Efficacy and Safety of Tirzepatide Once Weekly in Chinese Participants Without Type 2 Diabetes Who Have Obesity or Are Overweight With Weight-Related Comorbidities: A Randomized, Double-Blind, Placebo-Controlled Trial (SURMOUNT-CN)
Phase: PHASE3
Conditions: Obesity, Overweight, Metabolism and Nutrition Disorder
Sponsor: Eli Lilly and Company

 
 
 
Protocol I8F-MC-GPIA(a) 
 
 
Efficacy and Safety of Tirzepatide Once Weekly in Chinese Participants without Type 2 
Diabetes Who Have Obesity or are Overweight with Weight-Related Comorbidities: A 
Randomized, Double-Blind, Placebo-Controlled Trial (SURMOUNT-CN) 
 
NCT05024032 
 
Approval Date: 25-Aug-2021 
 
 
 
 
 
 

I8F-MC-GPIA(a) Clinical Protocol 
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LY3298176 
 
Protocol I8F-MC-GPIA(a) 
Efficacy and Safety of Tirzepatide Once Weekly in Chinese 
Participants without Type 2 Diabetes Who Have Obesity or 
are Overweight with Weight-Related Comorbidities: A 
Randomized, Double-Blind, Placebo-Controlled Trial  
(SURMOUNT-CN) 
Confidential Information 
The information contained in this document 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 
Protocol Electronically Signed and Approved by Lilly: 10 Jun 2020 
Amendment (a) Electronically Signed and Approved by Lilly on approval date provided 
below. 
 
 
Approval Date: 25-Aug-2021 GMT

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Table of Contents 
Section 
Page
Protocol I8F-MC-GPIA(a) Efficacy and Safety of Tirzepatide Once 
Weekly in Chinese Participants without Type 2 Diabetes Who Have 
Obesity or are Overweight with Weight-Related Comorbidities: A 
Randomized, Double-Blind, Placebo-Controlled Trial  
(SURMOUNT-CN) .................................................................................................................1
Table of Contents .............................................................................................................................2
1.
Synopsis ...................................................................................................................................9
2.
Schedule of Activities ............................................................................................................14
3.
Introduction ...........................................................................................................................21
3.1. 
Study Rationale ................................................................................................................21
3.2. 
Background.......................................................................................................................22
3.3. 
Benefit/Risk Assessment ..................................................................................................23
4.
Objectives and Endpoints ......................................................................................................24
5.
Study Design .........................................................................................................................27
5.1. 
Overall Design ..................................................................................................................27
5.1.1.
Overview of Study Periods ......................................................................................27
 
Visit Structure for all Office Visits ....................................................................27
 
Main Study Period ..............................................................................................28
5.1.1.2.1.
Screening Period ..........................................................................................28
5.1.1.2.2.
Treatment Period ..........................................................................................28
5.1.1.2.3.
Safety Follow-up Period ...............................................................................30
5.1.1.2.4.
Early Discontinuation Visit ..........................................................................30
5.2. 
Number of Participants .....................................................................................................30
5.3. 
End of Study Definition....................................................................................................30
5.4. 
Scientific Rationale for Study Design ..............................................................................30
5.5. 
Justification for Dose ........................................................................................................31
6.
Study Population ...................................................................................................................33
6.1. 
Inclusion Criteria ..............................................................................................................33
6.2. 
Exclusion Criteria .............................................................................................................34
6.3. 
Lifestyle Restrictions ........................................................................................................38
6.3.1.
Meals and Dietary Restrictions ................................................................................38
6.3.2.
Physical Activity ......................................................................................................39
6.4. 
Screen Failures .................................................................................................................39
7.
Treatments .............................................................................................................................40
7.1. 
Treatments Administered .................................................................................................40

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7.1.1.
Packaging and Labelling ..........................................................................................40
7.1.2.
Medical Devices .......................................................................................................40
7.2. 
Method of Treatment Assignment ....................................................................................40
7.2.1.
Selection and Timing of Doses ................................................................................40
7.3. 
Blinding ............................................................................................................................41
7.4. 
Dosage Modification ........................................................................................................41
7.4.1.
Tirzepatide ...............................................................................................................41
7.4.2.
Management of Participants with Gastrointestinal Symptoms ................................41
7.5. 
Preparation/Handling/Storage/Accountability .................................................................42
7.6. 
Treatment Compliance .....................................................................................................42
7.7. 
Concomitant Therapy .......................................................................................................43
7.8. 
Treatment after the End of the Study ...............................................................................43
8.
Discontinuation Criteria ........................................................................................................44
8.1. 
Discontinuation from Study Treatment ............................................................................44
8.1.1.
Permanent Discontinuation from Study Treatment .................................................44
8.1.2.
Temporary Discontinuation from Study Treatment .................................................45
8.1.3.
Discontinuation of Inadvertently Enrolled Participants ...........................................46
8.2. 
Discontinuation from the Study ........................................................................................46
8.2.1.
Participant disposition and timing of safety follow-up for the 
primary endpoint (52 weeks) ...................................................................................47
8.3. 
Lost to Follow-Up ............................................................................................................48
9.
Study Assessments and Procedures .......................................................................................49
9.1. 
Efficacy Assessments .......................................................................................................49
9.1.1.
Primary Efficacy Assessments .................................................................................49
9.1.2.
Secondary Efficacy Assessments .............................................................................49
9.1.3.
Patient-Reported Outcomes Assessments ................................................................49
 
Short Form 36 version 2, acute, 1 week recall version ......................................49
 
Impact of Weight on Quality of Life Lite Clinical Trials 
Version ...............................................................................................................50
 
EQ-5D-5L ...........................................................................................................50
 
Patient Global Impression of Status for Physical Activity .................................51
9.1.4.
Appropriateness of Assessments ..............................................................................51
9.2. 
Adverse Events .................................................................................................................51
9.2.1.
Serious Adverse Events ...........................................................................................52
 
Suspected Unexpected Serious Adverse Reactions ...........................................53
9.2.2.
Adverse Event Monitoring with a Systematic Questionnaire ..................................53
9.2.3.
Complaint Handling .................................................................................................54
9.2.4.
Follow-up of AEs and SAEs ....................................................................................54

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9.3. 
Treatment of Overdose .....................................................................................................55
9.4. 
Safety ................................................................................................................................55
9.4.1.
Electrocardiograms ..................................................................................................55
9.4.2.
Vital Signs ................................................................................................................55
9.4.3.
Laboratory Tests ......................................................................................................55
9.4.4.
Immunogenicity Assessments ..................................................................................56
9.4.5.
Other Tests ...............................................................................................................56
 
Physical Examinations .......................................................................................56
9.4.6.
Safety Monitoring ....................................................................................................57
 
Hepatic Safety Monitoring .................................................................................57
9.4.6.1.1.
Close Hepatic Monitoring ............................................................................57
9.4.6.1.2.
Comprehensive hepatic evaluation ...............................................................57
9.4.6.1.3.
Additional hepatic data collection (hepatic safety 
CRF) in study participants who have abnormal liver 
tests during the study ....................................................................................58
 
Depression, Suicidal Ideation, and Behavior Risk 
Monitoring ..........................................................................................................59
9.5. 
Pharmacokinetics ..............................................................................................................59
9.6. 
Pharmacodynamics ...........................................................................................................59
9.7. 
Genetics ............................................................................................................................59
9.7.1.
Whole Blood Sample[s] for Pharmacogenetic Research .........................................59
9.8. 
Biomarkers .......................................................................................................................59
9.9. 
Health Economics .............................................................................................................60
10.
Statistical Considerations ......................................................................................................61
10.1. Sample Size Determination ..............................................................................................61
10.1.1.
Statistical Hypotheses ..............................................................................................62
10.2. Populations for Analyses ..................................................................................................62
10.3. Statistical Analyses ...........................................................................................................63
10.3.1.
General Statistical Considerations ...........................................................................63
10.3.2.
Treatment Group Comparability ..............................................................................64
 
Participant Disposition .......................................................................................64
 
Participant Characteristics ..................................................................................64
 
Concomitant Therapy .........................................................................................64
 
Treatment Compliance .......................................................................................64
10.3.3.
Efficacy Analyses ....................................................................................................64
 
Primary Analyses ...............................................................................................64
 
Key Secondary Analyses ....................................................................................65
 
Tertiary/Exploratory Analyses ...........................................................................65
10.3.4.
Safety Analyses ........................................................................................................65

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Study Drug Exposure .........................................................................................65
 
Adverse Events ...................................................................................................65
 
Adverse Event of Special Interest ......................................................................66
 
Other Adverse Event Assessments .....................................................................66
10.3.4.4.1.
Gastrointestinal Events .................................................................................66
10.3.4.4.2.
Events Related to Potential Abuse Liability ................................................66
10.3.4.4.3.
Depression, Suicidal Ideation, and Behavior ...............................................66
10.3.4.4.4.
Central Laboratory Measures, Vital Signs, and 
Electrocardiograms .......................................................................................67
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses ........................................................67
10.3.6.
Evaluation of Immunogenicity .................................................................................67
10.3.7.
Other Analyses .........................................................................................................67
 
Patient Reported Outcomes ................................................................................67
 
Subgroup Analyses .............................................................................................67
10.3.8.
Interim Analyses ......................................................................................................68
11.
References .............................................................................................................................69
12.
Appendices ............................................................................................................................73

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List of Tables 
 
Table 
Page 
Table GPIA.1. 
Schedule of Activities .......................................................................................15 
Table GPIA.2. 
Objectives and Endpoints ..................................................................................24 
Table GPIA.3. 
Treatment Regimens ..........................................................................................40 
Table GPIA.4. 
Definition of population ....................................................................................62 
 
 
 

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List of Figures 
 
Figure 
Page 
Figure GPIA.1. Illustration of study design for Clinical Protocol I8F-MC-GPIA. ....................27 
Figure GPIA.2. Illustration of participant disposition and safety follow-up for Clinical 
Protocol I8F-MC-GPIA. ....................................................................................48 
 
 
 

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List of Appendices 
 
Appendix 
Page 
Appendix 1. 
Abbreviations and Definitions ...........................................................................74 
Appendix 2. 
Clinical Laboratory Tests ..................................................................................80 
Appendix 3. 
Laboratory Assessments for Hypersensitivity Events .......................................83 
Appendix 4. 
Study Governance Considerations ....................................................................85 
Appendix 5. 
Liver Safety: Suggested Actions and Follow-Up Assessments ........................89 
Appendix 6. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow up, and Reporting ..................................................................................91 
Appendix 7. 
Contraceptive Guidance and Collection of Pregnancy Information .................97 
Appendix 8. 
Protocol GPIA Standardized Protocols for the Measurement of Height, 
Weight, Waist Circumference, Vital Signs and Electrocardiogram ................100 
Appendix 9. 
Management of Gastrointestinal Symptoms ...................................................102 
Appendix 10. 
Provisions for Changes in Study Conduct During Exceptional 
Circumstances .................................................................................................103 
Appendix 11. 
Protocol Amendment [I8F-MC-GPIA(a)] Summary [Efficacy and 
Safety of Tirzepatide Once Weekly in Chinese Participants without 
Type 2 Diabetes Who Have Obesity or are Overweight with Weight-
Related Comorbidities: A Randomized, Double-Blind, Placebo-
Controlled Trial (SURMOUNT-CN)] .............................................................107 
 

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1. Synopsis 
Title of Study: 
Efficacy and Safety of Tirzepatide Once Weekly in Chinese Participants without Type 2 
Diabetes Who Have Obesity or are Overweight with Weight-Related Comorbidities:  A 
Randomized, Double Blind, Placebo Controlled Trial (SURMOUNT-CN) 
Rationale:  
Obesity is a chronic disease and its increasing prevalence is a public health concern associated 
with rising incidence of type 2 diabetes mellitus (T2DM), increased risk for premature death and 
increased risk for some cancers (Allison et al. 2008; AMA 2013; Council on Science and Public 
Health 2013).  Global Health Observatory (GHO) data showed,the number of Chinese people 
with obesity was below 0.1 million in 1975, rising to 43.2 million in 2014 and accounting for 
16.3% of global obesity (World Health Organization [WHO] 2014).  “Report on nutrition and 
chronic diseases of Chinese Residents (2015)”showed, rate of overweight (body mass index 
[BMI] ≥24 kg/m2) in adults age ≥18 years is 30.1%, and rate of obesity (BMI ≥28 kg/m2) is 
11.9%, increasing 7.3% and 4.8% compared to that in 2002, respectively.  Although loss of 5% 
to 10% body weight has been shown to reduce complications related to obesity and improve 
quality of life (Mertens and Van Gaal 2000; Knowler et al. 2002; Jensen et al. 2014; Li et al. 
2014; Warkentin et al. 2014), lifestyle therapies fail to achieve sustainable weight loss in the 
majority of patients with obesity (Dombrowski et al. 2014). 
The gut incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and 
glucagon-like peptide-1 (GLP-1), are secreted after meal ingestion and mediate the incretin 
effect.  Both hormones have effects on endocrine cells in the pancreas, increasing insulin 
biosynthesis and secretion, and modifying glucagon secretion (Skow et al. 2016).  Based on 
these properties, several GLP-1 receptor (GLP-1R) agonists have been approved for 
pharmacological treatment of T2DM (Tomlinson et al. 2016). 
In addition to its pancreatic effects, GLP-1R activation decreases gut motility, slows gastric 
emptying, and promotes satiety (presumably through a combination of GLP-1R activation in the 
central and peripheral nervous system), thereby regulating food intake and body weight (Baggio 
and Drucker 2007).  The US Food and Drug Administration (FDA) and the European Medicines 
Agency (EMA) approved the GLP-1R agonist liraglutide for the treatment of overweight and 
obesity (SAXENDA® package insert, 2014; SAXENDA® SmPc, 2015). 
Preclinical data indicate that GIP also exerts effects on appetite regulation and food intake, 
adipose tissue, and peripheral energy metabolism.  Although studies evaluating effects of GIP on 
body weight have yielded equivocal results, GIP receptor (GIPR) activation may play a role in 
body weight regulation, and targeting both the GLP-1R and the GIPR simultaneously may result 
in additive or synergistic effects of the 2 incretins on body weight (Coskun et al. 2018). 
Tirzepatide is a 39-amino acid synthetic peptide dual GIP and GLP-1 receptor agonist.  Its 
structure is based on the GIP sequence and includes a C20 fatty diacid moiety (Coskun et al. 
2018).  It is administered once weekly (QW) by subcutaneous (SC) injection. 

I8F-MC-GPIA(a) Clinical Protocol 
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As a dual GIP/GLP-1R agonist, tirzepatide could exceed the efficacy of selective GLP-1R 
analogs by recruiting metabolically active tissues not targeted by selective GLP-1R analogs (for 
example, adipose tissue as indicated by the observation of increased energy utilization) (Baggio 
and Drucker 2007) and has the potential to reach higher efficacy in target tissues, such as 
insulin-producing pancreatic beta-cells that express both GIPR and GLP-1R, before reaching its 
therapeutic limitation.  Pre-clinical studies in obese rodents demonstrate that tirzepatide-
administered animals lose more weight than animals treated with a selective GLP-1R agonist 
(GLP-1 RA).  This result appears to be due to both enhanced suppression of calorie intake and an 
increase in energy expenditure (Coskun et al. 2018). 
Phase 2 studies I8F-MC-GPGB and I8F-MC-GPGF provided initial safety, tolerability and 
efficacy data in the tirzepatide 1-to-15-mg dose range when used in treatment of patients with 
T2DM.  In the dose range of 5 to 15 mg, tirzepatide provided significantly greater reductions in 
hemoglobin A1c (HbA1c) and body weight compared with dulaglutide 1.5 mg QW.  Similar to 
the GLP-1R agonist class, most tirzepatide adverse events (AEs) were dose dependent and 
gastrointestinal (GI)-related, consisting mainly of nausea, vomiting, and diarrhea.  The majority 
of these events were transient and mild or moderate in severity.  Taking the pre-clinical and 
Phase 2 data together, combined GIP and GLP-1R stimulation with tirzepatide offers a potential 
new therapeutic option for chronic weight management (Coskun et al. 2018). 
Objective(s)/Endpoints: 
Objectives 
Endpoints 
Primary  
at 52 weeks, by dose analysis 
 
To demonstrate that tirzepatide 10 mg QW is superior 
to placebo at 52 weeks for 
• 
Percent change in body weight AND  
• 
Proportion of participants with ≥5% body 
weight reduction  
 
AND/OR 
 
To demonstrate that tirzepatide 15 mg QW is superior 
to placebo at 52 weeks for 
• 
Percent change in body weight AND  
• 
Proportion of participants with ≥5% body 
weight reduction 
 
• 
Mean percent change in body weight from 
randomization 
 
• 
Percentage of study participants who achieve 
≥5% body weight reduction from 
randomization 
 
Key Secondary (controlled for Type I error)  
at 20 weeks, by dose analysis 
 
To demonstrate that tirzepatide 10 mg and/or 15 mg 
QW are superior to placebo at 20 weeks for  
• 
Body weight 
• 
Mean change in body weight (kg) from 
randomization 

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Key Secondary (controlled for Type I error)  
at 52 weeks, by dose analysis 
 
For tirzepatide 10 mg and/or 15 mg QW doses, to 
demonstrate superiority to placebo in change from 
randomization for the following (measured at 52 
weeks, unless otherwise indicated): 
 
 
• 
Body weight  
 
• 
Percentage of participants who achieve  
o 
≥10% body weight reduction from 
randomization 
o 
≥15% body weight reduction from 
randomization 
• 
Waist circumference  
• 
Mean change in waist circumference (cm) 
from randomization 
Additional Secondary  
at 52 weeks, by dose analysis 
 
For tirzepatide 10 mg and/or 15 mg QW doses, to 
demonstrate superiority to placebo in change from 
baseline at 52 weeks for the following:  
 
 
• 
Body weight 
 
• 
Mean change in absolute body weight (kg) 
from randomization 
• 
Mean change in BMI (kg/m2) from 
randomization 
• 
Glycemic control 
• 
Mean change in HbA1c (%) from 
randomization 
• 
Mean change in fasting glucose (mmol/L) 
from randomization 
• 
Patient reported outcomes (SF-36v2 acute 
form physical functioning) 
• 
Mean change in SF-36v2 acute form physical 
functioning domain score from randomization 
• 
Patient reported outcomes (IWQOL-Lite-CT 
physical function composite) 
• 
Mean change in IWQOL-Lite-CT physical 
function composite score from randomization 
Additional Secondary  
at 52 weeks, pooled analysis 
 
For tirzepatide (10 and 15 mg combined) QW doses, to 
demonstrate superiority to placebo in change from 
baseline at 52 weeks for the following:  
 
• 
DBP 
 
• 
SBP 
 
 
• 
Mean change in DBP (mmHg) from 
randomization 
• 
Mean change in SBP (mmHg) from 
randomization 
 

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• 
Lipid parameters  
 
 
 
 
• 
Insulin 
• 
Mean change in fasting lipids (mmol/L) from 
randomization (total cholesterol, LDL 
cholesterol, HDL cholesterol, VLDL 
cholesterol, triglycerides, free fatty acids) 
 
• 
Mean change in fasting insulin from 
randomization 
 
Abbreviations:  BMI = body mass index; DBP = diastolic blood pressure; HbA1c = hemoglobin A1c; HDL = 
high-density lipoprotein; IWQOL-Lite-CT = Impact of Weight on Quality of Life-Lite-Clinical Trials; LDL = 
low-density lipoprotein; QW = once weekly; SBP = systolic blood pressure; SF-36v2 acute form = Short-Form 
36 Health Survey, version 2, acute form; VLDL = very low-density lipoprotein. 
 
Summary of Study Design: 
Study I8F-MC-GPIA(GPIA) is a Phase 3, multicenter, randomized, placebo-controlled, double-
blinded study of the safety and efficacy of 10 mg and 15 mg tirzepatide QW, compared with 
placebo for weight management when used in conjunction with a reduced-calorie diet and 
increased physical activity, in Chinese participants who do not have T2DM, and have obesity 
(BMI ≥28 kg/m2) or are overweight (BMI ≥24 kg/m2) with at least one weight related 
comorbidity.  Participants will be randomized to 52 weeks treatment to study the effects of 
tirzepatide on body weight reduction. 
Treatment Arms and Duration:   
Study participants will be randomized in a 1:1:1 ratio (tirzepatide 10 mg QW, tirzepatide 15 mg 
QW, and placebo QW), stratified by sex and presence of comorbidities (Y/N). 
All participants will undergo a 2-week screening period and a 52-week dose escalation and 
treatment period, followed by a 4-week safety follow-up period. 
Number of Subjects:  
Approximately 210 participants will be randomized in a 1:1:1 ratio to 10 mg tirzepatide (70 
participants), 15 mg tirzepatide (70 participants), and placebo (70 participants).  An upper limit 
of 70% enrollment of women will be used to ensure a sufficiently large sample of men. 
Statistical Analysis: 
Efficacy Analysis: 
The primary analysis model will be a mixed model for repeated measures (MMRM) for body 
weight percent change over time and longitudinal logistic regression for proportion of 
participants achieving at least 5% body weight reduction over time.  The response variable of 
MMRM will be the percent change in body weight from baseline values obtained at each 
scheduled post baseline visit.  The response variable of longitudinal logistic regression will be 
the proportion of participants achieving at least 5% body weight reduction at each scheduled post 
baseline visit.  The independent variables of both analysis models are treatment group 

I8F-MC-GPIA(a) Clinical Protocol 
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LY3298176 
(tirzepatide 10 mg, tirzepatide 15 mg, and placebo), visit, and treatment-by-visit interaction, 
stratification factors, and baseline body weight as a covariate.  An unstructured covariance 
structure will model relationship of within-patient errors.  The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom. 
Since the mean percent change in body weight and proportion of participants with ≥5% body 
weight reduction need to be achieved at the same time, no multiplicity adjustment is planned for 
these 2 tests. 
The primary efficacy analysis will be conducted using the data excluding data after 
discontinuation of study drug (Efficacy Analysis Set). 
Safety Analysis: 
Unless specified otherwise, safety assessments will compare safety of tirzepatide doses with 
placebo irrespective of adherence to study drug.  Thus, safety analysis will be conducted using 
Safety Analysis Set. 

