight loss.

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Currently, available pharmacological treatments, phenylpropanolamine (Acutrium®), liraglutide 
3 mg (Saxenda®), orlistat (Xenical® or Alli™), sibutramine (Meridia®), mazindol (Sanorex®), 
lorcaserin (BELVIQ®), phentermine (Adipex-P®)-topiramate (Topamax®) (Qsymia™), or 
naltrexone-bupropion (Contrave®) for weight loss have limited efficacy due to the mechanism of 
action or side effect profiles (Bluher 2019; Bonamichi et al. 2018; Yanovski et al. 2014).
Glucagon-like peptide-1 receptor agonists have demonstrated efficacy in BW reduction. 
Liraglutide (Saxenda) is the first agent from this class that has been approved for the treatment of 
obesity. After 56 weeks, treatment with Saxenda resulted in BW reduction of at least 5% when 
compared with placebo (Saxenda package insert, 2014; Mehta et al. 2017). Studies that 
investigated the mechanism of action of GLP-1 RAs have shown that these agents induce weight 
loss by reducing appetite and energy intake, with no effect on EE (van Can et al. 2014; Blundell 
et al. 2017).
Several clinical trials suggest that weight loss during a dietary intervention the human body 
switches to a more energy efficient state by reducing energy expenditure. Such metabolic 
adaptation has been proposed as the main cause of BW regain following cessation of dietary 
intervention (Martin et al. 2007; Redman et al. 2009; Rosenbaum et al. 2016; Maclean et al. 
2011). In Phase 1 and Phase 2 development, treatment with tirzepatide has shown clinically 
meaningful effect on BW regulation by suppressing appetite and reducing food intake, but no 
data are available from these studies on the effects on EE and substrate utilization. In a 
preclinical study, it was observed that reduced food intake may also be accompanied by 
increased EE in animals treated with tirzepatide, probably via more efficient substrate utilization, 
while GLP-1RA had no effect on EE, similar to observations in clinical trials. These results 
warrant further investigations of how dual GIPR/GLP-1R agonism affects regulation of energy 
balance in the human body (Frias et al. 2018; Coskun et al. 2018).
We hypothesized that tirzepatide may increase EE and reduce metabolic adaptation. Potential 
reduction in metabolic adaptation may result in a sustained and durable improvement in weight 
control. Study GPGU is designed to assess the effect of tirzepatide versus placebo on various 
aspects of EE, appetite and food intake, substrate (oxidation), and insulin sensitivity in obese, 
nondiabetic subjects targeting reduction in BW of 10% (±2%) by a mean of low-calorie diet.
The primary objective is to compare the effect of tirzepatide and placebo on sleep metabolic rate 
(SMR) assessed in a respiratory chamber (whole-room indirect calorimetry) after 18 weeks of 
treatment. The subjects will be closely monitored during the study for general safety and special 
safety issues attributable to incretins. The study is expected to provide important, new 
information on the key mechanisms of BW-lowering associated with treatment with a dual 
GIP/GLP-1 receptor agonist.
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 

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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 GIPRA/GLP-1RA is similar to the 
safety profile of the selective GLP-1RAs.  Potential risks, such as GI effects, acute pancreatitis, 
increases in heart rate, and hypoglycemic events are consistent with the risks associated with 
currently available long-acting GLP-1RAs.  To mitigate the risk of GI side effects, tirzepatide 
15 mg will be attained via step-wise dose escalation.  Details on the management of these AEs 
are provided in Section 7.7.1 (Management of Subjects with Gastrointestinal Symptoms). The 
monitoring plan for all AEs of special interest is included in this protocol, as well as treatment 
measures, when appropriate.
Since Study GPGU will enroll subjects without diabetes, no self-monitoring of plasma glucose 
(PG) is planned. Consistent with the mechanism of action of incretins, which are 
nonsecretagogues, 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. Section 7.4.1.1 (Management 
of Hypoglycemia) provides detailed information concerning the management of hypoglycaemia.
There are several possible AEs associated with the planned procedures in the study. The 
respiratory chamber will be used to obtain parameters needed to calculate respiratory quotient 
(RQ), EE, and substrate oxidation rates (see Appendix 6 for details). Some level of 
claustrophobia or discomfort may be experienced from staying in the respiratory chamber and 
being continuously monitored by a camera. The dual energy X-ray absorptiometry (DXA) scan 
will be used to measure the amount of bone, muscle, and fat in the body. Subjects may be 
exposed to a small amount of radiation during the procedure.  The radiation dose for a DXA scan 
is less than 1 mrem, which is less than a chest X-ray, or equal to about 12 hours of background 
radiation from the sun.
Subjects in Study GPGU are not expected to have direct health-related benefits. Potential risks
described above, are considered to be transient and long-term health risks are low. The majority 
of these risks are clinically detectable and manageable, and will be monitored during the study.
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 (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 

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aggregate, periodically during the course of the study, and can be found in Section 5 (Effects in 
Humans) of the IB.

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4. Objectives and Endpoints
Table GPGU.1 shows the objectives and endpoints of the study.
Table GPGU.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess the effect of tirzepatide versus placebo on 
SMR after 18 weeks (±1 week) of treatment

The change from baseline to Week 18 in SMR, as 
measured in the respiratory chamber (whole-room 
calorimetry)
Secondary
To assess the effect of tirzepatide versus placebo after 
18 weeks (±1 week) of treatment:

Appetite and food intake

The change from baseline to Week 18 in appetite 
VAS

The change from baseline to Week 18 in food 
intake as assessed by ad libitum meal test

Energy expenditure 

The change from baseline to Week 18 in 24-hour
EE

Substrate oxidation rates

The change from baseline to Week 18 in 24-hour
RQ

The change from baseline to Week 18 in sleep RQ

The change from baseline to Week 18 in duration 
of periods with RQ<0.80

The change from baseline to Week 18 in fat, 
protein, and carbohydrate oxidation

Body weight and body composition

The change from baseline to Week 18 in BW

The change from baseline to Week 18 in body fat-
free mass

The change from baseline to Week 18 in body fat 
mass

The change from baseline to Week 18 in the 
percentage of body fat mass

Lipid metabolism

The change from baseline to Week 18 in 
triglycerides, cholesterol, LDL, VLDL, and HDL 
cholesterol, FFA, glycerol, 3-hydroxybutyrate, and 
acylcarnitines assessed during sMMTT

The change from baseline to Week 18 in ApoB-48, 
ApoB-100, ApoC-III, and LPL during sMMTT

The change from baseline to Week 18 in fasting 
concentration of leptin, adiponectin, IGFBP 1 and 
2

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Objectives
Endpoints
Secondary (continued)

Insulin sensitivity

The change from baseline to Week 18 in fasting 
insulin resistance (as measured by the HOMA2 
method [HOMA2-IR]) and postprandial insulin 
sensitivity indices (Matsuda, OGIS, and Stumvoll) 
assessed during sMMTT

Glucose control

The change from baseline to Week 18 in fasting 
and postmeal glucose during sMMTT

The change from baseline to Week 18 in 
hemoglobin A1c
Exploratory
To assess the effect of tirzepatide versus placebo after 
18 weeks (±1 week) of treatment:

GIPR signaling, lipid metabolism, carbohydrate 
metabolism, and insulin signaling pathways in 
subcutaneous adipose tissue

The change from baseline to Week 18 in markers 
of GIPR signaling, lipid metabolism, carbohydrate 
metabolism, and insulin signaling pathways as 
measured in exploratory mRNA expression, 
lipidomics, metabolomics, or targeted protein 
assays of subcutaneous adipose tissue biopsy 
samples, receptor expression, signal transduction, 
and metabolic changes in adipose tissue

Safety and tolerability

Adverse events

Safety laboratory parameters

Frequency of treatment-emergent anti-tirzepatide 
antibodies

Treatment-emergent depression and suicidal 
ideation as assessed using C-SSRS and PHQ-9
Abbreviations: ApoB-48 = apolipoprotein B-48; ApoB-100 = apolipoprotein B-100; ApoC-III = apolipoprotein 
C-III; BW = body weight; C-SSRS = Columbia-Suicide Severity Rating Scale; EE = energy expenditure; FFA = 
free fatty acid; GIPR = glucose-dependent insulinotropic polypeptide receptor; HDL = high-density lipoprotein; 
HOMA2 = Homeostatic Model Assessment of Insulin Resistance; HOMA2-IR = insulin resistance as measured 
by the HOMA2 method; IGFBP = insulin-like growth factor binding protein; LDL = low-density lipoprotein; 
LPL =  lipoprotein lipase; mRNA = messenger ribonucleic acid; OGIS = Oral Glucose Insulin Sensitivity; PHQ-
9 = Patient Health Questionnaire-9; RQ = respiratory quotient; sMMTT = standardized mixed-meal tolerance 
test; SMR = sleep metabolic rate; VAS = visual analog scale; VLDL = very low-density lipoprotein.

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5. Study Design
5.1.
Overall Design
This is a Phase 1, single-center, randomized, sponsor (study team members directly involved in 
study management)-, investigator- and subject-blind, placebo-controlled, parallel-arm study in 
obese subjects. This study is designed to assess differences in the mechanisms of action with 
respect to energy balance, lipid and carbohydrate metabolism, and insulin sensitivity between 
tirzepatide and placebo, in combination with a low-calorie diet in non-diabetic, obese subjects.
The primary objective of this study is to compare the 2 treatment groups for changes from 
baseline in sleep metabolic rate (SMR) after 18 weeks (±1 week) of treatment.
The subject will sign the informed consent form (ICF) before any study procedures are 
performed.  Eligibility for this study will be assessed at screening (Visit 1) and confirmed at 
lead-in (Visit 2). Screening procedures will be performed within 4 weeks prior to lead-in,
according to the Schedule of Activities (Section 2).
Eligible subjects will enter lead-in (Visit 2) within 2 weeks prior to randomization.  Subjects will 
perform baseline assessments in the clinical research unit (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 ratio to tirzepatide or placebo.
Tirzepatide 15 mg will be attained via step-wise dose escalation to reduce the risk of GI AEs.  
Tirzepatide dosing will start at a dose of 2.5 mg QW for 2 weeks, followed by a step-wise dose 
escalation to 5 mg QW for 2 weeks, and 10 mg QW for 4 weeks, until the 15-mg QW dose is 
reached and maintained for the remainder of the treatment period (10 weeks ±1 week).  Subjects 
will return to the CRU every week for QW dose administration for 18 weeks (±1 week).
Subjects in both groups will receive a standardized dietary intervention to target a BW reduction 
of 10% (±2%) after approximately 14 weeks of treatment. Between Week 14 and Week 18 
(±1 week), dietary intervention will shift to promoting maintenance of 10% weight loss
(Section 6.3.1) within target range prior to admission to the CRU and end-of-treatment
procedures to assess primary and secondary objectives. Description of these procedures is
provided in Section 2 (Schedule of Activities). Subjects will be readmitted to the CRU at 
Week 18 (±1 week) to perform end-of-treatment CRU study procedures.  These CRU study 
procedures will be performed in all patients, irrespective of whether they reached their BW target 
or not, and according to the same schedule as during the lead-in period.  
Section 2 (Schedule of Activities) presents all planned visits and procedures for this study. After 
the completion of the treatment period, a follow-up visit will be performed within 4 weeks of the 
last dose to assess subject safety and subsequently complete the subject’s participation.
Study governance considerations are described in detail in Appendix 3.
Figure GPGU.1 illustrates the study design.
Figure GPGU.2 illustrates the clinical research unit procedures.

