Clinical trial NCT04657016
Conditions: Obesity Overweight
Keywords: Diet Exercise Metabolism and Nutrition Disorder Behavioral Modification
Sponsor: Eli Lilly and Company
Start date: 2021-03-29; Completion date: 2023-05-12
Enrollment: 579 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study of tirzepatide in participants with obesity. The purpose of this study is to learn more about how tirzepatide maintains body weight or adds to weight loss after an intensive lifestyle modification program. The study will last about 2 years (29 visits).

Detailed description:

Arms: arm 1: Participants received weekly doses of tirzepatide subcutaneously (SC) for 72 weeks, starting at 2.5 milligrams (mg) for 4 weeks. Subsequently, the dose was increased by 2.5 mg every 4 weeks up to the maximum tolerated dose (MTD) of either 10 mg or 15 mg. arm 2: Participants received matching placebo SC once weekly (QW).
Interventions: intervention 1: Tirzepatide intervention 2: Placebo
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
 
 
Protocol: I8F-MC-GPHM  
 
 
Eﬃcacy and Safety of TirzepaƟde Once Weekly Versus Placebo AŌer an Intensive Lifestyle Program 
in ParƟcipants Without Type 2 Diabetes Who Have Obesity or Are Overweight With Weight-Related 
ComorbidiƟes: A Randomized, Double Blind, Placebo-Controlled Trial (SURMOUNT-3) 
 
 
NCT04657016 
 
 
Approval Date: 19-Nov-2020 


CONFIDENTIAL
Protocol number I8F-MC-GPHM
1
Title Page
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.
Protocol Title: Efficacy and Safety of Tirzepatide Once Weekly versus Placebo After an 
Intensive Lifestyle Program in Participants without Type 2 Diabetes who have Obesity or are 
Overweight with Weight-Related Comorbidities: A Randomized, Double-Blind, Placebo-
Controlled Trial (SURMOUNT-3)
Protocol Number: I8F-MC-GPHM
Amendment number: This is the initial protocol.
Compound: LY3298176  
Study Phase: 3
Short Title: Effect of Tirzepatide versus Placebo after Intensive Lifestyle Program
(SURMOUNT-3)
Acronym: SURMOUNT-3
Sponsor Name: Eli Lilly and Company
Legal Registered Address: Indianapolis, Indiana USA  46285
Regulatory Agency Identifier Number(s)
IND: 139721
Approval Date: Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 19-Nov-2020 GMT


CONFIDENTIAL
Protocol number I8F-MC-GPHM
2
Medical Monitor Name and Contact Information will be provided separately.


CONFIDENTIAL
Protocol number I8F-MC-GPHM
3
Table of Contents
1.
Protocol Summary......................................................................................................6
1.1.
Synopsis.......................................................................................................................6
1.2.
Schema.......................................................................................................................11
1.3.
Schedule of Activities (SoA) ......................................................................................12
2.
Introduction..............................................................................................................18
2.1.
Study Rationale ..........................................................................................................18
2.2.
Background ................................................................................................................19
2.3.
Benefit/Risk Assessment ............................................................................................20
3.
Objectives and Endpoints.........................................................................................21
4.
Study Design .............................................................................................................23
4.1.
Overall Design............................................................................................................23
4.1.1.
Overview of Study Periods .........................................................................................23
4.1.2.
Study Procedures........................................................................................................27
4.2.
Scientific Rationale for Study Design .........................................................................28
4.3.
Justification for Dose..................................................................................................29
4.4.
End of Study Definition..............................................................................................30
5.
Study Population ......................................................................................................31
5.1.
Inclusion Criteria........................................................................................................31
5.2.
Exclusion Criteria.......................................................................................................33
5.3.
Lifestyle Considerations .............................................................................................37
5.3.1.
Meals and Dietary Restrictions ...................................................................................37
5.3.2.
Physical Activity ........................................................................................................38
5.4.
Screen Failures ...........................................................................................................39
6.
Study Intervention....................................................................................................40
6.1.
Study Intervention(s) Administered ............................................................................40
6.1.1.
Medical Devices.........................................................................................................40
6.2.
Preparation/Handling/Storage/Accountability.............................................................41
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................41
6.4.
Study Intervention Compliance...................................................................................42
6.5.
Concomitant Therapy .................................................................................................42
6.6.
Dose Modification......................................................................................................43
6.6.1.
Tirzepatide .................................................................................................................43
6.6.2.
Management of Participants with Gastrointestinal Symptoms.....................................43
6.7.
Intervention after the End of the Study........................................................................43
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................44
7.1.
Discontinuation of Study Intervention ........................................................................44
7.1.1.
Temporary Discontinuation ........................................................................................47
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................47
7.2.1.
Participant Disposition and Timing of Safety Follow-Up............................................49
7.2.2.
Discontinuation of Inadvertently Enrolled Participants ...............................................50


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Protocol number I8F-MC-GPHM
4
7.3.
Lost to Follow up .......................................................................................................50
8.
Study Assessments and Procedures .........................................................................51
8.1.
Efficacy Assessments .................................................................................................51
8.1.1.
Primary Efficacy Assessments....................................................................................51
8.1.2.
Secondary Efficacy Assessments ................................................................................51
8.1.3.
Patient-Reported Outcomes Assessments....................................................................51
8.2.
Safety Assessments ....................................................................................................53
8.2.1.
Physical Examinations................................................................................................53
8.2.2.
Vital Signs..................................................................................................................53
8.2.3.
Electrocardiograms.....................................................................................................53
8.2.4.
Clinical Safety Laboratory Assessments .....................................................................54
8.2.5.
Safety Monitoring.......................................................................................................55
8.2.6.
Depression, Suicidal Ideation and Behavior Risk Monitoring......................................57
8.3.
Adverse Events, Serious Adverse Events, and Product 
Complaints .................................................................................................................57
8.3.1.
Timing and Mechanism for Collecting Events ............................................................58
8.3.2.
Special Safety Topics .................................................................................................60
8.4.
Treatment of Overdose ...............................................................................................65
8.5.
Pharmacokinetics........................................................................................................65
8.6.
Pharmacodynamics.....................................................................................................65
8.7.
Genetics .....................................................................................................................65
8.8.
Biomarkers.................................................................................................................66
8.9.
Immunogenicity Assessments.....................................................................................66
8.10.
Health Economics.......................................................................................................67
9.
Statistical Considerations.........................................................................................68
9.1.
Statistical Hypotheses.................................................................................................68
9.2.
Sample Size Determination.........................................................................................68
9.3.
Populations for Analyses ............................................................................................69
9.4.
Statistical Analyses.....................................................................................................69
9.4.1.
General Considerations...............................................................................................69
9.4.2.
Treatment Group Comparability .................................................................................70
9.4.3.
Efficacy Analyses.......................................................................................................71
9.4.4.
Safety Analyses ..........................................................................................................72
9.4.5.
Pharmacokinetic/Pharmacodynamic Analyses ............................................................73
9.4.6.
Evaluation of Immunogenicity....................................................................................73
9.4.7.
Other Analyses ...........................................................................................................74
9.5.
Interim Analyses.........................................................................................................74
9.6.
Data Monitoring Committee (DMC)...........................................................................74
10.
Supporting Documentation and Operational Considerations ................................75
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................75
10.1.1.
Regulatory and Ethical Considerations........................................................................75
10.1.2.
Informed Consent Process ..........................................................................................75
10.1.3.
Data Protection...........................................................................................................76
10.1.4.
Committees Structure .................................................................................................76


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Protocol number I8F-MC-GPHM
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10.1.5.
Dissemination of Clinical Study Data .........................................................................76
10.1.6.
Data Quality Assurance ..............................................................................................77
10.1.7.
Source Documents......................................................................................................78
10.1.8.
Study and Site Start and Closure.................................................................................78
10.1.9.
Publication Policy.......................................................................................................79
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................80
10.3.
Appendix 3: Laboratory Assessments for Hypersensitivity 
Events ........................................................................................................................83
10.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................85
10.4.1.
Definition of AE.........................................................................................................85
10.4.2.
Definition of SAE.......................................................................................................86
10.4.3.
Definition of Product Complaint.................................................................................87
10.4.4.
Recording and Follow-Up of AE and/or SAE and Product 
Complaints .................................................................................................................87
10.4.5.
Reporting of SAEs......................................................................................................89
10.4.6.
Regulatory Reporting Requirements ...........................................................................90
10.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................91
10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ...............................................................................................................95
10.7.
Appendix 7: Protocol GPHM Standardized Protocols for the 
Measurement of Height, Weight, Waist Circumference, Vital 
Signs and Electrocardiogram ......................................................................................97
10.8.
Appendix 8: Suggested Visit Structure........................................................................99
10.9.
Appendix 9: Management of Gastrointestinal Symptoms..........................................100
10.10.
Appendix 10: Provisions for Changes in Study Conduct During 
Exceptional Circumstances.......................................................................................101
10.11.
Appendix 11: Abbreviations .....................................................................................105
11.
References...............................................................................................................110


CONFIDENTIAL
Protocol number I8F-MC-GPHM
6
1.
Protocol Summary
1.1.
Synopsis
Protocol Title: Efficacy and Safety of Tirzepatide Once Weekly versus Placebo After an 
Intensive Lifestyle Program in Participants without Type 2 Diabetes who have Obesity or are 
Overweight with Weight-Related Comorbidities: A Randomized, Double-Blind, Placebo-
Controlled Trial (SURMOUNT-3) 
Short Title: Effect of Tirzepatide versus Placebo after Intensive Lifestyle Program
(SUMROUNT-3)
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 (American Medical Association [AMA] 2013; Council on 
Science and Public Health 2013; Lauby-Secretan et al. 2016). The cornerstone of obesity 
treatment is lifestyle-based therapy combining reduced-calorie diet, physical activity, and 
behavioral counseling (NHLBI 2000; Jensen et al. 2014; Garvey et al. 2016). Evidence-based 
clinical approaches to caloric restriction include moderate energy deficits of 500 to 750 kcal/day 
based on calculation of an individual’s energy needs or more intensive low-calorie diets (LCDs) 
with gender-specific energy intake targets of 1200 to 1800 kcal/day. Ad libitum approaches
involving restriction or elimination of particular foods without specific energy targets may also 
be used (Jensen et al. 2014; Garvey et al. 2016). 
Lifestyle interventions lead to 5 to 10% body weight loss, which has been shown to reduce
obesity-related cardiovascular risk factors, and in some cases improve health-related quality of 
life (Mertens and Van Gaal 2000; Knowler et al. 2002; Jensen et al. 2014; Kolotkin and 
Andersen 2017). However, diet- and exercise-induced weight loss is not maintained in 80% of 
patients, in part due to metabolic adaptations that promote regain in response to caloric deficits 
(Leibel et al. 1995; Sumithran et al. 2011; Doucet et al. 2018). Moreover, greater weight losses 
can maximize metabolic and health-related quality of life benefits and may be required to realize 
clinically meaningful improvements in other obesity-related comorbidities such as sleep apnea, 
nonalcoholic steatohepatitis, and cardiovascular disease (Garvey et al. 2016; Kolotkin and 
Anderson 2017; Ryan and Yockey 2017).
There is widespread consensus that pharmacotherapy for weight management should only be 
used as an adjunct to lifestyle-based approaches (NHLBI 2000; Jensen et al. 2014; Garvey et al.
2016). There seems to be less clarity, however, on when and in whom obesity treatment should 
be advanced from lifestyle-based monotherapy to lifestyle plus medication combination therapy. 
While some guidelines recommend pharmacotherapy only after diet and exercise fail to achieve 
weight loss over 6 months (NHLBI 2000), others add that it should also be considered if initial 
weight loss is not maintained over time (Jensen et al. 2014), and still others imply that even 
responders to diet and exercise may benefit from additional weight loss with medications
(Garvey et al. 2016).


CONFIDENTIAL
Protocol number I8F-MC-GPHM
7
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 systems), thereby regulating food intake and body weight (Baggio 
and Drucker 2007). The US Food and Drug Administration and the European Medicines Agency 
approved the GLP-1R agonist liraglutide for the treatment of overweight and obesity 
(SAXENDA® package insert, 2014; SAXENDA summary of product characteristics, 2015).
Preclinical data indicate that GIP also 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 could 
potentially result in additive or synergistic effects of the 2 incretins on body weight (Coskun et
al. 2018).
Tirzepatide is 
 
 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
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) (Müller 
et al. 2018) and has the potential to reach higher efficacy in target tissues that express both GIPR 
and GLP-1R. Therefore, tirzepatide has the potential to impact several aspects of energy 
regulation and to be a treatment of overweight and obesity. 
In a 26-week Phase 2 study in patients with T2DM, tirzepatide 10 mg and 15 mg doses produced 
statistically significant and clinically relevant weight loss compared to placebo and compared to 
the GLP-1 R agonist, dulaglutide. Tirzepatide is subsequently being evaluated in Phase 3 studies 
in patients with obesity for its effects on weight loss as an adjunct to a 500 kcal/day deficit diet 
and increased physical activity. There is a need to better understand the benefits of tirzepatide 
after a more intensive lifestyle program, especially as current recommendations vary with 
regards to when to prescribe pharmacotherapy to diet and exercise responders and goals of 
treatment in such patients may range from promoting maintenance to augmenting the initial 
response.
Study 18F-MC-GPHM (GPHM; SURMOUNT-3) is a Phase 3, multicenter, randomized, 
parallel-arm, double-blind, placebo-controlled, 84-week study that will investigate the effects of 
treatment with maximum tolerated dose (MTD) of tirzepatide (10 mg or 15 mg QW), compared 
with placebo, on body weight management in study participants who do not have T2DM and 
have obesity (body mass index [BMI] ≥30 kg/m2) or are overweight (BMI ≥27 kg/m2) with at 
least 1 weight-related comorbid condition and achieved ≥5.0% weight loss after a 12-week lead-
in period with an intensive lifestyle modification program.
CCI


CONFIDENTIAL
Protocol number I8F-MC-GPHM
8
Objectives and Endpoints
Objectives
Endpoints
Primary
To demonstrate that tirzepatide MTD is superior to 
placebo from randomization for the following 
(measured at 72 weeks):

Percent change in body weight AND 

Proportion of participants with ≥5% body 
weight reduction 

Mean percent change in body weight

Percentage of study participants who achieve 
≥5% body weight reduction 
Key Secondary (controlled for type I error)
To demonstrate that tirzepatide MTD is superior to 
placebo from randomization for the following 
(measured at 72 weeks): 

Maintaining body weight reduction achieved 
during the 12-week lead-in period

Percentage of study participants who maintain 
≥80% of the body weight lost during the 
12-week lead-in period 

Body weight 

Percentage of study participants who achieve:
o
≥10% body weight reduction 
o
≥15% body weight reduction 

Waist circumference 

Mean change in waist circumference (cm)
Additional Secondary
To demonstrate that tirzepatide MTD is superior to 
placebo from randomization for the following 
(measured at 72 weeks): 

Body weight and BMI

Mean change in body weight (kg) 

Mean change in BMI (kg/m2)

Blood pressure 

Mean change in
o
systolic blood pressure (mmHg) 
o
diastolic blood pressure (mmHg)

Lipid parameters 

Mean change in: 
o
Total cholesterol (mg/dL)
o
HDL-cholesterol (mg/dL)
o
LDL-cholesterol (mg/dL)
o
VLDL-cholesterol (mg/dL)
o
Triglycerides (mg/dL)
o
Free fatty acids (mg/dL)


CONFIDENTIAL
Protocol number I8F-MC-GPHM
9
Objectives
Endpoints

Glycemic control

Mean change in 
o
fasting glucose (mg/dL)
o
HbA1c (%)

Insulin

Mean change in fasting insulin (pmol/L)

Patient-reported outcomes

Mean change in 
o
SF-36v2 acute form Physical 
Functioning domain score 
o
IWQOL-Lite-CT Physical Function 
composite score
To demonstrate that tirzepatide MTD is superior to 
placebo from Visit 2 for the following (measured at 
72 weeks):

Body weight and BMI

Waist circumference

Mean change in absolute body weight (kg)

Mean percent change in body weight

Mean change in BMI (kg/m2)

Mean change in waist circumference (cm)
Abbreviations: BMI = body mass index; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein;
IWQOL-Lite-CT = Impact of Weight on Quality of Life-Lite Clinical Trials Version; LDL = low-density 
lipoprotein; MTD = maximum tolerated dose; SF-36v2 acute form = Short Form-36 Version 2 Health Survey 
acute form; VLDL = very low-density lipoprotein.
Overall Design
Study GPHM is a Phase 3, multicenter, randomized, parallel-arm, double-blind, 
placebo-controlled, 84-week study that will investigate the effects of treatment with tirzepatide 
MTD (10 mg or 15 mg QW), compared with placebo, on body weight management in study 
participants who have obesity (BMI ≥30 kg/m2) or are overweight (BMI ≥27 kg/m2) with at least 
1 weight-related comorbid condition and achieved ≥5.0% weight loss after a 12-week lead-in 
period with an intensive lifestyle modification program.
Randomization at the end of the 12-week lead-in period will be stratified by country, sex, and 
percent weight loss at the end of lead-in (<10% versus ≥10%). 
Disclosure Statement: This is a study including 2 parallel treatment arms (tirzepatide MTD 
versus placebo) that is participant- and investigator-blinded.


CONFIDENTIAL
Protocol number I8F-MC-GPHM
10
Number of Participants:
Approximately 1100 participants will be screened and 800 participants enrolled into the 12-week 
intensive lifestyle modification lead-in period in order to get approximately 600 participants who 
will be randomized in a 1:1 ratio to tirzepatide MTD (300 participants) or placebo (300 
participants). An upper limit of 70% enrollment of women will be used to ensure a sufficiently 
large sample of men.
Intervention Groups and Duration:
Study participants will be randomized in a 1:1 ratio (tirzepatide MTD QW and placebo QW), 
stratified by country, sex and percent weight loss at the end of lead-in period (<10% versus 
≥10%).
Study GPHM will consist of 4 periods: a 2-week screening period; a 12-week lead-in period 
during which participants undertake an intensive lifestyle modification program to achieve 
≥5.0% body weight loss; a 72-week double-blind placebo-controlled dose escalation and 
treatment period; and a 4-week safety follow-up period.  
Data Monitoring Committee: No


CONFIDENTIAL
Protocol number I8F-MC-GPHM
11
1.2.
Schema
Abbreviations: MTD = maximum tolerated dose, QW = once weekly, (T) = telephone visit.


CONFIDENTIAL
Protocol number I8F-MC-GPHM
12
1.3.
Schedule of Activities (SoA)
The Schedule of Activities described below should be followed for all participants enrolled in Study GPHM. However, for those 
participants whose participation in this study is affected by exceptional circumstances (such as pandemics or natural disasters), please 
refer to Section 10.10 (Appendix 10) for additional guidance.
Visit
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 99 ED
801
Week of Treatment
-14 -12 -11 -10 -9
-8
-6 -4
-2
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 72
4 wks 
Post 
TxP
Allowable Deviation (days)
±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±7 ±7
±3
Fasting Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
X
X
X
X
X
X
Lifestyle Program Instruction only 
X
X
X
X
Informed consent
X
Inclusion and exclusion criteria 
review
X
X
Preexisting conditions and medical
history, including relevant surgical 
history
X
Medical history includes assessment of preexisting conditions (for example, history of gallbladder disease, cardiovascular 
disease, and medullary thyroid carcinoma) and substance usage (such as alcohol andtobacco).
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events and product 
complaints
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Evaluation or Clinical Assessments
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight measurements should be obtained per the detailed protocol guidance in Section 10.7. Body weight must be measured 
in the 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.
Waist circumference
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs (systolic and diastolic 
blood pressure, pulse rate)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital sign measurements should be taken before obtaining an ECG tracing and before collection of blood samples for 
laboratory testing, per the instructions in Section 10.7.
Physical examination
X
Electrocardiogram
X
X
X
X
X
X


CONFIDENTIAL
Protocol number I8F-MC-GPHM
13
Visit
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 99 ED
801
Week of Treatment
-14 -12 -11 -10 -9
-8
-6 -4
-2
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 72
4 wks 
Post 
TxP
Allowable Deviation (days)
±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±7 ±7
±3
Fasting Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
X
X
X
X
X
X
Lifestyle Program Instruction only 
X
X
X
X
ECG measurements should be obtained per the instructions in Section 10.7. ECGs should be collected at least 30 minutes prior 
to collection of blood samples for laboratory testing.
Participant Education and Assessment
Lifestyle Program Instruction
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Counselling on diet and exercise, to be performed by a dietician or equivalent qualified delegate, to include calculation of 
individualized energy requirement and behavior modification strategies to change dietary composition and amount of physical 
activity (See Section 5.3 for details). 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. After Week 0 (Visit 10, randomization), the remaining Lifestyle 
Program Instruction may be delivered by phone.
Review diet and exercise 
goals
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
All training should be repeated as needed to encourage participant compliance. Study personnel to provide reinforcement and 
encouragement for lifestyle modifications.  
Injection training with 
autoinjector demonstration 
device
X
Participant Diary (paper)
Dispense diary, instruct in use
X
X
X
X
X
X
X
X
X
X
All training should be repeated as needed to encourage participant compliance.
Diary review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient Reported Outcomes
PGIs
X
X
X
X
SF-36 v2, acute form
X
X
X
X
IWQOL-Lite-CT
X
X
X
X


CONFIDENTIAL
Protocol number I8F-MC-GPHM
14
Visit
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 99 ED
801
Week of Treatment
-14 -12 -11 -10 -9
-8
-6 -4
-2
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 72
4 wks 
Post 
TxP
Allowable Deviation (days)
±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±7 ±7
±3
Fasting Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
X
X
X
X
X
X
Lifestyle Program Instruction only 
X
X
X
X
EQ-5D-5L
X
X
X
X
Mental Health Questionnaires
PHQ-9
X
X
X
X
X
X
X
X
X
X
X
The PHQ-9 is self-administered and should be completed after assessment of adverse events.
C-SSRS (Baseline/Screening 
Version)
X
The C-SSRS 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.
C-SSRS (Since Last Visit Version)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
The C-SSRS should be administered after assessment of adverse events and capture information since most recent C-SSRS 
administration. 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.
Self-Harm Supplement Form
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
The Self-Harm Supplement Form should be administered after assessment of adverse events.
Self-Harm Follow-up Form
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
The Self-Harm Follow-up Form is only required if triggered by the Self-Harm Supplement Form, per instructions in the form.
Laboratory Tests and Sample Collections
Hematology
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
X
X


CONFIDENTIAL
Protocol number I8F-MC-GPHM
15
Visit
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 99 ED
801
Week of Treatment
-14 -12 -11 -10 -9
-8
-6 -4
-2
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 72
4 wks 
Post 
TxP
Allowable Deviation (days)
±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±7 ±7
±3
Fasting Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
X
X
X
X
X
X
Lifestyle Program Instruction only 
X
X
X
X
Chemistry panel (includes Cr 
for eGFR calculation and 
glucose)
X
X
X
X
X
X
X
X
X
X
The CKD-EPI equation will be used by the central lab to estimate and report eGFR.
Insulin
X
X
X
X
X
X
X
X
X
X
C-peptide
X
X
X
X
X
X
X
X
X
X
Lipid panel
X
X
X
X
X
X
Free fatty acids
X
X
X
X
X
X
Serum pregnancy 
X
X
For women of childbearing potential only.
Urine pregnancy (local)
X
X
X
X
X
X
X
X
A urine pregnancy test must be performed at Visit 10 with the result available prior to first injection of study drug(s) for 
women of childbearing potential only. Additional pregnancy tests (beyond those required by the SoA) 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.
Follicle-stimulating hormone 
test 
X
Follicle-stimulating hormone test is to be 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 more than 1 year without an 
alternative medical cause.  
Calcitonin
X
X
X
X
X
X
X
Pancreatic amylase
X
X
X
X
X
X
X
Lipase
X
X
X
X
X
X
X
Urinary albumin/creatinine 
ratio
X
X
X
X
X
X
Cystatin-c
X
X
X
X
X
X


CONFIDENTIAL
Protocol number I8F-MC-GPHM
16
Visit
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 99 ED
801
Week of Treatment
-14 -12 -11 -10 -9
-8
-6 -4
-2
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 72
4 wks 
Post 
TxP
Allowable Deviation (days)
±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±3 ±7 ±7
±3
Fasting Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
X
X
X
X
X
X
Lifestyle Program Instruction only 
X
X
X
X
Thyroid stimulating hormone
X
Immunogenicity (includes PK 
sample)
X
X
X
X
X
X
X
X
In the event of systemic drug hypersensitivity reactions (immediate or nonimmediate), additional unscheduled samples should 
be collected as detailed in Section 8.3.2.7 (Hypersensitivity Reactions). Immunogenicity samples and PK samples for 
immunogenicity must be taken prior to drug administration.
Stored Samples
Pharmacogenetic sample
X
Nonpharmacogenetic sample
X
X
X
X
X
X
X
X
Randomization and Dosing
Randomization
X
Dispense study intervention(s)
X
X
X
X
X
X
X
X
X
X
Observe participant administer 
study drug intervention
X
Participants should administer their first dose of study drug at the end of Visit 10, after other study procedures are completed.
Participant returns study drug 
intervention and injection supplies
X
X
X
X
X
X
X
X
X
X
X
Assess study intervention(s) 
compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


CONFIDENTIAL
Protocol number I8F-MC-GPHM
17
Abbreviations: CKD-EPI = Chronic Kidney Disease-Epidemiology; C-SSRS = Columbia Suicide Severity Rating Scale; Cr = creatinine; ED = early 
discontinuation; eGFR = estimated glomerular filtration rate; HbA1c = hemoglobin A1c; IWQOL-Lite-CT = Impact of Weight on Quality of Life-Lite-
Clinical Trials Version; PGIs = Patient Global Impression of status for physical activity; PHQ-9 = Patient Health Questionnaire-9; PK = pharmacokinetics; 
SF-36v2 acute form = Short Form-36 Version 2 Health Survey acute form; SoA = schedule of activities; TxP = treatment period; wks = weeks.
Note:

The visit date is determined in relation to the date of Visit 2 for the lead-in period and Visit 10 (randomization) for the treatment period.