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2. Schedule of Activities 
The Schedule of Activities described below should be followed for all participants enrolled in 
Study GPIA.  However, for those participants whose participation in this study is affected by 
exceptional circumstances (such as pandemics or natural disasters), please refer to Appendix 10 
for additional guidance. 
 

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LY3298176 
Table GPIA.1. 
Schedule of Activities 
Visita 
1 
2b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
99c 
EDd 
801e 
Week of Treatment 
-2 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
52 
 
4 wks Post 
TxP 
Allowable Deviation (days)f 
 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±3 
±3 
±7 
±3 
±7 
±3 
±7 
±7 
 
±7 
Fasting (>8 hours) Visita 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
  
X 
 
X 
X 
X 
X 
Telephone Visit 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Register study visit in IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Assessment 
Medical historyg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weighth 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
Waist circumference 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
Electrocardiogrami 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
Vital signs (3 sitting BP 
and HR)j 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Participant Education and Assessment 
Hand out diary, instruct in 
usek 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
Lifestyle Program 
instructionsl 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Review diet and exercise 
goalsk,m 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Injection training with 
Autoinjector 
demonstration devicek 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

I8F-MC-GPIA(a) Clinical Protocol 
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LY3298176 
Visita 
1 
2b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
99c 
EDd 
801e 
Week of Treatment 
-2 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
52 
 
4 wks Post 
TxP 
Allowable Deviation (days)f 
 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±3 
±3 
±7 
±3 
±7 
±3 
±7 
±7 
 
±7 
Fasting (>8 hours) Visita 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
  
X 
 
X 
X 
X 
X 
Telephone Visit 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
Dispense study drug 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
Observe participant 
administer study drugn 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant returns study 
drugs and injection 
supplies 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Review study participant 
diary, including study 
drug compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Laboratory Tests 
Serum pregnancy testo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testp 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Follicle-stimulating 
hormoneq 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry panel (include Cr 
for eGFR calculations and 
glucose) 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Lipid panel 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
Insulin 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
C-peptide 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Free fatty acids 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
Urinary albumin/creatinine 
ratio 
Xr 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
Cystatin-c 
Xr 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 

I8F-MC-GPIA(a) Clinical Protocol 
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Visita 
1 
2b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
99c 
EDd 
801e 
Week of Treatment 
-2 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
52 
 
4 wks Post 
TxP 
Allowable Deviation (days)f 
 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±3 
±3 
±7 
±3 
±7 
±3 
±7 
±7 
 
±7 
Fasting (>8 hours) Visita 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
  
X 
 
X 
X 
X 
X 
Telephone Visit 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
Calcitonin 
Xr 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
Hematology 
Xr 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
HbA1c 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Pancreatic amylase, lipase 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
Thyroid stimulating hormone 
Xr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity (includes PK 
sample)t, u  
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
Mental Health Questionnaires 
Patient Heath Questionnaire-
9 (PHQ-9)v 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
(Baseline/Screening 
Version)v 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
(Since Last Visit Version)v 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Self-Harm Supplement 
Formv,w 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Self-Harm Follow-up Formw 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PROsx 
Short-Form-36 Health Survey 
(SF-36), version 2, acute 
form 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 

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Visita 
1 
2b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
99c 
EDd 
801e 
Week of Treatment 
-2 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
52 
 
4 wks Post 
TxP 
Allowable Deviation (days)f 
 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±3 
±3 
±7 
±3 
±7 
±3 
±7 
±7 
 
±7 
Fasting (>8 hours) Visita 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
  
X 
 
X 
X 
X 
X 
Telephone Visit 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
Impact of Weight on Quality 
of Life-Lite for Clinical 
Trials (IWQOL-Lite-CT) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
EQ-5D-5L 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Patient Global Impression of 
Status (PGIS) for Physical 
Activity 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 

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Abbreviations:  ADA = antidrug antibodies; BP = blood pressure; CKD-EPI = Chronic Kidney Disease-Epidemiology; Cr = creatinine; C-SSRS = 
Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ED = early discontinuation; eGFR = estimated glomerular filtration rate; HbA1c = 
hemoglobin A1c; HR = heart rate; IWQoL-CT = Impact of Weight on Quality of Life-Lite for Clinical trials; IWRS = interactive web-response system; PGIS = 
Patient Global Impression of Status; PHQ-9 = Patient Health Questionnaire-9; PK = pharmacokinetics; PRO = patient-reported outcome; SF-36 = Short-Form 36 
Health Survey, version 2, acute form; TxP = treatment period; wks = weeks. 
 
a For all office visits, study participants should be reminded to report to the site in a fasting condition, after a period of approximately 8 hours without eating, 
drinking (except water), or any significant physical activity and before taking study drug(s).  Since some screening procedures need to be completed in the 
fasting state, Visit 1 may be conducted over more than 1 day to ensure necessary conditions are met. 
b Baseline assessments must be completed before processing in the IWRS. 
c Participants wanting to discontinue the study before Week 52 will be asked to return for Visit 99 at 52 weeks after randomization for the purpose of body 
weight and waist circumstance measurement, assessment of adverse events, concomitant medications, urine pregnancy test, and mental health questionnaire.  
If the participant is unwilling to attend Visit 99, it should be documented in the participant medical record that the participant has refused to attend.  
d Participants who are unable or unwilling to continue the study treatment for any reason will perform an ED visit.  If the participant is discontinuing during an 
unscheduled visit or a scheduled visit, that visit should be performed as the ED visit. 
e For participants who discontinue or complete the study within 52 weeks, Visit 801 (safety follow-up visit) should be performed 4 weeks after the last visit 
during the 52-week treatment period. 
f 
The visit date is determined in relation to the date of the randomization visit (± the allowed visit window). 
g Medical history includes assessment of preexisting conditions (including history of gall bladder disease, cardiovascular disease, and medullary thyroid 
carcinoma) and substance usage (such as alcohol and tobacco). 
h Weight measurements should be obtained per the instructions in Appendix 8.  Body weight must be measured in fasting state.  If the participant is not fasting, 
the participant should be called in for a new visit within the visit window to have the fasting body weight measured.  
i 
ECG should be collected at least 30 minutes prior to collection of blood samples for laboratory testing, including PK samples. 
j 
Vital sign measurements should be taken before obtaining an ECG tracing and before collection of blood samples for laboratory testing, per the instructions in 
Appendix 8. 
k All training should be repeated as needed to ensure participant compliance. 
l 
Counselling on diet and exercise, to be performed by a dietician or equivalent qualified delegate, to include calculation of individualized energy requirement 
and methods to change dietary composition and amount of physical activity.  The Lifestyle Program Instruction may be delivered on a separate day from the 
rest of that visit’s study procedures but must occur within the visit window.  Beginning at Week 8, the Lifestyle Program Instruction may be delivered by 
phone. 
m Study personnel to provide reinforcement and encouragement for lifestyle modifications. 
n Participants should administer their first dose of study drug on site at the end of the Visit 2, after other study procedures are completed. 
o A serum pregnancy test will be performed at Visit 1 for women of childbearing potential only. 
p A urine pregnancy test must be performed for all female participants at Visit 2.  The result should be available prior to the first injection of study drug(s) for 
women of childbearing potential only. Additional pregnancy tests (beyond those required per the Schedule of Activities) should be performed at any time 
during the trial if a menstrual period is missed, there is clinical suspicion of pregnancy, or as required by local law or regulation. For sites who can’t perform 
urine pregnancy test, a local serum pregnancy test can be performed instead. 
q Follicle-stimulating hormone test performed at Visit 1 for postmenopausal women at least 40 years of age with an intact uterus, not on hormone therapy, and 
who have had spontaneous amenorrhea for at least 12 months without an alternative medical cause. 

I8F-MC-GPIA(a) Clinical Protocol 
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r 
Screening visit assessment will be used to confirm eligibility. If calcitonin results are not available, a final review of eligibility will occur at Visit 2 before 
randomization can proceed. 
s 
The CKD-EPI equation will be used by the central lab to estimate and report eGFR. 
t 
In the event of systemic drug hypersensitivity reactions (immediate or non-immediate), additional unscheduled blood and urine samples will be collected as 
detailed in Appendix 6. 
u PK and ADA samples for immunogenicity must be taken prior to drug administration. 
v The C-SSRS, Self-Harm Supplement Form and PHQ-9 should be administered after assessment of adverse events.  For this study, the C-SSRS is adapted for 
the assessment of the ideation and behavior categories only.  The Intensity of Ideation and Lethality of Behavior sections are removed.  The C-SSRS 
questionnaire will be completed by investigators, while PHQ-9 will be completed by participants.  The Self-Harm Supplement Form is only required if 
responses to the C-SSRS indicate that the patient needs to be further evaluated for self-harm risk. 
w Self-Harm Follow-up Form is only required if triggered by the Self-Harm Supplement Form, per instructions in the form. Self-Harm forms will be completed 
by investigators. 
x All PROs should be completed before any other study procedures if the participant is not adversely affected by the fasting condition or completed after the 
participant has sufficiently recovered from the preceding visit procedures. 
 

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3. Introduction 
Obesity is a chronic disease and its increasing prevalence is a public health concern associated 
with rising incidence of type 2 diabetes mellitus (T2DM), increased risk for premature death and 
increased risk for some cancers (Allison et al. 2008; AMA 2013; Council on Science and Public 
Health 2013).  Although loss of 5% to 10% body weight has been shown to reduce complications 
related to obesity and improve quality of life (Mertens and Van Gaal 2000; Knowler et al. 2002; 
Jensen et al. 2014; Li et al. 2014; Warkentin et al. 2014), lifestyle therapies fail to achieve 
sustainable weight loss in the majority of patients with obesity (Dombrowski et al. 2014). 
3.1. Study Rationale 
The gut incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and 
glucagon-like peptide-1 (GLP-1), are secreted after meal ingestion and mediate the incretin 
effect.  Both hormones have effects on endocrine cells in pancreas, increasing insulin 
biosynthesis and secretion, stimulating beta-cell neogenesis and proliferation, and protecting beta 
cells from apoptosis.  They also exert actions on alpha cells, modifying glucagon secretion 
(Skow et al. 2016).  Based on these properties, several GLP-1 receptor (GLP-1R) agonists have 
been approved for pharmacological treatment of T2DM (Tomlinson et al. 2016). 
In addition to its pancreatic effects, GLP-1R activation decreases gut motility, slows gastric 
emptying, and promotes satiety (presumably through a combination of GLP-1R activation in the 
central and peripheral nervous system), thereby regulating food intake and body weight (Baggio 
and Drucker 2007).  The US Food and Drug Administration (FDA) and the European Medicines 
Agency (EMA) approved the GLP-1R agonist liraglutide for the treatment of overweight and 
obesity (SAXENDA® package insert, 2014; SAXENDA® SmPc, 2015). 
Preclinical data indicate that GIP exerts effects on appetite regulation and food intake, on 
adipose tissue and on peripheral energy metabolism.  Although studies evaluating effects of GIP 
on body weight have yielded equivocal results, GIP receptor (GIPR) activation may play a role 
in body weight regulation, and targeting both the GLP-1R and the GIPR simultaneously may 
result in additive or synergistic effects of the 2 incretins on body weight (Coskun et al. 2018). 
Tirzepatide is a 39-amino acid synthetic peptide with agonist activity at both the GIPR and 
GLP-1R.  Its structure is based on the GIP sequence and includes a C20 fatty di-acid moiety 
(Coskun et al. 2018).  It is administered once weekly (QW) by subcutaneous (SC) injection.  
As a dual GIP/GLP-1R agonist, tirzepatide could exceed the efficacy of selective GLP-1R 
analogs by recruiting metabolically active tissues not targeted by selective GLP-1R analogs (for 
example, adipose tissue as indicated by the observation of increased energy utilization) (Baggio 
and Drucker 2007) and has the potential to reach higher efficacy in target tissues, such as 
insulin-producing pancreatic beta-cells that express both GIPR and GLP-1R, before reaching its 
therapeutic limitation. 
In a 26-week Phase 2 study (I8F-MC-GPGB) of participants with T2DM, tirzepatide reduced 
body weight by 4.8 kg, 8.7 kg, and 11.3 kg at dose levels of 5, 10, and 15 mg, respectively, 

I8F-MC-GPIA(a) Clinical Protocol 
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whereas the weight loss observed in participants on dulaglutide, a selective GLP-1R agonist, 
used at the dose of 1.5 mg, was 2.7 kg (Frias et al. 2018). Similar to the GLP-1R agonist class, 
most of the tirzepatide adverse events (AEs) were dose dependent and gastrointestinal 
(GI)-related, consisting mainly of nausea, vomiting, and diarrhea.  The majority of these events 
were transient and mild or moderate in severity. 
Taking the preclinical and Phase 2 data together, combined GIP and GLP-1R stimulation with 
tirzepatide offers a potential new therapeutic option for chronic weight management (Coskun et 
al. 2018). 
Study I8F-MC-GPIA(GPIA) is a Phase 3, multicenter, randomized, placebo-controlled, double-
blinded study of the safety and efficacy of 10 mg and 15 mg tirzepatide QW, compared with 
placebo for weight management when used in conjunction with a reduced-calorie diet and 
increased physical activity, in Chinese participants who do not have T2DM, and have obesity 
(body mass index [BMI] ≥28 kg/m2) or are overweight (BMI ≥24 kg/m2) with at least one weight 
related comorbidity.  Participants will be randomized to 52 weeks treatment to study the effects 
on body weight reduction. 
3.2. Background 
Despite the extraordinarily adverse impact of overweight and obesity on patients and the 
healthcare system, there is a paucity of approved pharmacologic interventions to aid the 
treatment of obesity.  Only orlistat, a drug that blocks absorption of dietary fat, is approved in 
China as over-the-counter drug (Kim et al. 2014; Pilitsi et al. 2019).  Currently, bariatric surgery 
is considered as the most potent clinical intervention for weight management.  However, 
bariatric surgery has risks, including periprocedural complications.  For some individuals who 
have obesity/overweight, pharmacological management could be a preferred option.  In addition, 
bariatric surgery does not exclude pharmacological intervention before or after the intervention.  
Thus, there remains an unmet need in the pharmacologic treatment of obesity for drugs that are 
safe, efficacious and well tolerated. (Livingston et al. 2010) 
As a dual agonist, tirzepatide binds both GIP and GLP-1 receptors and combines the signaling of 
each receptor.  Preclinical studies in obese rodents demonstrate that tirzepatide-administered 
animals lose more weight than animals treated with a selective GLP-1 RA.  This result appears to 
be due to both enhanced suppression of calorie intake and an increase in energy expenditure 
(Coskun et al. 2018).  Tirzepatide has been associated with significant dose-dependent weight 
loss at both the 10 and 15 mg doses in Phase 2 studies (Frias et al. 2018). 
Dose selection for obesity treatment has been informed by 3 clinical trials:  a Phase 1 study, 
Study I8F-MC-GPGA (GPGA), and two Phase 2 studies, Study I8F-MC-GPGB (GPGB) and 
I8F-MC-GPGF (GPGF). 
Phase 1 Study GPGA was a combination of single ascending dose (SAD) and multiple ascending 
dose (MAD) studies in healthy subjects and a multiple dose study in patients with T2DM.  A 
total of 142 participants (89 healthy subjects and 53 patients with T2DM) received at least 1 dose 
of treatment.  Doses of tirzepatide ranged from: 

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 
0.25 mg to 8 mg in the SAD (with maximum tolerated dose achieved at 5 mg) 
 
multiple doses from 0.5 mg to 4.5 mg QW and titrated doses up to 10 mg QW for 4 
weeks in healthy subjects 
 
multiples doses at 0.5 mg and 5 mg QW and titrated to 15 mg QW for 4 weeks in 
patients with T2DM in the MAD 
The safety and tolerability and pharmacokinetic/pharmacodynamic (PK/PD) profiles of 
tirzepatide at doses and escalation regimens administered in this Phase 1 study supported further 
development of tirzepatide for QW dosing in patients with T2DM. 
Phase 2 studies I8F-MC-GPGB (GPGB) and I8F-MC-GPGF (GPGF) provided initial safety, 
tolerability and efficacy data for tirzepatide 10 mg and 15 mg when used in treatment of patients 
with T2DM.  Tirzepatide 10 mg and 15 mg provided significantly greater reductions in HbA1c 
and body weight compared with dulaglutide 1.5 mg QW.  The most common AEs, which were 
also dose dependent, were mild to moderate nausea, vomiting, and diarrhea.  Study GPGF 
showed that adjustments in the tirzepatide dose-escalation algorithm resulted in additional 
reductions in the frequency of GI AEs and reduced the frequency of treatment discontinuations 
due to GI AEs. 
3.3. Benefit/Risk Assessment 
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). 

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4. Objectives and Endpoints 
Table GPIA.2. shows the objectives and endpoints of the study. 
Table GPIA.2. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary  
at 52 weeks, by dose analysis 
 
To demonstrate that tirzepatide 10 mg QW is superior 
to placebo at 52 weeks for  
• 
Percent change in body weight AND  
• 
Proportion of participants with ≥5% body 
weight reduction  
 
AND/OR 
 
To demonstrate that tirzepatide 15 mg QW is superior 
to placebo at 52 weeks for  
• 
Percent change in body weight AND  
• 
Proportion of participants with ≥5% body 
weight reduction   
 
• 
Mean percent change in body weight from 
randomization 
 
• 
Percentage of study participants who achieve 
≥5% body weight reduction from 
randomization   
 
Key Secondary (controlled for Type I error)  
at 20 weeks, by dose analysis 
 
To demonstrate that tirzepatide 10 mg and/or 15 mg 
QW are superior to placebo at 20 weeks for  
• 
Body weight 
• 
Mean change in body weight (kg) from 
randomization 
Key Secondary (controlled for Type I error)  
at 52 weeks, by dose analysis 
 
For tirzepatide 10 mg and/or 15 mg QW doses, to 
demonstrate superiority to placebo in change from 
randomization for the following (measured at 52 
weeks, unless otherwise indicated):  
 
 
• 
Body weight  
 
• 
Percentage of participants who achieve  
o 
≥10% body weight reduction from 
randomization 
o 
≥15% body weight reduction from 
randomization 
• 
Waist circumference  
• 
Mean change in waist circumference (cm) 
from randomization 

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Additional Secondary  
at 52 weeks, by dose analysis 
 
For tirzepatide 10 mg and/or 15 mg QW doses, to 
demonstrate superiority to placebo in change from 
baseline at 52 weeks for the following:  
 
 
• 
Body weight 
 
• 
Mean change in absolute body weight (kg) 
from randomization  
• 
Mean change in BMI (kg/m2) from 
randomization 
• 
Glycemic control 
• 
Mean change in HbA1c (%) from 
randomization 
• 
Mean change in fasting glucose (mmol/L) 
from randomization 
• 
Patient reported outcomes (SF-36v2 acute 
form physical functioning) 
• 
Mean change in SF-36v2 acute form physical 
functioning domain score from randomization 
• 
Patient reported outcomes (IWQOL-Lite-CT 
physical function composite) 
• 
Mean change in IWQOL-Lite-CT physical 
function composite score from randomization 
Additional Secondary  
at 52 weeks, pooled analysis 
 
For tirzepatide (10 and 15 mg combined) QW doses, to 
demonstrate superiority to placebo in change from 
baseline at 52 weeks for the following:  
 
 
• 
DBP 
 
• 
SBP 
 
 
• 
Lipid parameters 
 
 
• 
Insulin 
• 
Mean change in DBP (mmHg) from 
randomization 
• 
Mean change in SBP (mmHg) from 
randomization 
 
• 
Mean change in fasting lipids (mmol/L) from 
randomization (total cholesterol, LDL 
cholesterol, HDL cholesterol, VLDL 
cholesterol, triglycerides, free fatty acids) 
 
• 
Mean change in fasting insulin from 
randomization 
 
Tertiary/Exploratory  
 
To assess changes from baseline in patient-reported 
outcomes: 
Mean change from randomization to week 52 regarding 
the following parameters:  
• 
SF-36v2 acute form Mental Component 
Score (MCS) 

I8F-MC-GPIA(a) Clinical Protocol 
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LY3298176 
• 
To assess changes from baseline in health-
related quality of life as measured by the SF-
36v2 acute form 
• 
To assess changes from baseline in obesity-
related quality of life as measured by the 
IWQOL-Lite-CT  
• 
To assess changes from baseline in health 
status as measured by the EQ-5D-5L 
 
• 
SF-36v2 acute form Physical Component 
Score (PCS) 
• 
SF-36v2 acute form Role-Physical domain 
(RP) 
• 
SF-36v2 acute form Bodily Pain domain 
(BP) 
• 
SF-36v2 acute form General Health domain 
(GH) 
• 
SF-36v2 acute form Vitality domain (VT) 
• 
SF-36v2 acute form Social Functioning 
domain (SF) 
• 
SF-36v2 acute form Role-Emotional domain 
(RE) 
• 
SF-36v2 acute form Mental Health domain 
(MH) 
• 
IWQOL-Lite-CT total score  
• 
IWQOL-Lite-CT Physical composite score  
• 
IWQOL-Lite-CT Psychosocial composite 
score 
• 
EQ-5D-5L utility score 
• 
EQ-5D-5L VAS score 
 
Pharmacokinetics 
• 
To characterize the PK of tirzepatide 10 mg 
and 15 mg QW and evaluate the relationship 
between tirzepatide exposure and safety, 
tolerability, and efficacy measures. 
 