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Abbreviations: DXA = dual energy X-ray absorptiometry; FCI = Food Craving 
Inventory; FPQ = Food Preference Questionnaire; QW = once weekly; 
sMMTT = standardized mixed-meal tolerance test; VAS = visual analog scale.
Figure GPGU.1.
Illustration of study design for Protocol I8F-MC-GPGU.

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Abbreviations:  DXA = dual energy X-ray absorptiometry; FCI = Food Craving 
Inventory; FPQ = Food Preference Questionnaire; sMMTT = standardized mixed-meal 
tolerance test; VAS = visual analog scale. 
Figure GPGU.2.
Illustration of clinical research unit procedures.
5.2.
Number of Participants
Up to 56 subjects may be enrolled (ie, randomized) to maximize the probability that 
approximately 46 subjects complete the study assuming a 15% discontinuation rate.  For 
purposes of this study, a subject completes the treatment period when all scheduled procedures 
through Week 18 (Visit 20), as shown in Section 2 (Schedule of Activities), have been finished.
A subject completes the study when all scheduled procedures through Week 22 (Visit 21) have 
been completed.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in Section 2
(Schedule of Activities) for the last subject.
5.4.
Scientific Rationale for Study Design
Study GPGU will employ a parallel-group design to minimize the confounding effects of 
changes in BW and, potentially, other metabolic parameters on the primary efficacy measure of 
SMR.

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Placebo is chosen as the comparator to enable determination of the effect on parameters of 
energy balance (food intake and EE) attributable specifically to tirzepatide. An active GLP-1RA
comparator was considered as unnecessary since the results of EE and substrate utilization 
studies showed no effect of selective GLP-1RAs on the outcomes of interest (van Can et al. 
2014; Blundell et al. 2017).
The primary study measure SMR was chosen as the most reproducible measure of EE, since it is 
not influenced by activity or food intake.
The secondary study measures, such as other parameters of EE, appetite and food intake, 
substrate oxidation, BW and body composition, lipid metabolism, insulin sensitivity, and glucose 
control, 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 evaluation of objectives of Study GPGU. The timing of endpoint 
measurements (Week 18 [Visit 20]) was determined based on exposure response modeling of 
tirzepatide’s effect on weight loss as observed in a Phase 2 clinical study (Frias et al. 2018).
To avoid the confounding effect of changes in glucose regulation on EE, the study will enroll 
nondiabetic, obese subjects, only. Subjects in both study groups will target same BW lowering 
range by means of a low-calorie diet to minimize the confounding effect of BW changes on the 
primary study measure. The weight loss target of 10% (±2%) was chosen as it matches expected 
BW change with the 15-mg dose of tirzepatide at study endpoint, based on data from Phase 2 
trials. 
The dose justification for tirzepatide is provided in Section 5.5 (Justification of Dose).
The rationale for the sample size is provided in Section 10.1 (Sample Size Determination).
5.5.
Justification for Dose
The tirzepatide dose of 15 mg administered SC QW is selected based on current preclinical 
pharmacology, toxicology, and clinical data, and is the highest maintenance dose planned for 
evaluation in the Phase 3 program.
The tirzepatide treatment period will consist of a step-wise dose escalation.  Tirzepatide dosing 
will start at a low dose of 2.5 mg QW and will be escalated to 15 mg QW as described in 
Section 5.1 (Overall Study Design).  The step-wise increments are based on cumulative 
understanding of safety and GI tolerability from Phase 1 and 2 studies and are expected to 
minimize GI tolerability concerns in this obese population by permitting adequate time for 
development of tolerance to GI events.
While a steeper dose escalation scheme with a higher starting dose of 5 mg, escalating to 15 mg 
within 7 weeks was previously implemented in Phase 2 and was found to be safe, this scheme 
was associated with some GI tolerability concerns.
To minimize the incidence of GI tolerability events, this study will employ a lower starting dose 
of 2.5 mg to initiate the dose escalation, permitting 8 weeks of step-wise dose escalation prior to 
attaining a maintenance dose of 15 mg at Week 9.  Steady-state exposures are expected to be 

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attained within 4 weeks of starting 15 mg dose of tirzepatide. Treatment will be continued for 
10 weeks (±1 week) after commencing the 15-mg maintenance dose.
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.

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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 4 weeks prior to lead-in.  Eligible subjects will enter lead-in 
(Visit 2) within 2 weeks 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 of the following criteria at 
screening:
Subject Characteristics
[1]
Are obese (body mass index of 30 kg/m2 to 45 kg/m2, inclusive), and 
nondiabetic male or female subjects, as determined by medical history,
physical examination, and laboratory assessments at screening, and have at 
least one of the following metabolic impairments (Alberti and Zimmet 1998; 
American Diabetes Association 2019; Grundy et al. 2005; Huang 2009; NIH
[WWW]):

Waist circumference ≥102 cm (40 inches) or ≥88 cm (35 inches) for 
males and females, respectively;

High-density lipoprotein (HDL) cholesterol concentration <50 mg/dL 
for females and <40 mg/dL for males (or being on medicine to treat low 
HDL cholesterol);

Serum triglycerides concentration ≥150 mg/dL or on medication to treat 
elevated triglycerides;

Systolic blood pressure >130 mm Hg and/or diastolic blood 
pressure >85 mm Hg or already being treated with anti-hypertension 
medications;

Impaired glucose tolerance defined as at least one of the following:

Fasting plasma glucose (PG) >100 mg/dL and <125 mg/dL;

Postglucose challenge PG (oral glucose tolerance test [OGTT])
≥140 mg/dL and <200 mg/dL;

Hemoglobin A1c between ≥5.7% and <6.5%;

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
Insulin resistance as measured by the Homeostatic Model Assessment of 
Insulin Resistance (HOMA2-IR) >1.8 (Matthews et al. 1985; Levy et al. 
1998);
[2]
Must be weight stable (no dietary weight loss/gain greater than 3 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 60 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 as 
well as 1 additional highly effective (less than 1% failure rate) method 
of contraception (such as combination oral contraceptives, implanted 
contraceptives, or intrauterine devices) or effective method of 
contraception (such as diaphragms with spermicide or cervical sponges) 
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 90 days.
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 (eg, 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 (90 days).

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 
90 days following last dose of investigational product (IP).

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
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 (eg, calendar, ovulation, 
symptothermal, postovulation 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, (see contraception guidance below), for the entirety of the 
study.  Contraception must continue following completion of IP 
administration for 30 days.
o
Women of child-bearing 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 48 hours prior to exposure 
and at other times as specified in Section 2 (Schedule of 
Activities).
o
Two forms of effective contraception, where at least 1 form is 
highly effective (less than 1% failure rate, such as combination 
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.

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

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o
Postmenopausal – defined as either
i.
A woman at least 50 years of age with an intact uterus, not
on hormone therapy, who has had either
a) cessation of menses for at least 1 year, or
b) at least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone >40 mIU/mL; or
ii.
A woman 55 or older not on hormone therapy, who has had 
at least 6 months of spontaneous amenorrhea; or
iii.
A woman at least 55 years of age 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]
Are willing and able to participate in the dietary intervention part of the study, 
in the opinion of the investigator;
[8]
Have given written informed consent approved by Eli Lilly and Company 
(Lilly) and the institutional review board (IRB) governing the site.
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening:
Medical Conditions - General
[9]
Have a history or current CV (for example, myocardial infarction, congestive 
heart failure, cerebrovascular accident, venous thromboembolism, etc), 
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 acute or chronic pancreatitis or a history of acute idiopathic pancreatitis;
or have other GI disorders (for example, relevant esophageal reflux or gall 
bladder disease) that could be aggravated by GLP-1 analogs; subjects who 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;
[11] Have a known clinically significant gastric emptying abnormality (eg, gastric 
outlet obstruction) or have undergone gastric bypass (bariatric) surgery or 
restrictive bariatric surgery (eg, Lap-Band®);

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[12] 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;
[13] Are currently diagnosed with any form of diabetes; or have fasting and/or 
postglucose challenge PG (OGTT) compatible with diabetes, and/or
hemoglobin A1c value ≥6.5% at screening (Visit 1); subjects with borderline 
glucose intolerance are eligible (see Section 6.1 Inclusion Criteria [1]);
[14] 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;
[15] Have blood pressure of >160/90 mm Hg and/or pulse rate of <50 or >100 bpm 
(sitting) at screening with or without stable doses [at least 3 months prior to 
screening] of anti-hypertension medications;
[16] 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;
[17] Have evidence of human immunodeficiency virus (HIV) and/or positive HIV 
antibodies at screening;
[18] Have evidence of hepatitis B or positive hepatitis B surface antigen and/or 
evidence of hepatitis C virus (HCV) or hepatitis C antibody with confirmed 
presence of hepatitis C virus ribonucleic acid (RNA) at screening (a positive 
HCV antibody at screening will need an additional HCV RNA assay –
detectable HCV RNA means a subject will meet exclusion criteria).  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.
[19] Have serum aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) >2.5X the upper limit of normal (ULN) or total bilirubin (TBL) >1.5X 
ULN; subjects with nonalcoholic fatty liver disease are allowed to participate;
[20] 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;