For all office visits, remind participants 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 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. Eligible participants enter a lifestyle modification lead-in period, during which they 
receive instruction in an intensive dietary (1200 kcal/day for women or 1500 kcal/day for men) and exercise program to achieve a ≥5.0% body weight 
loss. 

On Lifestyle Program Instruction Only Visits, all spontaneously reported adverse events by participant will be documented by the investigator and any 
qualified designee. 

Visit 10 assessments must be completed before processing in the interactive web-response system (IWRS).

Visit 99 is only applicable to participants who discontinue the double-blind study treatment prematurely (after Week 0 and before Week 72) and decline 
to complete the remaining scheduled study visits. Participants wanting to discontinue the study treatment after randomization and before Week 72 will 
be asked to return for Visit 99 (72 weeks ±7 days after Visit 10) primarily for body weight measurement and assessment of adverse events. 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. 

Participants who are unable or unwilling to continue the study intensive lifestyle intervention (during lead-in period) or study drug intervention (during 
treatment period) 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 an ED visit. 

Visit 801 (safety follow-up visit) should be performed 4 weeks after the last visit of the participant’s treatment period (after randomization, see 
Section 4.1.1.2.3)


CONFIDENTIAL
Protocol number I8F-MC-GPHM
18
2.
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 (American Medical Association [AMA] 2013; Council on 
Science and Public Health 2013; Lauby-Secretan et al. 2016). The cornerstone of obesity 
treatment is lifestyle-based therapy combining reduced-calorie diet, physical activity and 
behavioral counseling (NHLBI 2000; Jensen et al. 2014; Garvey et al. 2016). Evidence-based 
clinical approaches to caloric restriction include moderate energy deficits of 500 to 750 kcal/day 
based on calculation of an individual’s energy needs or more intensive low-calorie diets (LCDs) 
with gender-specific energy intake targets of 1200 to 1800 kcal/day. Ad libitum approaches
involving restriction or elimination of particular foods without specific energy targets may also 
be used (Jensen et al. 2014; Garvey et al. 2016). 
These lifestyle interventions lead to 5 to 10% body weight loss that has been shown to reduce
obesity-related cardiovascular risk factors, and in some cases improve health-related quality of 
life (Mertens and Van Gaal 2000; Knowler et al. 2002; Jensen et al. 2014; Kolotkin and 
Andersen 2017). However, diet- and exercise-induced weight loss is not maintained in 80% of 
patients, in part due to metabolic adaptations that promote regain in response to caloric deficits 
(Leibel et al. 1995; Sumithran et al. 2011; Doucet et al. 2018). Adjunctive therapies, including 
medications, devices, and surgical treatments, for obesity are evolving as are the clinical 
guidelines for the application of these therapies in the clinical management of patients with 
obesity.
2.1.
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 the 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 systems), 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 summary of product characteristics, 
2015).
Preclinical data indicate that GIP also exerts effects on appetite regulation and food intake as 
well as on 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 


CONFIDENTIAL
Protocol number I8F-MC-GPHM
19
a role in body weight regulation and targeting both the GLP-1R and the GIPR simultaneously 
could potentially result in additive or synergistic effects of the 2 incretins on body weight 
(Coskun et al. 2018).
Tirzepatide is 
 
 
 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 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) (Müller et al.
2018) and has the potential to reach higher efficacy in target tissues that express both GIPR and 
GLP-1R. Therefore, tirzepatide has the potential to impact several aspects of energy regulation 
and be a treatment for overweight and obesity.  
There is widespread consensus that pharmacotherapy for weight management should only be 
used as an adjunct to lifestyle-based approaches (NHLBI 2000; Jensen et al. 2014; Garvey et al.
2016). There seems to be less clarity, however, on when and in whom obesity treatment should 
be advanced from lifestyle-based monotherapy to lifestyle plus medication combination therapy. 
While some guidelines recommend pharmacotherapy only after diet and exercise fail to achieve 
weight loss over 6 months (NHLBI 2000), others add that it should also be considered if initial 
weight loss is not maintained over time (Jensen et al. 2014), and still others imply that even 
responders to diet and exercise may benefit from additional weight loss with medications
(Garvey et al. 2016). There is a need to better understand the benefits of tirzepatide after initial 
success with lifestyle-induced weight loss, especially as current recommendations vary and goals 
of treatment in such patients may range from promoting maintenance to augmenting weight loss.  
Study 18F-MC-GPHM is a Phase 3, multicenter, randomized, parallel-arm, double-blind, 
placebo-controlled, 84-week study that will investigate the effects of treatment with maximum 
tolerated dose (MTD) of tirzepatide (10 mg or 15 mg QW), compared with placebo, on body 
weight management in study participants who have obesity (body mass index [BMI] ≥30 kg/m2) 
or are overweight (BMI ≥27 kg/m2) with at least one weight-related comorbid condition and 
achieved ≥5.0% weight loss after a 12-week lead-in period with an intensive lifestyle 
modification program.
2.2.
Background
There remains an unmet need in the pharmacologic treatment of obesity for drugs that are safe, 
efficacious, and well tolerated. There are currently only a few medications FDA-approved for 
long-term use for the treatment of obesity that yield a placebo-adjusted average weight loss
between 3% and 7% (Srivastava and Apovian 2018; FDA 2020). Although moderate weight loss 
of 5% to 10% in individuals with obesity/overweight has long been shown to yield significant 
metabolic benefits including improvements in cholesterol, blood pressure, and glucose 
parameters (Goldstein 1992; Wing et al. 2011), greater weight loss can maximize these benefits 
and may be required to realize clinically meaningful improvements in other obesity-related 
comorbidities such as sleep apnea, non-alcoholic steatohepatitis, and cardiovascular disease 
(Ryan and Yockey 2017). In addition to moderate efficacy, some centrally-acting weight-loss 
agents to date have had adverse neurocognitive, psychiatric or cardiovascular effects, further 
limiting their application in clinical practice (Srivastava and Apovian 2018). 
CCI


CONFIDENTIAL
Protocol number I8F-MC-GPHM
20
Weight loss induced by GLP-1R agonists, while appearing to be centrally-mediated through a 
combination of hormonal inputs to satiety centers (van Bloemendaal et al. 2014), has not been 
consistently associated with changes in mental health or with potential for addiction in long-term 
studies conducted to establish cardiovascular safety in patients with diabetes (Marso et al. 2016a,
2016b, Gerstein et al. 2019). Tirzepatide, which is both a GLP-1R and GIPR agonist, has been 
associated with predominantly mild to moderate gastrointestinal (GI) adverse effects similar to 
currently marketed GLP-1R agonists, but has also demonstrated significant weight loss at both 
the 10-mg and 15-mg doses in Phase 2 studies with nearly half of the participants in each dose 
arm achieving >10% weight loss (Frias et al. 2018).
Tirzepatide dose selection for obesity treatment has been informed by 3 clinical trials: a Phase 1 
study, Study I8F-MC-GPGA (GPGA), and 2 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) study in healthy subjects followed by 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:
0.25 mg to 8 mg in the SAD (with maximum tolerated dose [MTD] achieved at 5 mg) in 
healthy subjects,
multiple doses in the MAD from 0.5 mg to 4.5 mg QW and titrated doses up to 10 mg 
QW for 4 weeks in healthy subjects, and 
multiple doses at 0.5 mg and 5 mg QW and titrated to 15 mg QW for 4 weeks in patients 
with T2DM.  
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 GPGB and GPGF provided initial safety, tolerability and efficacy data in the 
tirzepatide 1-mg to 15-mg dose-range when used in treatment of patients with T2DM. In the dose 
range of 5 mg to 15 mg, tirzepatide provided significantly greater reductions in hemoglobin A1c
(HbA1c) and body weight compared with placebo. In addition, the 10-mg and 15-mg dose arms 
demonstrated significantly greater weight loss compared to the GLP-1R agonist, dulaglutide 1.5 
mg QW. The most common adverse events (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. 
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of tirzepatide may be found in the Investigator’s Brochure (IB).


CONFIDENTIAL
Protocol number I8F-MC-GPHM
21
3.
Objectives and Endpoints
Objectives
Endpoints
Primary
To demonstrate that tirzepatide MTD is superior to 
placebo from randomization for the following 
(measured at 72 weeks) 

Percent change in body weight AND 

Proportion of participants with ≥5% body 
weight reduction 

Mean percent change in body weight

Percentage of study participants who achieve 
≥5% body weight reduction 
Key Secondary (controlled for type I error)
To demonstrate that tirzepatide MTD is superior to 
placebo from randomization for the following 
(measured at 72 weeks): 

Maintaining body weight reduction achieved 
during the 12-week lead-in period

Percentage of study participants who maintain 
≥80% of the body weight lost during the 
12-week lead-in period 

Body weight 

Percentage of study participants who achieve:
o
≥10% body weight reduction 
o
≥15% body weight reduction 

Waist circumference 

Mean change in waist circumference (cm)
Additional Secondary
To demonstrate that tirzepatide MTD is superior to 
placebo from randomization for the following 
(measured at 72 weeks): 

Body weight and BMI

Mean change in body weight (kg) 

Mean change in BMI (kg/m2)

Blood pressure 

Mean change in 
o
systolic blood pressure (mmHg) 
o
diastolic blood pressure (mmHg)

Lipid parameters 

Mean change in: 
o
Total cholesterol (mg/dL)
o
HDL-cholesterol (mg/dL)
o
LDL-cholesterol (mg/dL)
o
VLDL-cholesterol (mg/dL)
o
Triglycerides (mg/dL)


CONFIDENTIAL
Protocol number I8F-MC-GPHM
22
Objectives
Endpoints
o
Free fatty acids (mg/dL)

Glycemic control

Mean change in
o
fasting glucose (mg/dL)
o
HbA1c (%)

Insulin

Mean change in fasting insulin (pmol/L)

Patient-reported outcomes

Mean change in 
o
SF-36v2 acute form Physical 
Functioning domain score 
o
IWQOL-Lite-CT Physical Function 
composite score
To demonstrate that tirzepatide MTD is superior to 
placebo from Visit 2 for the following (measured at 
72 weeks):

Body weight and BMI

Waist circumference

Mean change in absolute body weight (kg)

Mean percent change in body weight

Mean change in BMI (kg/m2)

Mean change in waist circumference (cm)
Abbreviations: BMI = body mass index; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein;
IWQOL-Lite-CT = Impact of Weight on Quality of Life-Lite Clinical Trials Version; LDL = low-density 
lipoprotein, MTD = maximum tolerated dose; SF-36v2 acute form = Short Form-36 Version 2 Health Survey 
acute form; VLDL = very low-density lipoprotein.


CONFIDENTIAL
Protocol number I8F-MC-GPHM
23
4.
Study Design
4.1.
Overall Design
Study 18F-MC-GPHM is a Phase 3, multicenter, randomized, parallel-arm, double-blind 
placebo-controlled, 84-week study that will investigate the effects of treatment with MTD of
tirzepatide (10 mg or 15 mg QW), compared with placebo, on body weight management in study 
participants who have obesity (BMI ≥30 kg/m2) or are overweight (BMI ≥27 kg/m2) with at least 
one weight-related comorbid condition and achieved ≥5.0% weight loss after a 12-week lead-in 
period with an intensive lifestyle modification program.
Study GPHM will consist of 4 periods: a 2-week screening period; a 12-week lead-in period 
during which participants undertake an intensive lifestyle modification program to achieve 
≥5.0% body weight loss; a 72-week double-blind placebo-controlled treatment period (including 
a 20-week dose escalation period); and a 4-week safety follow-up period. Study participants who 
achieve at least 5.0% weight loss will be randomized in a 1:1 ratio (tirzepatide MTD QW or
placebo) at the end of the lead-in period. An upper limit of 70% enrollment of women will be 
used to ensure a sufficiently large sample of men.
4.1.1.
Overview of Study Periods
4.1.1.1.
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 a period of 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. See Section 10.8 for a suggested order of activities that occurs at office 
visits. 
4.1.1.2.
Main Study Period 
4.1.1.2.1.
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. The participant must sign 
the informed consent form (ICF) before the study procedures are performed, as outlined in the 
SoA, Section 1.3. Since some screening procedures need to be completed in the fasting state 
(approximately 8 hours without eating, drinking [except water], or any significant physical 
activity), 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 at Visit 1 will continue to Visit 2. 
The Mental Health questionnaires (Patient Health Questionnaire-9 [PHQ-9], Columbia-Suicide 
Severity Rating Scale [C-SSRS], and C-SSRS Self-Harm Form) should be completed after the 
assessment for AEs.


CONFIDENTIAL
Protocol number I8F-MC-GPHM
24
Visit 2
At Visit 2, the screening laboratory results will be reviewed. For all participants who remain 
eligible, lifestyle program instruction will be provided by a dietician, or equivalent qualified 
delegate, for an intensive dietary and exercise program.  
Patient-reported outcomes (PROs) questionnaires should be administered as early as possible, as 
per Suggested Visit Structure (Section 10.8). Preferred administration order is:  
1. Patient Global Impression of status for physical activity (PGIs)
2. Short Form-36 version 2 Health Survey (SF-36v2) acute form 
3. Impact of Weight on Quality of Life-Lite-Clinical Trials Version (IWQOL-Lite-CT)
4. EQ-5D-5L.  
The Mental Health questionnaires should be completed after the assessment for AEs.
4.1.1.2.2. Intensive Lifestyle Modification Lead-in Period
During the intensive lifestyle modification lead-in period (Visits 2-10), participants will receive 
instruction from a dietician, or equivalent qualified delegate, according to local standards, to 
reduce their daily caloric energy intake to approximately

1200 kcal/day for women, or 

1500 kcal/day for men 
for a period of 12 weeks (Heymsfield et al. 2003). The dietary intervention may include up to 
2 meal replacements per day. Participants will be encouraged to exercise on a regular basis, with 
a recommendation of at least 150 minutes per week of moderate intensity activity (for example, 
brisk walking). Participants will be counselled on behavior modification strategies to help 
implement and adhere to the diet and exercise recommendations. For more details see 
Sections 5.3.1 and 5.3.2.
Participants who have >5.0% weight loss at Visit 10 will then proceed to randomization to either 
tirzepatide or placebo.
Mental Health questionnaires should be completed after the assessment of AEs.   
4.1.1.2.3.
Treatment Period
Visit 10 (Randomization)
At Visit 10, eligible participants will perform all required randomization study procedures 
(including the collection of all laboratory measures and questionnaires) prior to randomization 
and prior to taking the first dose of study drug. Only participants who have achieved >5.0% 
weight loss at Visit 10 will be randomized and continue in the study. 
Participants will be provided diaries and be trained to record key study information, as 
appropriate. 
PRO questionnaires should be administered as early as possible, as per Suggested Visit Structure 
(Section 10.8). Preferred administration order is:  
1. PGIs


CONFIDENTIAL
Protocol number I8F-MC-GPHM
25
2. SF-36 v2 acute form
3. IWQOL-Lite-CT
4. EQ-5D-5L.
Mental Health questionnaires should be completed after the assessment of AEs.  
Participants will receive consultation with a dietician or qualified delegate, according to local 
standards, to set lifestyle goals for caloric intake and physical activity (Section 5.3) during the 
treatment period.
Following randomization, study site personnel will demonstrate use of the autoinjector (also 
referred to as single-dose pen) using the provided demonstration device and observe the study 
participant inject the first dose of tirzepatide or placebo. The date, time and location 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 72-week dose escalation and treatment period.  
End of Visit 10 to Visit 28
During the treatment period, office visits will occur as indicated in the SoA (Section 1.3).  
Telephone visits will occur at 4-week intervals between the office visits starting at Visit 17.  
Office visit procedures should be conducted according to the SoA (Section 1.3), and will include

weight, waist circumference and vital signs measurements 

laboratory testing 

administration of PRO questionnaires

collection of AEs, product complaints and concomitant medications  

Mental Health questionnaires

review of participant diary information (to include reinforcement and compliance 
assessments for study drug administration and lifestyle goals)

drug dispensing.
Patient-reported outcomes questionnaires should be administered as early as possible, as per 
Suggested Visit Structure (Section 10.8). Preferred administration order is the same as Visit 2. 
Mental Health questionnaires should be completed after the assessment of AEs.  
Dietician consultations occur every 12 weeks from Week 0 to Week 72. Study drug and injection 
supplies will be returned per the SoA (Section 1.3) and according to local requirements. New 
supplies will be dispensed as needed.
The starting dose of tirzepatide 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 to 12.5 to 15 mg) 
up to MTD (either 10 mg or 15 mg). 


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Interventions to optimize study drug tolerance and adherence may be employed throughout the 
study and include, but are not limited to, brief temporary interruptions and use of additional 
medications to manage GI symptoms (for example, nausea, vomiting, and diarrhea, see 
Section 6.6.2. for details). 
During the first 24 weeks of the treatment period (20-week dose escalation plus 4 weeks),
participants unable to tolerate 2.5 mg or 5 mg despite the above measures will be discontinued 
from the study drug but remain in the study for continued follow up. For participants unable to 
tolerate any dose escalation between 7.5 mg and 15 mg inclusive, despite the above measures, 
the investigator should contact Lilly to consider a dose de-escalation step with subsequent 
re-escalation in a blinded fashion to reach either the 10-mg or 15-mg dose as described below 
(only 1 cycle of dose de-escalation and re-escalation is permitted during the first 24 weeks of the 
treatment period):

7.5 mg to 5 mg, then the dose is increased by 2.5 mg every 4 weeks up to MTD (either 
10 mg or 15 mg)

10 mg to 7.5 mg, then the dose is increased by 2.5 mg every 4 weeks up to MTD (either 
10 mg or 15 mg)

12.5 mg to 10 mg, then the dose is increased by 2.5 mg every 4 weeks up to MTD (either 
10 mg or 15 mg)

15 mg to 12.5 mg, then the dose is increased by 2.5 mg every 4 weeks up to MTD (either 
10 mg or 15 mg)
Participants who tolerate 15 mg will continue on 15 mg as their MTD dose.
Participants who tolerate 10 mg, but do not tolerate 12.5 mg or 15 mg even after one 
de-escalation and re-escalation attempt, will continue on 10 mg as their MTD dose.
Participants who tolerate 12.5 mg but do not tolerate 15 mg even after 1 de-escalation and 
re-escalation attempt, will continue on 10 mg as their MTD dose.
Participants who do not tolerate up to 10 mg even after 1 de-escalation and re-escalation attempt,
will be discontinued from the study drug but remain in the study for continued follow up.
At each of the 8 scheduled treatment period telephone visits, procedures will include

collection of AEs, product complaints, and concomitant medications

administration of Mental Health questionnaires, and

review of participant diary information (to include reinforcement and compliance 
assessments for study drug administration and lifestyle goals).
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).


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Visit 99
Visit 99 is only applicable to participants who discontinue the study treatment prematurely 
(between Visit 10 and Visit 28) and decline to complete the remaining scheduled study visits. 
These participants will be asked to return for Visit 99 at 72 weeks ±7 days after randomization
(Section 7.2.1). This visit is critical to ensure complete data collection for the primary 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,

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. 
4.1.1.2.4.
Early Discontinuation of Treatment Visit
Participants unable or unwilling to continue the study intensive lifestyle intervention (during 
lead-in period) or study drug intervention (during treatment period) for any reason will perform 
an early discontinuation (ED) visit (Section 7.2.1). If the participant is discontinuing during an 
unscheduled visit or a scheduled visit, that visit should be performed as an ED visit. Procedures 
should be completed according to the SoA. Patient-reported outcomes questionnaires should be 
administered as early as possible, as per Suggested Visit Structure (Section 10.8). Administration 
of Mental Health questionnaires should follow assessment of AEs.
4.1.1.3.
Safety Follow-Up Period
Visit 801
All randomized participants are required to complete a safety follow-up visit (Visit 801), 
according to the SoA. Participants discontinuing the study drug early and performing an ED visit 
will also be asked to perform the safety follow-up visit (see Section 7.2). 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.
Visit 801 (safety follow-up visit) should be performed 4 weeks after the last visit in the treatment 
period (Visit 28 or Visit 99) or 4 weeks after the ED visit for randomized participants who 
decline to return for Visit 99.  
4.1.2.
Study Procedures
Participants will perform study procedures listed in the SoA (Section 1.3).
Study participants will be permitted to use concomitant medications that they require during the 
study, except certain excluded medications (see Section 5.2) that may interfere with the 
assessment of efficacy and safety characteristics of the study treatments.  
Study governance considerations are described in detail in Section 10.1 (Appendix 1).