 
• 
Population PK and PD parameters 
Abbreviations: BMI = body mass index; BP = Bodily Pain domain; GH = General Health domain; HbA1c = 
hemoglobin A1c; HDL = high-density lipoprotein; IWQOL-Lite-CT = Impact of Weight on Quality of Life-Lite 
for Clinical trials; LDL = low-density lipoprotein; MCS = Mental Component Score; MH = Mental Health 
domain; PCS = Physical Component Score; PD = pharmacodynamics; PK = pharmacokinetics; QW = once 
weekly; RE = Role-Emotional domain; RP = Role-Physical domain; SBP = systolic blood pressure; SF = Social 
Functioning domain; SF-36v2 acute form = Short-Form-36 Health Survey, version 2, acute form; VAS = visual 
analogue scale; VLDL = very low-density lipoprotein; VT = Vitality domain. 

I8F-MC-GPIA(a) Clinical Protocol
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5. Study Design 
5.1. Overall Design 
Study GPIA is a Phase 3, multicenter, randomized, double-blinded, placebo-controlled study that 
will investigate the effects of treatment with tirzepatide 10 mg and 15 mg QW compared with
placebo on weight loss in Chinese participants without T2DM who either have obesity (BMI ≥28 
kg/m2) or overweight (BMI ≥24 kg/m2 ) with the presence of at least one weight-related 
comorbidity.  The co-primary endpoints will be mean percent change in body weight and 
proportion of participants reaching ≥5% total body weight loss, measured from randomization to 
Week 52. 
Study participants will be randomized in a 1:1:1 ratio (tirzepatide 10 mg QW, tirzepatide 15 mg 
QW, and placebo).  An upper limit of 70% enrollment of women will be used to ensure a 
sufficiently large sample of men. 
All participants will undergo a 2-week screening period and a 52-week dose escalation and 
treatment period, followed by a 4-week safety follow-up period. 
Figure GPIA.1. illustrates the study design.
Abbreviations:  QW=once weekly; T = telephone visit. 
Figure GPIA.1. 
Illustration of study design for Clinical Protocol I8F-MC-GPIA. 
5.1.1. Overview of Study Periods 
 Visit Structure for all Office Visits 
On all designated fasting office visits, study participants are required to report to the site in a 
fasting condition, after approximately 8 hours without eating, drinking (except water), or 
performing any significant physical activity.  If a participant is adversely affected by the fasting 
condition, they are allowed to eat, however, specific study procedures need to be completed 
while fasting. 

I8F-MC-GPIA(a) Clinical Protocol
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 Main Study Period  
5.1.1.2.1. Screening Period 
Visit 1 
The purpose of screening procedures at Visit 1 is to establish initial eligibility, and to obtain 
blood samples for laboratory assessments needed to confirm eligibility.  Participants should 
arrive to the clinic in the fasting state (after approximately 8 hours without eating, drinking 
[except water], or any significant physical activity).  The participant must sign the informed 
consent form (ICF) before the study procedures are performed, as outlined in the Schedule of 
Activities, Section 2.  Visit 1 may be conducted over more than 1 day to ensure necessary 
conditions are met.  Participants who meet all applicable inclusion criteria and none of the 
applicable exclusion criteria (Sections 6.1 and 6.2) at Visit 1 will continue to Visit 2.  
5.1.1.2.2. Treatment Period 
Randomization (Visit 2) 
At Visit 2, eligible participants will perform all required baseline study procedures (including the 
collection of all baseline laboratory measures and questionnaires) prior to randomization and 
prior to taking the first dose of study drug.  Participants should arrive to the clinic in the fasting 
state (after a period of approximately 8 hours without eating, drinking [except water], or any 
significant physical activity and before taking study drug(s)).  The mental health questionnaires 
(Patient Heath Questionnaire-9 [PHQ-9], Columbia-Suicide Severity Rating Scale [C-SSRS], 
and Self-Harm Form) should be completed after the assessment for AEs. 
Participants will receive an initial consultation with a qualified dietitian, according to local 
standards, to set lifestyle goals for caloric intake and physical activity (Sections 6.3.1 and 6.3.2). 
Following randomization, study site personnel will demonstrate use of the autoinjector and 
observe the study participant inject the first dose of tirzepatide or placebo.  The date and time of 
the first dose of study drug will be recorded on the electronic case report form (eCRF).  
Beginning at randomization, all participants will receive study drug according to the randomized 
treatment arm for the duration of the 52-week dose escalation and treatment period. 
Treatment Period (End of Visit 2 to Visit 15): 
During the treatment period, visits will occur every 4 weeks through 52 weeks.  The participant 
should be fasting for all office visits.  Weeks 28, 32, 40 and 48 are telephone visits. 
Office visit procedures should be conducted according to the Schedule of Activities (Section 2), 
and will include 
• weight, waist circumference, and vital signs measurements  
• review of participant diary information (to include reinforcement and compliance 
assessments for study drug administration and lifestyle goals) 
• administration of questionnaires  
• laboratory testing  
• drug dispensing, and 

I8F-MC-GPIA(a) Clinical Protocol 
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• collect AEs and concomitant medications.   
Patient-Reported Outcomes (PROs) questionnaires should be administered as early as possible, 
prior to any other study procedures.  All PROs should be completed before any other study 
procedures if the participant is not adversely affected by the fasting condition or completed after 
the participant has sufficiently recovered from the preceding visit procedures.  Mental Health 
Questionnaires should be completed after the assessment of AEs. 
Dietitian consultations start at Week 0 and continue at Weeks 4, 8, 12, 24, 36, 44, 52 and early 
discontinuation (ED).  Study drug and injection supplies will be returned per the Schedule of 
Activities (Section 2) and according to local requirements.  New supplies will be dispensed as 
needed. 
Study drug dose escalation is double-blinded and will be managed via the interactive 
web-response system (IWRS).  The starting dose is 2.5 mg QW (or matching placebo) for 4 
weeks, then the dose is increased by 2.5 mg (or matching placebo) every 4 weeks (2.5 to 5 to 7.5 
to 10 mg) for those randomized to 10 mg, continuing to 12.5 to 15 mg for those randomized to 
15 mg.  The dose is then maintained for the remainder of the study. 
At each of the 4 scheduled telephone visits, procedures will include: 
• reinforcement and compliance assessments for study drug administration and lifestyle 
goals  
• listing of concomitant medications  
• 
AE assessment (see Schedule of Activities Section 2), and  
• 
completion of the mental health questionnaires (after the AE assessment). 
Participants should be instructed to contact the investigative site for assistance as soon as 
possible if they experience any difficulties administering their study medication.  Participants 
should also be advised about the appropriate course of action in the event that study drug is not 
taken at the required time (late/missing doses). 
Study participants will be permitted to use concomitant medications that they require during the 
study, except certain excluded medications (see Section 6.2) that may interfere with the 
assessment of efficacy and safety characteristics of the study treatments. 
Visit 99 
Visit 99 is only applicable to participants who discontinue the study treatment prematurely 
before 52 weeks and decline to complete the remaining study visits but are willing to return for 
Visit 99 at 52 weeks after randomization.  This visit is critical to ensure complete data collection 
for the primary weight loss endpoint. 
Participants should attend this visit in the fasting state.  Procedures to be completed are: 
• measurement of weight and waist circumference 
• listing of concomitant medications 
• urine pregnancy test 

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• assessment of AEs, and  
• completion of the mental health questionnaires (after the AE assessment) 
For participants unwilling to attend this visit, their refusal to attend should be documented in the 
participant medical record. 
5.1.1.2.3. Safety Follow-up Period 
Visit 801 
All participants are required to complete Visit 801, a safety follow-up visit.  Participants 
discontinuing the study early and performing an early discontinuation (ED) visit will also be 
asked to perform the safety follow-up visit.  During the safety follow-up period, participants will 
not receive study drug.  Participants are also required to return any remaining study diaries to the 
study site at the end of this period. 
For participants who discontinue or complete the study within the first 52 weeks, Visit 801 
(safety follow-up visit) should be performed 4 weeks after the last treatment visit (Visit 99 or 15, 
respectively) or 4 weeks after the ED visit for those who decline to return for Visit 99. 
5.1.1.2.4. Early Discontinuation Visit 
Participants unable or unwilling to continue the study treatment for any reason will perform an 
ED visit.  Procedures should be completed according to the Schedule of Activities (Section 2).  
Patient-reported outcomes questionnaires should be completed as early as possible, prior to other 
study procedures.  Administration of Mental Health Questionnaires should follow assessment for 
AEs (see Section 8.2). 
5.2. Number of Participants 
Approximately 210 participants will be randomized in a 1:1:1 ratio to 10 mg tirzepatide (70 
participants), 15 mg tirzepatide (70 participants), and placebo (70 participants). 
5.3. End of Study Definition 
Section 8.2 describes the criteria used to determine if a participant has completed the study. 
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the Schedule of Activities (Section 2). 
5.4. Scientific Rationale for Study Design 
Tirzepatide is a 39-amino acid synthetic peptide with agonist activity at both the GIPR and 
GLP-1R.  Its structure is based on the GIP sequence and includes a C20 fatty di-acid moiety 
(Coskun et al. 2018).  It is administered QW by SC injection.  
As a dual GIP/GLP-1R agonist, tirzepatide could exceed the efficacy of selective GLP-1R 
agonists by recruiting metabolically active tissues not targeted by selective GLP-1R agonists (for 
example, adipose tissue as indicated by the observation of increased energy utilization) (Baggio 
and Drucker 2007) and has the potential to reach higher efficacy in target tissues, such as 
insulin-producing pancreatic beta-cells that express both GIPR and GLP-1R, before reaching its 

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therapeutic limitation.  Results from a Phase 2 study (GPGB) demonstrated that tirzepatide use in 
participants with T2DM was associated with a substantial, dose-dependent weight loss, greater 
than the weight change observed with dulaglutide, a specific GLP1R agonist.  General safety 
characteristics of all studied doses of tirzepatide were similar to that of the GLP-1R agonist class, 
consisting mainly of nausea, vomiting, and diarrhea.  In general, these events were transient and 
mild or moderate in severity, with few severe episodes.  Although GI AEs were more common at 
15-mg arm of tirzepatide, the dose demonstrated the highest efficacy in terms of weight loss.  
This suggests that tirzepatide has the potential to become a medication for chronic weight 
management.  An optimized dose escalation regimen being used in global Phase 3 studies for 
both diabetes and chronic weight management, and being proposed in the study GPIA to 
improve tolerability should enable a use of higher doses to maximize effects on body weight. 
Study GPIA is designed to determine the comparative benefits and risks of tirzepatide 10 mg or 
15 mg QW versus placebo in Chinese participants who have obesity or overweight.  A 
double-blinded design was selected to minimize participant and investigator bias in assessments 
for efficacy, safety, and study drug tolerability. 
A placebo comparator was selected for this trial in accordance with regulatory guidance (FDA 
2007; EMA 2016).  In addition, all participants, regardless of treatment assignment, will receive 
lifestyle modification counselling consistent with current guidelines for weight management 
(Jensen et al. 2013).  Specifically, participants will consult with a dietitian, or equivalent 
qualified delegate, throughout the study to achieve at least a 500 kcal/day energy deficit through 
a combination of caloric restriction and increased physical activity (see Section 6.3).  
The planned duration of treatment for the primary endpoint at 52 weeks allows for a 40-week 
treatment period at the dose achieved 10 mg and 32-week treatment period at the dose achieved 
15 mg following dose escalation.  This duration is considered appropriate to assess the full 
effects and benefit/risk of each maintenance dose of tirzepatide compared with placebo on body 
weight.   
The effects of drug cessation will be assessed in the 4-week safety follow-up/observational 
period. 
To minimize the potential confounding effect of changes to concomitant medications, 
participants will be permitted to use concomitant medications that do not interfere with the 
assessment of efficacy or safety characteristics of the study treatments. 
5.5. Justification for Dose 
Tirzepatide doses of 10 mg, and 15 mg QW will be evaluated in this study.  These doses and 
associated escalation schemes were selected based on assessment of safety, efficacy (weight 
loss), and GI tolerability data, followed by exposure-response modeling of data in patients in 
Phase 1 and 2 studies.  
In a 26-week Phase 2 study (GPGB) of participants with T2DM, tirzepatide reduced body weight 
by 8.7 kg, and 11.3 kg at dose levels of 10, and 15 mg, respectively, whereas the weight loss 

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observed in participants on dulaglutide, a selective GLP-1R agonist, used at the dose of 1.5 mg, 
was 2.7 kg (Frias et al. 2018).   
Similar to the GLP-1R agonist class, most of the tirzepatide AEs were dose dependent and 
GI-related, consisting mainly of nausea, vomiting, and diarrhea.  In general, these events were 
mild or moderate in severity, with few severe episodes, and transient.  
Tirzepatide doses of 10 mg, and 15 mg were selected based principally on the following criteria 
• each dose provides robust weight loss relative to placebo 
• the percent of patients achieving >10% weight loss is higher with 15 mg than 10 mg, and  
• safety and tolerability were supported by Phase 2 results and/or PK/PD modeling. 
A subsequent Phase 2 study (GPGF) evaluating different titration schemes demonstrated that 
slower dose escalation and smaller dose increments might improve tolerability.  Dosing 
algorithms starting at a low dose of 2.5 mg accompanied by dose escalation of 2.5 mg increments 
every 4 weeks should permit time for development of tolerance to GI events and are predicted to 
minimize GI tolerability concerns. The maximum proposed dose of 15 mg maintains 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.

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6. Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
6.1. Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Type of Participant and Disease Characteristics 
1. Have a BMI 
• ≥28 kg/m2 or 
• ≥24 kg/m2 and previously diagnosed with at least one of the following weight 
related comorbidities: 
o Hypertension:  treated or with systolic blood pressure (SBP) ≥130 
mm Hg or diastolic blood pressure ≥80 mm Hg 
o Dyslipidemia:  treated or with low-density lipoprotein (LDL) ≥4.1 
mmol/L (160 mg/dL) or triglycerides ≥1.7 mmol/L (150 mg/dL), or 
high-density lipoprotein (HDL) <1.0 mmol/L (40 mg/dL) for men or 
HDL<1.3 mmol/L (50 mg/dL) for women 
o Obstructive sleep apnea 
o Cardiovascular disease (for example, ischemic cardiovascular disease, 
New York Heart Association [NYHA] Functional Class I-III heart 
failure) 
2. Have a history of at least one self-reported unsuccessful dietary effort to lose body 
weight 
3. In the investigator’s opinion, are well-motivated, capable, and willing to  
• learn how to self-inject study drug, as required for this protocol (visually impaired 
persons who are not able to perform the injections must have the assistance of a 
sighted individual trained to inject the study drug; persons with physical limitations 
who are not able to perform the injections must have the assistance of an individual 
trained to inject the study drug) 
• inject study drug (or receive an injection from a trained individual if visually 
impaired or with physical limitations) 
• follow study procedures for the duration of the study, including, but not limited to: 
follow lifestyle advice (for example, dietary restrictions and exercise plan), maintain 
a study diary, and complete required questionnaires 
Participant Characteristics 
4. Are 18 years or older 
a. Male participants: 

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• Male participants with partners of childbearing potential should be willing 
to use reliable contraceptive methods throughout the study and for 4 
months after the last injection. 
b. Female participants: 
• Female participants 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  
o postmenopausal, defined as either  
 a woman at least 40 years of age with an intact uterus, not 
on hormone therapy, who has cessation of menses for at 
least 1 year without an alternative medical cause, AND a 
follicle-stimulating hormone ≥40 mIU/mL; women in this 
category must test negative in pregnancy test prior to study 
entry  
or 
 a woman 55 or older not on hormone therapy, who has had 
at least 12 months of spontaneous amenorrhea 
or 
 a woman at least 55 years of age with a diagnosis of 
menopause prior to starting hormone replacement therapy 
• Female participants of child-bearing potential (not surgically sterilized and 
between menarche and 1-year postmenopausal) must: 
 test negative for pregnancy at Visit 1 based on a serum 
pregnancy test 
AND 
 if sexually active, agree to use 2 forms of effective 
contraception, where at least 1 form is highly effective, for the 
duration of the trial and for 30 days thereafter (Appendix 7) 
 not be breastfeeding 
Informed Consent 
5. Have given written informed consent to participate in this study in accordance with 
local regulations and the ethical review board (ERB) governing the study site  
6.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 

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Medical Conditions 
Diabetes-related 
6. Have type 1 diabetes mellitus (T1DM) or T2DM, history of ketoacidosis, or hyperosmolar 
state/coma 
7. Have HbA1c ≥6.5% or fasting serum glucose (FSG) ≥7.0 mmol/L, as determined by the 
central laboratory at Visit 1 
Obesity-related 
8. Have a self-reported change in body weight >5 kg within 3 months prior to screening 
9. Have a prior or planned surgical treatment for obesity (excluding liposuction or 
abdominoplasty if performed >1 year prior to screening) 
10. Have or plan to have endoscopic and/or device-based therapy for obesity or have had 
removal within the last 6 months (for example, mucosal ablation, gastric artery 
embolization, intragastric balloon and duodenal-jejunal endoluminal barrier) 
Other medical 
11. Have renal impairment measured as estimated glomerular filtration rate (eGFR) <30 
mL/min/1.73 m2, calculated by Chronic Kidney Disease-Epidemiology as determined by 
central laboratory during screening 
12. Have a known clinically significant gastric emptying abnormality (for example, severe 
gastroparesis or gastric outlet obstruction) or chronically take drugs that directly affect GI 
motility 
13. Have had a history of chronic or acute pancreatitis  
14. Have a thyroid stimulating hormone (TSH) <0.4 or >6.0 mIU/L at screening visit  
Note:  Participants receiving treatment for hypothyroidism may be included, provided their 
thyroid hormone replacement dose has been stable for at least 3 months. 
Note:  TSH values above the normal range can, in some participants, suggest subclinical 
hypothyroidism.  If, in the investigator’s opinion, the participant has subclinical 
hypothyroidism and may require initiation of thyroid hormone replacement during the 
course of the study, the participant should be excluded from the study.  
15. Have obesity induced by other endocrinologic disorders (for example, Cushing syndrome) 
or diagnosed monogenetic or syndromic forms of obesity (for example, Melanocortin 4 
Receptor deficiency or Prader Willi Syndrome) 
16. Have a history of significant active or unstable Major Depressive Disorder (MDD) or other 
severe psychiatric disorder (for example schizophrenia, bipolar disorder, or other serious 
mood or anxiety disorder) within the last 2 years 

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Note: Participants with MDD or generalized anxiety disorder whose disease state is 
considered stable and expected to remain stable throughout the course of the study, in the 
opinion of the investigator, may be considered for inclusion if they are not on excluded 
medications 
17. Have any lifetime history of a suicidal attempt 
18. Have a PHQ-9 score of 15 or more at Visit 1 or 2, prior to randomization.  
19. On the C-SSRS at Visits 1 or 2, prior to randomization:  
o answered "yes" to Question 4 or Question 5 on the "Suicidal Ideation" portion of the 
C-SSRS, or 
o answered "yes" to any of the suicide-related behaviors on the Suicidal Behavior 
portion of the C-SSRS. 
and  
o the ideation or behavior occurred within the past month  
20. Have uncontrolled hypertension (systolic blood pressure above or equal to 160 mmHg 
and/or diastolic blood pressure above or equal to 100 mmHg) 
21. Have any of the following cardiovascular conditions within 3 months prior to 
randomization: acute myocardial infarction, cerebrovascular accident (stroke), unstable 
angina, or hospitalization due to congestive heart failure (CHF) 
22. Have NYHA Functional Classification IV CHF 
23. Have acute or chronic hepatitis, signs and symptoms of any other liver disease other than 
nonalcoholic fatty liver disease, or any of the following, as determined by the central 
laboratory during screening: 
o Alanine aminotransferase (ALT) level >3.0x the upper limit of normal (ULN) for the 
reference range 
or 
o Alkaline phosphatase (ALP) level >1.5x the ULN for the reference range 
or 
o Total bilirubin (TBL) level >1.2x the ULN for the reference range (except for cases 
of known Gilbert’s Syndrome) 
Note:  Participants with nonalcoholic fatty liver disease (NAFLD) are eligible to participate in 
this trial if their ALT level is ≤3.0x ULN for the reference range.   
24. Have a calcitonin level (at Visit 1) of: 
o ≥20 ng/L at Visit 1, if eGFR ≥60 mL/min/1.73 m2 
o  ≥35 ng/L at Visit 1, if eGFR <60 mL/min/1.73 m2 

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25. Have a family or personal history of medullary thyroid carcinoma (MTC) or Multiple 
Endocrine Neoplasia (MEN) syndrome type 2 
26. Have a history of an active or untreated malignancy or are 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 less than 5 years 
27. Have any other condition not listed in this section (for example, hypersensitivity or 
intolerance) that is a contraindication to GLP-1R agonists 
28. Have a history of any other condition (such as known drug or alcohol abuse, diagnosed 
eating disorder or other psychiatric disorder) that, in the opinion of the investigator, may 
preclude the participant from following and completing the protocol 
29. Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or awaiting an 
organ transplant 
30. Have any hematological condition that may interfere with HbA1c measurement (for 
example, hemolytic anemias, sickle cell disease) 
Prior/Concomitant Therapy 
31. Are receiving or have received within 3 months prior to screening chronic (>2 weeks or 14 
days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, 
intra-articular, or inhaled preparations) or have evidence of a significant, active autoimmune 
abnormality (for example, lupus or rheumatoid arthritis) that has required (within the last 
3 months) or is likely to require, in the opinion of the investigator, concurrent treatment with 
systemic glucocorticoids (excluding topical, intra-ocular, intranasal, intra-articular or 
inhaled preparations) in the next 12 months 
32. Have current or history of (within 3 months prior to randomization) treatment with 
medications that may cause significant weight gain, including but not limited to: tricyclic 
antidepressants, atypical antipsychotic and mood stabilizers for example:   
• imipramine 
• amitriptyline 
• mirtazapine 
• paroxetine 
• phenelzine 
• chlorpromazine 
• thioridazine 
• clozapine 
• olanzapine 
• valproic acid and its derivatives, and 
• lithium 
Note:  Selective serotonin reuptake inhibitors other than paroxetine are permitted. 