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[21] Have a history of drug or alcohol abuse or a positive drug screen (unless the 
positive testing is due to a drug prescribed to the subject by a health care 
professional); and/or smoke >10 cigarettes per day or the equivalent; or are 
unable or unwilling to refrain from nicotine use during CRU admission;
[22] Have had a blood transfusion or severe blood loss within the last 3 months or 
have known hemoglobinopathy, hemolytic anemia, sickle cell anemia, or have 
a hemoglobin value <11 g/dL (males) or <10 g/dL (females), or any other 
condition known to interfere with hemoglobin A1c measurement;
[23] 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), or are unwilling to stop 
alcohol consumption 24 hours before dosing and until discharge from the 
CRU;
[24] Have any lifetime history of a suicide attempt;
[25] Have a Patient Health Questionnaire-9 (PHQ-9) score of 15 or more at 
screening;
[26] 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
[27] Have a history of atopy or clinically significant multiple or severe drug 
allergies, or severe posttreatment hypersensitivity reactions (including, but not 
limited to, erythema multiforme major, linear immunoglobulin A dermatosis, 
toxic epidermal necrolysis, or exfoliative dermatitis).
Prior/Concomitant Therapy - General
[28] Have been treated with prescription drugs that promote weight loss (eg, 
sibutramine, mazindol, phentermine, phentermine-topiramate combination, 
lorcaserin, phenylpropanolamine, naltrexone/bupropion, liraglutide) or similar 
other BW loss medications, including over-the-counter medications (eg, 
Alli®) within 6 months prior to screening or between screening and 
randomization;
[29] 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;

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[30] Have been treated with any glucose-lowering agent during the last 3 months 
prior to screening (Visit 1) or between screening and randomization (Visit 2);
[31] 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.
[32] Use of other medications not listed above may result in exclusion of the subject
at the discretion of the investigator in consultation with the sponsor;
Prior/Concurrent Clinical Trial Experience
[33] Are persons who have previously completed or withdrawn from this study;
[34] Have previous exposure to tirzepatide or known allergies to tirzepatide or
GLP-1 receptor agonists; 
[35] 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
[36] 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;
[37] Are Eli Lilly and Company employees;
[38] 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.
All subjects, regardless of the group to which they are randomized, will receive a comprehensive 
dietary intervention to produce 10% (±2%) weight loss by Week 14, at which time the focus of 
the intervention will shift to promoting weight maintenance until the end of treatment period at 
Week 18 (±1 week), when end-of-treatment assessments in the CRU will be performed. 
This weight goal should be achieved by providing each subject with a personalized energy intake 
target that, if adhered to, should result in weight loss of 10% (±2%) over 14 weeks.  The weight 
goal should be achieved by promoting energy restriction, not by increasing physical activity.  
Subjects will be instructed to maintain their current activity levels.
The personalized energy intake targets will be generated with mathematical models of energy 
balance (Thomas et al. 2009; Thomas et al. 2010; Thomas et al. 2011). The models avoid the 
problems associated with the static 3,500 kcal/pound rule (Thomas et al. 2013) and are well 
validated (Thomas et al. 2009; Thomas et al. 2010; Thomas et al. 2011; Pieper et al. 2011).

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Subjects will receive structured meal plans that reflect their energy intake target and include an 
abundance of portion-controlled foods and meal replacements, including nutrition shakes and 
bars, and frozen or shelf-stable entrees. The meal plans will be consistent with dietary guidelines
(ie, approximately 55% carbohydrate, 15% protein, and 30% fat [USDA 2015, WWW]), and 
include lean sources of protein (poultry, seafood) and whole grains.
In addition to providing personalized energy intake targets and meal plans, the models will be 
used to help subjects adhere to their diet and achieve their weight loss goal. This will be 
accomplished by using the models to generate personalized weight graphs or weight loss 
nomograms that display subjects’ predicted weight over time assuming adherence to the energy 
intake target. An upper and lower limit to the weight loss goal that reflects approximately 8% 
and 12% weight loss will also be graphed, thus providing a zone of acceptable weights.
Subjects’ actual weights will be graphed against this zone and adherence to the energy intake 
target will be demarcated by subjects’ actual weights being in the zone (Thomas et al. 2015; 
Martin et al. 2015; Martin et al. 2016). Subjects will be provided with their personalized weight 
graph and a BodyTrace© scale that automatically transmits weights to the internet, where the 
weights can be retrieved by the subject and the interventionist at the site. Subjects will be 
instructed to weigh daily at the same time and plot their weight on their weight graph. They will 
also be told that the interventionist will track their weight using the same method at the site. 
Should a subject have difficulty following the meal plan and adhering to the energy intake target, 
his/her actual weights will be out of the zone and the interventionist will offer supportive 
strategies, described below, to help the subject adhere to the diet and achieve the desired 10% 
(±2%) weight loss goal.
Subjects will meet weekly with their interventionist at the site to receive support to foster 
adherence to the energy intake target and weight loss goal. Subjects will be instructed on the use 
of strategies that have been found to promote weight loss, including self-monitoring of food 
intake, stimulus control, use of portion-controlled foods and meal replacements, and meal 
planning (Rickman et al. 2011). The interventionist will also conduct remote sessions via phone, 
for example, if subjects need additional support in meeting their goal.
6.3.1. Meals and Dietary Restrictions
Subjects shall fast for at least 10 hours overnight prior to each outpatient visit where fasting 
samples are drawn or weight measurements taken.  Subjects will fast for at least 10 hours prior to 
dosing, after which subjects will receive a meal or snack.  For outpatient visits that require 
fasting, a snack (eg, granola bar, juice, or coffee) will be provided.  During inpatient visits and 
long days at the CRU, a meal will be provided.  Water can be consumed freely.  Subjects will 
only consume meals provided by the CRU during inpatient stays.  While not resident in the CRU, 
subjects will be required to follow the plan described in Section 6.3 (Lifestyle and Dietary 
Requirements).
6.3.2. Caffeine, Alcohol, and Tobacco
No alcohol, caffeine, and/or methylxanthine-containing products will be allowed at least 
12 hours before each CRU admission, and each outpatient visit and throughout the duration of 

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each CRU visit. Between CRU 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 
admission.  When certain study procedures are in progress at the CRU, subjects may be required 
to remain recumbent or sitting. While in the respiratory chamber, the intensity of any physical 
activity can be no higher than walking around the chamber or stretching (no push-ups or sit-ups).
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.  Individuals 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 Day -1 of the lead-in period to ensure only eligible 
subjects enter the study.

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7. Treatment
7.1.
Treatment Administered
Subjects will receive tirzepatide or placebo administered SC QW for 18 weeks (±1 week).
Table GPGU.2 shows the study treatments and dose escalation for tirzepatide and placebo.
Table GPGU.2.
Study Treatments and Dose Escalation
Dose Escalation Schemes (dose in mg)
Treatment
Week
1-2a
Week
3-4 a
Week
5-8 a
Week
9-18 a
Tirzepatide
1 × 2.5-mg PFS
1 × 5-mg PFS
1 × 10-mg PFS
1 × 15-mg PFS
Placebo
1 × PFS
1 × PFS
1 × PFS
1 × PFS
Abbreviation:  PFS = prefilled syringe
a
Interval may change based on visit window.
All treatments will be administered QW at the CRU.  Dosing will occur at approximately the 
same time of day and day of the week every week in all groups.  The actual time of dosing will 
be recorded in the subject’s electronic case report form (eCRF). All injections will be 
administered into the SC tissue of the abdominal wall.  Injection sites will be alternated weekly 
between 4 sites (right and left upper quadrants and right and left lower quadrants) of the 
abdominal wall.
Whenever possible, IP administration should be carried out by the same personnel.  Additional 
details are provided in Section 7.3 (Blinding).  The personnel who dispenses or administers IP
will be unblinded to IP. Any unblinded staff will not be performing any study assessments with 
subjects.  
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.
The site will be instructed to discard used medications according to local regulations.
7.1.1. Packaging and Labeling
All strengths of tirzepatide will be provided as prefilled syringes (PFS) containing 0.5 mL 
solution and provided in individual cartons to be dispensed.  Placebo will also be provided as 
matching 0.5 mL PFS.

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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 ratio to receive 
tirzepatide or placebo.  Assignment to treatment will be determined by a randomization table 
with treatment codes.
7.2.1. Selection and Timing of Doses
The doses will be administered QW according to the randomization schedule, on the same day of 
the week and at approximately the same time of the day.  Visit windows should be used for 
dosing only when the subject is unable to attend the CRU on the scheduled day.  The actual time 
of all dose administrations will be recorded in the subject’s eCRF. If a subject does not receive 
her/his planned treatment dose on the scheduled 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.
7.3.
Blinding
This study is a sponsor (study team members directly involved in study management)-, 
investigator-, and subject-blind study.  Blinding will be maintained throughout the conduct of the 
study as described in the separate Blinding and Unblinding Plan.  To preserve the blinding of the 
study for treatment allocation, all study site personnel, except site staff who dispense and 
administer study medication, will be blinded to treatment allocation. Tirzepatide and placebo 
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 the treatment 
administration.
If a subject’s study treatment assignment is unblinded, 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 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 can be interrupted temporarily following the guidance provided in Section 8.1.2
(Temporary Interruption of IP).