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4.2.
Scientific Rationale for Study Design
Tirzepatide is 
 
 
 It is administered QW by 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) (Müller 
2018) 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. 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 GLP-1R 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. These data suggest that tirzepatide has 
the potential to be a pharmacologic treatment for chronic weight management. 
Although GI AEs were more common in the 15-mg arm of tirzepatide in the Phase 2 study 
(GPGB), this dose demonstrated the highest efficacy in terms of weight loss. An optimized dose 
escalation regimen proposed in the current Phase 3 Study (GPHM) to improve tolerability (and 
supported by a dose-escalation algorithm from study GPGF and PK/PD modelling) should 
enable a use of the 15-mg dose to maximize effects on body weight.
Study GPHM is designed to determine the impact of treatment with tirzepatide MTD (10 mg or
15 mg QW) compared with placebo on body weight management after an intensive lifestyle 
modification program in study participants without T2DM who have obesity or are overweight.
Study GPHM consists of a lead-in period of 12 weeks during which participants will undertake 
an intensive lifestyle modification program (Heymsfield et al. 2003). Traditionally, guidelines 
have restricted pharmacotherapy use to those who do not respond to diet and exercise but newer 
guidelines are recommending the addition of pharmacotherapy in those who lose weight with 
diet and exercise but may not be able to maintain the weight loss or may require additional 
weight loss. The goal of the lead-in period, therefore, is to identify participants who initially 
respond to lifestyle-based therapy so that the benefit of tirzepatide can be evaluated in this 
population. Only those participants who achieve >5.0% weight loss during the intensive lifestyle 
lead-in period will be randomized. 
A low-calorie diet (LCD) was chosen for the lead-in period because it is a discrete, structured 
and intensive intervention that is recognized as the centerpiece of dietary therapy for overweight 
and obesity (NHLBI 2000). In those who can adhere to it, an LCD may achieve greater weight 
loss in the short-term than the moderate 500 kcal/day deficit diet being applied in combination 
with tirzepatide throughout the obesity Phase 3 program. Moreover, an LCD was chosen over the 
option of a very low-calorie diet (VLCD) because VLCDs are only used in limited circumstances 
by specialized practitioners experienced in their use and with special monitoring and 
supplementation (NHLBI 2000). Because VLCDs are not recommended as routine therapy for 
overweight or obesity, using a VLCD would have affected the generalizability of the results. 
CCI


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Clinical trials have also shown that LCDs are as effective as VLCDs at 1 year in achieving 
weight loss (Wadden et al. 1994).
After randomization, participants in both the placebo and MTD tirzepatide arms will continue to 
receive lifestyle modification counselling consistent with current guidelines for weight 
management (Jensen et al. 2014; NHLBI 2013). Specifically, participants will consult with a 
dietician, or equivalent qualified delegate, throughout the post-randomization treatment period to 
achieve an approximately 500 kcal/day energy deficit through a combination of caloric 
restriction and increased physical activity (see Section 5.3).
The planned duration of treatment for the primary endpoint at 72 weeks allows for a 52-week 
treatment period at the dose achieved following dose escalation to either 10 mg or 15 mg. This 
duration is considered appropriate to assess the full effects and balance of risk and benefit for 
tirzepatide MTD compared with placebo on body weight and is consistent with regulatory 
guidelines (FDA 2007; EMA 2016). A placebo comparator was selected for this trial in 
accordance with regulatory guidance (FDA 2007; EMA 2016). 
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 and safety characteristics of the study treatments.
4.3.
Justification for Dose
Tirzepatide MTD (10 mg or 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 in Phase 1 and 2 studies in patients with T2DM, followed by 
exposure-response modeling of the data that predicted weight loss in patients with overweight or 
obesity.
In a 26-week, Phase 2 study (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, 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 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.
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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4.4.
End of Study Definition
Section 7.2 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 SoA for the last participant in the trial globally.


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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1.
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 of:

≥30 kg/m2 or 

≥27 kg/m2 and previously diagnosed with at least 1 of the following
weight-related comorbidities 
o
Hypertension: treated or with systolic blood pressure ≥130 mmHg 
or diastolic blood pressure ≥80 mmHg
o
Dyslipidemia: treated or with low-density lipoprotein (LDL)
≥160 mg/dL (4.1 mmol/L) or triglycerides ≥150 mg/dL
(1.7 mmol/L), or high-density lipoprotein (HDL) <40 mg/dL 
(1.0 mmol/L) for men or HDL <50 mg/dL (1.3 mmol/L) for
women 
o
Obstructive sleep apnea 
o
Cardiovascular disease (for example, ischemic cardiovascular 
disease, New York Heart Association [NYHA] Functional 
Classification Class I-III heart failure) 
2. Have a history of at least 1 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 
following lifestyle advice (for example, dietary restrictions, exercise plan), 
maintaining a study diary, and completing required questionnaires
Participant Characteristics
4. Are at least 18 years of age and age of majority per local laws and regulations
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 5 half-
lives of study drug plus 90 days, corresponding to 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) or congenital anomaly (such as
Mullerian agenesis) or 
o
Post-menopausal – 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; 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:
o
test negative for pregnancy at Visit 1 based on a serum pregnancy 
test
o
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 
plus 30 days, corresponding to 2 months after the last injection,
and
o
not be breastfeeding
Note: Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
Informed Consent
5. Capable of giving signed informed consent as described in Section 10.1 (Appendix 1),
which includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.


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5.2.
Exclusion Criteria
Participants are excluded from study enrollment if they meet any of the following criteria at 
screening:
Medical Conditions
Diabetes-Related
6. Have Type 1 diabetes mellitus (T1DM) or T2DM, history of ketoacidosis, or 
hyperosmolar state/coma 
7. Have at least 1 laboratory value suggestive of diabetes mellitus during screening, 
including 1 or more of:  HbA1c ≥6.5% (≥48 mmol/mol), fasting glucose ≥126 mg/dL 
(≥7.0 mmol/L), or random glucose ≥200 mg/dL (≥11.1 mmol/L) 
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 
device removal within the last 6 months prior to screening

mucosal ablation 

gastric artery embolization 

intragastric balloon 

duodenal-jejunal endoluminal liner
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 (CKD-EPI) 
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 a history of chronic or acute pancreatitis 
14. Have thyroid-stimulating hormone (TSH) outside of the range of 0.4-6.0 mIU/L at the
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 and their 
TSH at screening falls within the range indicated above.


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Note:  Participants with a history of subclinical hypothyroidism but a TSH at screening 
within the range indicated above, may be included if in the investigator’s opinion, the 
patient is unlikely to require initiation of thyroid hormone replacement during the course 
of 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
Note: Participants with MDD or generalized anxiety disorder whose disease state is 
considered stable for the past 2 years 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 a lifetime history of suicide attempt
18. Have a PHQ-9 score of 15 or more at Visit 1 
19. On the C-SSRS at any time from Visit 1 to Visit 2:

a "yes" answer to Question 4 (Active Suicidal Ideation with Some Intent to Act, 
Without Specific Plan) on the "Suicidal Ideation" portion of the C-SSRS
or

a "yes" answer to Question 5 (Active Suicidal Ideation with Specific Plan and 
Intent) on the "Suicidal Ideation" portion of the C-SSRS 
or 

a "yes" answer to any of the suicide-related behaviors (actual attempt, interrupted 
attempt, aborted attempt, preparatory act or behavior) on the "Suicidal Behavior" 
portion of the C-SSRS 
and

the ideation or behavior occurred within the past month 
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 Visit 2:

acute myocardial infarction 

cerebrovascular accident (stroke)

unstable angina, or 

hospitalization due to congestive heart failure (CHF)
22. Have NYHA Functional Classification Class IV CHF


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23. Have acute or chronic hepatitis, signs and symptoms of any other liver disease other than 
nonalcoholic fatty liver disease (NAFLD), or any of the following, as determined by the 
central laboratory during screening:

alanine aminotransferase (ALT) level >3.0X upper limit of normal (ULN) for the 
reference range

alkaline phosphatase (ALP) level >1.5X ULN for the reference range, or

total bilirubin (TBL) level >1.2X ULN for the reference range (except for 
cases of known Gilbert’s Syndrome)
Note: Participants with NAFLD are eligible to participate in this trial if their ALT 
level is ≤3.0X ULN for the reference range.
24. Have a serum calcitonin level (at Visit 1) of

≥20 ng/L, if eGFR ≥60 mL/min/1.73 m2

≥35 ng/L, if eGFR <60 mL/min/1.73 m2
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 history of use of marijuana or tetrahydrocannabinol (THC)-containing products 
within 3 months of enrollment or unwillingness to abstain from marijuana or THC-
containing products use during the trial
Note: If a participant has used cannabidiol oil during the past 3 months but agrees to 
refrain from use for the duration of the study, the participant can be enrolled. 
30. Have had a transplanted organ (corneal transplants [keratoplasty] are allowed) or are 
awaiting an organ transplant
31. Have any hematological condition that may interfere with HbA1c measurement (for 
example, hemolytic anemias, sickle cell disease)
Prior/Concomitant Therapy
32. Are receiving or have received within 3 months prior to screening chronic (>2 weeks or 
14 days) systemic glucocorticoid therapy (excluding topical, intra-ocular, intranasal, 
intra-articular, or inhaled preparations) or have evidence of a significant, active 
autoimmune abnormality (for example, lupus or rheumatoid arthritis) that has required 


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36
(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) during the course of the study
33. Have current treatment with or history of (within 3 months prior to Visit 2 ) treatment 
with medications that may cause significant weight gain, including but not limited to:
tricyclic antidepressants, atypical antipsychotics, and mood stabilizers
Examples:

imipramine 

amitriptyline 

mirtazapine

paroxetine

phenelzine

chlorpromazine

thioridazine

clozapine

olanzapine

valproic acid (and its derivatives), or

lithium
Note:  Selective serotonin reuptake inhibitors (SSRIs) other than paroxetine are 
permitted. 
34. Have taken, within 3 months prior to Visit 2, medications (prescribed or 
over-the-counter) or alternative remedies that promote weight loss  
Examples include, but are not limited to:

Saxenda (liraglutide 3.0 mg)

Xenical®/Alli® (orlistat)

Meridia® (sibutramine)

Acutrim® (phenylpropanolamine)

Sanorex® (mazindol)

Apidex® (phentermine)

BELVIQ® (lorcaserin)

Bontril® (phendimetrazine)

QsymiaTM (phentermine/topiramate combination)

Contrave® (naltrexone/bupropion) 
Note: Use of metformin, or any other glucose-lowering medication, whether prescribed 
for polycystic ovarian syndrome (PCOS) or diabetes prevention is not permitted.
35. Have started implantable or injectable contraceptives (such as Depo Provera®) within 
18 months prior to screening


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Prior/Concurrent Clinical Study Experience
36. Are currently enrolled in any other clinical study involving an investigational product
(IP) or any other type of medical research judged not to be scientifically or medically 
compatible with this study
37. Within the last 30 days, have participated in a clinical study and received treatment, 
whether active or placebo. If the study involved an IP, 5 half-lives or 30 days, whichever 
is longer, should have passed
38. Have previously completed or withdrawn from this study or any other study investigating 
tirzepatide after receiving at least 1 dose of IP
Other Exclusions
39. Are investigator site personnel directly affiliated with this study and/or their immediate 
families. Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted
40. Are Lilly employees
5.3.
Lifestyle Considerations
Per the SoA (Section 1.3), participants will consult with a dietician, or equivalent qualified 
delegate, according to local standards, to receive lifestyle management counseling at 
Weeks -12, -11, -10, -9, -8, -6, -4 and -2 prior to randomization and then at Weeks 0, 12, 24, 36, 
48, 60 and 72 post-randomization.
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.
5.3.1.
Meals and Dietary Restrictions
During the intensive lifestyle modification lead-in period, participants will receive instruction 
from a dietician, or equivalent qualified delegate, to reduce their daily caloric energy intake to 
approximately 1200 kcal/day for women or 1500 kcal/day for men for 12 weeks. During this
lead-in period, up to 2 liquid meal replacements per day are permitted, but not required, to 
achieve the targeted energy deficit. In addition to the diet modification, participants will be 
encouraged to exercise on a regular basis, with a recommendation of at least 150 minutes per 
week of moderate intensity activity (for example, brisk walking). Participants will be counseled 
on behavior modification strategies to help implement and adhere to the diet and exercise 
recommendations. Participants who achieve a ≥5.0% body weight loss at the end of the 12-week 
lead-in period (Week 0) will proceed to randomization to either tirzepatide or placebo.  
After randomization, participants will be advised to maintain their daily energy intake at 
500 kcal below their individualized energy requirements (Garvey et al. 2016), as calculated by 
the Food and Agriculture Organization of the United Nations/World Health Organization 
[WHO]/United Nations University (FAO/WHO/UNU) estimates of human energy requirements, 
using a “sedentary” physical activity level (PAL) of 1.3 (FAO/WHO/UNU 2004).


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Participants will be encouraged to maintain moderate intensity physical activity of at least 
150 minutes per week. Liquid meal replacement is permitted but will not be provided during the 
post-randomization treatment period. The recommended macronutrient distribution will be

maximum 30% of energy from fat 

approximately 20% of energy from protein

approximately 50% of energy from carbohydrates, and

an energy deficit of approximately 500 kcal/day compared to the participant’s estimated 
total energy expenditure (TEE). 
To encourage adherence, it is recommended that behavior modification tools be used, such as 
completion of a 3-day diet and exercise log prior to each counseling visit. During each visit, the 
participant’s diet will be reviewed and behavior modification strategies to maximize adherence 
will be provided as needed.
The hypocaloric diet will be continued throughout the treatment period. If a BMI ≤22 kg/m2 is 
reached, the recommended energy intake should be recalculated with no kcal deficit for the 
remainder of the trial.
Total energy expenditure is calculated by multiplying the estimated Basal Metabolic Rate (BMR) 
(see table below) with a PAL value of 1.3 (FAO/WHO/ UNU 2004), which reflects an inactive 
lifestyle. This calculation provides a conservative estimate of caloric requirements:
TEE (kcal/day) = BMR X 1.3
Equations for Estimating BMR in kcal/Day*
Sex
Age
BMR (kcal/day)
Men
18-30 years
15.057 X actual weight in kg + 692.2
31-60 years
11.472 X actual weight in kg + 873.1
>60 years
11.711 X actual weight in kg + 587.7
Women
18-30 years
14.818 X actual weight in kg + 486.6
31-60 years
8.126 X actual weight in kg + 845.6
>60 years
9.082 X actual weight in kg + 658.5
Abbreviation: BMR = basal metabolic rate; WHO = World Health Organization.
*Revised WHO equations (adapted from: FAO/WHO/UNU 2004).
5.3.2.
Physical Activity
At Visit 2 and all subsequent visits, participants will be advised to increase their physical activity 
to moderate intensity (for example, brisk walking) for at least 150 minutes per week.


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5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled in the study. A minimal set of screen failure information is required 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 serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. 


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6.
Study Intervention
Study intervention is defined as any study drug intervention, investigational intervention(s), 
marketed product(s), placebo, or medical device(s) intended to be administered to/used by a 
study participant according to the study protocol.
6.1.
Study Intervention(s) Administered
Arm Name
Tirzepatide MTD
Placebo
Dose 
10 mg or 15 mg QW
N/A
Route of 
Administration
SC
Sourcing
Provided centrally by the sponsor and dispensed via IWRS
Packaging and 
Labeling
Study drug intervention will be provided in autoinjectors (single-dose pens)
packaged in cartons to be dispensed. Clinical study materials will be 
labeled according to country regulatory requirements.
Abbreviations: IWRS = interactive web-response system; MTD = maximum tolerated dose; N/A = not applicable;
QW = once-weekly; SC = subcutaneous.
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, time, and injection site location of all dose administrations will be recorded in the diary 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 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 SC in the abdomen or thigh using the injection supplies 
provided; a caregiver may administer the injection in the participant’s upper arm. The injection-
site location of all dose administrations will be recorded in the diary by the participant. 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 each week.
6.1.1.
Medical Devices
The combination products provided for use in the study are tirzepatide investigational 
autoinjector (or matching placebo). Any AE resulting from device deficiencies, misuse, or 
malfunctions must be detected, documented, and reported by the investigator throughout the 
study (see Section 10.4.3).


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6.2.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study drug intervention received and any discrepancies 
are reported and resolved before use of the study drug intervention.

Only participants randomized in the study may receive study drug intervention. Only 
study personnel may supply, prepare, or administer study drug intervention. All study
drug 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 study personnel.

The investigator or authorized study personnel are responsible for study drug intervention 
accountability, reconciliation, and record maintenance (for example, receipt, 
reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study drug
interventions are provided in the study training materials.
6.3.
Measures to Minimize Bias: Randomization and Blinding
This is a double-blind, randomized study.
Participants who meet all criteria for enrollment will undergo a 12-week intensive lifestyle 
modification lead-in period. Those who achieve ≥5.0% weight loss at Visit 10 will be 
randomized to one of the study treatment groups (tirzepatide MTD or placebo) for the duration 
of the treatment period. Assignment to treatment groups will be determined by a 
computer-generated random sequence using an IWRS. Participants will be randomized in a 
1:1 ratio to receive tirzepatide MTD or placebo.  
The randomization will be stratified by country, sex (female, male), and percent weight loss at 
the end of lead-in (<10% versus ≥10%).
Investigators, site staff, clinical monitors and participants will remain blinded to the treatment 
assignments until the study is complete.
Emergency unblinding for AEs 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. 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’s 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.


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6.4.
Study Intervention Compliance
Participant compliance with study drug intervention will be assessed at each visit (after 
randomization). 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 office visit to the study site for the purpose of performing drug 
accountability.
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 the 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 study drug 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.
6.5.
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, see 
Section 5.2) 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, 
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, PCOS, diabetes 
prevention). Management of incident diabetes should be performed by participants’ usual care 
providers.
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.
Non-study medications taken by participants who are screened but not enrolled will not be 
reported to Lilly unless an SAE or AE occurs that the investigator believes may have been 
caused by a study procedure.


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6.6.
Dose Modification
6.6.1.
Tirzepatide
Tirzepatide is given QW by SC injection. There are no restrictions on the time of day each 
weekly dose of tirzepatide is given, but it is advisable to administer the SC injections on the 
same day of the week and similar time each week. If a dose of tirzepatide is missed, the 
participant should take it as soon as possible unless it is within 72 hours of the next dose, in 
which case, that dose should be skipped and the next dose should be taken at the appropriate time
(see Section 6.1).  
Study drug dose modification is not permitted, except for management of intolerable GI 
symptoms from Week 0 to Week 24 (see Section 6.6.2).  
6.6.2.
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 counseled 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) (see Section 10.9). 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 immediately, either alone or in combination 
with symptomatic medication, which can also be utilized to manage symptoms. Management of 
study drug after interruptions >1 dose is discussed in Section 7.1.1.
During the first 24 weeks of the treatment period (20-week dose-escalation plus 4 weeks), if 
intolerable GI symptoms (for example, nausea, vomiting, or diarrhea) persist despite the above 
measures, the investigator should contact Lilly to consider a dose de-escalation step with 
subsequent re-escalation (Section 4.1.1.2.3). During the remaining treatment period (Week 24 to 
Week 72), dose de-escalation with subsequent re-escalation, or dose de-escalation to a lower 
maintenance dose, is not permitted. Those with intolerable GI symptoms that develop after 
24 weeks and persist despite the above measures (for example, dietary counseling, symptomatic 
medication, and interruption of study drug for one dose) should discontinue study drug but 
remain in the study for continued follow-up. 
6.7.
Intervention after the End of the Study
Tirzepatide will not be made available to participants after conclusion of the study.


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study drug intervention. If intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for any trial endpoint at the end of the study.
See the SoA for data to be collected at the time of discontinuation of study drug intervention and 
follow-up and for any further evaluations that need to be completed.
In some instances, it may be necessary for a participant to permanently discontinue the intensive 
lifestyle intervention during the 12-week lead-in phase. If the intensive lifestyle intervention is 
discontinued during the lead-in period, the participant will be permanently discontinued from the 
study.
Possible reasons leading to permanent discontinuation of intensive lifestyle intervention 
during lead-in period or study drug intervention during treatment period:

Participant Decision
o
The participant requests to discontinue intensive lifestyle intervention during the lead-
in period or study drug intervention during treatment period.

Clinical Considerations
o
Initiation of open-label GLP-1R agonist or DPP-4 inhibitor, if participants will not or 
cannot discontinue them
o
BMI ≤18.5 kg/m2 is reached at any time 
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 or MEN syndrome type 2
o
Significant elevation of serum calcitonin (Section 8.3.2.4)
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) 
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 discontinuation 
is the appropriate measure to be taken
o
Inadvertent enrollment if continued intensive lifestyle intervention or treatment with 
study drug would not be medically appropriate or not allowed per local regulations
o
PHQ-9 score ≥15.  