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33. Have taken within 3 months prior to randomization, medications (prescribed or 
over-the-counter) or alternative remedies intended to promote weight loss.  Examples 
include, but are not limited to 
• Xenical® (orlistat) 
Note:  Use of metformin or any other glucose-lowering medication, whether prescribed for 
polycystic ovary syndrome or diabetes prevention is not permitted. 
34. Have started implantable or injectable contraceptives (such as Depo-Provera®) within 18 
months prior to screening 
Prior/Concurrent Clinical Study Experience 
35. Are currently enrolled in any other clinical study involving an investigational product or any 
other type of medical research judged not to be scientifically or medically compatible with 
this study  
36. Within the last 30 days, have participated in a clinical study and received treatment, whether 
active or placebo.  If the study involved an investigational product, 5 half-lives or 30 days, 
whichever is longer, should have passed 
Other Exclusions 
37. Are investigator site personnel directly affiliated with this study and/or their immediate 
family (immediate family is defined as a spouse, parent, child, or sibling, whether biological 
or legally adopted) 
38. Are Eli Lilly and Company (Lilly) employees 
6.3. Lifestyle Restrictions 
Per the Schedule of Activities (Section 2), participants will consult with a dietician, or equivalent 
qualified delegate, according to local standards, to receive lifestyle management counseling at 
Weeks 0, 4, 8 and 12 during dose escalation and then at Week 24, 36, 44, 52 and ED.(Section 2). 
Diet and exercise goals established during the lifestyle consultation and the importance of 
adherence to the lifestyle component of the trial will be reinforced at each trial contact by study 
staff. 
6.3.1. Meals and Dietary Restrictions 
At Visit 2 and subsequent visits study participants will receive diet counselling by a 
dietician/nutritionist, or equivalent qualified delegate, according to local standard.  Dietary 
counseling will consist of advice on healthy food choices and focus on calorie restriction using a 
hypocaloric diet with macronutrient composition of:  
• approximately 20%-30% of energy from fat  
• approximately 15%-20% of energy from protein 
• approximately 40-55% of energy from carbohydrates, and  

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• with an energy deficit of approximately 500 kcal/day compared to the participant’s total 
daily energy  or use the equation: (body height (cm) - 105) × 25 kcal/day as calorie 
restrict diet energy target (Committee of China expert consensus of medical nutrition 
therapy to patients who are overweight or obese, 2016; Ge et al. 2018) 
To encourage adherence, it is recommended that a 3-day food and exercise diary be completed 
prior to each counseling visit.  During each visit, the participant’s diet is reviewed and advice to 
maximize adherence is provided if needed. 
The hypocaloric diet is continued after randomization and throughout the treatment period.  If a 
BMI ≤20 kg/m2 is reached the recommended energy intake should be recalculated with no kcal 
deficit for the remainder of the trial. Also, it is recommended total daily energy is at least 1000 
kcal for women and at least 1200 kcal for men.   
6.3.2. Physical Activity 
At Visit 2 and all subsequent visits, participants will be advised to increase their physical activity 
to at least 150 minutes per week. 
6.4. Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study, but are 
not subsequently randomly assigned to the study intervention.  A minimal set of screen failure 
information should be collected to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and 
to respond to queries from regulatory authorities.  Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) should not 
be rescreened.  

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7. Treatments 
7.1. Treatments Administered 
This study involves a comparison of 10 mg and 15 mg tirzepatide administered by subcutaneous 
injection once weekly with placebo.  Table GPIA.3 shows the treatment regimens. 
Table GPIA.3. 
Treatment Regimens 
ARM Name 
Tirzepatide 10 mg 
Tirzepatide 15 mg 
Placebo 
Dosea 
10 mg QW 
15 mg QW 
N/A 
Route of Administration 
SC 
SC 
SC 
Sourcing 
Provided centrally by the Sponsor and dispensed via IWRS 
Abbreviations:  IWRS = interactive web response service; N/A= not available, QW= once-weekly, SC= 
subcutaneous 
a Tirzepatide treatment will follow a fixed dose escalation that initiated at 2.5 mg QW for 4 weeks and increased by 
2.5 mg every 4 weeks (2.5 mg to 5 mg to 7.5 mg to 10 mg to 12.5 mg to 15 mg) until the desired dose is achieved 
and maintained for the duration of the study. 
7.1.1. Packaging and Labelling 
Study Intervention will be provided in investigational autoinjectors, packaged in cartons to be 
dispensed.  Clinical study materials will be labeled according to China regulatory requirements. 
7.1.2. Medical Devices  
The investigational combination products provided for use in the study are tirzepatide 
investigational autoinjectors (or matching placebo).  Any medical device related adverse event, 
including those resulting from malfunctions of the device, must be detected, documented, and 
reported by the investigator throughout the study (see Section 9.2.3). 
7.2. Method of Treatment Assignment 
Participants who meet all criteria for enrollment will be randomized to one of the study treatment 
groups at Visit 2.  Assignment to treatment groups will be determined by a computer-generated 
random sequence using an IWRS.  Participants will be randomized in a 1:1:1 ratio to receive 
tirzepatide 10 mg, tirzepatide 15 mg, or placebo.   
The randomization will be stratified by sex (female, male) and presence of comorbidities (Y/N). 
7.2.1. Selection and Timing of Doses 
There are no restrictions on the time of day each weekly dose of study drug is given, but it is 
advisable to administer the SC injections on the same day and same time each week.  The actual 
date and time of all dose administrations will be recorded by the participant.  If a dose of study 
drug is missed, the participant should take it as soon as possible unless it is within 72 hours of 

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the next dose, in which case, that dose should be skipped and the next dose should be taken at the 
appropriate time.  The day of weekly administration can be changed if necessary, as long as the 
last dose was administered 72 or more hours before.   
All participants will inject study drug subcutaneously in the abdomen or thigh by following the 
Instructions for Use provided for the study, and using the injection supplies provided; a caregiver 
may administer the injection in the participant’s upper arm.  A new autoinjector will be used for 
each injection.  If study drug is to always be injected in the same body region, participants 
should be advised to rotate injection sites. 
7.3. Blinding 
This is a double-blind study. 
Investigators, site staff, clinical monitors and participants will remain blinded to the treatment 
assignments until the study is completed. 
Emergency unblinding may be performed through the IWRS.  This option may be used ONLY if 
the participant’s well-being requires knowledge of the participant’s treatment assignment.  All 
emergency unblinding events are recorded and reported by the IWRS. 
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be discontinued from the study drug.  In cases where there are ethical reasons to 
have the participant remain in the study, the investigator must obtain specific approval from a 
Lilly clinical research physician (CRP) for the participant to continue in the study. 
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a participant’s treatment assignment is warranted for medical management of the event.  The 
participant safety must always be the first consideration in making such a determination.  If a 
participant’s treatment assignment is unblinded, Lilly must be notified immediately.  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 
7.4. Dosage Modification 
7.4.1. Tirzepatide 
Study drug dose modification is not permitted, except for management of intolerable GI 
symptoms (see Section 7.4.2). 
7.4.2. Management of Participants with Gastrointestinal Symptoms 
Participants who experience intolerable GI symptoms (for example: nausea, vomiting, or 
diarrhea) at any time during the study, should first be counselled on dietary behaviors that may 
help mitigate nausea and vomiting, (for example, eating smaller meals, splitting 3 daily meals 
into 4 or more smaller ones, and stopping eating when they feel full).  If symptoms persist, the 
participant should be prescribed, at the investigator’s discretion, symptomatic medication (for 
example, antiemetic or antidiarrheal medication).  A temporary interruption of study drug for 1 

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dose is permitted, provided the participant has taken the last 3 weekly doses.  Study treatment 
should be resumed at the assigned dose immediately, either alone or in combination with 
symptomatic medication (Appendix 9).  Management of study drug after interruptions >1 dose is 
discussed in Section 8.1.2. 
If intolerable GI symptoms (for example, nausea, vomiting, or diarrhea) persist despite the above 
measures, the investigator should contact Lilly to consider reinitiating study drug at the next 
lowest maintenance dose in a blinded fashion (for example, 15 mg and 12.5 mg reduced to 10 
mg, 10 mg or lower reduced to placebo, the lower dose will be maintained for the rest of the 
study, with no re-escalation allowed). 
If intolerable GI symptoms persist despite symptomatic treatment, temporary drug interruption, 
and resumption at a lower dose of study drug, the participant should be discontinued from the 
study drug.  Only 1 dose reduction per participant will be permitted during the course of the 
study.  All participants who discontinue study drug should continue to attend scheduled study 
visits.  All dose adjustments will be managed through IWRS. 
7.5. Preparation/Handling/Storage/Accountability 
• The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
• Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply study intervention. 
• All study intervention must be stored in a secure, 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 intervention (includes study drug and autoinjectors) accountability, 
reconciliation, and record maintenance (for example, receipt, reconciliation, and final 
disposition records). 
• Study site staff must regularly assess whether the participant is correctly administering 
the assigned study drug and storing the study drug according to the provided instructions. 
7.6. Treatment Compliance 
Participant compliance with study intervention will be assessed at each visit.  Compliance will be 
assessed by direct questioning and counting of unused study drug and/or empty cartons returned. 
Study drug compliance will be determined by the following:  
• Study drug administration data will be recorded by the participant and reviewed 
by the investigator at each study visit. 
• The participants will be instructed to return any unused study drug and/or empty 
cartons at the next visit to the study site for the purpose of performing drug 
accountability. 

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Treatment compliance for each visit interval is defined as taking at least 75% of the required 
doses of study drug.  Similarly, a participant will be considered significantly noncompliant if he 
or she is judged by the investigator to have intentionally or repeatedly taken more than the 
prescribed amount of medication (more than 125%). 
In addition to the assessment of a participant’s compliance with study drug administration, other 
aspects of compliance with the study treatments will be assessed at each visit based on the 
participant’s adherence to the visit schedule, completion of study diaries, and any other 
parameters the investigator considers necessary. 
Participants considered to be poorly compliant with their medication and/or the study procedures 
will receive additional training and instruction, as required, and will be reminded of the 
importance of complying with the protocol. 
7.7. Concomitant Therapy 
Participants will be permitted to use concomitant medications that they require during the study, 
except certain medications (for example, other medications for weight management) that may 
interfere with the assessment of efficacy and safety characteristics of the study treatments. 
Participants who develop diabetes during the study may initiate medication for glucose control 
per local standard of care, with the exception of dipeptidyl peptidase-4 (DPP-4) inhibitors or 
GLP-1R agonists.  Initiation of metformin for the treatment of diabetes is permitted, but 
metformin should not be initiated during the study for the treatment of other metabolic 
conditions (for example, polycystic ovary syndrome, diabetes prevention). 
Investigative site staff will inform participants that they must consult with the investigator or a 
designated site staff member upon being prescribed any new medications during the study.  This 
may not be possible when initiated for treatment of medical emergencies, in which case, the 
participant will inform the investigator or a designated site staff member as soon as possible.   
Nonstudy medications taken by participants who are screened but not randomized will not be 
reported to Lilly unless an SAE or AE occurs that the investigator believes may have been 
caused by a study procedure. 
7.8. Treatment after the End of the Study 
Tirzepatide will not be made available after conclusion of the study to participants. 

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8. Discontinuation Criteria 
8.1. Discontinuation from Study Treatment 
8.1.1. Permanent Discontinuation from Study Treatment 
Possible reasons leading to permanent discontinuation of investigational product: 
• Participant Decision 
o The participant requests to discontinue investigational product. 
• Clinical considerations 
o Initiation of open-label GLP-1R agonist or DPP-4 inhibitor, if participants will not or 
cannot discontinue them 
o Intolerable GI symptoms despite management as described in Section 7.4.2.  
o BMI ≤18.5kg/m2 is reached at any time during the treatment period  
Note: The investigator should contact the Sponsor CRP to discuss whether it is 
medically appropriate for the participant to continue study treatment 
o Diagnosis of T1DM 
o Diagnosis of MTC after randomization 
o Significant elevation of serum calcitonin (Appendix 6)  
o Diagnosis of acute or chronic pancreatitis  
o Diagnosis of 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 
o If the investigator, after consultation with the sponsor-designated medical monitor, 
determines that a systemic hypersensitivity reaction has occurred related to study drug 
administration, the participant should be permanently discontinued from the 
investigational drug 
o Onset of pregnancy in a female participant  
o Occurrence of any other treatment-emergent AE (TEAE), SAE, or clinically significant 
finding for which the investigator believes that permanent study drug discontinuation is 
the appropriate measure to be taken 
o Inadvertent enrollment if continued treatment with study drug would not be medically 
appropriate (Section 8.1.3) 
o PHQ-9 score ≥15 
o Participants should be referred to a Mental Health Professional (MHP) to assist 
in deciding whether the participant should be discontinued from study drug.  If 
a participant’s psychiatric disorder can be adequately treated with 
psycho- and/or pharmacotherapy, then the participant, at the discretion of the 
Investigator (in agreement with the MHP), may be continued in the trial on 
randomized therapy.   
o In addition, study drug may be discontinued if participants 
o answered "yes" to Question 4 or Question 5 on the "Suicidal Ideation" portion 
of the C-SSRS, or 

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o answered "yes" to any of the suicide-related behaviors on the Suicidal Behavior 
portion of the C-SSRS. 
A psychiatrist or appropriately trained professional may assist in the decision to discontinue 
the participant. 
• Discontinuation due to a hepatic event or liver test abnormality.  
o Participants who are discontinued from investigational product due to a hepatic event 
or liver test abnormality should have additional hepatic safety data collected via eCRF. 
o Discontinuation of the investigational product for abnormal liver tests should be 
considered by the investigator when a participant meets one of the following conditions 
after consultation with the Lilly designated medical monitor: 
 ALT or AST >8x ULN 
 ALT>2x baseline value OR ≥300U/L, whichever occurs first, if 
baseline ALT≥2x ULN 
 ALT or AST >5x ULN for more than 2 weeks 
 ALT or AST >3x ULN and TBL >2x ULN or international normalized 
ratio (INR) >1.5  
 ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%) 
 ALP >3x ULN 
 ALP >2.5x ULN and TBL >2x ULN 
 ALP >2.5x ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
Participants who stop the study drug permanently should continue to attend all scheduled study 
visits to collect all planned efficacy and safety measurements.  Participants who are unwilling to 
attend all scheduled visits and stop the study prior to 52 weeks, should return for a final weight 
measurement (Visit 99).  If participants are unwilling to attend visit 99, their refusal to attend 
should be documented in the patient medical record. 
Participants discontinuing from the investigational product prematurely for any reason should 
complete adverse event and other follow-up procedures per Section 2 (Schedule of Activities), 
Section 9.2 (Adverse Events), and Section 9.4 (Safety) of this protocol. 
8.1.2. Temporary Discontinuation from Study Treatment  
In certain situations after randomization, the investigator may need to temporarily interrupt study 
drug.  Every effort should be made by the investigator to maintain participants on study drug and 
to restart study drug after any temporary interruption, as soon as it is safe to do so.  Distribution 
of study medication at the correct dose will be per IWRS instructions.   

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• If the study drug interruption is ≤2 consecutive doses, the drug will be restarted at last 
administered dose, as per the escalation schedule.   
• If the interruption is >2 consecutive doses, the participant will restart study drug at 5 
mg (per IWRS instructions) and repeats dose escalation scheme. 
• If study drug interruption is due to an AE, the event is to be documented and followed 
according to the procedures in Section 9.2 of this protocol.   
• If the study drug interruption is due to intolerable persistent GI AE (for example, 
nausea, vomiting, or diarrhea), the participants should be treated as suggested in 
Section 7.4.2. 
Investigators should inform the Sponsor that study drug has been temporarily interrupted.  The 
data related to temporary interruption of study treatment will be documented in source 
documents and entered on the eCRF.   
8.1.3. Discontinuation of Inadvertently Enrolled Participants 
If the sponsor or investigator identify a participant who did not meet enrollment criteria and was 
inadvertently enrolled, the investigator and the Sponsor CRP must agree whether continuing the 
study treatment is medically appropriate.  If the investigator and the sponsor CRP agree it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
sponsor CRP to allow the inadvertently enrolled participant to continue in the study with or 
without treatment with investigational product.  Safety follow up is as outlined in Section 2 
(Schedule of Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety) of the protocol. 
8.2. Discontinuation from the Study 
Participants will be discontinued in the following circumstances:  
• enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be 
scientifically or medically compatible with this study 
• participation in the study needs to be stopped for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and good clinical 
practice (GCP) 
• investigator decision 
o the investigator decides that the participants should be discontinued from 
the study 
o if the participant, 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 participant requests to be withdrawn from the study 

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To minimize the amount of missing data and to enable assessment of study objectives as planned 
in the study protocol, every attempt will be made to keep participants in the study irrespective of 
the following: 
• adherence to or discontinuation from study drug 
• adherence to visit schedule 
• missing assessments 
• study drug discontinuation due to AE  
• development of comorbidities 
• development of adverse clinical outcomes 
The circumstances listed above are not valid reasons for discontinuation from the study.  
Participants who agree to provide information relevant to any trial endpoint at the end of the 
study are not considered to have discontinued from the study. 
Participants discontinuing from the study prematurely for any reason should complete adverse 
event and other safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse 
Events), and Section 9.4 (Safety) of this protocol. 
8.2.1. Participant disposition and timing of safety follow-up for the 
primary endpoint (52 weeks) 
 
 

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Abbreviations:  ED=early discontinuation; Pt= participant; wks=weeks 
Figure GPIA.2. 
Illustration of participant disposition and safety follow-up for 
Clinical Protocol I8F-MC-GPIA. 
8.3. Lost to Follow-Up 
A participant 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 participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site. 
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those 
who did not get investigational product.  Public sources may be searched for vital status 
information.  If vital status is determined, this will be documented, and the participant will not be 
considered lost to follow-up. 
Eli Lilly and Company personnel will not be involved in any attempts to collect vital status 
information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 4. 