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7.4.1. Special Treatment Considerations
7.4.1.1.
Management of Hypoglycemia
Tirzepatide is an incretin which acts on the pancreatic β cell as a nonsecretagogue, therefore, the 
risk of hypoglycemia is very low. 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. For hypoglycemia reporting see 
Section 9.2.2.1 (Hypoglycemia).
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by sponsor, during transfer for all IP received and any 
discrepancies are reported and resolved before use of the study treatment.
Only subjects enrolled in the study may receive IP or study materials, and only authorized site 
staff may supply or administer IP. 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
The IP will be administered at the study site and documentation of treatment administration will 
occur at the site.  Subjects will be considered compliant if they received at least 75% of their
scheduled doses for each dosing interval (Weeks 1 to 2, Weeks 3 to 4, Weeks 5 to 8, and 
Weeks 9 to endpoint) during the treatment period. When assessing treatment compliance, the 
missed doses (Section 7.2.1 Selection and Timing of Doses) and interrupted doses (Section 8.1.2
Temporary Interruption of IP) will be taken into consideration.  Subjects who are repeatedly 
(2 or more episodes) noncompliant with the maintenance dose 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 excluded medications in this study prior to 
randomization (glucose-lowering and weight-lowering agents, systemic glucocorticoids). These 
medications are also not allowed during the treatment period. Erroneous use of excluded 
medications for up to 14 days would not qualify for discontinuation.  If used for >14 days during 
the entire treatment period or for any duration during the final 4 weeks of the treatment period, 
these subjects will discontinue treatment immediately and will be discontinued from the study 
after performing the early termination (ET) and safety follow-up visits. Subjects who use any of 
the medications from these classes for <14 days any time prior to the final 4 weeks of the 

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treatment period will be requested to stop these treatments and will be allowed to continue in the 
study.
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.  These 
medications include hormone replacement therapy (stable for at least 3 months), blood pressure 
medication, and statins.
Additional drugs are to be avoided during the study unless required to treat an AE or for the 
treatment of an ongoing medical problem. Acetaminophen (1 g, maximum 3 g/24 hours) may be 
administered at the discretion of the investigator for treatment of headaches or other conditions 
associated with pain.  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 transcribed into the eCRF.
7.7.1. Management of Subjects with Gastrointestinal Symptoms
The tirzepatide dose escalation schemes have been designed to minimize the development of 
intolerable GI symptoms.  The dose escalation period for tirzepatide is considered to be 8 weeks 
to reach the 15-mg maintenance dose. Steady-state exposures are expected to be attained within 
4 weeks of starting the 15-mg dose of tirzepatide. Treatment will be continued for 10 weeks
(±1 week) after commencing the 15-mg maintenance dose. During the dose escalation period, 
every effort should be made by the investigator to be able to escalate and maintain subjects on 
the corresponding IP 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.

Temporarily interrupt study per guidance provided in Section 8.1.2 (Temporary 
Interruption of IP).
7.8.
Treatment after the End of the Study
Not applicable.  Tirzepatide will not be made available to subjects after completion of the study.

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8. Discontinuation Criteria
Subjects discontinuing from the study prematurely for any reason should complete the ET visit
and safety follow-up visit procedures per Section 2 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 8.1.3 Discontinuation of Inadvertently 
Enrolled Subjects)

If a subject is diagnosed with acute or chronic pancreatitis 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 a subject is diagnosed with a significant IP-related hypersensitivity reaction

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 >8X ULN for healthy subjects

ALT or AST >5X ULN for more than 2 weeks or

ALT or AST >3X ULN and TBL >2X ULN or international normalized ratio >1.5 or

ALT or AST >3X ULN the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%)

Alkaline phosphatase (ALP) >3X ULN

ALP>2.5X ULN and TBL >2X ULN

ALP>2.5 ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%).

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
Drug-related vomiting requiring intravenous (IV) hydration treatment or causing severe 
distress (prevents daily activities and results in no appetite, or requires an emergency 
department visit, or hospitalization), that cannot be resolved by temporary interruption of 
IP (Section 8.1.2 Temporary Interruption of IP).
Subjects who discontinue IP early will be also discontinued from the study after performing the 
ET visit and safety follow-up visit procedures, as specified in Section 2 (Schedule of Activities).
8.1.2. Temporary Interruption of Investigational Product
In certain situations after randomization, for example, if GI tolerability AEs occur, the 
investigator may need to temporarily interrupt IP. Temporary interruptions are allowed during 
the dose escalation period (ie, while the dose is lower than 15 mg) and not during the 
maintenance phase of dosing with 15 mg.  Investigators should immediately inform the sponsor, 
that IP has been temporarily interrupted.  During an event that requires temporary interruption of 
study treatment, only 1 dose may be skipped.  Every effort should be made by the investigator to 
maintain subjects on IP and to restart IP after temporary interruption, as soon as it is assessed as 
safe to do so. The subject should resume study treatment administration at the scheduled dose 
level, per protocol.  If 2 or more episodes of study interruptions occur in the same subject, these 
cases will be reviewed by the investigator (or his/her designee) and Lilly to assess the feasibility 
of the subject’s further participation in the study.  If IP interruption is due to an AE, the event 
will be documented and followed according to the procedures in Section 9.2 (Adverse Events).  
The data related to temporary interruption of study treatment will be documented in source 
documents and entered into the eCRF.
8.1.3. 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 from the study 
in the following circumstances:

Enrollment in any other clinical study involving an IP 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

Investigator Decision

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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 5 provides a summary of the approximate number and volume of invasive samples, for
all sampling, during the study.
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 
(ie, outside stipulated time allowances) in performing procedures or obtaining samples due to 
legitimate clinical issues (eg, 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 balance, lipid and carbohydrate metabolism, and insulin sensitivity are considered 
efficacy measures.  The planned assessments will be performed at baseline and at the end of the 
treatment period at 18 weeks (±1 week).
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. Primary Efficacy Assessment and Procedure
The primary efficacy measure in the study is the change from baseline to Week 18 (Visit 20) in 
SMR for comparison of tirzepatide with placebo.  The change in SMR will be measured in the 
respiratory chamber (whole-room calorimetry).

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The SMR extrapolated to 24 hours will be calculated:

SMR = average SMR*1440, where average SMR is the average minute by minute EE for 
the sleep time period.
9.1.2. Secondary Efficacy Assessments and Procedures
The change from baseline to Week 18 (Visit 20) for the following secondary efficacy measures 
will be used for secondary objectives to compare tirzepatide with placebo.
Secondary efficacy measure to assess the effect of study treatment on appetite, measured by
visual analog scale (VAS), and food intake:

appetite (VAS) for hunger, fullness, satiety, prospective food consumption, desire for 
specific foods, and the overall appetite score, assessed at fasting and during standardized 
mixed-meal tolerance test (sMMTT) (van Can et al. 2014; Flint et al. 2000; Flint et al. 
2013);

food intake assessed by ad libitum meal test (see Appendix 6, Section 6.5 for description 
of parameters);
Secondary efficacy measure to assess the effect of study treatment on EE:

24-hour EE, defined as the total EE for the 23-hour measurement period in the respiratory 
chamber extrapolated to 24 hours;
EE = 3.941*total oxygen consumption [VO2] + 1.106*total carbon dioxide production 
[VCO2] – 2.17*[urinary nitrogen] (Weir JB deV 1949);
Secondary efficacy measure to assess the effect of study treatment on substrate oxidation rates:

24-hour respiratory quotient (RQ), defined as the ratio of VCO2 to VO2 during the 
23-hour measurement period in the respiratory chamber and extrapolated to 24 hours;
RQ = VCO2/VO2;

sleep RQ, defined as the ratio of VCO2 to VO2 during sleep time points;

RQ<0.80, defined as the cut point for high lipid oxidation of RQ; lipid oxidation will be 
calculated and corrected for protein oxidation; the total number of minutes with 
RQ <0.80, termed “lipid oxidation duration,” during each 23-hour measurement period 
will be recorded; protein oxidation will be determined from urine nitrogen that will be 
collected during 2 periods for each calorimeter day;

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
substrate oxidation for fat, protein, and carbohydrates (Frayn 1983; Jéquier et al. 1987);
Protein Oxidation = 6.25*[urinary nitrogen]
Fat Oxidation = 1.689*[VO2] – 1.689*[VCO2] – 0.324*[protein oxidation]
Carbohydrate Oxidation = 4.113*[VCO2] – 2.907*[VO2] – 0.375*[protein oxidation]
Secondary efficacy measure to assess the effect of study treatment on BW and body 
composition:

BW (kg)

body fat-free mass (kg) measured by the difference between BW and body fat mass

body fat mass (kg) measured using DXA

Percentage of body fat mass measured using DXA
Secondary efficacy measure to assess the effect of study treatment on lipid metabolism:

triglycerides, cholesterol, low-density lipoprotein (LDL), very low-density lipoprotein
(VLDL), and HDL cholesterol, free fatty acid (FFA), glycerol, 3-hydroxybutyrate, and 
acylcarnitines assessed during sMMTT;

apolipoprotein B-48 (ApoB-48), apolipoprotein B-100 (ApoB-100), apolipoprotein C-III 
(ApoC-III), and lipoprotein lipase (LPL) during sMMTT.

leptin, adiponectin, insulin-like growth factor binding protein (IGFBP) 1 and 2 at fasting
Secondary efficacy measure to assess the effect of study treatment on insulin sensitivity:

fasting insulin resistance as measured by the HOMA2 method (HOMA2-IR) (Hill et al. 
2013) and postprandial insulin sensitivity indices (Matsuda [Matsuda and DeFronzo 
1999], Oral Glucose Insulin Sensitivity [OGIS] Index [Mari et al. 2001], and Stumvoll 
Index [Stumvoll et al. 2000]); assessed during sMMTT (Hill et al. 2013);
Secondary efficacy measure to assess the effect of study treatment on glucose control:

fasting and postmeal glucose (total and incremental area under the concentration versus 
time curve (AUC) from time zero to 240 minutes after start of the meal [AUC0-240min]) 
during sMMTT;

hemoglobin A1c
9.1.3. Exploratory Efficacy Assessments and Procedures
The change from baseline to Week 18 (Visit 20) for following exploratory efficacy measures will 
be used for exploratory objectives to compare tirzepatide with placebo.

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Exploratory efficacy measure to assess the effect of study treatment on GIPR signaling, lipid 
metabolism, carbohydrate metabolism, and insulin signaling pathways in SC adipose tissue:

markers of GIPR signaling, lipid metabolism, carbohydrate metabolism, and insulin 
signaling pathways as measured in exploratory messenger ribonucleic acid (mRNA)
expression, lipidomics, metabolomics, or targeted protein assays of SC adipose tissue 
biopsy samples, receptor expression, signal transduction, and metabolic changes in 
adipose tissue.
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 IP or the study, 
or that caused the subject to discontinue the IP 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 AE/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, including clinically significant signs and symptoms of the disease under treatment in 
the study.  Additionally, site personnel will record any change in the condition(s) and the 
occurrence and nature of any AEs.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment or pathologies.
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the IP, 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.

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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 subject or may require intervention to prevent 
one of the other outcomes listed in the definition above.
Study site personnel must alert the Lilly CRP/CP, 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.
Although all AEs are recorded in the eCRF after signing informed consent, SAE reporting to the 
sponsor begins after the subject has signed informed consent and has received IP.  However, if 
an SAE occurs after signing informed consent, but prior to receiving IP, AND is considered 
reasonably possibly related to a study procedure then it MUST be reported.
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.
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 guidances.