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
Participants should be referred to a Mental Health Professional (MHP) to 
assist in deciding whether the participant should be discontinued. 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.  
o
Participants with C-SSRS responses at any visit indicative of suicidal ideation or 
behavior should have intensive lifestyle or study drug interventions discontinued and 
be referred to an MHP. Both interventions may be restarted, if the MHP and the 
investigator agree it is appropriate for the participant. Responses that should prompt 
mental health referral and cessation of intensive lifestyle intervention or study drug
intervention are

a “yes” answer to Question 4 (Active Suicidal Ideation with Some Intent to 
Act, Without Specific Plan) on the "Suicidal Ideation" portion of the C-SSRS
or

a “yes” answer to Question 5 (Active Suicidal Ideation with Specific Plan and 
Intent) on the "Suicidal Ideation" portion of the C-SSRS 
or 

a “yes” answer to any of the suicide-related behaviors (actual attempt, 
interrupted attempt, aborted attempt, preparatory act or behavior) on the 
“Suicidal Behavior” portion of the C-SSRS 
Note: 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 intensive lifestyle intervention or study drug 
intervention due to a hepatic event or liver test abnormality should have additional 
hepatic safety data collected via eCRF.
o
Discontinuation of intensive lifestyle intervention or study drug intervention 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 aspartate aminotransferase (AST) >8X ULN

ALT >2X baseline value or ≥300 U/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%)


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
ALP >3X ULN

ALP >2.5X ULN and TBL >2X ULN

ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Note: In this study baseline may refer to lead-in enrollment visits or randomization visit, 
whichever is the most recent point of reference.
The following are also applicable if developing/occurring during intensive lifestyle lead-in 
period:

Ketoacidosis or hyperosmolar state/coma

Uncontrolled hypertension (systolic blood pressure above or equal to 160 mmHg 
and/or diastolic blood pressure above or equal to 100 mmHg)

Diagnosis of any of the following cardiovascular conditions:
o
Acute myocardial infarction
o
Cerebrovascular accident (stroke)
o
Unstable angina
o
Hospitalization due to CHF, or
o
NYHA Functional Classification Class IV CHF

Chronic (>2 weeks or >14 days) systemic glucocorticoid therapy (excluding topical, 
intra-ocular, intranasal, intra-articular, or inhaled preparations) or evidence of a 
significant, active autoimmune abnormality (for example, lupus or rheumatoid 
arthritis) that has required or is likely to require, in the opinion of the investigator, 
concurrent treatment with systemic glucocorticoids (excluding the ones mentioned 
above)

Surgical treatment or endoscopic and/or device-based therapy for obesity

Initiation of treatment with medications that may significantly impact body weight  
(please refer to Section 5.2. for details)

Initiation of implantable or injectable contraceptives (such as Depo Provera®)
The following are also applicable during study drug intervention period (after 
randomization): 

Intolerable GI symptoms despite management as described in Section 6.6.2

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.
Participants who stop intensive lifestyle intervention permanently should perform an early 
discontinuation (ED) visit and discontinue from the study. Participants who stop the study drug 
permanently should perform an ED visit and continue to attend all scheduled study visits to 
collect all planned efficacy and safety measurements. Randomized participants who are 
unwilling to attend all scheduled visits and stop the study treatment prior to 72 weeks, should 


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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.
See the SoA for data to be collected at the time of intervention discontinuation and follow-up and 
for any further evaluations that need to be completed.
7.1.1.
Temporary Discontinuation
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 drug at the correct dose will be per IWRS instructions.  
If study drug interruption is…
then…
2 consecutive doses or less 
participant restarts study drug at last administered dose, as 
per escalation schedule.
3 consecutive doses or more 
participant restarts study drug at 5 mg (managed by IWRS) 
and repeats dose escalation scheme.
due to an AE
the event is to be documented and followed according to the 
procedures in Section 8.3 of this protocol.
due to intolerable persistent GI 
AE
participants should be treated as suggested in Section 6.6.2.
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.
7.2.
Participant Discontinuation/Withdrawal from the Study
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 clinical outcomes
The circumstances listed above are not valid reasons for discontinuation from the study. 
A participant may withdraw from the study:


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
at any time at his/her own request 

at the request of his/her designee (for example, parents or legal guardian)

at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons

if enrolled in any other clinical study involving an IP or enrolled in any other 
type of medical research judged not to be scientifically or medically 
compatible with this study

if the participant, for any reason, requires treatment (for example, 
pharmacological, device-based or surgical) that has been demonstrated to be 
effective for treatment of the study indication, discontinuation from the study 
occurs prior to introduction of the new treatment
Female participants will be withdrawn from the study if the participant becomes pregnant.
Participation in the study can be stopped for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and Good Clinical Practice (GCP). 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.
At the time of discontinuing from the study, if possible, an ED visit should be conducted, as 
shown in the SoA. See the SoA for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. The participant will be 
permanently discontinued from either the intensive lifestyle intervention or study drug 
intervention, and from the study at that time.
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant
withdraws from the study, he/she may request destruction of any samples taken and not tested,
and the investigator must document this in the site study records.


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7.2.1.
Participant Disposition and Timing of Safety Follow-Up 
Abbreviations:  ED = early discontinuation; wk(s) = week(s).


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7.2.2.
Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and was 
inadvertently enrolled, the investigator and the sponsor CRP must agree whether continuing the 
study drug intervention is medically appropriate. Participants identified as being inadvertently 
enrolled during lead-in period should be discontinued. Continuation of inadvertently enrolled 
participants in the study, with or without study drug treatment, requires documented approval 
from the sponsor CRP. Safety follow up should be performed as outlined in Section 1.3 (SoA), 
Section 8.3 (Adverse Events, Serious Adverse Events, and Product Complaints), and Section 8.2
(Safety Assessments) of the protocol.
7.3.
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 or designee 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 enrolled, including those who 
did not get IP. Public sources may be searched for vital status information. If vital status is 
determined to be deceased, this will be documented, and the participant will not be considered 
lost to follow-up.
Lilly 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 Section 10.1
(Appendix 1).


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8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA.

Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue 
or discontinue intensive lifestyle intervention or study drug intervention

Adherence to the study design requirements, including those specified in the 
SoA, is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that
potential participants meet all eligibility criteria. The investigator will maintain 
a screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable
8.1.
Efficacy Assessments
8.1.1.
Primary Efficacy Assessments
The primary efficacy measurement in this study is body weight. Body weight measurements will 
be collected at specific clinic visits as summarized in the SoA. Methods for measuring body 
weight are described in Section 10.7.
8.1.2.
Secondary Efficacy Assessments
The following secondary efficacy measures will be collected at the times shown in the SoA
(Section 1.3)

BMI (derived using body weight in kilograms divided by the square of height in 
meters)

Waist circumference (measuring method is described in Section 10.7)

Fasting insulin (measured through central lab)

HbA1c (measured through central lab)

Fasting glucose (measured through central lab)

Blood pressure (measuring method is described in Section 10.7)

Lipids (measured through central lab)
8.1.3.
Patient-Reported Outcomes Assessments
The self-administered questionnaires will be translated into the native language of the region, 
linguistically validated and administered according to the SoA (Section 1.3). 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.


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8.1.3.1.
Short-Form 36 Version 2 Health Survey, Acute Form, 1-Week Recall Version
The SF-36v2 acute form, 1-week recall version is a 36-item generic, participant-administered 
measure designed to assess the following 8 domains

Physical functioning 

Role-physical

Bodily pain

General health

Vitality

Social functioning 

Role-emotional 

Mental health 
The Physical Functioning domain assesses limitations due to health “now” while the remaining 
domains assess functioning “in the past week.” Each domain is scored individually and 
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 (3-, 5- or 6- point scales). 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 (SD) of 10; higher scores indicate better levels of function and/or better health 
(Maruish 2011).
8.1.3.2.
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 2 primary domains of obesity-related health-related quality of life 
(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, 2019). 
8.1.3.3.
EQ-5D-5L
Generic HRQoL will be assessed using the EQ-5D-5L (EuroQoL Research Foundation 2019). 
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) (Dolan 
1997). In addition, the EQ Visual Analog Scale records the respondent’s self-rated health status 


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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, scoring, organizing, and presenting the data collected can be found in the 
EQ-5D-5L User Guide (EuroQoL Research Foundation 2019). 
8.1.3.4.
Patient Global Impression of Status for Physical Activity 
Study participants will be asked to complete a PGIs item specifically developed for this study. 
This is a participant-rated assessment of current limitation on physical activity due to health and is 
rated on a 5-point scale ranging from “1- not at all limited” to “5- extremely limited”.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of 
the cardiovascular, respiratory, GI and neurological systems, as well as thyroid 
exam. Height, weight, and waist circumference will also be measured and 
recorded, per Section 10.7.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.2.2.
Vital Signs

For each participant, vital signs measurements should be conducted according 
to the SoA (Section 1.3) and following the study-specific recommendations 
included in Section 10.7 (Appendix 7).

Any clinically significant findings from vital signs measurement that result in a 
diagnosis should be reported to Lilly or its designee as an AE via the eCRF.
8.2.3.
Electrocardiograms
For each participant, single-tracing 12-lead electrocardiograms (ECGs) should be collected 
according to the SoA.
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 participant management, should any clinically 
relevant findings be identified. Any clinically significant findings from ECGs that result in a 
diagnosis 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 


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data analysis and report-writing purposes, unless a cardiology overreading of the ECGs is 
conducted prior to completion of the final study report (in which case, the overread data would be 
used).
8.2.4.
Clinical Safety Laboratory Assessments

See Section 10.2, Appendix 2: “Clinical Laboratory Tests” for the list of 
clinical laboratory tests to be performed and to the SoA for the timing and 
frequency.
Note: see Section 10.2 Appendix 2: “Clinical Laboratory Tests” for clinical 
laboratory tests reported or not reported to the investigator

The investigator must review the laboratory results, document this review, and
report any clinically relevant changes occurring during the study as an AE. The 
laboratory results must be retained with source documents unless a Source 
Document Agreement or comparable document cites an electronic location that 
accommodates the expected retention duration. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 4 weeks after the last dose of study 
intervention should be repeated until the values return to normal or most recent 
baseline or are no longer considered clinically significant by the investigator or 
medical monitor.
○
If such values do not return to normal/most recent baseline within a period 
of time judged reasonable by the investigator, the etiology should be 
identified and the sponsor notified.
○
All protocol-required laboratory assessments, as defined in Section 10.2, 
must be conducted in accordance with the SoA, standard collection 
requirements, and laboratory manual.

If laboratory values from non-protocol specified laboratory assessments 
performed at an investigator-designated local laboratory require a change in 
participant management or are considered clinically significant by the 
investigator (for example, SAE, AE, or dose modification), then report the 
information as an AE.
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.


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8.2.5.
Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods. The study team will review safety reports in a blinded fashion according to the schedule 
provided in the Trial-Level Safety Review plan. Lilly will also review SAEs within time frames 
mandated by company procedures. The Lilly CRP will, as appropriate, consult with the 
functionally independent Global Patient Safety therapeutic area physician or clinical scientist.
8.2.5.1.
Hepatic Safety Monitoring
Close Hepatic Monitoring 
Laboratory tests (Section 10.6, Appendix 6), including ALT, AST, ALP, TBL, direct bilirubin, 
gamma-glutamyl transferase, and creatine kinase, should be repeated within 48 to 72 hours to 
confirm the abnormality and to determine if it is increasing or decreasing, if 1 or more of these 
conditions occur: 
If a participant with baseline results of…
develops the following elevations:
ALT or AST <1.5X 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: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal.
Note: In this study baseline may refer to lead-in enrollment visits or randomization visit, 
whichever is the most recent point of reference.
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, and 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. 


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Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and lab results stabilize. Monitoring of ALT, AST, ALP, and TBL 
should continue until levels normalize or return to approximate baseline levels.
Comprehensive Hepatic Evaluation
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions occur: 
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 ≥2X baseline (except for patients with 
Gilbert’s syndrome)
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal.
* Hepatic signs/symptoms are severe fatigue, nausea, vomiting, jaundice, right upper quadrant abdominal pain, fever, 
rash, and/or eosinophilia >5%. 
Note: In this study baseline may refer to lead-in enrollment visits or randomization visit, 
whichever is the most recent point of reference.
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for prothrombin-time-INR; tests for viral hepatitis A, B, 
C, or E; tests for autoimmune hepatitis; and an abdominal imaging study (for example, ultrasound 
or computed tomography (CT) scan).
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus, 
cytomegalovirus, Epstein-Barr virus, acetaminophen levels, acetaminophen protein adducts, urine 
toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl glucuronide, and blood
phosphatidylethanol. Based on the circumstances and the investigator’s assessment of the 
participant’s clinical condition, the investigator should consider referring the participant for a 
hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography,
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy. 


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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 (CRFs) 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 intensive lifestyle intervention or study drug intervention due to a 
hepatic event
Note: the interval between the 2 consecutive blood tests should be at least 2 days. 
Note: In this study baseline may refer to lead-in enrollment visits or randomization visit, 
whichever is the most recent point of reference.
8.2.6.
Depression, Suicidal Ideation and Behavior Risk Monitoring
Patients who have obesity or are overweight 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. 
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. Consideration 
should be given to discontinuing intensive lifestyle intervention or the study drug intervention in 
participants who experience signs of suicidal ideation or behavior, following a risk assessment
(Section 7.1).
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 8.3.2.13).
8.3.
Adverse Events, Serious Adverse Events, and Product Complaints
The definitions of the following events can be found in Section 10.4 (Appendix 4):

Adverse events (AEs)


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
Serious adverse events (SAEs)

Product complaints (PCs)
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study drug intervention, or study procedures (for example, 
intensive lifestyle intervention), or that caused the participant to discontinue the study 
intervention (see Section 7).
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences.
After the initial 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 7.3). For product 
complaints, the investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality. Further information on 
follow-up procedures is provided in Section 10.4 (Appendix 4).
8.3.1.
Timing and Mechanism for Collecting Events
This table describes the timing, deadlines, and mechanism for collecting events.
Event
Collection Start
Collection Stop
Timing for 
Reporting to 
Sponsor or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
Adverse Event
AE
signing of the 
informed consent 
form (ICF) 
the safety follow-
up visit OR 
participation in 
study has ended
As soon as possible 
upon site awareness
AE eCRF
N/A
Serious Adverse Event
SAE and SAE 
updates – prior 
to start of study
drug
intervention 
and deemed 
reasonably 
possibly related 
with study 
procedures
signing of the 
informed consent 
form (ICF)
start of study drug
intervention
Within 24 hours of 
awareness
SAE eCRF 
SAE paper 
form


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Event
Collection Start
Collection Stop
Timing for 
Reporting to 
Sponsor or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
SAE and SAE 
updates – after 
start of study 
drug
intervention
start of study 
drug intervention
The safety follow-
up visit OR 
participation in 
study has ended
Within 24 hours of 
awareness
SAE eCRF 
SAE paper 
form
SAE – after 
participant’s 
study 
participation 
has ended and
the investigator 
becomes aware
After 
participant’s 
study 
participation has 
ended
N/A
Promptly
SAE paper form
N/A
Pregnancy
Pregnancy in
female 
participants and 
female partners 
of male 
participants
After the start of 
study 
intervention
Four months after 
the last injection 
for female 
partners of male 
participants and 2 
months after the 
last injection for 
female 
participants
Within 24 hours of 
learning of the 
pregnancy
eCRF 
SAE paper 
form
Product Complaints
PC associated 
with an SAE or 
might have led 
to an SAE
Start of study
drug intervention
End of study drug 
intervention
Within 24 hours of 
awareness
Product 
Complaint form
N/A
PC not 
associated with 
an SAE
Start of study
drug intervention
End of study drug
intervention
Within 1 business 
day of awareness
Product 
Complaint form
N/A


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Event
Collection Start
Collection Stop
Timing for 
Reporting to 
Sponsor or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
Updated PC 
information
—
—
As soon as possible 
upon site awareness
Originally 
completed 
Product 
Complaint form 
with all changes 
signed and dated 
by the investigator
N/A
PC (after 
participant’s 
study 
participation 
has ended and
the investigator 
becomes aware)
After 
participant’s 
study 
participation has 
ended
N/A
Promptly
Product 
Complaint form
N/A
Abbreviations: AE = adverse event; eCRF = electronic case report form; N/A = not applicable; PC = product 
complaint; SAE = serious adverse event. 
8.3.2. Special Safety Topics
8.3.2.1.
Hypoglycemia 
Upon 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 diabetes during the study will be provided with glucometers. 
Participants without diabetes may be given glucometers to assist in the evaluation of reported 
symptoms consistent with hypoglycemia at the investigator’s discretion. Participants receiving 
glucometers will be provided a diary to record relevant information (for example, glucose values, 
symptoms).
All hypoglycemic episodes will be recorded on a specific eCRF (Hypoglycemic Events eCRF) 
and should not be recorded on the AE eCRF, 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 SAE eCRFs, and reported to Lilly as an SAE. All hypoglycemic events collected 
on the hypoglycemic eCRF will be considered as treatment-emergent (TE) and included in the 
analysis of incidence and rate of hypoglycemic events. 


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Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the BG 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 2020 American 
Diabetes Association position statement on glycemic targets (ADA 2020):
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 BG
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 BG <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 BG <70 mg/dL (<3.9
mmol/L).
Clinically Significant Hypoglycemia (Level 2):

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).  
8.3.2.2.
Pancreatitis 
Diagnosis of Acute Pancreatitis
Acute pancreatitis is an AE of interest in all studies with tirzepatide, including this study. The 
diagnosis of acute pancreatitis requires 2 of the following 3 features (Banks et al. 2006; Koizumi 
2006): 


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
abdominal pain, characteristic of acute pancreatitis (that is, epigastric pain radiating to 
the back, often associated with nausea and vomiting)

serum amylase (total, pancreatic, or both) and/or lipase ≥3X ULN

characteristic findings of acute pancreatitis on CT scan or magnetic resonance imaging 
(MRI)
If acute pancreatitis is suspected, the investigator should

obtain appropriate laboratory tests, including pancreatic amylase (p-amylase) and 
lipase

perform imaging studies, such as abdominal CT scan with or without contrast, 
abdominal MRI, or gallbladder ultrasound
Note: Abdominal ultrasound may be used as an alternative method only if CT and MRI 
cannot be performed.

evaluate for possible causes of acute pancreatitis, including alcohol use, 
gallstone/gallbladder disease, hypertriglyceridemia, and concomitant medications.
Discontinuation for Acute Pancreatitis
If acute pancreatitis is diagnosed after randomization, the participant must discontinue use of the 
IP, but will continue in the study.
Case Adjudication and Data Entry
An independent clinical endpoint committee (CEC) will adjudicate all suspected cases of acute 
pancreatitis. 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. 
Asymptomatic Elevation of Pancreatic Amylase and/or Lipase
Serial measures of pancreatic enzymes have limited clinical value for predicting episodes of acute 
pancreatitis in asymptomatic patients (Nauck et al. 2017; Steinberg et al. 2017a, 2017b). 
Therefore, further diagnostic follow-up of cases of asymptomatic elevation of pancreatic enzymes 
(lipase and/or p-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. 
8.3.2.3.
Thyroid Malignancies and C-Cell Hyperplasia 
Individuals with personal or family history of MTC and/or MEN syndrome type 2 will be 
excluded from the study. Participants who are diagnosed with MTC and/or MEN syndrome type 2 
during the study will have intensive lifestyle intervention or study drug intervention 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, papillary carcinoma and others) and measurements of calcitonin. 
These 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. 


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8.3.2.4.
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.
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 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.  

Serum calcitonin value ≥20 ng/L and <35 ng/L AND ≥50% increase from the baseline
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.

Serum calcitonin value ≥35 ng/L AND ≥50% over the baseline 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 serum calcitonin value ≥35 ng/L AND ≥50% over the baseline 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.
Note: In this study baseline may refer to lead-in enrollment visits or randomization visit, 
whichever is the most recent point of reference.
8.3.2.5.
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.


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8.3.2.6.
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 
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 10.4 must be reported as SAEs.
8.3.2.7.
Hypersensitivity Reactions
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 national and international 
guidelines.
In the case of generalized urticaria or anaphylaxis, additional blood and urine samples should be 
collected as described in Section 10.3, Appendix 3, “Laboratory Testing for Hypersensitivity 
Events”. Laboratory results are provided to the sponsor via the central laboratory.
8.3.2.8.
Injection-Site Reactions
Symptoms of a local injection-site reaction may include erythema, induration, pain, pruritus, and 
edema. If an injection site event is reported, the AE will be recorded, and additional data will be 
provided to the sponsor in the eCRF.  
Injection site reactions will be collected on the eCRF separate from the hypersensitivity reaction 
eCRF. At the time of AE occurrence, samples will be collected for measurement of tirzepatide
antidrug antibodies (ADA) and tirzepatide concentration.
8.3.2.9.
Antidrug Antibodies
The occurrence of ADA formation will be assessed as outlined in Section 8.9.
8.3.2.10. Hepatobiliary Disorders
All events of TE 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 8.2.5.1.
8.3.2.11. Severe Gastrointestinal Adverse Events 
Tirzepatide may cause severe GI AEs, such as nausea, vomiting, and diarrhea. Information about 
severe GI AEs as well as antiemetic/antidiarrheal use will be collected in the eCRF/AE form. For 
detailed information concerning the management of GI AEs, please refer to Section 6.6.2.
8.3.2.12. Acute Renal Events
Renal safety will be assessed based on repeated renal function 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 


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GLP-1R agonists (Aroda and Ratner 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.
8.3.2.13.
Depression, Suicidal Ideation or Behavior Monitoring
Participants will be monitored for depression and suicidal ideation or behavior through AE 
collection and by using the C-SSRS and the PHQ-9. Participants will be referred to an 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 Question 4 (Active Suicidal Ideation with Some Intent to Act, 
Without Specific Plan) on the “Suicidal Ideation” portion of the C-SSRS
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
8.4.
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.
8.5.
Pharmacokinetics
Not applicable.
8.6.
Pharmacodynamics
Samples to assess the PD properties of tirzepatide are included in the efficacy measures and not 
applicable in this section.
8.7.
Genetics
A whole blood sample will be collected for pharmacogenetic analysis as specified in the SoA 
(Section 1.3) where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either now 
or in the future. Samples will be used to investigate variable response to tirzepatide and to 
investigate genetic variants thought to play a role in obesity. Assessment of variable response may 
include evaluation of AEs or differences in efficacy.  
All samples will be coded with the participant number. These samples and any data generated can 
be linked back to the participant only by the investigator site personnel.  


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Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and/or 
Ethical Review Boards (ERBs)/ Institutional Review Boards (IRBs) impose shorter time limits. 
This retention period enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development of 
tirzepatide or after tirzepatide become(s) commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named. However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, and candidate gene studies. Regardless of 
technology utilized, genotyping data generated will be used only for the specific research scope 
described in this section.
8.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of participant response (including safety), and 
clinical outcome. Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including deoxyribonucleic acid (DNA), 
proteins, lipids, and other cellular elements.
Serum and plasma samples for biomarker research (non-pharmacogenetic stored sample) will be 
collected at the times specified in the SoA (Section 1.3) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
tirzepatide, pathways associated with obesity, mechanism of action of tirzepatide, and/or research 
method or in validating diagnostic tools or assay(s) related to obesity.  
All samples will be coded with the participant number. These samples and any data generated can 
be linked back to the participant only by the investigator site personnel.  
Samples will be retained at a facility selected by Lilly or its designee for a maximum 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and ERBs 
impose shorter time limits. This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later in 
the development of tirzepatide or after tirzepatide become(s) commercially available.
8.9.
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 SoA
(Section 1.3).
For immunogenicity testing, venous blood samples will be collected from each participant 
according to the SoA (Section 1.3) 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 will be collected as detailed in Section 8.3.2.7 (Hypersensitivity Reactions).


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Instructions for the collection and handling of blood samples will be provided by the sponsor. The 
actual date and time (24-hour clock time) of each sampling will be recorded. Samples 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 ADAs in the presence of 
tirzepatide at a laboratory approved by the sponsor. Antibodies may be further characterized for 
their ability to neutralize the activity of tirzepatide on GIP and GLP-1 receptors. Positive 
tirzepatide ADA samples will be tested for cross-reactivity with native GIP and GLP-1, and, if 
positive, may then be tested for neutralizing antibodies against native GIP and/or GLP-1. In vivo 
laboratory indicators for effect on weight loss and PK will be utilized to detect potential 
neutralizing effect of ADA against tirzepatide.
Treatment-emergent ADAs are defined in Section 9.4.6.  
Samples will be retained for a maximum of 15 years after the last participant visit, or for a shorter 
period if local regulations and ERBs allow, at a facility selected by the sponsor. The duration 
allows the sponsor to respond to future regulatory requests related to tirzepatide. Any samples 
remaining after 15 years will be destroyed. 
Concentrations of tirzepatide will be assayed using a validated liquid chromatography mass 
spectrometry method. Bioanalytical samples collected to measure tirzepatide concentrations will 
be retained for a maximum of 1 year following last subject visit for the study. During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses such as metabolism 
work, protein binding, and/or bioanalytical method cross-validation.
8.10.
Health Economics
Health Economics parameters are not evaluated in this study.