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9. Study Assessments and Procedures 
Appendix 2 lists the laboratory tests that will be performed for this study.  Repeat or unscheduled 
samples may be taken for safety reasons or for technical issues with the samples. 
Unless otherwise stated in the 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 
9.1.1. Primary Efficacy Assessments 
The primary efficacy measurement in this study is the body weight.  Body weight measurements 
will be collected at specific clinic visits as summarized in the Schedule of Activities (Section 2).  
Methods for measuring body weight are described in Appendix 8. 
9.1.2. Secondary Efficacy Assessments 
The following secondary efficacy measures will be collected at the times shown in the Schedule 
of Activities (Section 2) and analyzed in a manner controlled for type I error:  
• 
Body weight (measuring method is described in Appendix 8) 
• 
Waist circumference (measuring method is described in Appendix 8) 
• 
HbA1c (%) (measured through central lab) 
• 
Fasting glucose (mmol/L) (measured through central lab) 
• 
Blood pressure (measuring method is described in Appendix 8) 
• 
Fasting lipids (mmol/L) (measured through central lab) 
• 
Fasting insulin (measured through central lab) 
9.1.3. Patient-Reported Outcomes Assessments 
The self reported questionnaires will be administered according to the Schedule of Activities 
(Section 2).  At these visits, the questionnaires should be completed before the participant has 
discussed their medical condition or progress in the study with the investigator and/or site staff if 
the participant is not adversely affected by their fasting condition. 
 Short Form 36 version 2, acute, 1 week recall version 
The SF 36v2 acute, 1 week recall version is a 36 item generic, patient-administered measure 
designed to assess the following 8 domains of health-related quality of life (HRQoL) “in the past 
week,” except for the Physical Functioning domain, which assesses an individual’s physical 
function in terms of how their health limits them “now” (i.e., currently): 
• Physical Functioning  
• Role Physical 
• Bodily Pain 

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• General Health 
• Vitality 
• Social Functioning  
• Role Emotional, and  
• Mental Health 
Information from these 8 domains are further aggregated into 2 health component summary 
scores:  Physical Component Summary and Mental Component Summary.  Items are answered 
on Likert scales of varying lengths.  Scoring of each domain and both summary scores are norm 
based and presented in the form of T scores, with a mean of 50 and standard deviation of 10; 
higher scores indicate better levels of function and/or better health (Maruish 2011). 
 Impact of Weight on Quality of Life Lite Clinical Trials Version 
The IWQOL-Lite-CT is a 20-item, obesity-specific PRO instrument developed for use in obesity 
clinical trials.  It assesses two primary domains of obesity-related HRQoL: physical (7 items), 
and psychosocial (13 items).  A 5-item subset of the physical domain – the physical function 
composite is also supported.  Items in the physical function composite describe physical impacts 
related to general and specific physical activities.  All items are rated on either a 5-point 
frequency (“never” to “always”) scale or a 5-point truth (“not at all true” to “completely true”) 
scale. (Kolotkin et al. 2017, 2018).  
EQ-5D-5L
Generic health-related quality of life will be assessed using the EQ-5D-5L (EuroQoL Group 
2015).  The EQ-5D-5L is a standardized 5-item instrument for use as a measure of health 
outcome.  It provides a simple descriptive profile and a single index value for health status that 
can be used in the clinical and economic evaluation of health care as well as population health 
surveys.  The EQ-5D-5L comprises 5 dimensions of health (mobility, self care, usual activities, 
pain/discomfort, and anxiety/depression).  The 5L version, introduced in 2005, scores each 
dimension at 5 levels (no problems, slight problems, moderate problems, severe problems, 
unable to perform/extreme problems), for a total of 3125 possible health states.  In addition to the 
health profile, a single health state index value can be derived based on a formula that attaches 
weights to each of the levels in each dimension.  This index value ranges between less than 0 
(where 0 is a health state equivalent to death; negative values are valued as worse than dead) to 1 
(perfect health).  In addition, the EQ Visual Analog Scale records the respondent’s self-rated 
health status on a vertical graduated (0 to 100) visual analog scale.  In conjunction with the 
health state data, it provides a composite picture of the respondent’s health status.   
The EQ-5D-5L is used worldwide and is available in more than 170 different languages.  Details 
on the instrument, and scoring, organizing, and presenting the data collected can be found in the 
EQ-5D-5L User Guide (EuroQoL Group 2015).  

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 Patient Global Impression of Status for Physical Activity 
Study participants will be asked to complete a Patient Global Impression of status (PGIS) item 
specifically developed for this study.  This is a patient-rated assessment of current health 
limitation and is rated on a 5-point scale ranging from “1 not at all limited” to “5 extremely 
limited.”
9.1.4.  Appropriateness of Assessments 
Efficacy and safety assessments included in this study are generally regarded as reliable and 
accurate with respect to the efficacy and safety assessments in individuals and populations with 
Obesity. 
9.2. Adverse Events 
All AEs will be collected from the signing of the ICF until the time points specified in the 
Schedule of Activities (Section 2). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open ended and non 
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
Investigators are responsible for monitoring the safety of participants 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 participant. 
The investigator is responsible for the appropriate medical care of participants during the study. 
Investigators must document their review of each laboratory safety report. 
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the participant to discontinue the investigational product 
before completing the study.  The participant 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. 
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect. 
The investigator will record all relevant AE and SAE information in the eCRF.  After the ICF is 
signed, study site personnel will record via eCRF the occurrence and nature of each participant’s 
preexisting conditions, including clinically significant signs and symptoms of the disease under 
treatment in the study.  In addition, site personnel will record any change in the condition(s) and 
any new conditions as AEs.  Investigators should record their assessment of the potential 
relatedness of each AE to protocol procedure, investigational product, via eCRF. 
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.   

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A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device and/or study procedure and the AE. 
The investigator answers yes/no when making this assessment. 
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study. 
If a participant’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF, clarifying if possible, the circumstances 
leading to any dosage modifications, or discontinuations of treatment. 
Please refer to Appendix 6 Adverse Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting. 
9.2.1. Serious Adverse Events 
An SAE is any AE from this study that results in one of the following outcomes: 
• 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 participant or may require 
intervention to prevent one of the other outcomes listed in the definition above.  
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
• when a condition related to the drug delivery system necessitates medical or surgical 
intervention to preclude either permanent impairment of a body function or permanent 
damage to a body structure, the serious outcome of “required intervention” will be 
assigned. 
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  The SAE reporting to the sponsor begins after the participant has signed the ICF and has 
received investigational product.  However, if an SAE occurs after signing the ICF, but prior to 
receiving investigational product, the SAE should be reported to the sponsor per SAE-reporting 
requirements and timelines (see Section 9.2) if it is considered reasonably possibly related to 
study procedure. 
Study site personnel must alert Lilly 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 

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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.  Participants with a serious hepatic AE should have additional data collected using 
the eCRF. 
Pregnancy (during maternal or paternal exposure to investigational product) 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.  
Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, and ectopic pregnancy) are considered SAEs. 
Investigators are not obligated to actively seek AEs or SAEs in participants once they have 
discontinued and/or completed the study (the participant disposition CRF 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 or she considers the event reasonably possibly related to 
the study treatment or study participation, the investigator must promptly notify Lilly. 
 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 identifies as related to investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the 
identification, recording, and expedited reporting of SUSARs that are consistent with global 
regulations and the associated detailed guidances.  
9.2.2. Adverse Event Monitoring with a Systematic Questionnaire  
Patients with overweight and obesity are at increased risk for depression (Luppino et al. 2010).  
Depression can increase the risk for suicidal ideation and behavior.  Therefore, study participants 
will be screened at trial entry and monitored during the study for depression, 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 (Section 9.4.6). 
The C-SSRS 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 “0” (not at all) to “3” (nearly every day), was developed for use in primary 
care settings (Kroenke et al. 2001). 

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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.  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. 
9.2.3. Complaint Handling 
A product complaint is any written, electronic, or oral communication that alleges a deficiency 
related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a 
Lilly product after it is released for distribution.  When the ability to use the product safely is 
impacted, the following are also product complaints: 
• Deficiencies in labeling information, and 
• Use errors for device or combination products due to ergonomic design elements of the 
product. 
Sponsor collects product complaints on investigational products, medical devices, and drug 
delivery systems used in clinical studies in order to ensure the safety of study participants, 
monitor quality, and to facilitate process and product improvements.  Complaints are also 
collected on comparators and other clinical trial material supplied, as required. 
Participants will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational drug, medical device, or drug delivery system so 
that the situation can be assessed. 
As required by local regulations, and per instructions on the complaint form, the investigator will 
report to the sponsor and to their IRB/IEC any unanticipated adverse device effect or UADE 
(unanticipated problem that resulted in an SAE), or any device related product complaint that 
could have led to an SAE had precautions not been taken. 
• For complaints associated with an SAE, report within 24 hours of site/trial 
personnel becoming aware of the product complaint. 
• For any complaint that might have led to an SAE if appropriate action had not 
been taken, the intervention had not occurred, or circumstances had been less 
fortunate, report within 24 hours of site personnel becoming aware of the product 
complaint. 
• For complaints not associated with an SAE, report within one business day of 
site/trial personnel becoming aware of the product complaint, or per the protocol. 
9.2.4. Follow-up of AEs and SAEs 
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined 
in Section 2). 

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9.3. Treatment of Overdose 
Study drug overdose (more than the specified number of injections) will be reported as an AE.  
In the event of overdose, refer to the IB for tirzepatide. 
9.4. Safety 
Planned time points for all safety assessments are provided in the Schedule of Activities (Section 
2). 
9.4.1. Electrocardiograms 
For each participant, electrocardiograms (ECGs) should be collected according to the Schedule 
of Activities (Section 2) and Appendix 8. 
Electrocardiograms will initially 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 participant is still present, for immediate subject management, should any clinically 
relevant findings be identified.  Any clinically significant findings from ECGs that result in a 
diagnosis and that occur after the participant receives the first dose of the investigational 
treatment should be reported to Lilly or its designee as an AE via the eCRF. 
All digital ECGs will be obtained using centrally provided ECG machines and will be 
electronically transmitted to a designated central ECG laboratory.  The central ECG laboratory 
will perform a basic quality control check (for example, demographics and study details) and 
then store the ECGs in a database.  At a future time, the stored ECG data may be overread by a 
cardiologist at the central ECG laboratory for further evaluation of machine-read measurements 
or to meet regulatory requirements.  The machine-read ECG intervals and heart rate may be used 
for data analysis and report-writing purposes, unless a cardiologist overreading of the ECGs is 
conducted prior to completion of the final study report (in which case, the overread data would 
be used). 
9.4.2. Vital Signs 
For each participant, vital signs should be measured according to the Schedule of Activities 
(Section 2) and Appendix 8. 
Any clinically significant findings from vital signs measurement that result in a diagnosis and 
that occur after the participant receives the first dose of study treatment should be reported to 
Lilly or its designee as an AE via the eCRF. 
9.4.3. Laboratory Tests 
• For each participant, laboratory tests detailed in Appendix 2 should be conducted 
according to the Schedule of Activities (Section 2).  
• With the exception of laboratory test results that may unblind the study, Lilly or 
its designee will provide the investigator with the results of laboratory tests 
analyzed by a central vendor, if a central vendor is used for the clinical trial.   

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• Any clinically significant findings from laboratory tests that result in a diagnosis 
and that occur after the participant receives the first dose of investigational 
product should be reported to Lilly or its designee as an AE via eCRF. 
9.4.4. Immunogenicity Assessments 
Where local regulations and ERBs allow, blood samples for immunogenicity testing will be 
collected to determine antibody production against tirzepatide as specified in the Schedule of 
Activities (Section 2). 
At the visits and times specified in the Schedule of Activities (Section 2), blood samples will be 
collected to determine antibody production against tirzepatide.  To interpret the results of 
immunogenicity, a PK sample will be collected at the same time points as the immunogenicity 
sample.  All samples for immunogenicity should be taken predose when applicable and possible.  
In the event of systemic drug hypersensitivity reactions (immediate or nonimmediate), additional 
unscheduled samples should be collected as detailed in Appendix 6 (Hypersensitivity Events).  
Instructions for the collection and handling of blood samples will be provided by the sponsor.  
Sample collected at Visit 801 will assess immunogenicity at washout of tirzepatide (5 half-lives 
post end of treatment). 
Immunogenicity will be assessed by a validated assay designed to detect and titer antidrug 
antibody (ADA) in the presence of tirzepatide at a laboratory approved by the Sponsor.  Samples 
with detected ADA will be tested for cross-reactive binding to native GIP and GLP-1. 
Antibodies may be further evaluated for their ability to neutralize the activity of tirzepatide.  In 
vivo laboratory indicators for glycemic control (fasting blood glucose and HbA1c), effect on 
weight loss and PK will be utilized to detect potential neutralizing effect of ADA against 
tirzepatide. 
Treatment-emergent antidrug antibodies are defined in Section 10.3.6. 
ADA and hypersensitivity samples will be stored as per local regulation/EC requirement. 
Samples will be immediately destroyed once tirzepatide is launched for weight management 
indication or there is no further request on testing the samples from China authority. 
9.4.5. Other Tests  
 Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, GI and neurological systems, as well as a thyroid exam.  
Height, weight, and waist circumference will also be measured and recorded, per 
Appendix 8. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 

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9.4.6. Safety Monitoring 
 Hepatic Safety Monitoring 
9.4.6.1.1. Close Hepatic Monitoring
Laboratory tests (Appendix 2), including ALT, AST, ALP, TBL, direct bilirubin (D. Bil), 
gamma-glutamyl transferase (GGT), and creatine kinase (CK), should be repeated within 48 to 
72 hours to confirm the abnormality and to determine if it is increasing or decreasing, if one or 
more of these conditions occur: 
If a participant with baseline results of:  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN 
ALP <1.5x ULN 
ALP ≥2x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for patients with Gilbert’s syndrome) 
 
 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥1.5x baseline (except for patients with Gilbert’s 
syndrome) 
Abbreviations: ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST= aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal. 
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor.  At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, history of alcohol 
drinking and other substance abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and lab results stabilize.  Monitoring of ALT, AST, ALP, and 
TBL should continue until levels normalize or return to approximate baseline levels. 
9.4.6.1.2. Comprehensive hepatic evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions occur: 
If a participant with baseline 
results of... 
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN with hepatic signs/symptoms*, or  
ALT or AST ≥5x ULN 
ALP <1.5x ULN 
ALP ≥3x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for patients with Gilbert’s syndrome) 

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

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 Depression, Suicidal Ideation, and Behavior Risk Monitoring 
Due to increased risk for depression (Luppino et al. 2010), suicidal ideation and behavior, 
participants with overweight and obesity will be screened at trial entry and monitored during the 
study for depression, suicidal ideation and behavior as explained in section 9.2.2.   
Participants should be monitored appropriately and observed closely for suicidal ideation and 
behavior or any other unusual changes in behavior, especially at the beginning and end of the 
course of treatment, or at the time of dose changes, either increases or decreases.  
Baseline and treatment emergent assessment of depression, suicidal ideation and behavior will be 
monitored during the study using the C-SSRS and PHQ-9 (Section 9.2.2).  Consideration should 
be given to discontinuing the study medication in participants who experience signs of suicidal 
ideation or behavior, following a risk assessment (Section 8.1). 
9.5. Pharmacokinetics 
Pharmacokinetic samples will be collected from all randomized participants.  
Plasma tirzepatide concentrations will only be determined from blood samples obtained from 
participants receiving tirzepatide treatment.  Blood samples for PK assessment will be collected 
at times specified in the Study Schedule (Section 2).  At each visit, one PK sample will be 
collected at fasting state before IP administration.  
The date and time of the most recent tirzepatide SC injection administered prior to collecting the 
PK sample must be recorded on the eCRF from the study diaries. 
The date and time at which each sample was drawn must be recorded on the laboratory accession 
page.  
Concentrations of tirzepatide will be assayed using a validated liquid chromatography mass 
spectrometry method. 
Bioanalytical samples collected to measure tirzepatide concentration will be retained for a 
maximum of 1 year following last participant visit for the study.. 
9.6. Pharmacodynamics 
Samples to assess the PD properties of tirzepatide are included in the efficacy measures and not 
applicable in this section. 
9.7. Genetics 
9.7.1. Whole Blood Sample[s] for Pharmacogenetic Research 
Not Applicable. 
9.8. Biomarkers  
Not Applicable. 

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9.9. Health Economics 
Health Economics and Medical Resource Utilization Parameters are not evaluated in this study. 

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10. Statistical Considerations 
10.1. Sample Size Determination 
Approximately 210 participants will be randomly assigned to study intervention (70 participants 
per intervention group). 
The sample size determination assumes that evaluation of superiority of tirzepatide 10 mg and 
tirzepatide 15 mg to placebo will be conducted in parallel, each at a 2-sided significance level of 
0.025 using a 2-sample t-test.  Additionally, a difference of at least 11% mean body weight 
percentage reduction from randomization at 52 weeks for tirzepatide 10 mg and/or tirzepatide 15 
mg compared with placebo, a common standard deviation (SD) of 11%, and a drop-out rate of 
25% are assumed for statistical power calculations.  Under the assumptions above, randomizing 
210 participants in a 1:1:1 ratio to tirzepatide 10 mg (70), tirzepatide 15 mg (70), and placebo 
(70) provides more than 90% power to demonstrate superiority of each tirzepatide dose to 
placebo. 
The chosen sample size and randomization ratio also provides >90% power to establish 
superiority of tirzepatide 10 mg and tirzepatide 15 mg doses to placebo in term of proportion of 
participants achieving at least 5% body weight reduction at 52 weeks, conducted in parallel using 
a Chi-square test, each at a 2-sided significance level of 0.025, assuming 25% placebo-treated 
participants and 90% tirzepatide-treated participants achieving the goal and a dropout rate of 
25%. 
 
 

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10.1.1. Statistical Hypotheses 
The alternative hypotheses for the primary objective are the following:  
H10,1: tirzepatide 10 mg QW is superior to placebo for percent change in body weight from 
randomization AND proportion of participants who achieve ≥5% body weight reduction at 
52 weeks. 
H15,1: tirzepatide 15 mg QW is superior to placebo for percent change in body weight from 
randomization AND proportion of participants who achieve ≥5% body weight reduction at 52 
weeks  
The above two hypotheses will be tested in parallel, each at a 2-sided significance level of 0.025. 
The alternative hypotheses for the key secondary objective controlling for type 1 error rate are 
the following:  
H10,2:  tirzepatide 10 mg QW is superior to placebo for change in body weight (kg) from 
randomization at 20 weeks. 
H15,2:  tirzepatide 15 mg QW is superior to placebo for change in body weight (kg) from 
randomization at 20 weeks. 
H10,3:  tirzepatide 10 mg QW is superior to placebo for proportion of participants who achieve 
≥10% body weight reduction at 52 weeks. 
H15,3:  tirzepatide 15 mg QW is superior to placebo for proportion of participants who achieve 
≥10% body weight reduction at 52 weeks. 
H10,4:  tirzepatide 10 mg QW is superior to placebo for proportion of participants who achieve 
≥15% body weight reduction at 52 weeks.  
H15,4:  tirzepatide 15 mg QW is superior to placebo for proportion of participants who achieve 
≥15% body weight reduction at 52 weeks. 
H10,5:  tirzepatide 10 mg QW is superior to placebo for change from randomization in waist 
circumference (cm) at 52 weeks. 
H15,5:  tirzepatide 15 mg QW is superior to placebo for change from randomization in waist 
circumference (cm) at 52 weeks. 
The details of type I error rate control strategy for the above key secondary objectives will be 
provided in the statistical analysis plan (SAP). 
10.2. Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Table GPIA.4. 
Definition of population 
Population 
Description 
Entered  
All participants who sign informed consent. 

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Randomized 
All participants who are randomly assigned a study treatment. 
Modified Intent-to-Treat 
(mITT)   
All randomly assigned participants who are exposed to at least 1 dose of study 
drug.  Participants will be included in the treatment group they were 
randomized to. 
Efficacy Analysis Set (EAS) 
Data obtained during treatment period from mITT, excluding data after 
discontinuation of study drug (last dose date + 7 days). 
Full analysis set (FAS) 
Data obtained during treatment period from mITT, regardless of adherence to 
study drug. 
Safety Analysis Set (SS) 
Data obtained during the entire study from mITT, regardless of adherence to 
study drug. 
Per Protocol Set (PPS) 
Participants included in the randomized population who have completed Week 
52 of study treatment without permanent discontinuation of IP and without 
significant protocol deviations through Week 52 that would significantly 
impact the primary objective. 
Treatment group will be defined on the basis of the treatment the participants 
actually receive. 
Abbreviations: EAS = Efficacy Analysis Set, FAS = Full Analysis Set, IP = investigational product; mITT = 
Modified Intent-to-Treat, PPS = Per Protocol Set, SS = Safety Analysis Set. 
10.3. Statistical Analyses 
10.3.1. General Statistical Considerations 
Statistical analysis of this study will be the responsibility of Lilly or its designee.  Any change to 
the data analysis methods described in the protocol will require an amendment ONLY if it 
changes a principal feature of the protocol.  Any other change to the data analysis methods 
described in the protocol, and the justification for making the change, will be described in the 
SAP or the clinical study report.  Additional exploratory data analyses may be conducted as 
deemed appropriate. 
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and the confidence interval will be calculated at 95%, 2-sided.  In statistical summaries and 
analyses, data will be analyzed as randomized. 
Unless specified otherwise, efficacy and safety will be assessed using the modified 
intention-to-treat (mITT) population, which consists of all randomized participants who are 
exposed to at least 1 dose of study drug.  Baseline is defined as the last non-missing data 
collected at randomization (prior to first dosing of study drug).  Unless specified otherwise, 
safety assessments will compare safety of tirzepatide doses with placebo irrespective of 
adherence to study drug.  Thus, safety analysis will be conducted using safety analysis set (SS). 
Summary statistics for continuous measures will include sample size, mean, SD, median, 
minimum, and maximum.  The analysis model to make comparisons among treatment groups 
relative to continuous measurements assessed over time will be a mixed model for repeated 
measures (MMRM), with terms of treatment, visit, and treatment-by-visit interaction, 
stratification factors, and baseline measurement as a covariate.  An unstructured covariance 
structure will model relationship of within-patient errors. 