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9.2.2. Adverse Events of Special Interest
9.2.2.1.
Hypoglycemia
Subjects will be trained during Visit 2 about signs and symptoms of hypoglycemia and how to 
treat hypoglycemia.
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 2017):
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).
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 BG to normal is considered sufficient 
evidence that the event was induced by a low BG concentration.  

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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, it needs to be recorded as serious on the AE 
eCRF and reported to Lilly as an SAE.
To avoid duplicate reporting, all consecutive PG 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
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:

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 ≥3X ULN

characteristic findings of acute pancreatitis on computed tomography (CT) scan or 
magnetic resonance imaging (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.

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Each subject will have measurements of amylase and lipase, part of 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 ≥3X 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 will be warranted, it should follow Lilly standard algorithm for the monitoring 
of pancreatic enzymes (refer to Appendix 7).
All suspected cases of acute or chronic pancreatitis will be adjudicated by an independent 
clinical endpoint committee. In addition, all cases of pancreatic hyperenzymemia that undergo 
additional diagnostic follow-up, as well as the AEs of severe or serious abdominal pain of 
unknown etiology will also be submitted to the adjudication committee to assess for possible 
pancreatitis or other pancreatic disease. Relevant data from subjects with possible, probable, or 
definite acute or chronic pancreatitis and those with severe or serious abdominal pain will be 
entered into a specifically designed eCRF page by study site or Lilly staff. The adjudication 
committee representative will enter the results of adjudication in a corresponding eCRF page.
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 values ≥20 pg/mL at screening.  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. This data will be captured in the specific 
section of the eCRFs.  The purpose of calcitonin measurements is to assess the potential of study 
treatments to affect thyroid C-cell function, which includes development of C-cell hyperplasia 
and neoplasms.
Subjects who develop calcitonin increases ≥50% of the mean of the screening value AND an 
absolute value ≥20 pg/mL and <35 pg/mL after randomization, will be asked to repeat the 
measurement within 1 month. If this repeat value is increasing (≥10% increase), the subject will 
be encouraged to undergo additional endocrine assessment and longer term follow-up by an 
endocrinologist to exclude a serious adverse effect on the gland. Subjects who develop 
calcitonin increases ≥50% of the mean of the screening value AND an absolute value ≥35 pg/mL 
after randomization will immediately undergo additional endocrine assessment and longer term 
follow-up by an endocrinologist.  Investigational product should be discontinued in situations 
when post randomization calcitonin value is ≥35 pg/mL.  If the calcitonin value decrease below 
35 pg/mL on repeat tests, IP should be restarted if, in the opinion of the investigator, it is safe to 
do so. If the increased calcitonin value is observed in a subject who has administered a 
medication that is known to increase serum calcitonin, this medication should be stopped and
calcitonin levels should be measured after an appropriate washout period.

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For subjects who require additional endocrine assessment because of increased calcitonin
concentration per criteria provided in this section, data from the additional assessment will be
collected in the specific section of the eCRF.
9.2.2.4.
Major Adverse Cardiovascular Events
Deaths and nonfatal CV AEs will be adjudicated by a committee of physicians external to Lilly 
with cardiology expertise.  The nonfatal CV AEs to be adjudicated include the following:

myocardial infarction

hospitalization for unstable angina

hospitalization for heart failure

coronary interventions (such as coronary artery bypass graft or percutaneous coronary 
intervention)

cerebrovascular events, including cerebrovascular accident (stroke) and transient 
ischemic attack
9.2.2.5.
Supraventricular Arrhythmias and Cardiac Conduction Disorders
Treatment-emergent cardiac conduction disorders should be further evaluated.  Subjects who 
develop any event from this group of disorders should undergo an ECG. Additional diagnostic 
tests to determine exact diagnosis should be performed, as needed. The specific diagnosis will 
be recorded as an AE. Events that meet criteria for serious conditions as described in 
Section 9.2.1 (Serious Adverse Events) must be reported as SAEs.
9.2.2.6.
Hypersensitivity Events
All allergic or hypersensitivity reactions will be reported by the investigator as either AEs or, if 
any serious criterion is met, as SAEs.  Additional data, such as type of reaction and treatment 
received, will be collected for any AEs or SAEs that the investigator deems related to IP via a 
eCRF created for this purpose. Additional serum samples should also be collected as outlined in 
Section 9.6.1 (Immunogenicity Assessments). 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 receive another glucose-lowering treatment, judged by the investigator to be 
appropriate based on the subject’s clinical status, and will be discontinued from the study 
(Section 8.1.1 Permanent Discontinuation from Study Treatment).
9.2.2.7.
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.

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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.
9.2.2.8.
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 9.4.5.1 (Hepatic Safety) and Appendix 4.
9.2.2.9.
Severe Gastrointestinal Adverse Events
Tirzepatide 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 7.7.1 (Management of Subjects with Gastrointestinal Symptoms).
9.2.2.10. 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.

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9.2.2.11. Major Depressive Disorder/Suicidal Ideation Monitoring Using the C-
SSRS and PHQ-9 Questionnaires
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 and monitored during the study for depression, and suicidal ideation 
and behavior.
Baseline and treatment-emergent assessment of depression, suicidal ideation, and behavior will 
be monitored during the study using the C-SSRS and PHQ-9 as specified in the Schedule of 
Activities (Section 2).  Before administering the C-SSRS or the PHQ-9, study site personnel will 
question the participant about any change in the preexisting condition(s) and the occurrence and 
nature of any AEs.  These questionnaires should be administered after assessment of AEs.  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.
Nonserious AEs obtained through the questionnaire are recorded and analyzed separately.  Only 
serious AEs elicited through the C-SSRS or PHQ-9 are to be recorded as AEs via the eCRF and 
reported to Lilly or its designee within 24 hours as SAEs.  
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.  
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).
9.2.3. 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 IP so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of tirzepatide is considered any dose higher than the 
dose assigned through randomization or as defined by protocol.  There is no specific antidote.  
The subject 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.

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9.4.
Safety
9.4.1. Laboratory Tests
For each subject, laboratory tests to assess PD and safety of study treatment will be performed 
throughout the study according to Section 2 (Schedule of Activities). A detailed list of 
laboratory analytes is provided in Appendix 2. Any clinically significant findings from 
laboratory tests that result in a diagnosis and that occur after the subject receives the first dose of 
the IP should be reported to Lilly, or its designee, as an AE via eCRF.
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 heart level. Each measurement of sitting heart rate and 
blood pressure is 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.
9.4.3. Electrocardiograms
For each subject, a single 12-lead digital ECG for safety will be collected according to Section 2
(Schedule of Activities).
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 
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 the first dose of the IP should be reported to 
Lilly, or its designee, as an AE via eCRF.

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9.4.4. Physical Examinations
Physical examinations and routine medical assessments will be conducted as specified in 
Section 2 (Schedule of Activities) and as clinically indicated.
9.4.5. Safety Monitoring
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study.
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

safety laboratory analytes including glucose, amylase, and lipase 

serious and nonserious AEs, including AEs of interest (GI events, hypoglycemia, 
injection-site reactions, hypersensitivity reactions) and reported and adjudicated 
pancreatitis
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
9.4.5.1.
Hepatic Safety
If a study subject experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X 
ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, ALP, 
TBL, direct bilirubin, gamma-glutamyl transferase, and creatinine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator based on 
consultation with the Lilly CP or CRP.  Monitoring should continue until levels normalize and/or 
are returning to approximate baseline levels. 
Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥5X ULN on two or more consecutive blood tests

elevated serum TBL to ≥2X ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests

patient/subject discontinued from treatment due to a hepatic event or abnormality 
of liver tests

hepatic event considered to be a SAE
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), 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 

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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.
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 
2 years following last subject visit for the study.  During this time, samples remaining after the 
bioanalyses may be used for exploratory analyses such as metabolism, protein binding work,
and/or bioanalytical method cross-validation.
9.6.
Pharmacodynamics
The sample(s) will be stored for up to a maximum of 1 year after the last subject visit for the 
study at a facility selected by the sponsor.
Briefly, PD assessments will include parameters of energy expenditure, appetite (appetite 
sensations and desire for specific foods) and food intake, substrate utilization (oxidation), 
metabolic flexibility, and insulin sensitivity. A detailed description of PD efficacy measures is 
provided in Section 9.1 (Efficacy Assessments). A description of procedures for obtaining the 
samples for PD parameters is detailed in Appendix 6.
9.6.1. Immunogenicity Assessments
For immunogenicity testing, venous blood samples of approximately 10 mL will be collected
from each subject according to Section 2 (Schedule of Activities) to determine antibody
production against tirzepatide. Additional samples may be collected if there is a possibility that
an AE is immunologically mediated. All samples for immunogenicity testing should have a
time-matched sample for PK analysis where relevant.  Detailed instructions on the sample 
collections will be provided by Lilly or its designee. The actual date and 24-hour clock time of 
each sampling will be recorded.
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 evaluated for 
their ability to neutralize the activity of the 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.
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).

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Subjects who have clinically significant TE-ADA at early discontinuation or at the safety 
follow-up visit, may be asked to return for additional follow-up testing. 
A clinically significant TE-ADA will be defined as any TE-ADA with:

a high titer (≥1280) or an increasing titer from last measured value, and/or

an association with a moderate-to-severe injection site reaction or systemic 
hypersensitivity AE
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.
9.6.2. Body Weight and Waist Circumference 
Weight will be measured according to the schedule provided in Section 2 (Schedule of 
Activities).  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. 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.
9.7.
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 type 2 diabetes, obesity, 
and/or diabetic complications.  Assessment of variable response may include evaluation of AEs
or differences in efficacy.

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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.  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, PD, 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.
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 type 2 diabetes, obesity, 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.  
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 or is commercially available.
9.9.
Health Economics
This section is not applicable for this study.