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9.
Statistical Considerations
9.1.
Statistical Hypotheses
The alternative hypothesis for the primary objective is the following:
H1: QW tirzepatide MTD is superior to placebo for mean percent change in body weight AND 
proportion of participants who achieve ≥5% body weight reduction from randomization to
72 weeks.
The above hypothesis will be tested at 2-sided significance level of 0.05.
The alternative hypotheses for the key secondary objectives controlling for type 1 error rate are 
the following: 
H2: QW tirzepatide MTD is superior to placebo for percentage of participants who maintain ≥80% 
of the body weight lost during the 12-week lead-in period.
H3: QW tirzepatide MTD is superior to placebo for proportion of participants who achieve ≥10% 
body weight reduction from randomization to 72 weeks.
H4: QW tirzepatide MTD is superior to placebo for proportion of participants who achieve ≥15% 
body weight reduction from randomization to 72 weeks.
H5: QW tirzepatide MTD is superior to placebo for mean change in waist circumference (cm) 
from randomization to 72 weeks.
9.2.
Sample Size Determination
Approximately 1100 participants will be screened and 800 participants enrolled into the 12-week 
lead-in period in order to achieve approximately 600 participants randomly assigned to study drug 
intervention (300 participants per treatment group). 
The sample size determination assumes that evaluation of superiority of tirzepatide MTD (10 mg 
or 15 mg) to placebo will be conducted at a 2-sided significance level of 0.05 using a 2-sample 
t-test. Additionally, a difference of at least 12% mean body weight percentage reduction from 
randomization at 72 weeks for tirzepatide MTD compared to placebo, a common SD of 10%, and 
a dropout rate of 25% are assumed for statistical power calculations. Under the assumptions 
above, randomizing 600 participants in a 1:1 ratio to MTD (300 participants) and placebo (300
participants) provides more than 90% power to demonstrate superiority of tirzepatide MTD to 
placebo. 
The chosen sample size and randomization ratio also provides >90% power to establish 
superiority of tirzepatide MTD to placebo in terms of proportion of participants achieving at least 
5% body weight reduction from randomization at 72 weeks, based on a Chi-square test at a 2-
sided significance level of 0.05, assuming 20% placebo treated participants and 46% tirzepatide 
treated participants achieve the goal and a dropout rate of 25%.


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9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Entered
All participants who sign informed consent
Enrolled
All participants who are enrolled in 12-week lead-in period 
Randomized
All participants who are randomly assigned a study drug.  
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 to which they were 
randomized.
Efficacy Analysis Set (EAS)
Data obtained during the double-blind treatment period from the mITT
population, excluding data after discontinuation of study drug (last dose date + 7 
days)
Full Analysis Set (FAS)
Data obtained during the treatment period from mITT population, regardless of 
adherence to study drug. 
Safety Analysis Set (SS)
Data obtained during the treatment plus follow up period from the mITT
population, regardless of adherence to study drug. 
9.4.
Statistical Analyses
9.4.1. General 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 
statistical analysis plan (SAP) or the clinical study report (CSR). 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 (CI) will be calculated at 95%, 2-sided. In statistical summaries 
and analyses, data will be analyzed as randomized.
Unless specified otherwise, efficacy analyses will be conducted using efficacy analysis set (EAS) 
and safety analyses will be conducted using safety analysis set (SS). 
Unless otherwise specified, for analyses in the double-blind period, baseline is defined as the last 
non-missing data collected prior to or at randomization (prior to first dosing of study drug); for 
analyses in the lead-in period, baseline is defined as the last non-missing data collected prior to or 
at study entry (Visit 1 and Visit 2).  


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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, treatment-by-visit interaction, stratification 
factors and baseline measurement as a covariate. An unstructured covariance structure will model 
relationship of within-patient errors.
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, 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.
9.4.2.
Treatment Group Comparability
9.4.2.1.
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, enrolled, randomized, and 
receiving at least 1 dose of study drug will be summarized by treatment group. Of the randomized 
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 summarized by treatment group.
A Kaplan-Meier analysis of time from randomization to premature discontinuation from study 
and/or study treatment by treatment group will be provided. 
9.4.2.2.
Participant Characteristics
Demographics will be summarized for all enrolled participants. 
Demographics will also be summarized by treatment group for all randomized participants. 
9.4.2.3.
Concomitant Therapy 
Concomitant medication, including previous therapy, will be summarized by treatment group for 
all randomized participants. 
9.4.2.4.
Treatment Compliance
Frequency counts and percentages of participants compliant to study drug will be summarized by 
treatment arms and visits for FAS. 


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9.4.3.
Efficacy Analyses
9.4.3.1.
Primary Analyses
There will be 2 estimands of interest in comparing efficacy of tirzepatide MTD with placebo. For 
the FDA, the primary efficacy analysis will be guided by the “hybrid” estimand and will be 
conducted using the FAS. This assessment will analyze percent change in body weight obtained at 
the 72-week visit using an analysis of covariance (ANCOVA) and the percentage of participants 
achieving at least 5% body weight reduction obtained at the 72-week visit using a logistic 
regression model. Both models (ANCOVA and logistic regression model) will include terms of
treatment, stratification factors, and baseline body weight as a covariate. Missing data solely due 
to a pandemic or natural disaster (after other reasons for missing data are ruled out) will be 
considered missing at random, and missing data will be imputed using all non-missing data of the 
primary outcome measurement from the same treatment arm. Missing data of the primary 
outcome measurement due to all other Intercurrent Events (ICEs) will be imputed based on 
retrieved dropouts in the same treatment arm, defined as observed primary outcome 
measurements from participants in the same treatment group who had their efficacy assessed after
early discontinuation of study drug. In cases where there are not enough retrieved dropouts to 
provide a reliable imputation model (for example, the model implemented by the SAS program 
does not converge), an alternative multiple imputation method with reference to the placebo 
group (that is, placebo multiple imputation) will be used. Analysis will be conducted with 
multiple imputations.  
For all other purposes, the primary efficacy analyses will be guided by the “efficacy” estimand, 
which represents efficacy prior to discontinuation of study drug, and conducted using the EAS. 
The primary analysis model will be an MMRM for body weight percentage change over time and 
a longitudinal logistic regression for proportion of participants achieving at least 5% body weight 
reduction over time. The response variable of the MMRM will be the percent change in body 
weight from baseline values obtained at each scheduled post baseline visit. The response variable 
of the longitudinal logistic regression will be the proportion of participants achieving at least 5% 
body weight reduction at each scheduled post randomization visit. 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 needs to be achieved at the same time, no multiplicity adjustment is planned for 
these 2 tests.
9.4.3.2.
Key Secondary Efficacy Analyses

Superiority of tirzepatide MTD to placebo for the percentage of participants who maintain 
≥80% of the body weight lost during the 12-week lead-in period

Superiority of tirzepatide MTD to placebo for the proportion of participants who achieve 
≥10% body weight reduction from randomization to 72 weeks 

Superiority of tirzepatide MTD to placebo for the proportion of participants who achieve 
≥15% body weight reduction from randomization to 72 weeks 

Superiority of tirzepatide MTD to placebo for the mean change in waist circumference 
(cm) from randomization to 72 weeks 


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Additional details, including analysis methods for key secondary endpoints and the strategy for 
controlling the 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. 
9.4.3.3.
Other Secondary Efficacy Analyses
All other efficacy analyses will be guided by “efficacy” estimand and will be conducted using 
EAS. Details will be provided in the SAP.
9.4.4.
Safety Analyses
Unless specified otherwise, safety assessments will be guided by an estimand comparing the 
safety of tirzepatide MTD with placebo irrespective of adherence to study drug. Thus, safety 
analyses will be conducted using SS. 
9.4.4.1.
Study Drug Exposure
Study drug exposure will be calculated for each participant and summarized by treatment group.
9.4.4.2.
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, and discontinuation due to AE (DCAE)
will be summarized by treatment group.
9.4.4.3.
Special Safety Topics
This section includes areas of interest whether due to observed safety findings, potential findings 
based on drug class, or agreed upon consultation with regulatory agencies for the reasons 
previously mentioned.
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

MDD/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 the incidence of AESIs will be provided by treatment. The details of 
analysis of AESI will be provided in the SAP.


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9.4.4.4.
Other Adverse Event Assessments 
9.4.4.4.1. Gastrointestinal Events
Summaries and analyses for incidence and severity of nausea, vomiting, and diarrhea will be 
provided by each treatment.  
9.4.4.4.2. Events Related to Potential Abuse Liability
Summaries and analyses for incidence of potential abuse liability TEAEs will be provided by
treatment. The details will be provided in the SAP.
9.4.4.4.3. Depression, Suicidal Ideation and Behavior
In addition to the summary of TEAEs, suicidal ideation and behavior will be assessed by C-SSRS, 
and depression related symptoms will be assessed using the PHQ-9. 
The analysis details will be provided in the SAP.
9.4.4.4.4. 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 TE 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 the SAP.
9.4.5.
Pharmacokinetic/Pharmacodynamic Analyses
No PK/PD analyses are planned for this study. 
9.4.6.
Evaluation of Immunogenicity 
The frequency and percentage of participants with preexisting ADA and with 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 (1:10) of the ADA assay if no ADAs were 
detected at baseline (treatment-induced ADA) or those with a 4-fold (2 dilutions) increase in titer 
compared to baseline if ADAs were detected at baseline (treatment-boosted ADA). For the TE 
ADA+ participants, the distribution of maximum titers will be described. The frequency of 
neutralizing antibodies, if assessed, and cross reactivity to native GIP and GLP-1 may also be
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.


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9.4.7.
Other Analyses
9.4.7.1.
Health Outcomes
Analyses of actual and change from randomization in the domains and/or summary scores of
patient-reported outcomes questionnaires will be conducted using the EAS. The details on 
questionnaire-specific analyses will be provided in the SAP.
9.4.7.2.
Subgroup Analyses for Primary Analysis
Details of the subgroup analyses will be provided in the SAP.  
The following subgroup variables will be considered (but not limited to):

age (<65 years and ≥65 years)

sex (female and male)

race 

ethnicity 

BMI at study entry (<30, ≥30 and <35, ≥35 and <40, ≥40 kg/m2)

percent body weight loss at the end of lead-in (<10% and ≥10%)
The outcome measures for the subgroup analyses will include:

percent change in body weight from randomization to 72 weeks

proportion of participants achieving at least 5% body weight reduction from randomization 
to 72 weeks.
9.5.
Interim Analyses 
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended.
9.6.
Data Monitoring Committee (DMC)
Not applicable.


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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the 
following:
o
Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines
o
Applicable ICH Good Clinical Practice (GCP) Guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (for 
example, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants.

Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants.

The investigator will be responsible for the following:
○
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC
○
Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures
○
Providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 Code of Federal Regulations (CFR), ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations

Investigator sites are compensated for participation in the study as detailed in the 
clinical trial agreement (CTA).
10.1.2.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study, 
including the risks and benefits, to the participant or his/her legally authorized 
representative and answer all questions regarding the study.


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
Study participants must be informed that their participation is voluntary. Study 
participants or their legally authorized representative will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative and is kept on file.
10.1.3.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets or tissue samples 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/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 who will be required to give 
consent for his/her data to be used as described in the informed consent.

The participant must be informed that his/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.

The sponsor has processes in place to ensure data protection, information security 
and data integrity. These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach.
10.1.4.
Committees Structure
Prospective adjudication of major adverse cardiovascular events and pancreatic AEs will be 
performed for this study. Sections 8.3.2.2, and 8.3.2.5 outline additional information on 
pancreatic and cardiovascular adjudication committees. 
10.1.5.
Dissemination of Clinical Study Data
Required clinical trial registries (for example, ClinicalTrials.gov) will be updated with the results 
from registered clinical trials regardless of the research outcome in accordance with local laws 
and regulations. 
All CSRs, amendments and addenda will be submitted to external regulatory authorities, external 
partners (as applicable) and sites. 


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The publication policy for Study GPHM is outlined in Section 10.1.9 and further described in the 
CTA.
10.1.6.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (for example, 
laboratory data). The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.

Monitoring details describing strategy (for example, risk-based initiatives in 
operations and quality such as risk management, mitigation strategies, and 
analytical risk-based monitoring), methods, responsibilities and requirements, 
including handling of noncompliance issues and monitoring techniques are 
provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (for 
example, contract research organizations).

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the time period outlined in the CTA 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor.

In addition, sponsor 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 sponsor or its representatives, and/or regulatory agencies at 
any time. Investigators will be given notice before an audit occurs.


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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 system (EDC) 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 (COA) data (participant-focused outcome instrument) 
and other data (for example, diary), will be collected by the participant, caregiver, or authorized 
study personnel, via a paper source document and will be transcribed by the authorized study 
personnel into the EDC system.
Data collected via the sponsor-provided data capture system(s) 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 system(s). 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. Data will subsequently be transferred from the central vendor to the 
sponsor data warehouse.
Data from complaint forms submitted to sponsor will be encoded and stored in the global product 
complaint management system.
10.1.7.
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.

Definition of what constitutes source data can be found in study training material.
10.1.8.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.


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The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and assure 
appropriate participant therapy and/or follow-up.
10.1.9.
Publication Policy
In accordance with the sponsor’s publication policy, the results of this study will be submitted for 
publication by a peer-reviewed journal.

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 GPHM is described in the CTA.


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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed below will be performed by a central lab unless designated as 
local in the SoA and in the table below.
●
In circumstances where the sponsor approves local laboratory testing in lieu of 
central laboratory testing (in the table below), the local laboratory must be 
qualified in accordance with applicable local regulations.

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 and are denoted in the table below.


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Clinical Laboratory Tests
Hematologya
Clinical Chemistrya
Hemoglobin
Bicarbonate
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils, segmented
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Uric acid
Platelets
Calcium
Glucose
Urine Chemistriesa
Albumin
Albumin
Creatine kinase (CK)
Creatinine
Cystatin-Ca
Hormones (females)
Pregnancy Test serum a and/or urine (local)
Follicle-stimulating hormone (FSH)a
HbA1ca
Endocrinea
Calcitonin
Pancreas (exocrine)a
Thyroid-stimulating hormone (TSH)
Pancreatic amylase
Lipase
Nonpharmacogenetic Stored Samplesa,b
Serum
EDTA plasma
P800 plasma
Immunogenicitya,b
Anti-tirzepatide antibodies
Anti-tirzepatide antibody neutralization
Pharmacokinetic Sample for Immunogenicity
Lipid Panela
Pharmacogenetics Samplea,b
Whole blood (EDTA)
Triglycerides
VLDL-C
HDL-C
LDL-Cc
Total cholesterol
Free Fatty Acidsa
Insulina
C-peptidea
Calculations
a
eGFR (calculated by CKD-EPI equation)
UACR
Abbreviations: CKD-EPI = Chronic Kidney Disease-Epidemiology; eGFR = estimated glomerular filtration rate; 
EDTA = ethylenediaminetetraacetic acid; HbA1c = hemoglobin A1c; HDL-C = high-density lipoprotein
cholesterol; LDL-C = low-density lipoprotein cholesterol; RBC = red blood cells; UACR = urine albumin to 
creatinine ratio; VLDL-C = very low-density lipoprotein cholesterol; WBC = white blood cells.


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a
All tests will be performed by a Lilly-designated central laboratory, unless otherwise noted.
b
Results will not be provided to the investigative sites.
c    This value will be calculated. If triglycerides are >400 mg/dL, the direct LDL will be assayed.


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10.3.
Appendix 3: 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 table below summarizes the laboratory parameters that will be evaluated. These laboratory 
tests are bundled in the hypersensitivity laboratory testing kit.


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Clinical Lab Tests for Hypersensitivity Events
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 
N-methylhistamine testing is performed in addition to tryptase testing. Collect the 
first void urine sample following the event. Obtain a follow-up urine sample for 
N-methylhistamine 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.
Drug-specific IgE
Will be performed if a validated assay is available.
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigative sites.
Basophil activation test
Will be performed if a validated assay is available.
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigative sites.
Note: The basophil activation test is an in vitro cell based assay that only requires 
a serum sample. It is a surrogate assay for drug specific IgE, but is not specific for 
IgE.
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; IgE = immunoglobulin E; IL = interleukin; PK = pharmacokinetic.


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10.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.4.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product and which does not necessarily have a causal relationship with the study 
intervention. An AE can therefore be any unfavourable and unintended sign (including an
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related to 
progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after intensive lifestyle intervention or study drug 
intervention administration even though they may have been present before the start of the 
study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug 
intervention or a concomitant medication. 

“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as an AE or SAE if they fulfill the definition of an AE or SAE. 
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 


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that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
10.4.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (for example, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been admitted to hospital for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (for example, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect

Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.


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f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.

Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
g.
Resulted in medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function.
10.4.3.
Definition of Product Complaint
Product Complaint

A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness or 
performance of a study intervention. When the ability to use the study intervention safely 
is impacted, the following are also product complaints:
o
Deficiencies in labeling information, and
o
Use errors for device or drug-device combination products due to ergonomic 
design elements of the product.

Product complaints related to study interventions used in clinical trials are collected in 
order to ensure the safety of participants, monitor quality, and to facilitate process and 
product improvements.

Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can be 
assessed.

An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE.
10.4.4.
Recording and Follow-Up of AE and/or SAE and Product Complaints
AE, SAE, and Product Complaint Recording

When an AE/SAE/product complaint occurs, it is the responsibility of the investigator to 
review all documentation (for example, hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event.

The investigator will then record all relevant AE/SAE/product complaint information in 
the participant’s medical records, in accordance with the investigator’s normal clinical 
practice. Adverse event/SAE information is reported on the appropriate (e)CRF page and 


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product complaint information is reported on the Product Complaint form.
Note: An event may meet the definition of both a product complaint and an AE/SAE. In 
such cases, it should be reported as both a product complaint and as an AE/SAE.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor or designee in lieu of completion of the (e)CRF page for AE/SAE 
and the Product Complaint form for product complaints.

There may be instances when copies of medical records for certain cases are requested by 
sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the sponsor or designee.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories:

Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living.

Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the research participant.

Severe: A type of AE that interrupts usual activities of daily living, significantly affects 
clinical status, or may require intensive therapeutic intervention. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the
intensity of an event, and both AEs and SAEs can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between intensive lifestyle 
intervention or study drug intervention and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to intensive lifestyle intervention 
or study drug intervention administration will be considered and investigated.


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
The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor or designee. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the sponsor or designee.

The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor or designee with a copy of any 
post-mortem findings, including histopathology.
10.4.5.
Reporting of SAEs
SAE Reporting via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE will be the electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes available.

After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the sponsor contact for SAE reporting by telephone.

Contacts for SAE reporting can be found in study training material. 
SAE Reporting via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 


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information to the sponsor contacts for SAE reporting.

Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in study training material.
10.4.6.
Regulatory Reporting Requirements
SAE Regulatory Reporting

Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study intervention under clinical investigation are met.
●
The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under 
clinical investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRB/IEC, and 
investigators.
●
An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (for example, summary or listing of SAEs) from 
the sponsor will review and then file it along with the IB and will notify the 
IRB/IEC, if appropriate, according to local requirements.


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10.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).
If fertility is unclear (for example, amenorrhea in adolescents or 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 women 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: Determination 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
o
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 an FSH ≥40 mIU/mL; or 
o
A woman 55 or older not on hormone therapy, who has had at least 12 months 
of spontaneous amenorrhea; or 
o
A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy (HRT). 

Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonestrogen 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.


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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 
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, and 
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 childbearing potential 
partners must agree to either remain abstinent (if this is their preferred and usual lifestyle) or use 
condoms plus 1 additional highly effective (less than 1% failure rate) method of contraception 
(such as combination oral contraceptives, implanted contraceptives, or intrauterine device) or
effective method of contraception (such as diaphragms with spermicide or cervical sponge) for 
the duration of the study and for 5 half-lives of study drug plus 90 days, which is approximately 4 
months after the last injection. Periodic abstinence (for example, calendar, ovulation, 


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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. 
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. 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. If pregnancy occurs during study drug intervention period, 
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. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant's pregnancy. 

The participants who become pregnant during the study drug intervention period
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.


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
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 

A spontaneous abortion (occurring at <20 weeks gestational age) or still birth 
(occurring at >20 weeks gestational age) is always considered to be an SAE and 
will be reported as such. 

Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
protocol. 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 intensive lifestyle intervention or study drug intervention. If the 
participant is discontinued from the study intervention, follow the standard 
discontinuation process for each study period.


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10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments 

For testing selected, analysis is required to be completed by the Lilly designated 
central laboratory, except for microbiology.

Local testing may be performed in addition to central testing when required for 
immediate participant management.

Results will be reported if a validated test or calculation is available.
Hepatic Evaluation Labs
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
Prothrombin Time, INR (PT-INR)
Ethyl Alcohol
Serology
Haptoglobin
Hepatitis A Virus (HAV) testing:
IgA (Quantitative)
HAV total antibody
IgG (Quantitative)
HAV IgM antibody
IgM (Quantitative)
Hepatitis B Virus (HBV) Testing:
Phosphatidylethanol (PEth)
Hepatitis B surface antigen (HBsAg)
Urine Chemistry
Hepatitis B surface antibody (Anti-HBs)
Drug Screen
Hepatitis B core total antibody (Anti-HBc)
Ethyl glucuronide (EtG)
Hepatitis B core IgM antibody
Other Serology
Hepatitis B core IgG antibody
Anti-nuclear antibody (ANA)


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Hematology
Clinical Chemistry
HBV DNAa
Anti-smooth muscle antibody (ASMA) b
Hepatis C Virus (HCV) Testing:
Anti-actin antibodyc
HCV antibody
Epstein-Barr Virus (EBV) Testing:
HCV RNAa
EBV antibody
Hepatitis D Virus (HDV) Testing:
EBV DNAa
HDV antibody
Cytomegalovirus (CMV) Testing:
Hepatitis E Virus (HEV) Testing:
CMV antibody
HEV IgG antibody
CMV DNAa
HEV IgM antibody
Herpes Simplex Virus (HSV) Testing:
HEV RNAa
HSV (Type 1 and 2) antibody
Microbiologyd
HSV (Type 1 and 2) DNAa
Culture:
Liver Kidney Microsomal Type 1 (LKM-1) Antibody
Blood
Urine
Abbreviations: Ig = immunoglobulin; INR = international normalized ratio.
a
Reflex/confirmation dependent on regulatory requirements, testing availability, or both.
b
This is not required if anti-actin antibody is tested.
c
This is not required if anti-smooth muscle antibody is tested.
d
Assayed by investigator-designated local laboratory ONLY. No central testing available.