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Kaplan-Meier method will be used for estimation of cumulative event-free survival rates over 
time, and cox proportional hazards regression analysis will be used to compare hazard rates 
among treatments. 
Summary statistics for categorical measures (including categorized continuous measures) will 
include sample size, frequency, and percentages.  Logistic regression will be used to examine the 
treatment difference in binary efficacy outcomes if there is a need to adjust for covariates.  
Otherwise, Fisher’s exact test will be used to examine the treatment difference in categorical 
outcomes. 
Summary statistics for discrete count measures will include sample size, mean, standard 
deviation (SD), median, minimum, and maximum.  The negative binomial regression model will 
be used for the treatment comparison of discrete count measures.  
Other statistical methods may be used, as appropriate, and details will be described in the SAP. 
10.3.2. Treatment Group Comparability 
 Participant Disposition 
A detailed description of participant disposition will be provided at the end of the study.  
Frequency counts and percentages of all participants screened, randomized, and receiving at least 
1 dose of study drug will be presented by treatment groups.  Of the mITT population, frequency 
counts and percentages of participants who completed the study, prematurely discontinued the 
study (and/or study drug), including reason for premature discontinuation, will be presented by 
treatment groups.   
A Kaplan Meier analysis of time from randomization to premature discontinuation from study 
and discontinuation from study drug by treatment group will be provided. 
 Participant Characteristics 
Demographics will be summarized by treatment group for all randomized participants. 
 Concomitant Therapy 
Concomitant medications, including previous therapy, will be summarized by treatment arm for 
SS. 
 Treatment Compliance 
Frequency counts and percentages of participants compliant to study drug will be summarized by 
treatment groups and visits for full analysis set (FAS). 
10.3.3. Efficacy Analyses 
 Primary Analyses 
The primary efficacy analysis will be conducted using the efficacy analysis set (EAS).  The 
primary analysis model will be a MMRM for body weight percent change over time and 
longitudinal logistic regression for proportion of participants achieving at least 5% body weight 
reduction over time.  The response variable of MMRM will be the percent change in body 

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weight from baseline values obtained at each scheduled post baseline visit.  The response 
variable of longitudinal logistic regression will be the proportion of participants achieving at 
least 5% body weight reduction at each scheduled post baseline visit.  The independent variables 
of both analysis models are treatment group (tirzepatide 10 mg, tirzepatide 15 mg, and placebo), 
visit, and treatment-by-visit interaction, stratification factors, and baseline body weight as a 
covariate.  An unstructured covariance structure will model relationship of within-patient errors.  
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
Since the mean percent change in body weight and proportion of participants with ≥5% body 
weight reduction need to be achieved at the same time, no multiplicity adjustment is planned for 
these 2 tests. 
 Key Secondary Analyses 
• superiority of each tirzepatide dose (10 mg and 15 mg) to placebo for change from 
randomization in change of body weight (kg) at 20 weeks visit 
• superiority of each tirzepatide dose to placebo for the proportion of study participants 
who achieve ≥10% body weight reduction at 52 weeks visit 
• superiority of each tirzepatide dose to placebo for the proportion of study participants 
who achieve ≥15% body weight reduction at 52 weeks visit 
• superiority of each tirzepatide dose to placebo for change from randomization in waist 
circumference (cm) at 52 weeks visit 
Additional details, including analysis methods for key secondary endpoints and the strategy for 
controlling overall type 1 error rate at a 2-sided alpha of 0.05 of primary and key secondary 
endpoint evaluation, will be provided in the SAP. 
 Tertiary/Exploratory Analyses  
All exploratory efficacy analysis will be conducted using EAS.  Details will be provided in the 
SAP. 
10.3.4. Safety Analyses 
Unless specified otherwise, safety assessments will compare safety of tirzepatide doses with 
placebo irrespective of adherence to study drug.  Thus, safety analysis will be conducted using 
SS.   
 Study Drug Exposure 
Exposure to each study treatment will be calculated for each participant and summarized by 
treatment group. 
  Adverse Events 
Adverse events will be coded from the actual term using the Medical Dictionary for Regulatory 
Activities (MedDRA) and reported with preferred terms and system organ class.  Counts and 
proportions of participants experiencing events will be reported for each treatment group, and 
Fisher’s exact test will be used to compare the treatment groups. 
The proportion of participants experiencing TEAE, SAE, discontinuation due to AE and DEATH 
will be summarized by treatment group. 

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  Adverse Event of Special Interest 
The following AEs are AEs of special interest (AESI) for this study: 
• Severe hypoglycemia 
• Major adverse cardiovascular events (adjudicated).  Includes, but not limited to 
cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization 
for heart failure. 
• Treatment-Emergent Supraventricular arrhythmias and Cardiac Conduction Disorders 
• Hepatobiliary disorders.  Includes biliary colic, cholecystitis, and other gallbladder 
disease 
• Severe GI events 
• Acute renal events 
• Major Depressive Disorder/Suicidal Behavior and Ideation   
• Pancreatitis (adjudicated) 
• C-Cell Hyperplasia and thyroid malignancies 
• Allergic/Hypersensitivity Reactions, includes injection site reactions and ADA formation. 
Summaries and analyses for incidence of AESIs will be provided by treatment.  The details of 
analysis of AESI will be provided in SAP. 
 Other Adverse Event Assessments  
10.3.4.4.1. Gastrointestinal Events 
Summaries and analyses for incidence and severity of nausea, vomiting, and diarrhea will be 
provided by each treatment. 
10.3.4.4.2. Events Related to Potential Abuse Liability 
Two clusters of preferred terms for AEs suggestive of abuse liability will be analyzed.  The first 
cluster includes Standardized MedDRA Queries (SMQ) of Drug abuse and dependence 
[20000101].  The second cluster is a Lilly Search Cluster “additional abuse potential” terms, 
which are additional terms suggestive of abuse liability that are not included in the SMQ Drug 
abuse and dependence [20000101]. 
Summaries and analyses for incidence of potential abuse liability terms will be provided by 
treatment.  The details will be provided in SAP.  
10.3.4.4.3. Depression, Suicidal Ideation, and Behavior 
In addition to the summary of TEAEs, suicide-related events will be assessed by C-SSRS, and 
depression related symptoms will be assessed using PHQ-9. 
Suicidal ideation, suicidal behavior, and self-injurious behavior without suicidal intent, based on 
the C-SSRS, will be listed by participant and visit.  
The PHQ-9 total score will be summarized by treatment groups.   
The analysis details will be provided in the SAP. 

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10.3.4.4.4. Central Laboratory Measures, Vital Signs, and Electrocardiograms 
Actual values and change from randomization to post-randomization values of central laboratory 
measures, vital signs, and selected ECG parameters will be summarized at each scheduled visit.  
Change from randomization to post-randomization value will be summarized for participants
who have both a randomization and at least 1 post randomization result.
The percentages of participants with treatment-emergent abnormal, high, or low measures 
(including laboratory, vital, and ECG parameters) at any time will be summarized and compared 
between treatment groups using Fisher’s exact test. 
The analysis details will be provided in SAP. 
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses 
All plasma tirzepatide concentration-time data will be pooled and evaluated using conventional 
methods.  Details about the analyses to be conducted will be contained in the PK/PD analysis 
plan. 
10.3.6. Evaluation of Immunogenicity 
The frequency and percentage of participants with preexisting ADA and with 
treatment-emergent (TE) ADA+ to tirzepatide will be tabulated.  Treatment-emergent ADAs are 
defined as those with a titer 2-fold (1 dilution) greater than the minimum required dilution if no 
ADAs were detected at baseline (treatment-induced ADA), or those with a 4-fold (2 dilutions) 
increase in titer compared with baseline if ADAs were detected at baseline (treatment-boosted 
ADA).  For the TE ADA+ participants the distribution of maximum titers will be described.  The 
frequency of ADA cross-reactive to endogenous counterparts (native GIP and GlP-1) maybe 
tabulated in TE ADA+ participants. 
The relationship between the presence of antibodies and the PK parameters and PD response 
including safety and efficacy to tirzepatide may be assessed. 
10.3.7. Other Analyses 
 Patient Reported Outcomes 
Analyses of actual and change from baseline in the participant reported health outcomes in EAS 
will be conducted using an analysis of covariance (ANCOVA).  The details on 
questionnaire-specific analyses will be provided in the SAP. 
 Subgroup Analyses  
Details of the subgroup analyses will be shown in the SAP. 
The following subgroup variables will be considered (but not limited to): 
• Age (<65 years and ≥65 years); 
• Sex (female and male) 
• Baseline BMI (<28, ≥28) 
The outcome measures for the subgroup analyses will include: 

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• percent change in body weight from randomization at 52 weeks 
• proportion of participants achieving at least 5% body weight reduction at 52 weeks 
10.3.8. Interim Analyses 
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly medical director, or designee, will be consulted to determine 
whether it is necessary to amend the protocol. 

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Livingston EH. The incidence of bariatric surgery has plateaued in the U.S. Am J Surg. 
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Luppino FS, de Wit LM, Bouvy PF, Stijnen T, Cuijpers P, Penninx BW, Zitman FG. 
Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal 
studies. Arch Gen Psychiatry. 2010;67(3):220-229.  
Maruish ME, ed. User’s manual for the SF-36v2 Health Survey. 3rd ed. Lincoln, RI: Quality 
Metric Incorporated; 2011.  
Mertens IL, Van Gaal LF. Overweight, obesity, and blood pressure: the effects of modest weight 
reduction. Obes Res. 2000;8(3):270-278.  
Nauck MA, Meier JJ, Schmidt WE. Incretin-based glucose-lowering medications and the risk of 
acute pancreatitis and/or pancreatic cancer: Reassuring data from cardio-vascular outcome 
trials. Diabetes Obes Metab. 2017;19(9):1327-1328.  
Pilitsi E, Farr OM, Polyzos SA, Perakakis N, Nolen-Doerr E, Papathanasiou AE, Mantzoros CS. 
Pharmacotherapy of obesity: Available medications and drugs under investigation. 
Metabolism. 2019; 92:170-192. 
Report on nutrition and chronic diseases of Chinese Residents (2015). Available at: 
http://www.gov.cn/xinwen/2015-06/30/content_2887030.htm 
SAXENDA® [EMA summary of product characteristics (SmPC)]. Novo Nordisk, Bagsvaerd, 
Denmark. Available at: https://ec.europa.eu/health/documents/community-
register/2015/20150323131125/anx_13112 5_en.pdf.  Accessed April 10, 2019.  
SAXENDA® [package insert] Novo Nordisk, Bagsvaerd, Denmark. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206321Orig1s000lbl.pdf. 
Accessed March 2, 2019.  
Skow MA, Bergmann, NC, Knop FK. Diabetes and obesity treatment based on dual incretin 
receptor activation: “twincretins”. Diabetes Obes Metab. 2016;18(9):847-854. 
Steinberg WM, Buse JB, Ghorbani MLM, Ørsted DD, Nauck MA;LEADER Steering 
Committee;LEADER Trial Investigators. Amylase, lipase, and acute pancreatitis in people 
with type 2 diabetes treated with liraglutide: results from the LEADER Randomized Trial. 
Diabetes Care. 2017a;40(7):966-972.  
Steinberg WM, Rosenstock J, Wadden TA, Donsmark M, Jensen CB, DeVries JH. Impact of 
liraglutide on amylase, lipase, and acute pancreatitis in participants with overweight/obesity 
and normoglycemia, prediabetes, or type 2 diabetes: secondary analyses of pooled data from 
the SCALE clinical development program. Diabetes Care. 2017b;40(7):839-848.  
Tomlinson B, Hu M, Zhang Y, Chan P, Liu ZM. An overview of new GLP-1 receptor agonists 
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Warkentin LM, Das D, Majumdar SR, Johnson JA, Padwal RS. The effect of weight loss on 
health-related quality of life: systematic review and meta-analysis of randomized trials. Obes 
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Weinberg ME, Bacchetti P, Rushakoff RJ. Frequentlyrepeated glucose measurements 
overestimate the incidence of inpatient hypoglycemia and severe hyperglycemia. J Diabetes 
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[WHO] World Health Organization. Global Health Observatory (GHO) data – Overweight and 
obesity; 2014. Available at 
https://www.who.int/gho/publications/world_health_statistics/2014/en/. Last accessed 
16August 2019. 

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12. Appendices 

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Appendix 1. Abbreviations and Definitions 
Term 
Definition 
ADA 
anti-drug antibodies 
AE 
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event 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.  
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BG 
blood glucose 
BMI 
body mass index 
BP 
blood pressure 
CHF 
congestive heart failure 
CK 
creatine kinase 
CKD-EPI 
Chronic Kidney Disease-Epidemiology 
CIOMS 
Council for International Organizations of Medical Sciences 
CMV 
Cytomegalovirus 
complaint 
A product complaint is any written, electronic, or oral communication that alleges a 
deficiency related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a Lilly product after it is released for distribution.  When the ability to 
use the product safely is impacted, the following are also product complaints:  
a. 
Deficiencies in labeling information, and 
b. Use errors for device or combination products due to ergonomic design elements of 
the product. 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 

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CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
case report form 
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. 
C-SSRS 
 Columbia-Suicide Severity Rating Scale 
CT 
computed tomography 
D.Bil 
direct bilirubin 
DBP 
diastolic blood pressure 
DPP-4 
dipeptidyl-peptidase-4 
EAS 
efficacy analysis set 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
ED 
early discontinuation 
EDC 
electronic data capture 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
enroll 
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment. 
enter 
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives. 
ERB 
ethical review board 
ERCP 
endoscopic retrograde cholangiopancreatography 
FAS 
full analysis set 
FSG 
fasting serum glucose 
FSH 
follicle-stimulating hormone 
GCP 
good clinical practice 
GGT 
gamma-glutamyl transferase 
GHO 
Global Health Observatory 

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GI 
Gastrointestinal 
GIP 
glucose-dependent insulinotropic polypeptide 
GIPR 
glucose-dependent insulinotropic polypeptide receptor 
GLP-1 
glucagon-like peptide-1 
GLP-1R 
glucagon-like peptide-1 receptor 
HbA1c 
hemoglobin A1c 
HDL 
high-density lipoprotein 
HDV 
hepatitis D virus 
HR 
heart rate 
HRT 
hormonal replacement therapy 
HRQoL 
health-related quality of life 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
Informed consent 
A process by which a patient 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 patient’s decision to participate.  Informed consent is documented by 
means of a written, signed and dated informed consent form. 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked. 
INR 
international normalized ratio 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, 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. 
IRB/IEC 
Institutional Review Boards /Independent Ethics Committees  
ITT 
intent to treat:  The principle that asserts that the effect of a treatment policy can be best 
assessed by evaluating on the basis of the intention to treat a patient (that is, the planned 
treatment regimen) rather than the actual treatment given.  It has the consequence that 
patients allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of 
treatment. 

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IWQOL-Lite-CT 
Impact of Weight on Quality of Life-Lite-Clinical trials 
IWRS 
interactive voice-response system/interactive web-response system 
MDD 
Major Depressive Disorder 
MedDRA 
Medical device 
incident 
Medical Dictionary for Regulatory Activities 
A medical device incident is any malfunction or deterioration in the characteristics 
and/or performance of a device as well as any inadequacy in the labeling or the 
instructions for use which, directly or indirectly, might lead to or might have led to a 
serious injury, death of a participant/user/other person, or to a serious deterioration in 
his/her state of health. 
MEN 
Multiple endocrine neoplasia 
MH 
Mental Health domain 
MHP 
Mental Health Professional 
mITT 
modified intentto-treat 
MMRM 
mixed-model for repeated measures 
MRI 
magnetic resonance imaging 
MRCP 
magnetic resonance cholangiopancreatography 
MTC 
medullary thyroid carcinoma 
NAFLD 
nonalcoholic fatty liver disease 
NYHA 
New York Heart Association 
PC 
Product Complaints 
PCOS 
polycystic ovary syndrome 
PGIS 
Patient Global Impression of status 
PHQ-9 
Patient Health Questionnaire-9 
PK/PD 
pharmacokinetics/pharmacodynamics 
PPS 
per protocol set 
PROs 
patient-reported outcomes 
PT 
prothrombin Time 
QW 
once weekly 
RE 
Role-Emotional domain 

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RP 
Role-Physical domain 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
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.  
SD 
standard deviation 
SF-36 v2 acute form 
Short-Form-36 Health Survey (SF-36), version 2 
SMQ 
Standardized MedDRA Queries 
SS 
Safety analysis set 
SUSARs 
suspected unexpected serious adverse reactions 
T1DM 
type 1 diabetes mellitus 
T2DM 
type 2 diabetes mellitus 
TBL 
total bilirubin level 
TE 
treatment emergent 
TEAE 
treatment-emergent adverse event:  An 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. 
TSH 
thyroid stimulating hormone 
TxP 
treatment period 
TZP 
Tirzepatide 
UADE 
unanticipated problem that resulted in an SAE 
ULN 
upper limit of normal 
VAS 
visual analogue scale 
VLDL 
very low density lipoprotein 
VT 
Vitality domain 

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WHO 
World health organization 
wks 
weeks 
 

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Appendix 2. Clinical Laboratory Tests  
● The tests detailed below will be performed by a central lab unless designed as 
local in the schedule of activities (Section 2) and in the table below. 
● Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
● Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
● Pregnancy Testing (Refer to Section 5.1 Inclusion Criteria for screening 
pregnancy criteria.) 
 
Investigators must document their review of each laboratory safety report.  
 
Laboratory results that could unblind the study will not be reported to 
investigative sites or other blinded personnel. 

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Clinical Laboratory Tests 
Hematologya 
Clinical Chemistrya 
Hemoglobin 
 
Hematocrit 
Sodium 
Erythrocyte count (RBC) 
 
Potassium 
Bicarbonate 
Mean cell volume 
Total bilirubin 
Mean cell hemoglobin concentration 
Direct bilirubin 
Leukocytes (WBC) 
 
Neutrophils, segmented 
Alanine aminotransferase (ALT) 
Lymphocytes 
 
Aspartate aminotransferase (AST) 
Alkaline phosphatase (ALP) 
Monocytes 
Blood urea nitrogen (BUN) 
Eosinophils 
Creatinine 
Basophils 
Uric acid 
Platelets 
Calcium 
 
Glucose 
Urine Chemistriesa 
Albumin 
Albumin 
Creatine kinase (CK) 
Creatinine 
 
 
 
 
Hormones (females) 
 
Pregnancy Testa serum and/or urine (local)b 
 
Follicle-stimulating hormonea,d 
 
Calculationsa 
 
eGFR (calculated by CKD-EPI equation)c 
 
Urine microalbumin/creatinine ratio
Cystatin-Ca 
 
 
Pancreas (exocrine) a 
HbA1ca  
Pancreatic amylase 
 
Lipase 
Endocrinea 
 
Calcitonina 
Immunogenicitya,e 
Thyroid-stimulating hormone (TSH)a 
Tirzepatide anti-drug antibody 
 
Pharmacokinetic Sample 
 
 
 
Lipid Panela  
 
Total cholesterol 
Insulina 
LDL-C 
 
HDL-C 
C-peptidea 
VLDL 
 
Triglycerides 
Free Fatty Acidsa 
 
 
 
Abbreviations:  CKD-EPI = Chronic Kidney Disease-Epidemiology; eGFR = estimated glomerular filtration rate; 
HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; LDL = low-density lipoprotein; PK = 
pharmacokinetics; RBC = red blood cells; VLDL = very low-density lipoprotein; WBC = white blood cells. 

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a All tests will be performed by a Lilly-designated central laboratory, unless otherwise noted. 
b A serum pregnancy test will be performed at Visit 1 for women of childbearing potential only. 
A local urine pregnancy test must be performed at Visit 2 with the result available prior to randomization and 
first injection of study drug(s) for women of childbearing potential only.  Additional pregnancy tests (beyond 
those required per the Schedule of Activities [Section 2]) should be performed at any time during the trial if a 
menstrual period is missed, there is clinical suspicion of pregnancy, or as required by local law or regulation. For 
sites which can’t perform local urine pregnancy test, a local serum pregnancy test can be performed instead. 
c Estimated glomerular filtration rate will be calculated by the central laboratory and included in laboratory result 
reports. 
d Follicle-stimulating hormone test performed at Visit 1 for postmenopausal women at least 40 years of age with 
an intact uterus, not on hormone therapy, and who have had spontaneous amenorrhea for at least 12 months 
without an alternative medical cause. 
e 
Results will not be provided to the investigative sites. 

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Appendix 3. Laboratory Assessments for Hypersensitivity 
Events  
Guidance for laboratory assessments for hypersensitivity events 
 
Laboratory assessments should be performed if the participant experiences generalized 
urticaria or if anaphylaxis is suspected 
 
Collect sample after the participant has been stabilized, and within 1 to 2 hours of the event; 
however, samples may be obtained as late as 12 hours after the event as analytes can remain 
altered for an extended period of time. Record the time at which the sample was collected. 
 