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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Up to 56 subjects are planned to be randomized so that approximately 46 subjects complete the 
study assuming 15% discontinuation rate. These 56 subjects will be randomized to QW 
tirzepatide or placebo in a 1:1 ratio. The estimated variability of the change in SMR from 
baseline is 117 kcal/day (Heilbronn et al. 2006). With an expected treatment difference of 
100 kcal/day, this provides at least 80% power for the comparison of tirzepatide versus placebo
based on 2 sample t-test using 2-sided test at alpha level of 0.05, and at least 85% power for the 
sensitivity analysis where only patients who achieve the target weight loss and are considered at 
least 90% compliant will be included for the assessment of the primary endpoint.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A summary 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 the IP and have evaluable data. Sensitivity analyses may be performed as deemed 
necessary. 
Safety analyses will be conducted for all randomized subjects, whether or not they completed all 
protocol requirements.
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 

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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 laboratory 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, 
analyses may be performed if warranted upon review of the data.
Vital signs will be summarized with respect to observed values and change from baseline by 
treatment at each time point using descriptive statistics. The analysis details will be provided in 
SAP.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Sparse PK samples will be collected across the 18-week (±1 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 to compare with expected 
tirzepatide PK based on historical understanding.  Additional tirzepatide PK parameters will not 
be derived. 
10.3.2.2. Pharmacokinetic Statistical Inference
No PK parameters will be derived, thus no statistical analyses of PK parameters are planned.
10.3.3. Pharmacodynamic Analyses
10.3.3.1. Pharmacodynamic Parameter Estimation
The following parameters will be measured at baseline and Week 18 (Visit 20), respectively, to 
assess the effect of study treatments on energy balance:
Measures of energy expenditure: 

SMR

24-hour EE
Measures of substrate oxidation (fat, protein, and carbohydrates):

24-hour RQ

Sleep RQ

Duration of periods with RQ<0.80

Fat, protein, and carbohydrates oxidation rates

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Measures of appetite and food intake: 

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) (van Can et al. 2014; Flint et al. 2000; Flint et al. 2013). The higher 
overall appetite score indicates less appetite and the lower score indicates more appetite.

Food intake assessed by ad libitum meal test
For other PD parameter estimations, please see Section 9.1.  Further details will be described in
the SAP. 
10.3.3.2. Pharmacodynamic Statistical Inference
The primary endpoint (SMR) will be analyzed using an analysis of covariance model 
(ANCOVA) to compare the effect of tirzepatide versus placebo. The dependent variable to be 
used in the model will be the change from baseline to 18 weeks in SMR. The independent 
variables will include treatment as a factor, baseline SMR and body composition parameter(s) as 
covariates. The primary analysis will be performed in all randomized subjects with evaluable 
data (modified intent-to-treat [mITT] population).  Similar analysis will also be performed in 
subjects who reach the BW target range of 10% (±2%) at Week 18 as a sensitivity analysis.
Other PD parameters that are scheduled to be measured only once postbaseline will be analyzed 
using a similar ANCOVA model with baseline measurement and treatment group as covariates. 
For parameters that are measured in the respiratory chamber, an adjustment for body 
composition parameter(s) as covariates may be applied if deemed appropriate. If the response is 
positive for all subjects and highly skewed, a log-transformation may be considered. Other 
parameters that are positive and skewed may be log-transformed.
The PD parameters that are scheduled to be measured at least twice postbaseline will be analyzed 
using a mixed-model repeated-measure method with restricted maximum likelihood estimation. 
The model will include the treatment, visit, and treatment-by-visit interaction as fixed effects, 
baseline value of the dependent variable as a covariate, and subject as a random effect. An 
unstructured variance-covariance matrix will be used to model the within-subject effects.
All PD analyses will performed in the mITT population and selected analyses also on-BW-target 
population.  All analyses will show least squares means of each treatment and the treatment 
difference in the original scale 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. 
10.3.4. Evaluation of Immunogenicity
The frequency and percentage of subjects with preexisting ADA and with TE-ADA+ to 
tirzepatide will be tabulated. Treatment-emergent ADA are defined as those with a titer 2-fold
(1 dilution) greater than the minimum required dilution (1:10) 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+ 

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subjects, the distribution of maximum titers will be described.  The frequency of neutralizing 
antibodies if performed, will be tabulated for TE-ADA+ subjects. If cross-reactivity to native 
GLP-1 and GIP or neutralizing antibodies against native GLP-1 and GIP assays are performed, 
the frequency of each will be reported.
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.

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Huang PL. A comprehensive definition for metabolic syndrome. Dis Model Mech. 
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Jéquier E, Acheson K, Schutz Y. Assessment of energy expenditure and fuel utilization in man.
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Kim J, Heshka S, Gallagher D, Kotler DP, Mayer L, Albu J, Shen W, Freda PU, Heymsfield SB. 
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Koizumi M, Takada T, Kawarada Y, Hirata K, Mayumi T, Yoshida M, Sekimoto M, Hirota M, 
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of acute pancreatitis: diagnostic criteria for acute pancreatitis. J Hepatobiliary Pancreat Surg.
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Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment (HOMA) 
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Luppino FS, de Wit LM, Bouvy PF, Stijnen T, Cuijpers P, Penninx BW, Zitman FG. 
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SR, Ravussin E. Effect of calorie restriction on resting metabolic rate and spontaneous 
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SB. New fat free mass - fat mass model for use in physiological energy balance equations. 
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model predicting individual weight change in humans. J Biol Dyn. 2011;5(6):579-599.
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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 subject 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
ANCOVA
analysis of covariance model
ApoB-48
apolipoprotein B-48
ApoB-100
apolipoprotein B-100
ApoC-III
apolipoprotein C-III
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC0-240min
area under the concentration versus time curve from time zero to 240 minutes after start of 
the meal
BG
blood glucose
blinding
A procedure in which one or more parties to the study are kept unaware of the treatment 
assignment(s).  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
CO2
carbon dioxide
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.

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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
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
CV
Cardiovascular
DXA
dual energy X-ray absorptiometry
ECG
Electrocardiogram
eCRF
electronic case report form
EE
energy expenditure
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.
enter
Subjects entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ET
early termination
FFA
free fatty acid
GCP
good clinical practice
GI
Gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide
GIPR
glucose-dependent insulinotropic polypeptide receptor
GIPRA
glucose-dependent insulinotropic polypeptide receptor agonism
GLP-1
glucagon-like peptide 1
GLP-1R
glucagon-like peptide 1 receptor
GLP-1RA
glucagon-like peptide 1 receptor agonism

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HCV
hepatitis C virus
HDL-C
high-density lipoprotein cholesterol
HIV
human immunodeficiency virus
HOMA2
Homeostatic Model Assessment of Insulin Resistance
HOMA2-IR
insulin resistance as measured by the HOMA2 method
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonization
IGFBP
insulin-like growth factor binding protein
informed consent
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.
Investigational 
product (IP)
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
IV
Intravenous
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.
LDL-C
low-density lipoprotein cholesterol
LPL
lipoprotein lipase
MAD
multiple-ascending dose
MEN 2
multiple endocrine neoplasia syndrome type 2
mITT
modified intent-to-treat
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid

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MTC
medullary thyroid carcinoma
PFS
prefilled syringes
PG
plasma glucose
PHQ-9
Patient Health Questionnaire-9
PK/PD
pharmacokinetic/pharmacodynamics
PR
pulse rate
QT
QT interval
QTc
QT interval corrected for heart rate
QW
once weekly
randomize
the process of assigning subjects to an experimental group on a random basis
RMR
resting metabolic rate
RQ
respiratory quotient
SAD
single-ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SC
Subcutaneous
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.  
sMMTT
standardized mixed-meal tolerance test
SMR
sleep metabolic rate
SUSARs
suspected unexpected serious adverse reactions
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 

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ULN
upper limit of normal
VAS
visual analog scale
VCO2
total CO2 production
VO2
total oxygen consumption
VLDL-C
very low-density lipoprotein cholesterol
WOCBP
woman 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)
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
Creatinine
Lipase (fasting)
Urinalysis
Amylase
Specific gravity
Triglycerideb
pH
Total cholesterolb
Protein
Hemoglobin A1c
Glucose
Ketones
Endocrine
Bilirubin
Follicle-stimulating hormonea
Urobilinogen
Calcitonin
Blood
Leukocytes
Serologyc
Microscopya
Hepatitis B surface antigen
Hepatitis C antibody, hepatitis C RNAd
HIV antibody
Pregnancy test (urine, serum)e
Drug and alcohol screenf
Abbreviations:  HIV = human immunodeficiency virus; RBC = red blood cells; WBC = white blood cells.
Note:  Results of these assays will be validated by the central or local laboratory at the time of testing. Additional
tests may be performed or auto-calculated by the laboratory as part of its standard panel that cannot be removed.  
Some of the above parameters are calculated from measured values. Omission of calculated values will not be
considered as a protocol violation.
a
If clinically indicated, per investigator’s discretion.
b
Triglyceride and total cholesterol concentrations in the safety panel will not be required on the days that the lipid
panel is performed.
c
At screening only (unless previously performed within the last 6 months with reports available for review).
d
See exclusion criteria (Section 6.2) for further details.