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10.7.
Appendix 7: Protocol GPHM 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 2017) 
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 one 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 empty their pockets, remove their footwear, outerwear (coat, 
jacket, etc.), and 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 kilogram.
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.


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
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 little 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 waist circumference.
Vital Sign Measurements

Vital sign measurements (blood pressure and heart rate, measured by pulse) should be 
taken before obtaining an 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, 2 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 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 subject 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 (collected with immunogenicity 
testing).


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10.8.
Appendix 8: Suggested Visit Structure
Abbreviations:  AE=adverse event; ECG=electrocardiogram; PRO=patient reported outcomes; SoA=Schedule of 
Activities


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10.9.
Appendix 9: Management of Gastrointestinal Symptoms
Abbreviation:  GI= gastrointestinal


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10.10.
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. 
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 conditions in which notification is required. 
To protect the safety of study participants, urgent changes may be implemented before approval 
but need to be reported as soon as possible. All approvals 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 GCP, 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,”

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.
1.
Remote visits


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In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for the reason of conducting a remote visit instead of an onsite visit and for any data 
missing because of missed in-person site 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 of study participant diary (including study 
drug compliance), review diet and exercise goals, lifestyle counseling, C-SSRS (Since 
Last Visit Version), Self-Harm Supplement Form, Self-Harm Follow-up Form (if 
applicable), and PHQ-9.
Mobile healthcare:
Healthcare visits may be performed by a mobile healthcare provider at locations other 
than the study site when participants cannot travel to the site due to an exceptional 
circumstance if written approval is provided by the sponsor. Procedures performed at 
such visits include, but are not limited to, weight and waist measurements, physical 
assessments, vital signs, ECG, PRO questionnaires administration, collection of blood 
samples and health information. 
Other alternative locations:  
Laboratory draws may be done at an alternate location in exceptional circumstances.
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and product complaints remain unchanged. Furthermore, 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.
2. Local laboratory testing option
Local laboratory testing may be conducted in lieu of central laboratory testing. The local 
laboratory must be qualified in accordance with applicable local regulations.
3. Study intervention and ancillary supplies (including participant diaries)
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, and

arranging delivery of study supplies.


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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.
4. Screening period guidance 
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at or prior to Visit 2 are valid for a maximum of 90 days. The following rules will be applied for 
active, not yet enrolled participants whose participation in the study must be paused due to 
exceptional circumstances:

If paused for less than 90 days from Visit 1 to Visit 2: the participant will proceed to 
the next study visit per the usual Schedule of Activities, provided that Visit 2 must be 
conducted within 90 days from Visit 1. 
o
The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay in the CRF.
o
Due to the pause in screening, sites should also reconfirm the impacted 
participant’s consent and document this confirmation in the source 
documentation.

If paused for more than 90 days from Visit 1 to Visit 2: The participant must be 
discontinued because of screening interruption due to an exceptional circumstance. 
This is documented as a screen failure in the CRF. The participant can reconsent and 
be rescreened as a new participant. The screening procedures per the usual SoA
should be followed, starting at Visit 1 to ensure participant eligibility by Visit 2.
5. Adjustments to visit windows 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA. To maximize the possibility that these visits can be conducted as 
on-site visits, 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.
Randomization visit (Visit 10) should be completed as per original schedule whenever possible 
and safe to do so. However, the visit may be brought forward no sooner than 7 days or extended 
up to 14 days relative to the target visit date. 


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Primary endpoint visit (Visit 28 or 99) should be completed as per original schedule whenever 
possible and safe to do so. However, the visit may be brought forward no sooner than 14 days or 
extended up to 28 days relative to the target visit date. 
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:

Sites will identify and document the details of how participants, visit 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 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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10.11.
Appendix 11: Abbreviations
Term
Definition
ADA
antidrug antibody
AE
adverse event: Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment. An 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
AMA
American Medical Association
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
baseline
A fixed point of reference that is used for comparison purposes. In this study baseline 
may refer to lead-in enrollment visits (Visit 1 and Visit 2) or randomization visit.
BG
blood glucose
BMI
body mass index
BMR
basal metabolic rate
CEC
clinical endpoint committee
CFR
Code of Federal Regulations
CHF
congestive heart failure
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease-Epidemiology
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, GCP, and applicable regulatory requirements.
CONSORT
Consolidated Standards of Reporting Trials


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CRP
clinical research physician: Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer.
CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
CT
computed tomography
CTA
Clinical Trail Agreement
DMC
Data monitoring committee
DNA
deoxyribonucleic acid
DPP-4
dipeptidyl-peptidase-4
EAS
efficacy analysis set
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
enroll
In this study enroll refers to all participants who enter the 12-week lead-in period at 
Visit 2.
enter
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives.
ERB
Ethical Review Board
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide
GIPR
glucose-dependent insulinotropic polypeptide receptor


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GLP-1
glucagon-like peptide-1
GLP-1R
glucagon-like peptide-1 receptor
HbA1c
hemoglobin A1c
HDL
high-density lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
HRQoL
health-related quality of life
IB
Investigator’s Brochure
ICF
informed consent form
ICH
The International Council for Harmonization 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.
INR
international normalization ratio
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.
IP
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 
IWQOL-Lite-CT
Impact of Weight on Quality of Life-Lite-Clinical Trials Version
IWRS
interactive web-response system
LCD
low calorie diet
LDL
low-density lipoprotein
MAD
multiple ascending dose
MDD
Major Depressive Disorder
MedDRA
Medical Dictionary for Regulatory Activities
MEN
multiple endocrine neoplasia
MHP
mental health professional


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mITT
modified intention-to-treat
MMRM
mixed model for repeated measures
MRI
magnetic resonance imaging
MTC
medullary thyroid carcinoma
MTD
maximum tolerated dose
NAFLD
nonalcoholic fatty liver disease
NYHA
New York Heart Association
p-amylase
pancreatic amylase
PAL
physical activity level
PCOS
polycystic ovarian syndrome
PGIs
Patient Global Impression of status
PHQ-9
Patient Health Questionnaire-9
PK/PD
pharmacokinetics/pharmacodynamics
PROs
patient-reported outcomes
QW
once weekly
randomized
All participants who are indiscriminately assigned a study drug.
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SD
standard deviation
SF-36v2
Short Form-36 Health Survey (SF-36), version 2 acute form
SoA
Schedule of Activities
SS
Safety analysis set
T1DM
Type 1 diabetes mellitus
T2DM
Type 2 diabetes mellitus


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TBL
total bilirubin level
TE
Treatment-emergent
TE ADA+
treatment-emergent antidrug antibody positive
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.
TEE
total energy expenditure
THC
tetrahydrocannabinol
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
VLCD
very low calorie diet
WHO
World Health Organization


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11.
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SAXENDA [package insert]. Bagsværd, Denmark: Novo Nordisk; 2014.
Skow MA, Bergmann NC, Knop FK. Diabetes and obesity treatment based on dual incretin 
receptor activation: “twincretins”. Diabetes Obe Metab. 2016;18(9):847-854.
https://doi.org/10.1111/dom.12685
Srivastava G, Apovian CM. Current pharmacotherapy for obesity. Nat Rev Endocrinol. 
2018;14(1):12-24. https://doi.org/10.1038/nrendo.2017.122
Steinberg WM, Buse JB, Ghorbani MLM, et al. 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. https://doi.org/10.2337/dc16-2747
Steinberg WM, Rosenstock J, Wadden TA, et al. 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. https://doi.org/10.2337/dc16-2684
Sumithran P, Prendergast LA, Delbridge E, et al. Long-term persistence of hormonal adaptations 
to weight loss. N Engl J Med. 2011;365(17):1597‐1604. 
https://doi.org/10.1056/NEJMoa1105816
Tomlinson B, Hu M, Zhang Y, et al. An overview of new GLP-1 receptor agonists for type 2 
diabetes. Expert Opin Investig Drugs. 2016;25(2):145-158. 
https://doi.org/10.1517/13543784.2016.1123249
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https://doi.org/10.1530/JOE-13-0414
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https://www.who.int/ncds/surveillance/steps/STEPS_Manual.pdf. 
Wing RR, Lang W, Wadden TA, et al. ; Look AHEAD Research Group. Benefits of modest 
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Leo Document ID = a1f37e94-98cb-4d3e-b822-c86293aa4b40
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PPD
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SAP_001.pdf: 
 
 
I8F-MC-GPHM StaƟsƟcal Analysis Plan Version 3 
 
 
Eﬃcacy and Safety of TirzepaƟde Once Weekly Versus Placebo AŌer an Intensive Lifestyle Program 
in ParƟcipants Without Type 2 Diabetes Who Have Obesity or Are Overweight With Weight-Related 
ComorbidiƟes: A Randomized, Double Blind, Placebo-Controlled Trial (SURMOUNT-3) 
 
 
NCT04657016 
 
 
Approval Date: 03-Feb-2023 


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PAGE 1 
Title Page  
Protocol Title: Efficacy and Safety of Tirzepatide Once Weekly versus Placebo After an 
Intensive Lifestyle Program in Participants without Type 2 Diabetes who have Obesity or are 
Overweight with Weight-Related Comorbidities: A Randomized, Double-Blind, Placebo-
Controlled Trial (SURMOUNT-3) 
Protocol Number: I8F-MC-GPHM 
Compound Number: LY3298176 
Short Title: Effect of Tirzepatide versus Placebo after Intensive Lifestyle Program 
(SURMOUNT-3) 
Acronym: SURMOUNT-3 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana USA 46285 
Regulatory Agency Identifier Number(s) 
 
IND 139721 
 
 
 
 
Confidential Information  
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of 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.  
 
 
 
Document ID: VV-CLIN-076448 
 
 
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Table of Contents  
Title Page ........................................................................................................................................1 
Table of Contents ...........................................................................................................................2 
List of Abbreviations .....................................................................................................................6 
Version History ..............................................................................................................................9 
1. 
Introduction ...................................................................................................................10 
1.1. 
Objectives, Endpoints, and Estimands ............................................................................11 
1.1.1. 
Objectives and Endpoints ...............................................................................................11 
1.1.2. 
Estimands ........................................................................................................................13 
1.2. 
Study Design ...................................................................................................................16 
2. 
Statistical Hypotheses ...................................................................................................18 
2.1. 
Multiplicity Adjustment ..................................................................................................18 
3. 
Analysis Sets ..................................................................................................................20 
4. 
Statistical Analyses .......................................................................................................21 
4.1. 
General Considerations ...................................................................................................21 
4.2. 
Participant Dispositions ..................................................................................................22 
4.3. 
Primary Endpoints Analysis ...........................................................................................23 
4.3.1. 
Definition of Endpoint ....................................................................................................23 
4.3.2. 
Main Analytical Approach ..............................................................................................23 
4.4. 
Secondary Endpoint(s) Analysis .....................................................................................26 
4.4.1. 
Key Secondary Analyses Subject to Type 1 Error Rate Control ....................................26 
4.4.2. 
Supportive Secondary Endpoints ....................................................................................27 
4.5. 
Exploratory Endpoints Analysis .....................................................................................30 
4.6. 
Safety Analyses...............................................................................................................32 
4.6.1. 
Extent of Exposure ..........................................................................................................33 
4.6.2. 
Adverse Events ...............................................................................................................34 
4.6.3. 
Additional Safety Assessments .......................................................................................35 
4.6.4. 
Patient Narratives ............................................................................................................38 
4.6.5. 
Special Safety Topics ......................................................................................................38 
4.7. 
Other Analyses ................................................................................................................54 
4.7.1. 
Health Outcomes .............................................................................................................54 
4.7.2. 
Subgroup Analyses .........................................................................................................56 
4.8. 
Interim Analyses .............................................................................................................58 
4.9. 
Changes to Protocol-Planned Analyses ..........................................................................58 
5. 
Sample Size Determination ..........................................................................................59 
6. 
Supporting Documentation ..........................................................................................60 
6.1. 
Appendix 1: Demographic and Baseline Characteristics ...............................................60 
6.1.1. 
Patient Characteristics .....................................................................................................60 
6.1.2. 
Historical Illnesses and Preexisting Conditions ..............................................................60 
6.1.3. 
Concomitant Therapy......................................................................................................60 
6.2. 
Appendix 2: Treatment Compliance ...............................................................................61 
6.3. 
Appendix 3: Important Protocol Deviations ...................................................................61 
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6.4. 
Appendix 4: Analyses for the Intensive Lifestyle Modification 
Lead-in Period.................................................................................................................61 
6.4.1. 
General Consideration ....................................................................................................61 
6.4.2. 
Patient Characteristics .....................................................................................................62 
6.4.3. 
Disposition ......................................................................................................................62 
6.4.4. 
Medical History, Preexisting Conditions, and Concomitant 
Medications .....................................................................................................................62 
6.4.5. 
Adverse Events ...............................................................................................................62 
6.4.6. 
Additional Safety Assessments .......................................................................................63 
6.4.7. 
Important Protocol Deviations ........................................................................................63 
6.5. 
Appendix 5: Clinical Trial Registry Analyses ................................................................63 
6.6. 
Appendix 6: Exceptional Circumstances Impact ............................................................63 
6.6.1. 
General Considerations ...................................................................................................64 
6.6.2. 
Exposure .........................................................................................................................64 
6.6.3. 
Protocol Deviations .........................................................................................................64 
6.6.4. 
Patient Disposition ..........................................................................................................64 
6.6.5. 
Adverse Events ...............................................................................................................64 
6.6.6. 
Major Depressive Disorder/Suicidal Ideation .................................................................64 
6.6.7. 
Local Laboratory Measurements ....................................................................................65 
6.6.8. 
Missing Data Due to Exceptional Circumstances ...........................................................65 
6.7. 
Appendix 7: Searching Criteria for Special Safety Topics .............................................65 
7. 
References ......................................................................................................................67 
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Table of Contents 
Table 
Page 
Table GPHM.1.1. 
Objectives and Endpoints ..........................................................................11 
Table GPHM.1.2. 
Attribute Description of Estimands for Secondary Endpoints ...................15 
Table GPHM.3.1. 
Description of Analysis Datasets ...............................................................20 
Table GPHM.4.1. 
Baseline and Postbaseline Definitions for Safety Groups .........................22 
Table GPHM.4.2. 
Secondary Measures Controlled for Type 1 Error .....................................26 
Table GPHM.4.3. 
Secondary Measures Not Controlled for Type 1 Error ..............................27 
Table GPHM.4.4. 
Exploratory Efficacy Analysis ...................................................................30 
Table GPHM.4.5. 
Categorical Criteria for Abnormal Treatment-Emergent Blood 
Pressure and Pulse Measurements .............................................................36 
Table GPHM.4.6. 
Selected Categorical Limits for ECG Data ................................................37 
Table GPHM.4.7. 
Sample Anti-Drug Antibodies (ADA) Assay Results ...............................43 
Table GPHM.4.8. 
Sample Clinical Anti-Drug Antibodies Interpretation Results ..................43 
Table GPHM.4.9. 
In Silico Classification for Cross-Reactive NAb .......................................44 
Table GPHM.4.10. 
Adverse Events for Analysis with Immunogenicity Results .....................47 
Table GPHM.6.1. 
Baseline and Postbaseline Definitions in Lead-in Period ..........................61 
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Table of Contents 
Figure 
Page 
Figure GPHM.1.1. 
Illustration of study design for Clinical Protocol I8F-MC-GPHM. ...........16 
Figure GPHM.2.1. 
Type 1 error control strategy for primary and key secondary 
efficacy endpoints. .....................................................................................19 
Figure GPHM.4.1. 
Flowchart of immunogenicity multitiered testing approach. .....................42 
 
 
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List of Abbreviations  
Term 
Definition 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event(s) of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
BG 
blood glucose 
BMI 
body mass index 
BP 
Bodily Pain 
CEC 
Clinical Evaluation Committee 
CI 
confidence interval 
CRF 
case report form 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTR 
Clinical Trial Registry 
DBP 
diastolic blood pressure 
EAS 
Efficacy Analysis Set 
eCRF 
electronic case report form 
ED 
early discontinuation 
eGFR 
estimated glomerular filtration rate 
FAS 
Full Analysis Set 
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 
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H 
Hypothesis 
HLT 
High-Level Term 
ICE 
intercurrent event 
ICH 
International Council for Harmonisation 
ISR 
injection site reaction 
IWQOL-Lite-CT 
Impact of Weight on Quality of Life-Lite-Clinical Trials Version 
Lilly 
Eli Lilly and Company 
LLT 
Lowest-Level Term 
MACE 
major adverse cardiovascular event(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMRM 
mixed model for repeated measures 
MRD 
minimum required dilution 
MTD 
maximum tolerated dose 
NAb(+/-) 
neutralizing antibody (positive/negative) 
PF 
Physical Function(ing) 
PG 
plasma glucose 
PGIS 
Patient Global Impression of Status for Physical Activity 
PHQ-9 
Patient Health Questionnaire 
PK 
pharmacokinetic(s) 
PT 
Preferred Term 
QTcF 
Fridericia’s corrected QT interval 
QW 
once weekly 
REML 
restricted maximum likelihood 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
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SF-36v2 
Short Form-36 Version 2 Health Survey acute form 
SI 
Système International 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
SS 
Safety Analysis Set 
TBL 
total bilirubin 
TE ADA (+/-) 
treatment-emergent anti-drug antibody (positive/negative) 
TEAE 
treatment-emergent adverse event 
TIMP 
Trial Issues Management Plan 
T2DM 
type 2 diabetes mellitus 
UACR 
urine albumin-to-creatinine ratio 
ULN 
upper limit of normal 
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Version History  
This Statistical Analysis Plan (SAP) for Study I8F-MC-GPHM (GPHM) is based on the protocol 
dated 19 November 2020.  
SAP Version History Summary 
SAP Version 
Approval Date 
Change 
Rationale 
1 
25 Mar 2021 
Not applicable 
Original version 
2 
07 Oct 2022 
Details can be found in SAP 
Version History 
Details can be found in SAP 
Version History 
3 
See date on Page 1 
See below 
See below 
 
The key changes of the SAP Version 3 are summarized below: 
1. 
In response to US Food and Drug Administration (FDA) feedback, clarified that 
the population-level summary for the “difference in response percentages between 
treatment conditions” is assessed by odds ratio (see Section 1.1.2.1). 
2. 
Clarified that placebo multiple imputation will be used for missing data 
imputation in Category 1 for treatment-regimen estimand if there are not enough 
retrieved dropouts to impute missing data in Category 2 (see Section 4.3.2.3). 
3. 
In response to US FDA feedback, added sensitivity analyses to evaluate the 
robustness of the primary efficacy results using different missing data imputation 
methods (see Section 4.3.2.4). 
4. 
Updated to add body weight at Visit 10 (Week 0) as an additional covariate to the 
mixed model for repeated measures (MMRM) models for the analyses of mean 
change in body weight, mean percent change in body weight, and mean change in 
body mass index (BMI) from Week -12 to Week 72. This covariate adjusts for 
body weight prior to randomization on the final outcome (see Section 4.4.2.1). 
5. 
Added exploratory endpoints to assess risk difference between tirzepatide 
maximum tolerated dose (MTD) and placebo arm for an unconditional effect in 
proportions of participants achieving body weight reduction targets (see Section 
4.5). 
 
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1. 
Introduction  
Changes to protocol-planned analyses are described in Section 4.9. 
 
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1.1. 
Objectives, Endpoints, and Estimands  
1.1.1. 
Objectives and Endpoints  
Table GPHM.1.1. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
 
To demonstrate that tirzepatide MTD is superior to 
placebo from randomization for the following 
(measured at 72 weeks):  
 Percent change in body weight AND  
 Proportion of participants with ≥5% body 
weight reduction  
 
 
 
 
Mean percent change in body weight 
 
Percentage of study participants who achieve ≥5% 
body weight reduction  
Key Secondary (controlled for type I error) 
 
To demonstrate that tirzepatide MTD is superior to 
placebo from randomization for the following 
(measured at 72 weeks):  
 
 
 
Maintaining body weight reduction achieved 
during the 12-week lead-in period 
 
Percentage of study participants who maintain 
≥80% of the body weight lost during the 12-week 
lead-in period  
 
Body weight  
 
Percentage of study participants who achieve: 
o ≥10% body weight reduction  
o ≥15% body weight reduction 
o ≥20% body weight reduction 
  
 
 
Waist circumference  
 
Mean change in waist circumference (cm) 
Additional Secondary 
 
Compare tirzepatide MTD QW with placebo from 
randomization for the following (measured at 72 
weeks):  
 
 
Body weight and BMI 
 
 
 
Mean change in body weight (kg)  
 
Mean change in BMI (kg/m2) 
 
 
Blood pressure  
 
Mean change in 
o systolic blood pressure (mmHg)  
o diastolic blood pressure (mmHg) 
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Objectives 
Endpoints 
 
Lipid parameters  
 
 
 
 
 
 
 
 
 
Glycemic control 
 
Mean change in:  
o Total cholesterol (mg/dL) 
o HDL-C (mg/dL) 
o Non-HDL-C (mg/dL) 
o LDL-C (mg/dL) 
o VLDL-C (mg/dL) 
o Triglycerides (mg/dL) 
o Free fatty acids (mg/dL) 
 
 
Mean change in  
o fasting glucose (mg/dL) 
o HbA1c (%) 
 
 
Insulin 
 
 
 
Mean change in fasting insulin (pmol/L) 
 
Patient-reported outcomes 
 
Mean change in  
o SF-36v2 acute form Physical Functioning 
domain score  
o IWQOL-Lite-CT Physical Function 
composite score 
 
Compare tirzepatide MTD QW with placebo from Visit 
2 for the following (measured at 72 weeks): 
 
 
Body weight and BMI 
 
 
 
 
Waist circumference 
 
 
 
 
 
 
Mean change in absolute body weight (kg) 
 
Mean percent change in body weight 
 
Mean change in BMI (kg/m2) 
 
 
 