Obtain a follow-up sample at the next regularly scheduled visit or after 4 weeks, whichever 
is later. 
The following table summarizes the laboratory tests for hypersensitivity events. These laboratory 
tests are bundled in the hypersensitivity laboratory testing kit. 
Hypersensitivity Tests 
Notes 
Selected test may be obtained in the event of 
anaphylaxis or systemic allergic/hypersensitivity 
reactions. 
Tirzepatide anti-drug antibodies 
(immunogenicity/ADA) 
Assayed by Lilly-designated laboratory. Results will 
not be provided to the investigative sites. 
Tirzepatide concentrations (PK) 
Assayed by Lilly-designated laboratory. Results will 
not be provided to the investigative sites. 
Tryptase 
Assayed by Lilly-designated laboratory. Results will 
not be provided to the investigative sites. 
Note: If a tryptase sample is obtained more than 2 
hours after the event (that is, within 2 to 12 hours), or 
is not obtained because more than 12 hours have lapsed 
since the event, obtain urine sample for N-
methylhistamine testing. Note that for tryptase serum 
samples obtained within 2 to 12 hours of the event, 
urine Nmethylhistamine testing is performed in 
addition to tryptase testing. Collect the first void urine 
following the event. Obtain a follow-up urine for 
Nmethylhistamine testing at the next regularly 
scheduled visit or after 4 weeks, whichever is later. 
N-methylhistamine 
Assayed by Lilly-designated laboratory. Results will 
not be provided to the investigative sites. 

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Complement (C3, C3a, and C5a) 
Assayed by Lilly-designated laboratory. Results will 
not be provided to the investigative sites. 
Cytokine panel (IL-6, IL-1β, IL-10) 
Assayed by Lilly-designated laboratory. Results will 
not be provided to the investigative sites. 
Abbreviations: ADA = anti-drug antibody; PK = pharmacokinetic. 

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Appendix 4. Study Governance Considerations 
Appendix 4.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Appendix 4.1.1. Informed Consent 
The investigator is responsible for: 
• ensuring that the participants 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 participant or legal 
representative.  This includes obtaining the appropriate signatures and dates 
on the informed consent form (ICF) prior to the performance of any protocol 
procedures and prior to the administration of investigational product. 
• answering any questions the participants may have throughout the study and 
sharing in a timely manner any new information that may be relevant to the 
participant’s willingness to continue his or her participation in the study. 
• ensuring that a copy of the ICF is provided to the participant or the 
participant’s legal representative and is kept on file. 
• ensuring that the medical record includes a statement that written informed 
consent was obtained before the participant was enrolled in the study and the 
date the written consent was obtained.  The authorized person obtaining the 
informed consent must also sign the ICF.  
Appendix 4.1.2. Recruitment 
Lilly or its designee is responsible for the central recruitment strategy for participants.  
Individual investigators may have additional local requirements or processes.  
Appendix 4.1.3. Ethical Review 
The investigator or an appropriate local representative must give assurance that the ethical 
review board (ERB) was properly constituted and convened as required by International Council 
for Harmonisation (ICH) guidelines and other applicable laws and regulations. 
Documentation of ERB 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, 
including any changes made by the ERBs, 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 ERB(s) should be provided with the following: 

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• the protocol and related amendments and addenda, current Investigator 
Brochure (IB) and updates during the course of the study 
• informed consent form  
• other relevant documents (for example, curricula vitae, advertisements) 
Appendix 4.1.4. Regulatory Considerations 
This study will be conducted in accordance with the protocol and with the: 
• consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines 
• applicable ICH GCP Guidelines 
• applicable laws and regulations 
Some of the obligations of the sponsor will be assigned to a third party. 
Appendix 4.1.5. Investigator Information 
Physicians with a specialty in endocrinology, cardiology, nephrology, internal medicine, family 
medicine, general medicine, or any other qualified physician with clinical research experience 
will participate as investigators in this clinical trial. 
Appendix 4.1.6. 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. 
Appendix 4.1.7. Final Report Signature 
The clinical study report (CSR) coordinating investigator will sign the final CSR for this study, 
indicating agreement that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study. 
The investigator with the most qualified participants will serve as the CSR coordinating 
investigator.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the CSR coordinating investigator. 
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study. 
Appendix 4.2. Data Quality Assurance 
To ensure accurate, complete, and reliable data, Lilly or its representatives will: 

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• provide instructional material to the study sites, as appropriate 
• provide sponsor start-up training to instruct the investigators and study coordinators.  
This training will provide instruction on the protocol, the completion of the electronic 
case report forms (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, and 
• review and verify data reported to detect potential errors.  
In addition, Lilly or its representatives will periodically check a sample of the participant data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives 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 ERBs with direct access to original source 
documents. 
Appendix 4.2.1. Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
An electronic data capture (EDC) system will be used in this study for the collection of CRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Additionally, clinical outcome assessment data (scales, self-reported diary data) will be collected 
by the subject/investigator site personnel, via a paper source document and will be transcribed by 
the investigator site personnel into the EDC system. 
Data collected via the sponsor-provided data capture systems will be stored at third parties.  The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture systems.  Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and electronic transfers will be provided to the investigator 
for review and retention.  Data will subsequently be transferred from the central vendor to the 
Lilly data warehouse. 
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system. 
Appendix 4.3. Study and Site Closure 

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Appendix 4.3.1. Discontinuation of Study Sites 
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP. 
Appendix 4.3.2. 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. 
Appendix 4.4. Publication Policy 
• 
The sponsor will comply with the requirements for publication of study results.  
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
• 
The publication policy for Study I8F-MC-GPIA is described in the Clinical Trial 
Agreement. 
 
Appendix 4.5. Data Protection 
• 
Participants will be assigned a unique identifier by the investigator.  Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information, which would make the participant identifiable 
will not be transferred. 
• 
The participant must be informed that his or her personal study-related data will be used 
by the sponsor in accordance with local data protection law.  The level of disclosure 
must also be explained to the participant. 
• 
The participant must be informed that his or her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
 
Appendix 4.6. Source Documents 
• 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained.  The investigator may need to request previous medical records or transfer 
records, depending on the study.  Also, current medical records must be available. 

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Appendix 5. Liver Safety: Suggested Actions and Follow-
Up Assessments 
Hepatic Evaluation Testing – Refer to protocol Hepatic Safety Monitoring Section 9.4.6.1 for 
guidance on appropriate test selection. 
• The Lilly-designated central laboratory must complete the analysis of all selected testing 
except for microbiology testing. 
• Local testing may be performed in addition to central testing when necessary for 
immediate patient management. 
• 
Results will be reported if a validated test or calculation is available. 
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs - Red Blood Cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs - White Blood Cells)  
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
    Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
    Lymphocytes 
Creatine kinase (CK) 
    Monocytes 
Other Chemistry   
    Basophils 
Acetaminophen 
    Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl Alcohol (EtOH) 
 Prothrombin Time, international normalized ratio 
(PT-INR) 
Haptoglobin 
Serology 
Immunoglobulin IgA (quantitative) 
Hepatitis A Virus (HAV) Testing: 
Immunoglobulin IgG (quantitative) 
    HAV Total Antibody 
Immunoglobulin IgM (quantitative) 
    HAV IgM Antibody 
Phosphatidylethanol (PEth) 
Hepatis B Virus (HBV) Testing: 
Urine Chemistry 
    Hepatitis B surface antigen (HBsAg) 
Drug Screen 
    Hepatitis B surface antibody (anti-HBs)  
Ethyl glucuronide (EtG) 
    Hepatitis B core total antibody (anti-HBc) 
Other Serology 

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    Hepatitis B core IgM antibody  
Anti-nuclear antibody (ANA) 
    Hepatitis B core IgG antibody  
Anti-smooth muscle antibody (ASMA) a 
    HBV DNA d 
Anti-actin antibody b 
Hepatis C Virus (HCV) Testing: 
Epstein-Barr Virus (EBV) Testing: 
    HCV antibody 
    EBV antibody 
    HCV RNA d 
    EBV DNA d 
Hepatitis D Virus (HDV) Testing: 
Cytomegalovirus (CMV) Testing: 
    HDV antibody 
    CMV antibody 
Hepatitis E Virus (HEV) Testing: 
    CMV DNA d 
    HEV IgG antibody 
Herpes Simplex Virus (HSV) Testing: 
    HEV IgM antibody 
    HSV (Type 1 and 2) antibody  
    HEV RNA d 
    HSV (Type 1 and 2) DNA d 
Microbiology c 
Liver Kidney Microsomal Type 1 (LKM-1) Antibody 
Culture: 
 
    Blood 
 
    Urine 
 
a Not required if anti-actin antibody is tested. 
b Not required if anti-smooth muscle antibody (ASMA) is tested. 
c Assayed ONLY by Investigator-designated local laboratory ONLY; no central testing available. 
d Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 

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Appendix 6. Adverse Events: Definitions and Procedures 
for Recording, Evaluating, Follow up, and Reporting 
Appendix 6.1. Special Safety Topics 
Appendix 6.1.1. Hypoglycemia  
Upon informed consent form (ICF) signing, all participants will be educated about signs and 
symptoms of hypoglycemia, how to treat hypoglycemia, and how to collect appropriate 
information for each episode of hypoglycemia. 
Hypoglycemia may be identified by spontaneous reporting of symptoms from participants 
(whether confirmed or unconfirmed by simultaneous glucose values) or by blood glucose (BG) 
samples collected during study visits.  All participants who develop T2DM during the study will 
be provided with glucometers.  Participants without diabetes may, at the investigator’s 
discretion, be given glucometers to assist in the evaluation of reported symptoms consistent with 
hypoglycemia. Participants receiving glucometers will be provided a diary to record relevant 
information (for example, glucose values, symptoms). 
Hypoglycemic episodes will be recorded on a specific electronic case report form (eCRF) and 
should not be recorded as adverse events (AEs) unless the event meets serious criteria.  If a 
hypoglycemic event meets severe criteria (see definition below), it should be recorded as serious 
on the AE and serious AE (SAE) eCRFs, and reported to Lilly as an SAE. 
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the plasma glucose [PG] values in this 
section refer to values determined by a laboratory or International Federation of Clinical 
Chemistry and Laboratory Medicine blood-equivalent glucose meters and strips) in accordance 
with the 2019 American Diabetes Association position statement on glycemic targets (American 
Diabetes Association 2019a): 
Glucose Alert Value (Level 1): 
• Documented symptomatic hypoglycemia is defined as any time a patient 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): 

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• Documented symptomatic hypoglycemia is defined as any time a participant 
feels that he or she is experiencing symptoms and/or signs associated with 
hypoglycemia and has a BG 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 BG <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 BG 
<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. 
To avoid duplicate reporting, all consecutive BG 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). 
Appendix 6.1.2. Pancreatitis 
Acute pancreatitis is defined as an AE of interest in all trials with tirzepatide, including this trial.  
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 upper limit of 
normal (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 central laboratory (and locally, if needed).  
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 participant must discontinue therapy with tirzepatide, but will 

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continue in the study.  A review of the participant’s concomitant medications should be 
conducted to assess any potential causal relationship with pancreatitis. 
Each 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 study drug(s). 
Each participant will have measurements of p-amylase and lipase (assessed at the central 
laboratory) as shown on the Schedule of Activities (Section 2) to assess the effects of the 
investigational doses of tirzepatide on pancreatic enzyme levels.  Serial measures of pancreatic 
enzymes have limited clinical value for predicting episodes of acute pancreatitis in asymptomatic 
participants (Nauck et al. 2017; Steinberg et al. 2017a, 2017b).  Thus, further diagnostic 
follow-up of cases of asymptomatic pancreatic hyperenzynemia (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 participant’s overall clinical condition.  Only cases of pancreatic 
hyperenzynemia that undergo additional diagnostic follow-up and/or are accompanied by 
symptoms suggestive of pancreatitis will be submitted for adjudication. 
All suspected cases of acute or chronic pancreatitis will be adjudicated by an independent 
clinical endpoint committee.  In addition, 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 participants with acute or chronic pancreatitis 
and those with severe or serious abdominal pain will be entered into a specifically designed 
eCRF page.  The adjudication committee representative will enter the results of adjudication in a 
corresponding eCRF page. 
Appendix 6.1.3. Thyroid Malignancies and C-Cell Hyperplasia 
Individuals with personal or family history of medullary thyroid carcinoma (MTC) and/or 
Multiple Endocrine Neoplasia syndrome type 2 (MEN-2) will be excluded from the study.  
Participants are diagnosed with MTC and/or MEN-2 during the study will have study drug 
stopped and should continue follow-up with an endocrinologist. 
The assessment of thyroid safety during the trial will include reporting of any case of thyroid 
malignancy (including MTC and papillary carcinoma) and measurements of calcitonin.  This 
data will be captured in specific eCRFs.  The purpose of calcitonin measurements is to assess the 
potential of tirzepatide to affect thyroid C-cell function, which may indicate development of 
C-cell hyperplasia and neoplasms.  
Appendix 6.1.4. Calcitonin Measurements 
If an increased calcitonin value (see definitions below) is observed in a participant who has been 
administered a medication that is known to increase serum calcitonin, then this medication 
should be stopped and calcitonin levels should be measured after an appropriate washout period. 

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For participants who require additional endocrine assessment because of increased calcitonin 
concentration as defined in this section, data from the follow-up assessment will be collected in 
the specific section of the eCRF. 
Calcitonin Measurements in Participants with eGFR ≥60 mL/min/1.73 m2  
A significant increase in calcitonin for participants with estimated glomerular filtration rate 
(eGFR) ≥60 mL/min/1.73 m2 is defined below.  If a participant’s laboratory results meet these 
criteria, these clinically significant laboratory results should be recorded as an AE.   
• calcitonin value ≥20 ng/L and <35 ng/L AND ≥50% increase from the screening value.  
These participants will be asked to repeat the measurement within 1 month.  If this repeat 
value is increasing (≥10% increase), the study drug should be stopped, and the participant 
encouraged to undergo additional endocrine assessment and longer-term follow-up by an 
endocrinologist to exclude any serious adverse effect on the thyroid. 
• calcitonin value ≥35 ng/L AND ≥50% over the screening value.  In these participants, 
study drug should be stopped, and the participant recommended to immediately undergo 
additional endocrine assessments and longer-term follow-up by an endocrinologist. 
Calcitonin Measurement in Participants with eGFR <60 mL/min/1.73 m2  
A significant increase in calcitonin for participants with eGFR <60 mL/min/1.73 m2 is defined as 
a calcitonin value ≥35 ng/L AND ≥50% over the screening value.  If a participant’s labs meet 
these criteria, these clinically significant labs should be recorded as an AE. 
In these participants, study drug should be discontinued (after first confirming the value) and the 
participant recommended to immediately undergo additional endocrine assessments and longer-
term follow-up by an endocrinologist to exclude any serious adverse effect on the thyroid. 
Appendix 6.1.5. Major Adverse Cardiovascular Events 
Deaths and nonfatal cardiovascular AEs will be adjudicated by a committee of physicians 
external to Lilly with cardiology expertise.  This committee will be blinded to treatment 
assignment.  The nonfatal cardiovascular AEs to be adjudicated include 
• myocardial infarction 
• hospitalization for unstable angina 
• hospitalization for heart failure 
• coronary interventions (such as coronary artery bypass graft or percutaneous coronary 
intervention), and  
• cerebrovascular events, including cerebrovascular accident (stroke) and transient 
ischemic attack. 
Appendix 6.1.6. Supraventricular Arrhythmias and Cardiac Conduction Disorders 
Treatment-emergent cardiac conduction disorders will be further evaluated.  Participants who 
develop any event from these groups of disorders should undergo an ECG, which should be 
submitted to the central reading center.  Additional diagnostic tests to determine exact diagnosis 

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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 must be reported as SAEs.  
Appendix 6.1.7. Hypersensitivity Events  
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions.  If such a reaction occurs, additional data describing each symptom should be provided 
to the sponsor in the eCRF.   
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study drug. It is recommended that participants 
who experience a systemic hypersensitivity reaction be treated per the local standard of care.   
In the case of generalized urticaria or anaphylaxis, additional blood and urine samples should be 
collected as described in Appendix 3. Laboratory results are provided to the sponsor via the 
central laboratory.  
All allergic or hypersensitivity reactions will be reported by the investigator as either AEs or, if 
any serious criterion is met, as SAEs.  Study drug(s) should be temporarily interrupted in any 
individual suspected of having a severe or serious allergic reaction to study drug(s).  Study 
drug(s) may be restarted when/if it is safe to do so, in the opinion of the investigator. 
Appendix 6.1.8. Injection Site Reactions 
Injection site reactions will be collected on the eCRF separate from the hypersensitivity reaction 
eCRF.  At the time of AE occurrence, samples may be collected if possible for measurement of 
tirzepatide antidrug antibody (ADA) and tirzepatide concentration. 
Appendix 6.1.9. Antidrug Antibodies 
The occurrence of ADA formation will be assessed as outlined in Section 9.4.4. 
Appendix 6.1.10. 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 8. 
Appendix 6.1.11. Severe Gastrointestinal Adverse Events 
Tirzepatide may cause severe gastrointestinal (GI) AEs, such as nausea, vomiting, and diarrhea.  
Information about severe GI AEs as well as antiemetic/antidiarrheal use will be collected in the 
eCRF/AE form.  For detailed information concerning the management of GI AEs, please refer to 
Section 7.4.2. 
Appendix 6.1.12. Acute Renal Events 
Renal safety will be assessed based on repeated renal functional assessment as well as 
assessment of AEs suggestive of acute or worsening of chronic renal failure.  Gastrointestinal 
AEs have been reported with tirzepatide, including nausea, diarrhea, and vomiting.  This is 
consistent with other glucagon‑like peptide‑1 receptor (GLP-1R) agonists (Aroda and Ratner 

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2011).  The events may lead to dehydration, which could cause a deterioration in renal function, 
including acute renal failure.  Participants should be advised to notify investigators in case of 
severe nausea, frequent vomiting, or symptoms of dehydration. 
Appendix 6.1.13. Depression, Suicidal Ideation or Behavior Monitoring 
Participants will be monitored for depression and suicidal ideation or behavior through AE 
collection and by using the Columbia-Suicide Severity Rating Scale (C-SSRS) and the Patient 
Health Questionnaire-9 (PHQ-9).  Participants will be referred to a Mental Health Professional 
(MHP) if in the opinion of the investigator it is necessary for the safety of the participant or if the 
participant had any of the following: 
• a PHQ-9 score ≥ 15 
• C-SSRS responses of  
o A “yes” answer to either Question 4 (Active Suicidal Ideation with Some Intent to 
Act, Without Specific Plan) 
or 
o A “yes” answer to Question 5 (Active Suicidal Ideation with Specific Plan and 
Intent) on the “Suicidal Ideation” portion of the C-SSRS 
or 
o 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. 

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Appendix 7. Contraceptive Guidance and Collection of 
Pregnancy Information 
Definitions 
Woman of Childbearing Potential: 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (for example; amenorrhea in athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered woman of childbearing potential: 
Article I. Premenarchal 
Article II. Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (for example; mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry. 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
Article III. Postmenopausal female 
• A postmenopausal state is defined as either 
• A woman at least 40 years of age with an intact uterus, not on hormone 
therapy, who has cessation of menses for at least 1 year without an alternative 
medical cause, AND a follicle-stimulating hormone (FSH) ≥40 mIU/mL; or  
• A woman 55 or older not on hormone therapy, who has had at least 12 months 
of spontaneous amenorrhea; or  
• A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy.  
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Guidance 
Contraceptive use by men and women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.   
Two forms of effective contraception, where at least 1 form is highly effective, will be used.  
Effective contraception may be used as the second therapy.  Barrier protection methods without 

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concomitant use of a spermicide are not a reliable or acceptable method.  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. 
Highly Effective Methods of Contraception: 
• Combined oral contraceptive pill and mini pill 
• NuvaRing 
• Implantable contraceptives 
• Injectable contraceptives (such as Depo-Provera®)  
• Intrauterine device (such as Mirena® and ParaGard®) 
• Contraceptive patch – ONLY women <198 pounds or 90 kg 
• Total abstinence (if this is their preferred and usual lifestyle) or in a same-sex relationship 
with no sexual relationship with males (as part of their preferred and usual lifestyle), and 
agrees to maintain this status throughout trial follow-up. 
Note:  periodic abstinence (for example, calendar, ovulation, symptothermal, postovulation 
methods), declaration of abstinence just for the duration of a trial, and withdrawal are not 
acceptable methods of contraception 
• Vasectomy – for men in clinical studies 
Note: Implantable contraceptives and injectable contraceptives (such as Depo-Provera®) are only 
permitted if started more than 18 months prior to screening.  Participants should not start these 
methods of contraception after being enrolled in the study. 
Effective Methods of Contraception (must use combination of 2 methods): 
• Male condom with spermicide 
• Female condom with spermicide 
• Diaphragm with spermicide 
• Cervical sponge 
• Cervical cap with spermicide 
Men, regardless of their fertility status, with nonpregnant women of child-bearing potential 
partners must agree to either remain abstinent (if this is their preferred and usual lifestyle) or use 
condoms plus one additional highly effective (less than 1% failure rate) method of contraception 
(such as combination oral contraceptives, implanted contraceptives or intrauterine device) or 
effective method of contraception (such as diaphragms with spermicide or cervical sponge) for 
the duration of the study and for 5 half-lives of study drug plus 90 days, which is approximately 
4 months after the last injection.   Periodic abstinence (for example, calendar, ovulation, 
symptothermal, and postovulation methods), declaration of abstinence just for the duration of a 
trial, 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 women of childbearing potential.  