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e
Pregnancy tests will be performed for women of childbearing potential. Serum pregnancy test is done at 
screening and follow-up and urine pregnancy is performed on Day -4 and Day 122.
f
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 informed consent (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 participant or the participant’s legal representative and 
retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for subjects.  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(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s). All ICFs must be compliant with the ICH guideline 
on good clinical practice (GCP).
The study site’s IRB(s) 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 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, each 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 electronic case report form 
(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.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with subjects in consultation with Lilly or its designee Clinical Research 
Physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol I8F-MC-GPGU Sampling Summary
Purpose
Blood Volume 
per Sample (mL)
Number of 
Blood Samples
Total Volume 
(mL)
Screening testsa,b
24
1
24
Safety laboratory tests (including hemoglobin A1c
and calcitonin)a,b
15
5
75
Tirzepatide pharmacokineticsc
3
5 (+3)
24
Pharmacodynamicsc
3-hydroxybutyrate (fasted)
2
2
4
3-hydroxybutyrate (fasted) during sMMTT
2
6 × 2
24
Acylcarnitine (fasted)
5
2
10
Acylcarnitine (fasted) during sMMTT
5
6 × 2
60
Adiponectin (fasted)
2
2
4
Adiponectin (fasted) during sMMTT
2
1 × 2
4
Free fatty acid (fasted)
2
2
4
Free fatty acid (fasted)during sMMTT
2
6 × 2
24
Glucose (fasted) 
2
2
4
Glucose (fasted) during sMMTT
2
11 × 2
44
Glycerol
2
2
4
Glycerol during sMMTT
2
6 × 2
24
IGFBP 1 and 2 (fasted)
5
2
10
IGFBP 1 and 2 (fasted) during sMMTT
5
1 × 2
10
Insulin (fasted)
2.5
2
5
Insulin (fasted) during sMMTT
2.5
9 × 2
45
Leptin (fasted)
2
2
4
Leptin (fasted) during sMMTT
2
1 × 2
4
Lipid panel (fasted): TG, total cholesterol,
LDL-C, VLDL-C, HDL-C
7.5
2
15
Lipid panel (fasted): TG, total cholesterol,
LDL-C, VLDL-C, HDL-C during sMMTT
7.5
6 × 2
90
Lipid panel (fasted): ApoB-48, ApoB-100,
ApoC-III
3.5
2
7
Lipid panel (fasted): ApoB-48, ApoB-100,
ApoC-III during sMMTT
3.5
6 × 2
42
Lipid panel: LPL
2.5
2
5
Lipid panel: LPL during sMMTT
2.5
6 × 2
30
OGTT at screening – glucose (2 mL) and
Insulin (2.5 mL)b
4.5
2
9
continued

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Protocol I8F-MC-GPGU Sampling Summary
Purpose
Blood Volume 
per Sample (mL)
Number of 
Blood Samples
Total Volume 
(mL)
Immunogenicityc
10
5 (+3)
80
Pharmacogeneticsc
10
1
10
Nonpharmacogenetic stored samplec (fasted)
11
5
55
Total
754
Total for clinical purposes [rounded up to nearest 10 mL]
760
Abbreviations:  ApoB-48 = apolipoprotein B-48; ApoB-100 = apolipoprotein B-100; ApoC-III = apolipoprotein 
C-III; HDL-C = high-density lipoprotein cholesterol; IGFBP = insulin-like growth factor-binding protein; 
LDL-C = low-density lipoprotein cholesterol; LPL = lipoprotein lipase; OGTT = oral glucose tolerance test;
sMMTT = standardized mixed-meal tolerance test; TG = triglycerides; VLDL-C = very low-density lipoprotein 
cholesterol.
a
Additional samples may be drawn if needed for safety purposes.  Triglycerides and total cholesterol will be 
excluded on study days where a lipid panel pharmacodynamics sample is collected.
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 6.
Efficacy Assessments
6.1.
Appetite Visual Analog Scale
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.  The parameters that will be obtained are 
listed in Section 9.1.2 (Secondary Efficacy Assessments and Procedures).
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 computer screen; 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 savoury?

Would you like to eat something fatty?
Subjects will see the line on a validated electronic device that will record the subject’s rating on 
the respective lines, ranging from 0 (“not at all”) to 100 (“extremely”).  In the case of technology 
failure, pen-and-paper VAS will be used and will include a 10-cm line. Only provided or printed 
(not copied) paper VAS can be used, as copying them alters the length line.  For assessment of 
postprandial appetite sensations and desire for specific foods during standardized mixed-meal 
tolerance test (sMMTT), the scores will be obtained immediately prior to the start of the meal 
(time point -10), and 60, 120, 180, and 240 minutes after the start of the meal.  Overall appetite 
score is calculated as described in Section 10.3.3.1 (Pharmacodynamic Parameter Estimation).

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6.2.
Retrospective Visual Analog Score
Visual analog score will be used to measure average ratings of appetite that subjects experienced 
over the past week. This method of collecting VAS data has been found to be consistent with 
daily assessments of satiety (Womble et al. 2003). These VAS items will be identical to those 
that are collected on the day of food intake testing, though the instructions to the subjects will be 
modified, as detailed here: 

How hungry did you feel over the past week?

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?
6.3.
Food Craving Inventory
The 33-item food craving inventory (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.  All items are scored 
in the following manner: 

Never = 1

Rarely = 2

Sometimes = 3

Often = 4

Always = 5
It is noted that the fruits/vegetables scale was not included in the White et al. paper (White et al. 
2002), though support for the scale was obtained and will be included in the study.
6.4.
Food Preference Questionnaire
The Food Preference Questionnaire (FPQ) (Geiselman et al. 1998) assesses preferences for 
72 foods in a 2 (high-fat, low-fat) by 3 (high-simple sugar, high-complex carbohydrate, 
low-carbohydrate/high-protein) matrix. Subjects rate each food hedonically on a 9-point Likert 
scale by rating how much they like each food, with 1 = dislike extremely, 5 = neither like nor 
dislike, and 9 = like extremely.  The FPQ has established reliability and validity (Geiselman et 
al. 1998).
6.5.
Ad Libitum Food Intake Test
Efforts will be made to schedule the baseline and follow-up food intake tests during the luteal 
phase of female subjects’ menstrual cycle, as assessed by the Menstrual Cycle Questionnaire. 

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Ad libitum intake will be recorded at lunch and dinner on Day -4 prior to entering the respiratory 
chamber. Subjects will complete a test lunch at 1200 hours. The test lunch will consist of 
ad libitum sandwiches, potato chips, cookies, water, and a choice of a sugar and artificially
sweetened soda or tea. Dinner will occur at 1830 hours and will consist of the Macronutrient 
Self-Selection Paradigm (MSSP) (Geiselman et al. 1998).  The MSSP provides subjects with a 
buffet meal that consists of 18 foods that vary in a 2 (High-Fat, Low-Fat) by 3 (High-Simple 
Sugar, High-Complex Carbohydrate, Low-Carbohydrate/High-Protein) matrix, similar to the 
FPQ.  Subjects will not be allowed to eat between test meals but can drink water.
Subjects will be instructed that they can eat as much or as little as they wish and that they should 
alert a site staff member when they are finished eating, at which time the subject will leave the 
test meal. Site staff will check on the subject 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. 
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 (USDA 
2018) or data from the food producer/manufacturer. 
Food intake will be quantified separately for lunch and dinner, and combined for lunch and 
dinner. The primary food intake variables are: 1) energy (kcal) intake, and 2) gram intake. 
Secondary food intake variables are: 1) grams of carbohydrate, protein, and fat (saturated and 
unsaturated) consumed, and 2) percent of energy (kcal) from carbohydrate, protein, and fat 
(saturated and unsaturated) consumed.
6.6.
Whole Room Calorimetry
Total carbon dioxide (CO2) production (VCO2) and total oxygen consumption (VO2) will be 
sampled and measured at 1-minute intervals over 23 hours in a respiratory chamber (whole-room 
calorimeter) as shown in Table GPGU.3.
This will be used to calculate respiratory quotient (RQ), energy expenditure (EE), and substrate 
oxidation rates. The chamber is a room approximately 27 000 liters with 2 windows, a bed, a 
desk and chair, a computer with internet access, a TV/DVD, a telephone, toilet facilities, a 
motion sensor, and a video camera. Subjects will be able to contact the nursing or chamber 
personnel at any time using the intercom or telephone, and will be monitored for safety and 
compliance using the video camera.
After entering the respiratory chamber at approximately 0800 hours, subjects will be instructed 
to rest awake on the bed for the first 30 minutes in the chamber, after which breakfast will be 
provided (approximately 0835 hours). Subjects will then be allowed approximately 4 hours of 
free time, after which lunch will be provided (approximately 1230 hours). Lunch will be 
followed by approximately 6.5 hours of free time until dinner is served at approximately 
1900 hours. The 3 meals will be ingested over a maximum 30-minute period. During periods of 
free time, subjects will not be allowed to sleep, and the intensity of any physical activity can be 
no higher than walking around the chamber or stretching (no push-ups or sit-ups).  After dinner, 

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subjects will be given more free time until “lights out” at approximately 2230 hours. Urine will 
be collected during the entire stay (2 times in 23 hours) in the respiratory chamber. Subjects will 
be awakened at approximately 0615 hour and instructed to void their bladder and then return to 
the bed. Subjects will then be instructed to rest awake on the bed for approximately 30 minutes. 
At the end of the 23-hour measurement period, the subjects will be removed from the chamber.
On the first day of the 2-day stay, approximate energy balance will be maintained by the 
calculation of the average EE of the first 7 hours in the chamber and used to predict 24 hour EE 
using previously determined equations (Lam et al. 2014). Calories provided with the dinner 
meal will be adjusted so that energy intake equals predicted 24-hour EE, rounded to the nearest 
100 calories. On the second day in the chamber, subjects will be fed the exact amount of calories 
they spent on the first day.
Activity counts will be recorded using a motion detector for the entire 23-hour measurement 
period and will be used to determine activity driven effects on EE and RQ. Average EE and RQ 
will be calculated for rest periods, sleep, and the entire 23-hour measurement. 

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Table GPGU.3.
Whole-Room Calorimeter Respiratory Quotient Measurements
Approx. 
Houra
Nominal 
Timinga
(hour)
Procedure: Activity
VCO2 and VO2
Activity Monitoring
Urine Collectionb
0800
0
Start of RQ measurement: resting on bed no sleep
Sampled at 1 minute 
intervals
Continuous activity 
monitoring
Entrance and exit into 
whole-room 
calorimeter
0835
0.5
End of bed rest: breakfast start
0900
1
Breakfast end: free time startc
1230
4.5
End of free time: lunch start
1300
5
Lunch end: free time startc
1900
11
End of free time: dinner start
1930
11.5
Dinner end: free time startc
2230
14.5
End of free time: lights out and bedtime
0000
16
Sleep RQ measurement start
0615
22.25
Sleep RQ measurement end
Subjects woken: void bladder
0630
22.5
Resting on bed no sleep
0700
23
End of bed rest. End of RQ measurement.
Abbreviations: RQ = respiratory quotient; VCO2 = carbon dioxide production; VO2 = oxygen consumption.
a
Subjects will enter the whole-room calorimeter in the morning at approximately 0800 hours after an approximately 10-hour overnight fast. The actual times 
given are approximate as the timing depends on the start time of the laboratory procedure.
b
Urine to be collected over 2 periods for each calorimeter day over 23 hours from entrance to exit. Start and end times of urine collections must be recorded, 
together with total volume of urine produced in each period.
A 15 mL aliquot will be retained for analysis of urinary nitrogen.
c
In “free time,” subjects will not be allowed to sleep, and the intensity of any physical activity can be no higher than walking around the chamber or stretching 
(no push-ups or sit-ups), until lights-out.