Mean change in waist circumference (cm) 
Abbreviations: BMI = body mass index; HbA1c = hemoglobin A1c; HDL-C = high-density lipoprotein cholesterol; 
IWQOL-Lite-CT = Impact of Weight on Quality of Life-Lite-Clinical Trials Version; LDL-C = low-density 
lipoprotein cholesterol; MTD = maximum tolerated dose; QW = once weekly; SF-36v2 acute form = Short 
Form-36 Version 2 Health Survey acute form; VLDL-C = very low-density lipoprotein cholesterol. 
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1.1.2. 
Estimands  
1.1.2.1. 
Estimands for Co-Primary Endpoints  
The primary clinical question of interest is: What is the intervention difference between the once 
weekly (QW) tirzepatide MTD (10 mg or 15 mg) and placebo in mean percent change in body 
weight and proportion of participants who achieve ≥5% body weight reduction from 
randomization to 72 weeks in participants without type 2 diabetes mellitus (T2DM), who have 
obesity (BMI ≥30 kg/m2), or are overweight (BMI ≥27 kg/m2) with at least 1 weight-related 
comorbid condition? 
For Primary Disclosure of Study GPHM, Including Submission to the US FDA 
The estimand is described by the following attributes: 
 Population - Participants qualifying for study entry and randomization per protocol 
criteria. 
 Co-primary endpoints - Percent change, from randomization to 72 weeks, in body weight 
AND participant status of achieving ≥5% body weight reduction from randomization to 
72 weeks. 
 Treatment condition of interest - Tirzepatide MTD versus placebo, regardless of study 
drug adherence.  
 Handling of intercurrent events (ICEs) - The ICEs leading to treatment discontinuation 
for any reason are addressed by the treatment condition of interest attribute and handled 
by treatment policy strategy as described in the International Council for Harmonisation 
(ICH) E9 (R1) Addendum. Further details can be found in Section 4.3.2.1. 
 Population-level summary - Difference in mean changes between treatment conditions 
AND difference in response percentage between treatment conditions as assessed by odds 
ratio. 
Rationale for Estimand 
The estimand was requested by the FDA. It aims at reflecting how participants with obesity, or 
overweight with weight-related comorbidities, are treated in clinical practice, and it considers 
both safety and efficacy. 
This de facto estimand is referred as the “treatment regimen” estimand in the latter sections of 
this document, which is equivalent to the “hybrid” estimand in the protocol. 
For All Other Purposes 
The estimand is described by the following attributes: 
 Population - Participants qualifying for study entry and randomization per protocol 
criteria. 
 Co-primary endpoints - Percent change from randomization to 72 weeks in body weight 
AND participant status of achieving ≥5% body weight reduction from randomization to 
72 weeks. 
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 Treatment condition of interest - Tirzepatide MTD versus placebo, excluding data after 
discontinuation of study drug.  
 Handling of ICEs - The ICEs leading to treatment discontinuation for any reason are 
addressed by the treatment condition of interest attribute and handled by the hypothetical 
strategy as described in the ICH E9 (R1) Addendum. 
 Population-level summary - Difference in mean changes between treatment conditions 
AND difference in response percentage between treatment conditions as assessed by odds 
ratio. 
Rationale for Estimand 
The estimand aims to reflect treatment efficacy in an envisaged scenario in which the ICEs 
leading to treatment discontinuation would not occur. 
This estimand is referred to as the “efficacy” estimand in the latter sections. 
1.1.2.2. 
Estimands for Secondary Endpoints  
 
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Table GPHM.1.2. 
Attribute Description of Estimands for Secondary Endpoints  
Estimand for Secondary 
Endpoints 
Population 
Endpoint 
Treatment Condition of 
Interest 
Handling of Intercurrent 
Events 
Population-Level Summary 
Key secondary related to 
mean change 
Same as 
estimands 
for co-
primary 
endpoints 
As 
described 
in Table 
GPHM.1.1 
For submission to the US FDA, 
follow the same manner of the 
treatment regimen estimand in 
Section 1.1.2.1; for all other 
purposes, the same manner of 
the efficacy estimand in 
Section 1.1.2.1 
For submission to the US FDA, 
follow the same manner of the 
treatment regimen estimand in 
Section 1.1.2.1; for all other 
purposes, follow the same 
manner of the efficacy estimand 
in Section 1.1.2.1 
Difference in mean changes 
between treatment conditions 
Key secondary related to 
percentage of participants 
meeting certain criteria 
Difference in percentage of 
participants between treatment 
conditions 
Other secondary related to 
mean change 
Same as 
estimands 
for co-
primary 
endpoints 
As 
described 
in Table 
GPHM.1.1 
Follow the same manner of the 
efficacy estimand in Section 
1.1.2.1 
Follow the same manner of the 
efficacy estimand in Section 
1.1.2.1 
Difference in mean changes 
between treatment conditions 
Note: Unless otherwise specified, the attributes of estimands for supporting exploratory objectives will follow the same manner of the efficacy estimand in 
Section 1.1.2.1.  
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1.2. 
Study Design  
Study GPHM is a Phase 3, multicenter, randomized, parallel-arm, placebo-controlled, 
double-blinded, 84-week study that will investigate the effects of treatment with the MTD of 
tirzepatide (10 mg or 15 mg QW) compared with placebo on body weight management of study 
participants who have obesity (BMI ≥30 kg/m2), or are overweight (BMI ≥27 kg/m2) with at 
least 1 weight-related comorbid condition, and achieved ≥5% weight reduction after a 12-week 
lead-in period with an intensive lifestyle modification program.  
Study GPHM will consist of 4 periods:  
 a 2-week screening period 
 a 12-week lead-in period during which participants undertake an intensive lifestyle 
modification program to achieve ≥5% body weight reduction 
 a 72-week, double-blind, placebo-controlled treatment period (including a 20-week dose 
escalation period), and  
 a 4-week safety follow-up period.  
Study participants who achieve at least 5% weight reduction will be randomized in a 1:1 ratio 
(tirzepatide MTD QW or placebo) at the end of the lead-in period. An upper limit of 70% 
enrollment of women will be used to ensure a sufficiently large sample of men. 
 
Abbreviations: MTD = maximum tolerated dose; QW = once weekly; (T) = telephone 
visit. 
Figure GPHM.1.1. 
Illustration of study design for Clinical Protocol I8F-MC-GPHM.  
 
The details about the overview of study periods and study visits can be found in the GPHM 
Protocol Section 4. The details of the unique visits not displayed in Figure GPHM.1.1 are 
provided below.  
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Visit 99 
Visit 99 is only applicable to participants who discontinue the study treatment prematurely 
(between Visit 10 and Visit 28) and decline to complete the remaining scheduled study visits. 
These participants will be asked to return for Visit 99 at 72 weeks ±7 days after randomization. 
This visit is critical to ensure complete data collection for the primary endpoint.  
Early Discontinuation of Treatment Visit 
Participants unable or unwilling to continue the study intensive lifestyle intervention (during the 
lead-in period), or study drug intervention (during treatment period) for any reason, will perform 
an early discontinuation (ED) of treatment visit. If the participant is discontinuing during an 
unscheduled visit or a scheduled visit, that visit should be performed as the ED visit.  
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2. 
Statistical Hypotheses  
The alternative hypothesis (H) for the primary objective is the following: 
 H1 - QW tirzepatide MTD is superior to placebo for mean percent change in body weight 
AND the proportion of participants who achieve ≥5% body weight reduction from 
randomization to 72 weeks. 
o The above hypothesis will be tested at 2-sided significance level of 0.05. 
The alternative hypotheses for the key secondary objectives controlling for type 1 error rate are 
the following: 
 H2 - QW tirzepatide MTD is superior to placebo for the proportion of participants who 
maintain ≥80% of the body weight lost during the 12-week lead-in period (per evaluation 
at 72 weeks). 
 H3 - QW tirzepatide MTD is superior to placebo for the proportion of participants who 
achieve ≥10% body weight reduction from randomization to 72 weeks. 
 H4 - QW tirzepatide MTD is superior to placebo for the proportion of participants who 
achieve ≥15% body weight reduction from randomization to 72 weeks. 
 H5 - QW tirzepatide MTD is superior to placebo for the proportion of participants who 
achieve ≥20% body weight reduction from randomization to 72 weeks. 
 H6 - QW tirzepatide MTD is superior to placebo for the mean change in waist 
circumference (cm) from randomization to 72 weeks. 
2.1. 
Multiplicity Adjustment  
For primary and key secondary efficacy objectives, the details of type I error control strategy are 
illustrated in Figure GPHM.2.1. Both efficacy estimand and treatment regimen estimand will be 
used to assess those objectives. As they are intended for different purposes, no multiplicity 
adjustments will be made for conducting separate analyses relative to the efficacy and treatment 
regimen estimands. In addition, no multiplicity adjustments will be made for evaluating other 
secondary and exploratory objectives and safety assessments. 
 
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Abbreviation: H = hypothesis. 
Figure GPHM.2.1. 
Type 1 error control strategy for primary and key secondary efficacy 
endpoints.  
 
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3. 
Analysis Sets  
For purposes of analysis, the following populations are defined. 
Table GPHM.3.1. 
Description of Analysis Datasets  
Population 
Description 
Entered 
All participants who sign informed consent 
Enrolled 
All participants who are enrolled in the 12-week lead-in period  
Randomized 
All participants who are randomly assigned a study drug 
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 to which they were 
randomized. 
Efficacy Analysis Set (EAS) 
Data obtained during the double-blind treatment period from the mITT 
population, excluding data after discontinuation of study drug (last dose date + 
7 days) 
Full Analysis Set (FAS) 
Data obtained during the treatment period from the mITT population, 
regardless of adherence to study drug 
Safety Analysis Set (SS) 
Data obtained during the treatment plus follow-up period from the mITT 
population, regardless of adherence to study drug 
Note: Unless otherwise specified, for analyses guided by the treatment regimen estimand, the FAS will be used. For 
analyses guided by the efficacy estimand, the EAS will be used, and for safety analysis, the SS will be used.  
 
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4. 
Statistical Analyses  
4.1. 
General Considerations  
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (Lilly) or its 
designee. Some analyses and summaries described in this analysis plan may not be conducted if 
not warranted by data (for example, few events to justify conducting an analysis). Additional 
analyses of the data 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 (CI) will be calculated at 95%, 2-sided.  
Unless specified otherwise, efficacy and safety will be assessed using the modified intent-to-treat 
(mITT) population, and data will be analyzed based on the assigned treatment (that is, not the 
actual treatment received by the participant). For submission to the US FDA to support the 
registration of tirzepatide for chronic weight management, the primary efficacy analysis will be 
conducted using the Full Analysis Set (FAS). For other purposes, the efficacy analysis of the 
double-blind period will be conducted using the Efficacy Analysis Set (EAS). Safety analysis of 
the double-blind period will be conducted using the Safety Analysis Set (SS).  
Unless otherwise specified, for analyses in the double-blind period, baseline is defined as the last 
nonmissing data collected prior to or at randomization (prior to the first dosing of study drug). 
For analyses in the lead-in period, baseline is defined as the start of screening and ends prior to 
the intensive lifestyle modification program (typically at Week -12).  
Summary statistics for continuous measures will include sample size, mean, standard deviation 
(SD), median, minimum, and maximum. The analysis model to make comparisons among 
treatment groups relative to continuous measurements assessed over time will be either analysis 
of covariance (ANCOVA) or an MMRM, with terms of treatment, visit, treatment-by-visit 
interaction, stratification factors, and corresponding baseline measurement as a covariate. An 
unstructured covariance structure will model the relationship of within-patient errors. 
The 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, SD, median, 
minimum, and maximum. 
For some specific safety-related parameters, the definition of baseline and postbaseline for the 
double-blind period is specified in Table GPHM.4.1. 
The definition of baseline and postbaseline during the intensive lifestyle modification lead-in 
period can be found in Appendix 4 (Section 6.4). 
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Table GPHM.4.1. 
Baseline and Postbaseline Definitions for Safety Groups  
Analysis Set 
Analysis Type 
Baseline  
Postbaseline  
SS  
1.1) Treatment-
emergent adverse 
events 
The baseline period is 
defined as ongoing at the 
time of the first dose of 
study drug in the double-
blind treatment period. 
Starts after the first dose of study 
treatment and ends at the end of the 
study period (including off-drug 
follow-up visit) 
SS 
1.2) Treatment-
emergent abnormal 
labsa, vital signs, and 
ECGs 
The last nonmissing 
assessment (scheduled 
or unscheduled) 
recorded at or prior to 
randomization to the 
double-blind treatment 
period 
Postbaseline will be defined as 
measurements after the randomization 
visit. All scheduled and unscheduled 
measurements will be included. 
 
SS  
1.3) Change from last 
baseline to Week xx 
and to last 
postbaseline for 
labsa, vital signs, and 
ECGs 
The last nonmissing 
assessment (scheduled 
or unscheduled) 
recorded during the 12-
week lead-in period 
Postbaseline will be defined as above 
(1.2). Only scheduled visits will be 
included. The early discontinuation 
visits are considered scheduled visits. 
Abbreviations: ECG = electrocardiogram; SS = Safety Analysis Set. 
a Immunogenicity-related analysis is specified in Section 4.6.5.6.  
 
For the primary and key secondary efficacy endpoint analyses subject to type 1 error rate control, 
data for participants with missing values at the 72-week visit will be imputed based on the 
method described in Section 4.3.2.3. Otherwise, missing values will not be explicitly imputed 
except for the parameters with only 1 postbaseline measure during the analysis period per the 
schedule of activity, where the last-observation-carried-forward (LOCF) approach will be 
applied to impute the endpoint when ED measure is available.  
End of study participation for a participant will be the earliest of date of death, date of 
withdrawal from further participation in the study, or date of safety follow-up visit (Visit 801). 
For participants considered to be lost to follow-up, end of study participation will be the date of 
lost to follow-up reported by the investigator. Participant data included in the database after the 
last date of study participation will be excluded from statistical analysis.  
Statistical summaries and results of statistical analyses will be displayed in the following order: 
Placebo, tirzepatide MTD. 
Not all analyses described in this SAP will necessarily be included in the clinical study reports 
(CSRs). Any analysis described in this SAP and not provided in the CSR would be available 
upon request. Not all displays will necessarily be created as a “static” display. Some may be 
incorporated into interactive display tools instead of or in addition to a static display. 
4.2. 
Participant Dispositions  
A detailed description of participant disposition will be provided at the end of the study.  
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Frequency counts and percentages of all participants screened, enrolled, randomized, and 
receiving at least 1 dose of study drug will be summarized by treatment group, if applicable. Of 
the randomized population, frequency counts and percentages of participants who completed the 
study or prematurely discontinued the study (and/or study drug), including the reason for 
premature discontinuation, will be summarized by treatment group. 
The study completion status for the randomized population is defined as following: participants 
with status reported via electronic case report form (eCRF) as “Completed” at the follow-up visit 
(Visit 801) will be considered as completers; otherwise, participants will be considered as 
noncompleters. A Kaplan-Meier analysis of time from randomization to premature 
discontinuation from the study and/or study treatment by treatment group will be provided.  
A similar summary for the intensive lifestyle modification lead-in period can be found in 
Appendix 4 (Section 6.4). 
4.3. 
Primary Endpoints Analysis  
For submission of Study GPHM to the US FDA to support the registration of tirzepatide for 
chronic weight management, both primary efficacy assessments will be guided by the treatment 
regimen estimand conducted using the FAS. Assessment of the primary objectives will be 
conducted with multiple imputation of missing data (see Section 4.3.2.3).  
For other regulatory agencies, publications, and other purposes, the assessment of efficacy 
objectives may be guided by the efficacy estimand using the EAS. 
4.3.1. 
Definition of Endpoint  
The primary efficacy measure will be percent change in body weight AND percentage of 
participants who achieve ≥5% body weight reduction from randomization at 72 weeks. The 
percent change in body weight at each nominal visit is defined as follows: 
(𝑝𝑜𝑠𝑡𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑏𝑜𝑑𝑦 𝑤𝑒𝑖𝑔ℎ𝑡 [𝑘𝑔] –  𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑏𝑜𝑑𝑦 𝑤𝑒𝑖𝑔ℎ𝑡 [𝑘𝑔]) 
/ 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑏𝑜𝑑𝑦 𝑤𝑒𝑖𝑔ℎ𝑡 [𝑘𝑔] ∗ 100.  
Both percent change in body weight and percentage of participants who achieve ≥5% body 
weight reduction will be summarized by treatment and nominal visit (week) from randomization 
to 72 weeks.  
4.3.2. 
Main Analytical Approach  
4.3.2.1. 
The Analysis Related to the Treatment Regimen Estimand  
The analysis related to treatment regimen estimand will be conducted using data in the FAS.  
The analysis for the mean percent change in body weight will be conducted utilizing ANCOVA. 
The response variable for the ANCOVA model will be percent change in body weight from 
randomization at 72 weeks. A logistic regression model will be used for the analysis of the 
percentage of participants achieving at least 5% body weight reduction obtained at the 72-week 
visit. Both models will include terms of treatment group, country/pooled country, and sex as 
fixed effects and baseline body weight as a covariate. The ANCOVA analysis will be conducted 
with hybrid imputation of missing body weight at 72 weeks (see Section 4.3.2.3 for details) and 
statistical inference over multiple imputation of missing data guided by Rubin (1987). For the 
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logistic regression, missing body weight data at 72 weeks will be imputed first, based on 
Section 4.3.2.3, then the continuous measurements will be categorized into status of achieving at 
least 5% body weight reduction (Yes or No).  
With the aid of the ANCOVA model, the 2-sided 95% CI for mean change in percentage of body 
weight from baseline to the Week 72 visit between tirzepatide MTD and placebo will be derived.  
With the aid of the logistic regression model, the 2-sided 95% CI and odds ratio for percentage 
of participants achieving at least 5% body weight reduction from baseline to the Week 72 visit 
between tirzepatide MTD and placebo will be derived.  
4.3.2.2. 
The Analysis Related to the Efficacy Estimand  
The analysis related to the efficacy estimand will be conducted utilizing data in the EAS. 
For the mean percentage of body weight change from randomization, an MMRM will be 
conducted. Restricted maximum likelihood (REML) will be used to obtain model parameter 
estimates, and the Kenward-Roger option will be used to estimate the denominator degrees of 
freedom. The response variable of MMRM will be the percent change in body weight from 
baseline values obtained at each scheduled postbaseline visit.  
For the percentage of participants achieving at least 5% body weight reduction from 
randomization to the 72 weeks visit, a logistic regression model will be used with the response 
variable of the percentage of participants achieving at least 5% body weight reduction (Yes or 
No), with the missing value imputed using the predicted value from MMRM analysis followed 
by dichotomization. The terms for the logistic regression model will be the same as those for the 
treatment regimen estimand. 
For the MMRM model, the independent variables of analysis model are treatment group, visit, 
and treatment-by-visit interaction; stratification factors (country and sex) as fixed effects; and 
baseline body weight as a covariate. An unstructured covariance structure will model the 
relationship of within-patient errors. If this model fails to converge, the following variance-
covariance structures will be tested in order until convergence is achieved:  
 heterogeneous Toeplitz 
 heterogeneous first order autoregressive 
 heterogeneous compound symmetry 
 Toeplitz 
 first order autoregressive, and 
 compound symmetry. 
The first covariance structure that converges will be used.  
With the aid of the MMRM analysis, the 2-sided 95% CI for mean percent change in body 
weight from randomization to the 72 weeks visit for tirzepatide MTD compared to placebo will 
be derived and summarized. The resulting least-squares-mean estimates of mean percent change 
in body weight from baseline will be plotted by visit and by study treatment. 
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With the aid of the logistic regression model, the 2-sided 95% CI and odds ratio for percentage 
of participants achieving at least 5% body weight reduction from randomization to the 72-week 
visit for tirzepatide MTD compared to placebo will be summarized.  
4.3.2.3. 
Methods for Hybrid Imputations  
For efficacy analyses relative to the treatment regimen estimand, the ICEs and the resulting 
missing values will be handled as follows: 
 Category 1 - For missing data solely due to exceptional circumstances, such as pandemic 
or natural disasters (after other reasons for missing data are ruled out), missing data are 
considered as missing at random. The missing data will be imputed using all non-missing 
data of the primary outcome measurement from the same treatment arm. 
 Category 2 - For missing data due to all other ICEs, missing data will be imputed based 
on retrieved dropouts in the same treatment arm, defined as observed primary outcome 
measurements, from participants in the same treatment group who had their efficacy 
assessed after ED of study drug. In cases where there are not enough retrieved dropouts 
to provide a reliable imputation model (for example, the model implemented by the 
statistical analysis software [SAS] program does not converge), an alternative multiple 
imputation method referencing the placebo group (that is, placebo multiple imputation) 
will be used. 
In cases where placebo multiple imputation method is used for missing data imputation in 
Category 2 due to not enough retrieved dropouts, the missing data in Category 1 will be imputed 
using all nonmissing data of the primary outcome measurement from the placebo group. 
4.3.2.4. 
Sensitivity Analysis Related to Treatment Regimen Estimand  
For submission of Study GPHM to the US FDA tirzepatide application for chronic weight 
management, additional sensitivity analyses of the primary efficacy outcomes will be conducted 
using the FAS and guided by treatment-regimen estimand, which represents the efficacy 
irrespective of adherence to study drug. This assessment will analyze percent change in body 
weight obtained at the 72-week visit using an ANCOVA and the percentage of participants 
achieving at least 5% body weight reduction obtained at the 72-week visit using a logistic 
regression model. The terms for both models will be the same as specified in Section 4.3.2.1. 
These analyses are intended to assess the robustness of primary efficacy results using different 
missing data imputation methods. 
 Retrieved dropout multiple imputation: missing values of change in body 
weight at the 72-week visit will be imputed based on observed body weight 
change from randomization values at the visit from participants in the same 
treatment group who had their efficacy assessed after early discontinuation of 
study drug. In cases where there are not enough retrieved dropouts to provide 
a reliable imputation model (for example, the model implemented by the SAS 
program does not converge), the placebo multiple imputation method 
(described below) will be used. 
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 Placebo multiple imputation: missing values of change in body weight at the 
72-week visit will be imputed based on observed body weight change from 
baseline values at the visit from participants in the placebo treatment group. 
 Return to baseline imputation: missing values of body weight at the 72-week 
visit will be imputed using the return-to-baseline multiple imputation method 
to account for within subject variability (Qu and Dai 2022).   
4.4. 
Secondary Endpoint(s) Analysis  
4.4.1. 
Key Secondary Analyses Subject to Type 1 Error Rate Control  
Table GPHM.4.2. 
Secondary Measures Controlled for Type 1 Error  
Objectives  
Relative to the Efficacy 
Measure 
Analysis Conducted in a Manner 
Similar to 
Additional Information 
Tirzepatide MTD 
QW is superior 
to placebo from 
randomization 
for maintaining 
body weight 
reduction 
achieved during 
the 12-week 
lead-in period 
(measured at 72 
weeks) 
Percentage of study 
participants who maintain 
≥80% of the body weight lost 
during the 12-week lead-in 
period 
Logistic model in Section 4.3.2.1 
for treatment regimen estimand 
and logistic model in Section 
4.3.2.2 for efficacy estimand  
 
Tirzepatide MTD 
QW is superior 
to placebo from 
randomization 
for body weight 
reduction 
(measured at 72 
weeks) 
Percentage of participants 
achieving body weight 
reduction ≥10%, ≥15%, and 
≥20% from randomization at 
72 weeks  
Logistic model in Section 4.3.2.1 
for treatment regimen estimand 
and logistic model in Section 
4.3.2.2 for efficacy estimand 
 