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Men 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 females (usual 
lifestyle). In these situations, men are not required to use contraception.  
Men should refrain from sperm donation for the duration of the study and for 5 half-lives of 
study drug plus 90 days after the last dose of study drug, corresponding to 4 months after the last 
injection. 
Collection of Pregnancy Information 
Male participants with partners who become pregnant: 
• 
The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study.  
• 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy.  The female 
partner will also be followed to determine the outcome of the pregnancy.  Information on the 
status of the mother and child will be forwarded to the sponsor.  Generally, the follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date.  Any termination 
of the pregnancy will be reported regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure.  
Female Participants who become pregnant: 
• The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study.  Information will be recorded on the appropriate 
form and submitted to the sponsor within 24 hours of learning of a participant’s pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy.  The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the Sponsor.  Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date.  Any termination of pregnancy 
will be reported, regardless of fetal status (presence or absence of anomalies) or indication 
for the procedure. 
• While pregnancy itself is not considered to be an adverse event (AE) or serious adverse 
event (SAE), any pregnancy complication or elective termination of a pregnancy will be 
reported as an AE or SAE.  A spontaneous abortion is always considered to be an SAE and 
will be reported as such.  Any poststudy pregnancy-related SAE considered reasonably 
related to the study intervention by the investigator will be reported to the sponsor as 
described in Section 9.2.4.  While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 

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Appendix 8. Protocol GPIA Standardized Protocols for the 
Measurement of Height, Weight, Waist Circumference, 
Vital Signs and Electrocardiogram 
The following information has been adapted from standardized physical measurement protocols 
for the World Health Organization’s STEPwise approach to Surveillance (STEPS) (WHO 2008)   
Measuring Height 
Step 1. Ask the participant to remove their footwear and any headgear (light headgear worn for 
religious reasons can remain, but this should be worn by the participant at every clinic visit when 
their height is measured). 
Step 2. Ask the participant to stand on the calibrated height measuring board (stadiometer) or 
against a wall with their feet together and their knees straight with their heels against the 
backboard, the stadiometer or the wall. 
Step 3. Ask the participant to look straight ahead without tilting their head up. 
Step 4. Ask the participant to breathe in and stand tall.  Measure and record the participant’s 
height in centimeters (cm) to 1 decimal place.  
 
Measuring Weight 
• Body weight measurements should be done in a consistent manner using a calibrated 
electronic scale capable of measuring weight in kilograms (kg) to one decimal place. 
• All weights for a given participant should be measured using the same scale, whenever 
possible, at approximately the same time in the morning after evacuation of bladder 
contents. 
• Body weight must be measured in fasting state.  If the participant is not fasting, the 
participant should be called in for a new visit within the visit window to have the 
fasting body weight measured. 
Step 1. Ask the participant to remove their footwear, outerwear (coat, jacket, etc.), any headgear 
(light headgear worn for religious reasons can remain, but this should be worn by the participant 
at every clinic visit when weight is measured). 
Step 2. Make sure the scale is placed on a firm, flat, even surface (not on carpet, on a sloping 
surface, or a rough, uneven surface). 
Step 3. Ask the participant to step onto the scale with 1 foot on each side of the scale. 
Step 4. Ask the participant to stand still with arms by sides and then record weight in kilograms 
(kg) to the nearest one-tenth kg. 
 

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Measuring Waist Circumference 
• Waist circumference should be measured in the horizontal plane and at the midpoint between 
the lower margin of the last palpable rib and the top of the iliac crest. 
• Measurements should be taken at the end of a normal expiration using a non-stretchable 
measuring tape.  The tape should lie flat against the skin without compressing the soft tissue. 
• 
The waist circumference should be measured twice, rounded to the nearest 0.5 cm.  The 
measuring tape should be removed between the 2 measurements.  Both measurements will be 
recorded in the eCRF.  If the difference between the 2 measurements exceeds 1 cm, this set 
of measurements should be discarded and the 2 measurements repeated. 
Step 1:  Ask the participant to wear light clothing (if available, patient gowns could also be 
used). 
Step 2:  Ask the participant to stand with their feet close together, arms at their side, body weight 
evenly distributed. 
Step 3:  Ask the participant to relax and measure the participant’s waste circumference. 
 
Vital Sign Measurements (blood pressure and heart rate) 
• Vital sign measurements (blood pressure and heart rate, measured by pulse) should be 
taken before obtaining an electrocardiogram (ECG) tracing and before collection of blood 
samples for laboratory testing 
• The participant should sit quietly for 5 minutes before vital signs measurements are taken 
• For each parameter, 3 measurements will be taken using the same arm, preferably the 
nondominant arm 
• The recordings should be taken at least 1 minute apart. Each measurement of sitting pulse 
and BP needs to be recorded in the electronic case report form (eCRF) 
• Blood pressure must be taken with an automated blood pressure instrument. 
• If blood pressure and pulse measurements are taken separately, pulse should be taken 
prior to blood pressure.  
Note: In the event pulse measurement cannot be taken via an automated blood pressure 
instrument, the preferred location for measurement of pulse is the radial artery. 
 
Electrocardiogram 
• All digital ECGs will be obtained using centrally provided ECG machines and will be 
electronically transmitted to a designated central ECG laboratory. 
• 12-lead ECGs should be obtained after the participant has rested in a supine position for 
at least 10 minutes. 
• Electrocardiograms should be collected at least 30 minutes prior to collection of blood 
samples for laboratory testing, including PK samples. 

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Appendix 9. Management of Gastrointestinal Symptoms 
 
Abbreviations: GI = gastrointestinal; IWRS = interactive web-response system.

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Appendix 10. Provisions for Changes in Study Conduct 
During Exceptional Circumstances 
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study.  
Examples include pandemics or natural disasters.  These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations.  
The Sponsor and study investigators will notify Ethical Review Boards (ERBs) as early as 
possible to communicate implementation of changes in study conduct due to exceptional 
circumstances.  To protect the safety of study participants, urgent changes may be implemented 
before such communications are made, but all changes will be reported as early as possible 
following implementation. 
After approval by local ERBs, regulatory bodies and any other relevant local authorities, 
implementation of these exceptional circumstance changes will not typically require additional 
notification to these groups, unless they have specific requirements in which notification is 
required (for example, upon implementation and suspension of changes).  All approvals and 
notifications must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants.  
Additional important considerations for making a change are compliance with Good Clinical 
Practice, enabling participants to continue safely in the study and maintaining the integrity of the 
study. 
Informed consent 
Additional consent from the participant will be obtained, if required, for: 
• participation in remote visits, as defined in Section “Remote Visits,” 

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• dispensation of additional study intervention during an extended treatment period,  
• alternate delivery of study intervention and ancillary supplies, and 
• provision of their personal or medical information required prior to implementation of 
these activities. 
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 
Remote visits 
Types of remote visits 
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments.  Assessments to be completed in this manner include, 
but are not limited to, concomitant medications, review study participant diary (including 
study drug compliance), review diet and exercise goals, Columbia-Suicide Severity 
Rating Scale (C-SSRS, Since Last Visit Version), Self-Harm Supplement Form, Self-
Harm Follow-up Form (if applicable), and Patient Health Questionnaire 9 (PHQ-9). 
Data capture 
In source documents and the case report form (CRF), the study site should capture the visit 
method, with a specific explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, serious adverse events (SAEs), and product complaints remain unchanged.  
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing.  However, central 
laboratory testing must be retained for hypersensitivity, immunogenicity and pharmacokinetic 
analyses as described in Section 9.4.4 and Appendix 3.  The local laboratory must be qualified in 
accordance with applicable local regulations.  Clinically significant laboratory findings that meet 
the definition of an adverse event must be recorded in the AE eCRF. 
Study intervention and ancillary supplies (including participant diaries) 

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When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the sponsor to determine appropriate actions.  These actions may 
include:   
• asking the participant to go to the site and receive study supplies from site staff 
without completion of a full study visit,  
• asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf,  
• arranging delivery of study supplies. 
These requirements must be met before action is taken: 
• Alternate delivery of study intervention should be performed in a manner that does 
not compromise treatment blinding and ensures product integrity.  The existing 
protocol requirements for product accountability remain unchanged, including 
verification of participant’s receipt of study supplies. 
• When delivering supplies to a location other than the study site (for example, 
participant’s home), the investigator, sponsor, or both should ensure oversight of 
the shipping process to ensure accountability and product quality (that is, storage 
conditions maintained and intact packaging upon receipt). 
• Instructions may be provided to the participant or designee on the final disposition 
of any unused or completed study supplies. 
 
Adjustments to visit windows  
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual Schedule of Activities.  To maximize the possibility that these visits 
can be conducted as on-site visits, minimize missing data, and preserve the intended conduct of 
the study, the windows for visits may be adjusted, upon further guidance from the sponsor.  This 
minimizes missing data and preserves the intended conduct of the study. 
 
This table describes the allowed adjustments to visit windows. 
Visit 
Number 
Tolerance 
Visit 15 or 
Visit 99 
The visit window may be brought forward within 14 days 
before the intended date, or extended up to 28 days after 
the intended date, upon specific guidance from the 
Sponsor. 
 
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study.  
Documentation 
Changes to study conduct will be documented 

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Sites will identify and document the details of how participants, visits types, and conducted 
activities were affected by exceptional circumstances.  Dispensing/shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
Source documents at alternate locations 
Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner. 

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Appendix 11. Protocol Amendment [I8F-MC-GPIA(a)] 
Summary [Efficacy and Safety of Tirzepatide Once 
Weekly in Chinese Participants without Type 2 Diabetes 
Who Have Obesity or are Overweight with Weight-
Related Comorbidities: A Randomized, Double-Blind, 
Placebo-Controlled Trial (SURMOUNT-CN)] 
Overview 
Protocol I8F-MC-GPIA(a) titled “Efficacy and Safety of Tirzepatide Once Weekly in Chinese 
Participants without Type 2 Diabetes Who Have Obesity or are Overweight with Weight-Related 
Comorbidities: A Randomized, Double-Blind, Placebo-Controlled Trial (SURMOUNT-CN)” 
has been amended.  The new protocol is indicated by amendment (a) and will be used to conduct 
the study in place of any preceding version of the protocol. 
The overall changes and rationale for the changes made to this protocol are described in the 
following table: 
Amendment Summary for Protocol I8F-MC-GPIA Amendment (a) 
Section # and Name 
Description of Change 
Brief Rationale 
2. Schedule of Activities 
Added an activity entitled 
“register study visit in IWRS” 
Activity was added to ensure all 
visits are registered, which allows 
monitoring of study activities 
using IWRS reports timely. 
2. Schedule of Activities 
Added a sentence to footnote v 
“The Self-Harm Supplement 
Form is only required if 
responses to the C-SSRS indicate 
that the patient needs to be 
further evaluated for self-harm 
risk.” 
 
Revised the wording in footnote 
w “Self-Harm forms will be 
completed by participants” to 
“Self-Harm forms will be 
completed by investigators”. 
Footnote v was revised to provide 
a clear instruction on the 
condition of completing Self-
Harm forms. 
 
Footnote w was revised to correct 
the error in the original protocol. 
2. Schedule of Activities 
and 
5.1.1.2.2 Treatment Period 
Removed activities for hand out 
diary at Visit 15 and Visit 99. 
The activities were removed to 
correct errors in the original 
protocol. 
7.1 Treatment Administered 
Added a footnote to Table 
GPIA.3 Treatment regimen. 
The footnote was added to 
provide a clear instruction on 
Tirzepatide dose escalation. 

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7.4.2 Management of Participants 
with Gastrointestinal Symptoms 
Revised the sentence “for 
example, 15 mg reduced to 10 
mg or 10 mg reduced to placebo” 
to “for example, 15 mg and 12.5 
mg reduced to 10 mg, 10 mg or 
lower reduced to placebo, the 
lower dose will be maintained for 
the rest of the study, with no re-
escalation allowed” 
The wording was rephrased to 
provide a more clear instruction 
on dose reduction. 
9.4.6.1 Hepatic Safety 
Monitoring 
For participants with baseline 
total bilirubin (TBL)≥1.5x upper 
limit of normal (ULN), close 
hepatic monitoring evaluation 
was changed to 
“TBL≥1.5xbaseline”, while 
comprehensive hepatic 
evaluation was changed to 
“TBL≥2xbaseline”. 
The evaluations were changed to 
correct the errors in original 
protocol, and be consistent with 
global patient safety standard 
language. 
Appendix 7. Contraceptive 
Guidance and Collection of 
Pregnancy Information 
Note regarding follicle 
stimulating hormone levels used 
to confirm a postmenopausal 
state in women has been deleted. 
The note could lead to 
misinterpretation of inclusion 
criterion 4. 
Appendix 7. Contraceptive 
Guidance and Collection of 
Pregnancy Information 
Added text “started more than” 
The sentence was revised to 
maintain consisitency with the 
text from the exclusion criteria. 
Appendix 10. Provisions for 
Changes in Study Conduct 
During Exceptional Circumstance 
An appendix describing 
mitigation for exceptional 
circumstances was added as 
Appendix 10. 
Language was added to address 
exceptional circumstances due to 
unforeseen widespread 
emergencies (such as pandemics 
or natural disasters). 
 

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Revised Protocol Sections 
Note: 
Deletions have been identified by strikethroughs. 
Additions have been identified by the use of underscore. 
2. Schedule of Activities 
The Schedule of Activities described below should be followed for all participants enrolled in 
Study GPIA.  However, for those participants whose participation in this study is affected by 
exceptional circumstances (such as pandemics or natural disasters), please refer to Appendix 10 
for additional guidance. 

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Table GPIA.1. 
Schedule of Activities 
Visita 
1 
2b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
99c 
EDd 
801e 
Week of Treatment 
-2 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
52 
 4 wks Post 
TxP 
Allowable Deviation (days)f 
 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±3 
±3 
±7 
±3 
±7 
±3 
±7 
±7 
 
±7 
Fasting (>8 hours) Visita 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
  
X 
 
X 
X 
X 
X 
Telephone Visit 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Register study visit in IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Assessment 
Medical historyg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weighth 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
Waist circumference 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
Electrocardiogrami 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
Vital signs (3 sitting BP 
and HR)j 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Participant Education and Assessment 
Hand out diary, instruct in 
usek 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
 
v The C-SSRS, Self-Harm Supplement Form and PHQ-9 should be administered after assessment of adverse events.  For this study, the C-SSRS is adapted for 
the assessment of the ideation and behavior categories only.  The Intensity of Ideation and Lethality of Behavior sections are removed.  The C-SSRS 
questionnaire will be completed by site staffinvestigators, while PHQ-9 will be completed by participants.  The Self-Harm Supplement Form is only required 
if responses to the C-SSRS indicate that the patient needs to be further evaluated for self-harm risk. 
w Self-Harm Follow-up Form is only required if triggered by the Self-Harm Supplement Form, per instructions in the form. Self-Harm forms will be completed 
by participantsinvestigators. 

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5.1.1.2.2. Treatment Period 
Visit 99 
Participants should attend this visit in the fasting state.  Procedures to be completed are: 
• measurement of weight and waist circumference 
• listing of concomitant medications 
• urine pregnancy test 
• hand out diary and instruct in use 
• assessment of AEs, and  
• completion of the mental health questionnaires (after the AE assessment) 
 
7.1 Treatments Administered 
This study involves a comparison of 10 mg and 15 mg tirzepatide administered by subcutaneous 
injection once weekly with placebo.  Table GPIA.3 shows the treatment regimens. 
Table GPIA.3. 
Treatment Regimens 
ARM Name 
Tirzepatide 10 mg 
Tirzepatide 15 mg 
Placebo 
Dosea 
10 mg QW 
15 mg QW 
N/A 
Route of Administration 
SC 
SC 
SC 
Sourcing 
Provided centrally by the Sponsor and dispensed via IWRS 
Abbreviations:  IWRS = interactive web response service; N/A= not available, QW= once-weekly, SC= 
subcutaneous 
a Tirzepatide treatment will follow a fixed dose escalation that initiated at 2.5 mg QW for 4 weeks and increased 
by 2.5 mg every 4 weeks (2.5 mg to 5 mg to 7.5 mg to 10 mg to 12.5 mg to 15 mg) until the desired dose is 
achieved and maintained for the duration of the study. 
 
7.4.2. Management of Participants with Gastrointestinal Symptoms 
Participants who experience intolerable GI symptoms (for example: nausea, vomiting, or 
diarrhea) at any time during the study, should first be counselled on dietary behaviors that may 
help mitigate nausea and vomiting, (for example, eating smaller meals, splitting 3 daily meals 
into 4 or more smaller ones, and stopping eating when they feel full).  If symptoms persist, the 
participant should be prescribed, at the investigator’s discretion, symptomatic medication (for 
example, antiemetic or antidiarrheal medication).  A temporary interruption of study drug for 1 
dose is permitted, provided the participant has taken the last 3 weekly doses.  Study treatment 
should be resumed at the assigned dose immediately, either alone or in combination with 

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symptomatic medication (Appendix 9).  Management of study drug after interruptions >1 dose is 
discussed in Section 8.1.2. 
If intolerable GI symptoms (for example, nausea, vomiting, or diarrhea) persist despite the above 
measures, the investigator should contact Lilly to consider reinitiating study drug at the next 
lowest maintenance dose in a blinded fashion (for example, 15 mg and 12.5 mg reduced to 10 
mg, or 10 mg or lower reduced to placebo, the lower dose will be maintained for the rest of the 
study, with no re-escalation allowed). 
 
9.4.6.1. Hepatic Safety Monitoring 
9.4.6.1.1. Close Hepatic Monitoring 
Laboratory tests (Appendix 2), including ALT, AST, ALP, TBL, direct bilirubin (D. Bil), 
gamma-glutamyl transferase (GGT), and creatine kinase (CK), should be repeated within 48 to 
72 hours to confirm the abnormality and to determine if it is increasing or decreasing, if one or 
more of these conditions occur: 
If a participant with baseline results 
of:  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN 
ALP <1.5x ULN 
ALP ≥2x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for patients with Gilbert’s 
syndrome) 
 
 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥1.52x baseline (except for patients with Gilbert’s 
syndrome) 
Abbreviations: ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST= aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal. 
9.4.6.1.2. Comprehensive hepatic evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions occur: 
If a participant with baseline 
results of... 
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN with hepatic signs/symptoms*, or  
ALT or AST ≥5x ULN 
ALP <1.5x ULN 
ALP ≥3x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for patients with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline with hepatic signs/symptoms*, or 
ALT or AST ≥3x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥21.5x baseline (except for patients with Gilbert’s syndrome)  

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* Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
Abbreviations: ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST= aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal. 
 
Appendix 7. Contraceptive Guidance and Collection of Pregnancy Information 
Women in the following categories are not considered woman of childbearing potential: 
Article I. Premenarchal 
Article II. Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (for example; mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry. 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
Article III. Postmenopausal female 
• A postmenopausal state is defined as either 
• A woman at least 40 years of age with an intact uterus, not on hormone 
therapy, who has cessation of menses for at least 1 year without an alternative 
medical cause, AND a follicle-stimulating hormone (FSH) ≥40 mIU/mL; or  
• A woman 55 or older not on hormone therapy, who has had at least 12 months 
of spontaneous amenorrhea; or  
• A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy.  
Note: A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal replacement 
therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with 
more than 1 FSH measurement (≥40 mIU/mL) is required. 
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
 
Highly Effective Methods of Contraception: 
• Combined oral contraceptive pill and mini pill 
• NuvaRing 
• Implantable contraceptives 
• Injectable contraceptives (such as Depo-Provera®)  
• Intrauterine device (such as Mirena® and ParaGard®) 

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• Contraceptive patch – ONLY women <198 pounds or 90 kg 
• Total abstinence (if this is their preferred and usual lifestyle) or in a same-sex relationship 
with no sexual relationship with males (as part of their preferred and usual lifestyle), and 
agrees to maintain this status throughout trial follow-up. 
Note:  periodic abstinence (for example, calendar, ovulation, symptothermal, postovulation 
methods), declaration of abstinence just for the duration of a trial, and withdrawal are not 
acceptable methods of contraception 
• Vasectomy – for men in clinical studies 
Note: Implantable contraceptives and injectable contraceptives (such as Depo-Provera®) are only 
permitted if started more than 18 months prior to screening.  Participants should not start these 
methods of contraception after being enrolled in the study. 
Appendix 10. Provisions for Changes in Study Conduct During Exceptional Circumstance 
The whole Appendix 10 section is newly added into this protocol. 

Leo Document ID = 194eb6d3-bf51-4d5b-8879-a45be036ac96
Approver:
Approval Date & Time: 25-Aug-2021 04:09:38 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 25-Aug-2021 20:06:16 GMT
Signature meaning: Approved
PPD
PPD