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6.7.
Oral Glucose Tolerance Test 
An oral glucose tolerance test (OGTT) will be performed during screening according to the
Schedule of Activities (Section 2).
Subjects shall maintain adequate carbohydrate intake 3 days before the scheduled OGTT.  
Subjects shall fast for at least 10 hours overnight before administration of the glucose. A 75-g
glucose dose will be given orally. Subjects should consume the glucose load within 5 minutes.  
Blood samples will be drawn for assessment of glucose and insulin at 0 hours (ie, prior to the 
oral glucose) and 2 hours after the initiation of the glucose load.
6.8.
Body Composition Measurements
Body composition will be determined using dual energy X-ray absorptiometry (DXA) scans (GE 
iDXA™ whole-body scanner).  Dual energy X-ray absorptiometry allows the noninvasive 
assessment of soft tissue composition by region with a precision of 1% to 3%. Subjects will lie 
in a supine position on the densitometer table in a hospital gown while the scanner emits low 
energy X-rays and a detector passes along the body.  Two distinct energies are used to determine 
body mineral and soft tissue content.  An attenuation ratio is determined from a known tissue 
content.  Variations of the attenuation ratio determine the fat content of the tissue at each pixel 
thereby calculating the percentage body fat.  The scans are analyzed with enCORE Windows-
based user interface.  The coefficient of variation for the body composition measurements of 
total body lean mass, fat mass, and percentage body fat is 0.5%, 0.8%, and 0.8%, respectively.  
The DXA scan will also be used to estimate muscle mass (Kim et al. 2004).  The scan takes 7 to 
13 minutes and the radiation dose is less than 1 mrem, which is less than a chest X-ray, or equal 
to about 12 hours of background radiation from the sun. The DXA scan will be performed in 
duplicate at each scheduled time point. The average value from the 2 tests will be used in 
parameter estimation and statistical analyses.
6.9.
Standard Mixed-Meal Tolerance Test
The key objectives of the sMMTT are to assess α and β cell function and indirectly insulin 
sensitivity under physiological conditions.  The parameters that will be obtained are listed in 
Section 9.1.2 (Secondary Efficacy Assessments and Procedures). The measurements that will be 
collected during the test and then used for parameter calculations are provided in Table GPGU.4.
Subjects will fast overnight for at least 10 hours before the start of the sMMTT.  
Before the start of sMMTT, an intravenous (IV) cannulas (catheter) will be inserted in one of the 
subject’s arm for serial blood sampling.
The sMMTT will be initiated between 0700 to 0730 hours with the subject in a seated position.  
The start of the meal will be defined as time point 0 (zero). The first blood sample collection 
time point will be at -10 minutes.  Immediately after the second blood sample (-1 minute), 
subjects will consume a fixed nutrient ratio mixed meal (approximately 23% fat, 33% protein, 
and 47% carbohydrate) consisting of High Protein Boost® over a 5-minute period maximum.  
The remaining blood samples will be collected over the next 4 hours for measurement of the 

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parameters of interest per schedule provided in Table GPGU.4.  Sampling times may be adjusted 
as necessary.
During the baseline assessment, the individual subjects’ characteristics (weight, height, age, and 
gender) will be used for the calculation of sedentary 24-hour energy expenditure based on the 
Lam equation (Lam et al. 2014).  A standard physical activity level (PAL) of 1.2 (20%) will be 
added to the calculated 24-hour sedentary energy expenditure to estimate daily energy 
requirement.  The sMMTT will account for 35% of the estimated daily energy requirement.
The individual sMMTTs will be identical at baseline and end of treatment.
The subject should refrain from eating until 4 hours after the meal (end of meal test). Water 
consumption will not be allowed during the first 2 hours after the start of the test.
After the end of the meal test procedure, the subject will be served a meal. All calculations and 
analyses are described in Section 9.1.2 (Secondary Efficacy Assessments and Procedures) 
and Section 10.3 (Statistical Analyses) and in the statistical analysis plan.

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Table GPGU.4.
Standardized Mixed-Meal Tolerance Test
Nominal Timing
(Minutes)
Meal
Sampling for Analysis
VAS
Blood Glucose
Insulin
3-hydroxybutyrate, 
Acylcarnitines, FFA, 
Glycerol
Leptin, 
Adiponectin, 
IGFBP 1 and 2
Lipid Panela
-10
X
X
X
X
X
X
-1
X
X
0
Start
5
Stop
15
X
X
30
X
X
60
X
X
X
X
X
90
X
X
X
X
120
X
X
X
X
X
150
X
180
X
X
X
X
X
210
X
240
X
X
X
X
X
Abbreviations:  FFA = free fatty acid; IGFBP = insulin-like growth factor binding protein; VAS = visual analogue scale.
a
Lipid panel: triglycerides, total cholesterol, low-density lipoprotein, very low-density lipoprotein, high-density lipoprotein, apolipoprotein B-48, 
apolipoprotein B-100, apolipoprotein C-III, and lipoprotein lipase. 

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6.10. Adipose Tissue Biopsy
Two grams of adipose tissue will be collected with the Mercedes lipoaspirate technique under 
sterile conditions and local anesthesia.  After cleansing the skin with povidone-iodine solution 
and placing a sterile drape, topical anesthesia containing 50%/50% ratio of lidocaine 
2%/bupivacaine 0.5% will be administered. Samples will be taken from the subcutaneous 
abdominal region.  The tissue will be divided into 4 aliquots and each aliquot will be 
immediately placed in sterile tubes for processing. Adipose tissue will be frozen upon collection 
using liquid nitrogen. Two grams of adipose tissue will allow for the assessment of tirzepatide 
effects on changes in markers of glucose-dependent insulinotropic polypeptide receptor signaling, 
lipid metabolism, carbohydrate metabolism, and insulin signaling pathways in exploratory assays.

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Appendix 7.
Pancreatic Monitoring

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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.
Protocol Amendment I8F-MC-GPGU(f) 
Summary - A Randomized, Placebo-Controlled, Parallel-
Arm Study to Investigate the Effect of Once-Weekly 
Tirzepatide on Energy Expenditure and Food Intake in 
Obese Subjects
Overview
Protocol I8F-MC-GPGU(e), A Randomized, Placebo-Controlled, Parallel-Arm Study to 
Investigate the Effect of Once-Weekly Tirzepatide on Energy Expenditure and Food Intake in 
Obese Subjects, 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 
not considered to be substantial.  The overall change and rationale for the change made to this 
protocol:

To clarify that subjects with current diagnosis of any form of diabetes will be excluded 
from the study.

The primary efficacy analysis was corrected and clarified regarding adjustment for body 
composition.

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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.
1 Protocol Synopsis
Statistical Analysis:
The primary PD parameter for analysis is sleep metabolic rate (SMR) measured using whole-
room indirect calorimetry (respiratory chamber), which will be analyzed using an analysis of 
covariance model (ANCOVA) to compare the effect of tirzepatide versus placebo.  The 
dependent variable to be used in the model will be the change from baseline to 18 weeks in 
SMRadjusted for body composition.  The independent variables will include treatment as a 
factor, and baseline SMR and body composition parameter(s) as covariates.  The primary 
analysis will be performed in all randomized subjects with evaluable data (modified intent-to-
treat [mITT] population).  Similar analysis will also be performed in subjects who reach the BW 
target range of -10% (±2%) at Week 18 as a sensitivity analysis.
Other PD parameters that are scheduled to be measured only once postbaseline will be analyzed 
using a similar ANCOVA model with baseline measurement and treatment group as covariates.  
For parameters that are measured in the respiratory chamber, an adjustment for body 
composition parameter(s) as covariates may be applied if deemed appropriate.  If the response is 
positive for all subjects and highly skewed, a log-transformation may be considered.  Other 
parameters that are positive and skewed may be log-transformed.
6.2 Exclusion Criteria 
[13]
Are currently diagnosed with any form of diabetesprior to entry; or have fasting and/or 
postglucose challenge PG (OGTT) compatible with diabetes, and/or hemoglobin A1c value 
≥6.5% at screening (Visit 1); subjects with borderline glucose intolerance are eligible (see 
Section 6.1 Inclusion Criteria [1]).
9.1.1. Primary Efficacy Assessment and Procedure
The primary efficacy measure in the study is the change from baseline to Week 18 (Visit 20) in 
SMR for comparison of tirzepatide with placebo.  The change in SMR will be measured in the 
respiratory chamber (whole-room calorimetry).

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The SMR extrapolated to 24 hoursand adjusted for body composition will be calculated:

SMR = average SMR*1440, where average SMR is the average minute by minute EE for 
the sleep time period.
10.1. Sample Size Determination
Up to 56 subjects are planned to be randomized so that approximately 46 subjects complete the 
study assuming 15% discontinuation rate.  These 56 subjects will be randomized to QW 
tirzepatide or placebo in a 1:1 ratio.  The estimated variability of the change in SMR from 
baseline is 117 kcal/day, when adjusted for body composition (Heilbronn et al. 2006). With an 
expected treatment difference of 100 kcal/day, this provides at least 80% power for the 
comparison of tirzepatide versus placebo based on 2 sample t-test using 2-sided test at alpha 
level of 0.05, and at least 85% power for the sensitivity analysis where only patients who achieve 
the target weight loss and are considered at least 90% compliant will be included for the 
assessment of the primary endpoint.
10.3.3.2. Pharmacodynamic Statistical Inference
The primary endpoint (SMR) will be analyzed using an analysis of covariance model 
(ANCOVA) to compare the effect of tirzepatide versus placebo.  The dependent variable to be 
used in the model will be the change from baseline to 18 weeks in SMR adjusted for body 
composition. The independent variables will include treatment as a factor and, baseline SMR 
and body composition parameter(s) as covariates.  The primary analysis will be performed in all 
randomized subjects with evaluable data (modified intent-to-treat [mITT] population).  Similar 
analysis will also be performed in subjects who reach the BW target range of 10% (±2%) at 
Week 18 as a sensitivity analysis.
Other PD parameters that are scheduled to be measured only once postbaseline will be analyzed 
using a similar ANCOVA model with baseline measurement and treatment group as covariates.  
For parameters that are measured in the respiratory chamber, an adjustment for body 
composition parameter(s) as covariates may be applied if deemed appropriate. If the response is 
positive for all subjects and highly skewed, a log-transformation may be considered.  Other 
parameters that are positive and skewed may be log-transformed.

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