Tirzepatide MTD 
QW is superior 
to placebo from 
randomization 
for waist 
circumference 
reduction 
(measured at 72 
weeks) 
Mean change in waist 
circumference (cm) from 
randomization at 72 weeks 
ANCOVA model in Section 
4.3.2.1 for treatment regimen 
estimand and MMRM model in 
Section 4.3.2.2 for efficacy 
estimand 
LSM estimates will be 
plotted by treatment 
through 72-weeks. 
Abbreviations: ANCOVA = analysis of covariance; LSM = least squares mean; MMRM = mixed model for repeated 
measures; MTD = maximum tolerated dose; QW = once weekly. 
Decision will be guided by the 2-sided p-values in each objective, and details will be included in 
Section 2.1. 
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For submission of Study GPHM to the US FDA to support the registration of tirzepatide for 
chronic weight management, the key secondary efficacy assessment will be guided by the 
treatment regimen estimand, conducted using the same population as the primary analysis. 
Assessment of the key secondary objective will be conducted with hybrid imputation of missing 
data (see Section 4.3.2.3).  
For other regulatory agencies, publications, and other purposes, the assessment of key secondary 
efficacy objectives may be guided by the efficacy estimand, using the same population as the 
primary analysis. 
4.4.2. 
Supportive Secondary Endpoints  
Unless otherwise specified, other secondary and exploratory efficacy analyses will be guided by 
the efficacy estimand, using the same population as the primary analysis.  
Analyses for labs will be performed for both Système International (SI) units and conventional 
(CN) units. 
4.4.2.1. 
Additional Secondary Efficacy Analyses  
Table GPHM.4.3. 
Secondary Measures Not Controlled for Type 1 Error  
Objective 
Relative to the Efficacy 
Measure 
Analysis Conducted 
in a Manner Similar 
to 
Additional Information 
Compare tirzepatide 
MTD QW with 
placebo from 
randomization for 
body weight and BMI 
reduction (measured 
at 72 weeks) 
Mean change in body 
weight (kg) from 
randomization  
MMRM model in 
Section 4.3.2.2 
LSM estimates through 
72 weeks will be plotted by 
study treatment. 
Mean change in BMI 
(kg/m2) from randomization  
MMRM model in 
Section 4.3.2.2 
LSM estimates through 
72 weeks will be plotted by 
study treatment.  
Compare tirzepatide 
MTD QW with 
placebo from 
randomization for 
blood pressure 
reduction (measured 
at 72 weeks) 
Mean change in systolic 
blood pressure (mmHg)  
MMRM model in 
Section 4.3.2.2 
LSM estimates through 
72 weeks will be plotted by 
study treatment.  
Mean change in diastolic 
blood pressure (mmHg)  
MMRM model in 
Section 4.3.2.2 
LSM estimates through 
72 weeks will be plotted by 
study treatment.  
Compare tirzepatide 
MTD QW with 
placebo from 
randomization for 
improvement in lipid 
parameters (measured 
at 72 weeks) 
Mean change in total 
cholesterol, HDL-C, non-
HDL-C, LDL-C, VLDL-C, 
triglycerides, and free fatty 
acids from randomization  
MMRM model in 
Section 4.3.2.2 
Estimated means through 
72 weeks will be plotted by 
study treatment. Log 
transformation will be adopted 
for lipid parameters.  
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Objective 
Relative to the Efficacy 
Measure 
Analysis Conducted 
in a Manner Similar 
to 
Additional Information 
Compare tirzepatide 
MTD QW with 
placebo from 
randomization for 
improvement of 
glycemic control 
(measured at 72 
weeks) 
Mean change in fasting 
glucose from randomization  
MMRM model in 
Section 4.3.2.2 
LSM estimates through 
72 weeks will be plotted by 
study treatment.  
Mean change in HbA1c 
from randomization 
MMRM model in 
Section 4.3.2.2 
LSM estimates through 
72 weeks will be plotted by 
study treatment.  
Compare tirzepatide 
MTD QW with 
placebo from 
randomization for 
insulin reduction 
(measured at 72 
weeks) 
Mean change in fasting 
insulin  
MMRM model in 
Section 4.3.2.2 
Estimated means through 72 
weeks will be plotted by study 
treatment. Log transformation 
will be adopted for fasting 
insulin.  
Compare tirzepatide 
MTD QW with 
placebo from 
randomization for 
improvement of 
patient-reported 
outcomes (measured 
at 72 weeks) 
Mean change in SF-36v2 
acute form Physical 
Functioning (PF) domain 
score from randomization 
ANCOVA model 
Use terms of treatment, 
stratification factors, and 
baseline SF-36v2 PF score as a 
covariate. Missing data will be 
imputed using LOCF. 
Compare tirzepatide 
MTD QW with 
placebo from 
randomization for 
improvement of 
patient-reported 
outcomes (measured 
at 72 weeks) 
Mean change in IWQOL-
Lite-CT PF composite score 
from randomization  
ANCOVA model 
Use terms of treatment, 
stratification factors, and 
baseline IWQOL-Lite-CT PF 
score as a covariate. Missing 
data will be imputed using 
LOCF.  
Compare tirzepatide 
MTD QW with 
placebo from Visit 2 
for body weight and 
BMI reduction 
(measured at 72 
weeks) 
Mean change in absolute 
body weight (kg) from 
Visit 2  
MMRM model in 
Section 4.3.2.2 with 
body weight at Visit 10 
(Week 0) as an 
additional covariate 
LSM estimates through 
72 weeks will be plotted by 
study treatment.  
Mean percent change in 
body weight from Visit 2 
MMRM model in 
Section 4.3.2.2 with 
body weight at Visit 10 
(Week 0) as an 
additional covariate 
 
Mean change in BMI 
(kg/m2) from Visit 2  
MMRM model in 
Section 4.3.2.2 with 
body weight at Visit 10 
(Week 0) as an 
additional covariate 
LSM estimates through 
72 weeks will be plotted by 
study treatment.  
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Objective 
Relative to the Efficacy 
Measure 
Analysis Conducted 
in a Manner Similar 
to 
Additional Information 
Compare tirzepatide 
MTD QW with 
placebo from Visit 2 
for waist 
circumference 
reduction (measured 
at 72 weeks) 
Mean change in waist 
circumference (cm) 
MMRM model in 
Section 4.3.2.2 
LSM estimates through 
72 weeks will be plotted by 
study treatment.  
Abbreviations: ANCOVA = analysis of covariance; BMI = body mass index; HbA1c = hemoglobin A1c; HDL-C = 
high-density lipoprotein cholesterol; IWQOL-Lite-CT = Impact of Weight on Quality of Life-Lite-Clinical Trials 
Version; LDL-C = low-density lipoprotein cholesterol; LOCF = last observation carried forward; LSM = least 
squares mean; MMRM = mixed model for repeated measures; QW = once weekly; SF-36v2 = Short Form 36 
version 2 Health Survey; VLDL-C = very low-density lipoprotein cholesterol. 
 
 
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4.5. 
Exploratory Endpoints Analysis  
Table GPHM.4.4. 
Exploratory Efficacy Analysis  
Objective 
Relative to the Efficacy Measure 
Analysis Conducted 
Compare tirzepatide MTD 
QW with placebo for body 
weight reduction at 72 
weeks 
Percentage of participants achieving ≥25% 
body weight reduction from randomization at 
72 weeks  
Logistic model in Section 4.3.2.2 
Compare tirzepatide MTD 
QW with placebo for body 
weight reduction at 72 
weeks 
Percentage of participants achieving ≥10%, 
15%, 20%, and 25% body weight reduction 
from Week -12 at 72 weeks  
Logistic model in Section 4.3.2.2 
Assess changes in BMI 
from Week -12 at Week 0  
Percentage of participants whose BMI shifts 
between clinically relevant categories, that is, 
from Week -12 (<25, 25 to <30, 30 to <35, 
35 to <40, ≥40) to Week 0 (<25, 25 to <30, 
30 to <35, 35 to <40, ≥40) 
Shift analysis will be conducted 
based on data from enrolled 
participants. 
Compare tirzepatide MTD 
QW with placebo for BMI 
shifts from Week 0 at 72 
weeks  
Percentage of participants whose BMI shifts 
between clinically relevant categories, that is, 
from Week 0 (<25, 25 to <30, 30 to <35, 35 
to <40, ≥40) to 72 weeks (<25, 25 to <30, 30 
to <35, 35 to <40, ≥40) 
Shift analysis will be conducted 
based on data from the EAS. 
Visualize tirzepatide MTD 
QW and placebo 
percentage of body weight 
reduction, from Week -12 
up to the safety follow-up 
after 72 weeks  
Percentage of body weight reduction from 
Week -12 to 72 weeks plus 4 weeks safety 
follow-up  
Time-course plot will be generated. 
Only the participants who complete 
the 72 weeks of treatment and have 
the safety follow-up visit (Visit 
801) will be included.  
Assess changes from 
Week -12 at Week 0 and 
compare tirzepatide MTD 
QW with placebo in 
parameters from Week -12 
at 72 weeks  
Mean change in  
 
systolic blood pressure  
 
diastolic blood pressure  
 
total cholesterol  
 
HDL-C 
 
non-HDL-C 
 
LDL-C 
 
VLDL-C 
 
triglycerides  
 
free fatty acids  
 
fasting glucose  
 
HbA1c  
 
fasting insulin  
For analysis from Week -12 at 
Week 0, change from baseline to 
postbaseline values at each 
scheduled visit will be summarized. 
Within-treatment difference will be 
assessed by a Wilcoxon signed-
rank test. 
For analysis from Week -12 at 72 
weeks, the MMRM model in 
Section 4.3.2.2 for parameters with 
repeated measurements will be 
used. An ANCOVA model for 
parameters with only 1 postbaseline 
measurement will be used. 
Assess changes in lipid 
parameters from Week -12 
at Week 0  
Percentage of participants whose Lipid 
parameters shift between clinically relevant 
categories: 
 
LDL-C (<70, 70 to <160, 160 to <190, 
≥190 mg/dL) 
 
HDL-C (male: <40, ≥40mg/dL, female: 
<50, ≥50mg/dL) 
Shift analysis will be conducted 
based on data from enrolled 
participants. 
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 
Triglycerides (<150, 150 to <170, 170 
to <500, ≥500mg/dL) 
Compare tirzepatide MTD 
QW with placebo for 
changes in lipid 
parameters from Week 0 
at 72 weeks  
Percentage of participants whose Lipid 
parameters shift between clinically relevant 
categories: 
 
LDL-C (<70 mg/dL, 70 to <160 mg/dL, 
160 to <190 mg/dL, ≥190 mg/dL) 
 
HDL-C (male: <40 mg/dL, ≥40mg/dL, 
female: <50 mg/dL, ≥50mg/dL) 
 
Triglycerides (<150 mg/dL, 150 to <170 
mg/dL, 170 to <500 mg/dL, 
≥500mg/dL) 
Shift analysis will be conducted 
based on data from the EAS. 
Assess change in fasting 
glucose category from 
Week -12 at Week 0 
Percentage of participant change in fasting 
glucose category, that is, from Week -12 
(<100 mg/dL, 100-125 mg/dL, ≥126 mg/dL) 
to Week 0 (<100 mg/dL, 100-125 mg/dL, 
≥126 mg/dL) 
Shift analysis will be conducted 
based on data from enrolled 
participants.  
Compare tirzepatide MTD 
QW with placebo for 
change in fasting glucose 
category from Week 0 at 
72 weeks  
Percentage of participant change in fasting 
glucose category, that is, from Week 0 
(<100 mg/dL, 100-125 mg/dL, ≥126 mg/dL) 
to 72 weeks (<100 mg/dL, 100-125 mg/dL, 
≥126 mg/dL) 
Shift analysis will be conducted 
based on data from the EAS. 
Assess change in HbA1c 
category from Week -12 
at Week 0  
Percentage of participant change HbA1c 
category, that is, from Week -12 (<5.7%, 
5.7% to 6.4%, ≥6.5%) to Week 0 (<5.7%, 
5.7% to 6.4%, ≥6.5%) 
Shift analysis will be conducted 
based on data from enrolled 
participants.  
Compare tirzepatide MTD 
QW with placebo for 
change in HbA1c category 
from Week 0 at 72 weeks 
Percentage of participant change HbA1c 
category, that is, from Week 0 (<5.7%, 
5.7% to 6.4%, ≥6.5%) to 72 weeks (<5.7%, 
5.7% to 6.4%, ≥6.5%) 
Shift analysis will be conducted 
based on data from the EAS 
Assess change for patient-
reported outcome 
measurements change 
from Week -12 to Week 0 
Mean change in patient-reported outcome 
measurements (Section 4.7.1) 
Data from Week -12 to Week 0 will 
be included. Change from baseline 
to postbaseline values at each 
scheduled visit will be summarized. 
Within-treatment difference will be 
assessed by a Wilcoxon signed-
rank test. 
Compare tirzepatide MTD 
QW with placebo for 
patient-reported outcome 
measurements change 
from Week 0 to 72 weeks 
Mean change in patient-reported outcome 
measurements (Section 4.7.1) 
 
Data from Week 0 to 72 weeks will 
be included. An ANCOVA model 
with terms of treatment (tirzepatide 
MTD, placebo), country/pooled 
country, sex, and corresponding 
baseline score as a covariate will be 
used. Missing data will be imputed 
using LOCF. 
Compare tirzepatide MTD 
QW with placebo for 
patient-reported outcome 
measurements change 
Mean change in patient-reported outcome 
measurements (Section 4.7.1) 
Data from Week -12 to 72 weeks 
will be included. An ANCOVA 
model with terms of treatment 
(tirzepatide MTD, placebo), 
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Abbreviations: ANCOVA = analysis of covariance; BMI = body mass index; EAS = Efficacy Analysis Set; 
HbA1c = hemoglobin A1c; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein 
cholesterol; LOCF = last observation carried forward; MMRM = mixed model for repeated measures; 
MTD = maximum tolerated dose; QW = once-weekly; VLDL = very low-density lipoprotein cholesterol.  
In addition, the following endpoint analyses to assess the risk difference in proportions for an 
unconditional treatment effect (Ge et al. 2011) between tirzepatide MTD and placebo arm may 
be conducted: 
 percentage of participants achieving at least 5% body weight reduction from 
randomization at 72 weeks 
 percentage of participants achieving at least 10% body weight reduction from 
randomization at 72 weeks 
 percentage of participants achieving at least 15% body weight reduction from 
randomization at 72 weeks 
 percentage of participants achieving at least 20% body weight reduction from 
randomization at 72 weeks 
 percentage of participants achieving at least 25% body weight reduction from 
randomization at 72 weeks 
4.6. 
Safety Analyses  
Unless specified otherwise, safety assessments for the double-blind period will be based on the 
SS (Table GPHM.3.1). All data collected between randomization and the end date of study 
participation will be included, regardless of the adherence to study drug.  
Safety outcomes during the intensity lifestyle modification lead-in period will also be 
summarized for all enrolled participants. Detailed analyses can be found in Appendix 4 (Section 
6.4).  
The statistical assessment of homogeneity of the distribution of categorical safety responses 
between tirzepatide and placebo will be conducted using Fisher’s exact test, unless specified 
otherwise. 
The mean change from baseline differences among treatments at all scheduled visits will be 
assessed via an MMRM using REML. Unless specified otherwise, if the safety parameter is 
assessed at 72 weeks, then the model will include country/pooled country, sex, percentage of 
body weight reduction at the end of lead-in (<10% and ≥10%), treatment group, visit, and 
treatment-by-visit interaction as fixed effects and baseline value of the safety parameter as a 
covariate. To model the covariance structure within participants, the unstructured covariance 
matrix will be used. If this model fails to converge, the covariance structures specified in Section 
4.3.2.2 will be tested in order until convergence is met. If the data do not warrant the MMRM 
model, then an ANCOVA model will be conducted.  
For selected parameters, time-to-first-event analysis via the Cox proportional hazards model may 
be conducted. Participants without the event will be censored at the end of study participation. 
from Week -12 to 72 
weeks 
country/pooled country, sex, and 
corresponding baseline score as a 
covariate will be used. Missing data 
will be imputed using LOCF. 
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For participants experiencing the event, the “time-to-first-event” will be the time (in weeks) from 
first dose to first occurrence of the event. 
Where necessary, the rate of events will be analyzed using a generalized linear mixed model, 
assuming the number of events follows a negative binomial distribution, with treatment as a 
fixed effect. The logarithm of days during the active treatment period will be adjusted as an 
offset, to account for possible unequal treatment duration of follow-up between participants. 
Unless otherwise specified, all the analyses listed in this section will be conducted using up to 72 
weeks treatment period, plus the safety follow-up (Visit 801), for all randomized participants. 
4.6.1. 
Extent of Exposure  
The summary of duration of follow-up (defined as time in days from the date of randomization to 
the date of the last study visit) and/or duration on study treatment (defined as time in days from 
the date of first dose of study treatment to the date of last dose of study treatment plus 7 days) 
will be provided by treatment group using data from the SS over 72 weeks, plus safety follow-up 
(Visit 801), for all randomized participants. 
For the summary of duration on study and study treatment, the frequency and percentage of 
participants falling into the following ranges will be summarized by planned treatment group as 
well:  
 >0 
 ≥4 weeks 
 ≥8 weeks 
 ≥12 weeks 
 ≥16 weeks 
 ≥20 weeks 
 ≥24 weeks 
 ≥36 weeks 
 ≥48 weeks 
 ≥52 weeks, and 
 ≥72 weeks. 
In addition, the frequency and percentages of participants falling into the following study and 
study treatment exposure ranges may be summarized by planned treatment group:  
 0 weeks  
 >0 to <4 weeks 
 ≥4 to <8 weeks  
 ≥8 to <16 weeks  
 ≥16 to <24 weeks  
 ≥24 to <36 weeks  
 ≥36 to <48 weeks  
 ≥48 to <52 weeks  
 ≥52 to <72 weeks, and  
 ≥72 weeks. 
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No p-values will be reported in these summaries, as they are intended to describe the study 
populations rather than test hypotheses about them. 
4.6.2. 
Adverse Events  
4.6.2.1. 
Treatment-Emergent Adverse Events  
A treatment-emergent adverse event (TEAE) is defined as an event that first occurred, or 
worsened in severity, after baseline (defined in Table GPHM.4.1). The Medical Dictionary for 
Regulatory Activities (MedDRA) Lowest-Level Term (LLT) will be used in the treatment-
emergent derivation. The maximum severity for each LLT during the baseline period, including 
ongoing medical history, will be used as baseline severity. Events with a missing severity during 
the baseline period will be treated as “mild” in severity for determining treatment-emergence. 
Events with a missing severity during the postbaseline period will be treated as “severe”, and 
treatment-emergence will be determined by comparing to baseline severity.  
For events occurring on the day of first taking study medication, the information collected in the 
case report form (CRF) (for example, treatment-emergent flag, start time of study treatment and 
event) will be used to determine whether the event was pre- or posttreatment. If the relevant 
information is not available, then the events will be counted as posttreatment. 
In an overview table, the counts and percentages of participants who experienced a TEAE, 
serious adverse event (SAE), death, or discontinued from study and/or study treatment due to an 
adverse event (AE) will be summarized by treatment.  
The counts and percentages of participants with TEAEs will be summarized by treatment using 
MedDRA Preferred Terms (PTs) nested within System Organ Class (SOC). Events will be 
ordered by decreasing frequency within SOC. System Organ Classes will be presented in 
alphabetical order. Statistical comparisons will be applied at both the SOC and PT levels. If 
necessary, the percentages of participants with TEAEs will also be summarized by treatment 
using MedDRA PT (without regard to SOC) by decreasing frequency.  
The counts and percentages of participants with TEAEs will be summarized by maximum 
severity and treatment using MedDRA PTs. For each participant and TEAE, the maximum 
severity for the MedDRA PT is the maximum postbaseline severity observed from all associated 
LLTs mapping to the MedDRA PT. Maximum severity will be determined based on the 
nonmissing severities. If all severities are missing for the defined postbaseline period of interest, 
it will show as missing in the table.  
4.6.2.2. 
Common Adverse Events  
The counts and percentages of participants with TEAEs, overall and common (common TEAEs 
occurred in ≥5% of participants in any treatment group before rounding), will be summarized by 
treatment using MedDRA PT. Events will be ordered by decreasing frequency. 
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4.6.3. 
Additional Safety Assessments  
4.6.3.1. 
Deaths  
A listing of all deaths during the study will be provided. The listing will include participant 
identification including the treatment, site number, participant number, date of death, age at the 
time of enrollment, sex, cause of death as reported by investigator, cause of death as adjudicated 
by the Clinical Evaluation Committee (CEC), and so on. 
4.6.3.2. 
Other Serious Adverse Events  
The counts and percentages of participants who experienced at least 1 SAE (including deaths and 
SAEs temporally associated with or preceding deaths) during the postbaseline period will be 
summarized by treatment using MedDRA PT nested within SOC. Events will be ordered by 
decreasing frequency within SOC. The SOCs will be in alphabetical order. 
A listing of all SAEs will be provided. The listing will include treatment, participant 
identification including the site number, participant number, date of event, age at the time of 
enrollment, sex, MedDRA SOC and PT, reported term, severity, outcome, relationship to study 
drug, time from first dose of study drug to the event, AE start date, AE end date, severity, and 
action taken related to study treatment. 
4.6.3.3. 
Other Significant Adverse Events  
The counts and percentages of participants who discontinued from study treatment or study due 
to an AE during the postbaseline period may be summarized by treatment group using MedDRA 
PT nested within SOC. Events will be ordered by decreasing frequency within SOC. 
4.6.3.4. 
Vital Signs  
In the case that multiple measurements of an individual vital sign (for example, sitting SBP) are 
collected at the same visit, the mean of these measurements will be used for the analysis.  
Vital signs (SBP, DBP, and pulse) will be summarized by treatment group at each planned visit. 
Change from baseline to postbaseline values for vital signs will be summarized for participants 
who have both a baseline and at least 1 postbaseline result. Treatment differences in mean 
change from baseline for vital signs will be assessed using the analysis model described in 
Section 4.6. Only planned measurements will be included in the mean change analyses.  
The counts and percentages of participants with treatment-emergent abnormal (high or low) vital 
signs (sitting SBP, DBP, and pulse) at any time during the entire study (including the off-drug 
follow-up time period) will be summarized by treatment for participants who have both baseline 
and at least 1 postbaseline result. A treatment-emergent high result is defined as a change from a 
value less than or equal to the high limit at baseline to a value greater than the high limit at any 
time that meets the specified change criteria during the postbaseline period. A treatment-
emergent low result is defined as a change from a value greater than or equal to the low limit at 
baseline to a value less than the low limit at any time that meets the specified change criteria 
during the postbaseline period. Both planned and unplanned measurements will be included in 
the analysis. The criteria for identifying participants with treatment-emergent vital signs 
abnormalities are listed in Table GPHM.4.5. 
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Table GPHM.4.5. 
Categorical Criteria for Abnormal Treatment-Emergent Blood 
Pressure and Pulse Measurements  
Parameter 
Low 
High 
Systolic BP (mm Hg) 
(Supine or sitting - 
forearm at heart level) 
≤90 and decrease from baseline ≥20 
≥140 and increase from baseline ≥20 
≥129 and increase from baseline ≥20 
Diastolic BP (mm Hg) 
(Supine or sitting - 
forearm at heart level) 
≤50 and decrease from baseline ≥10 
≥90 and increase from baseline ≥10 
Pulse (bpm) 
(Supine or sitting) 
<50 and decrease from baseline ≥15 
>100 and increase from baseline ≥15 
Abbreviation: BP = blood pressure. 
 
In addition, the following analyses will be conducted by treatment:  
 counts and percentages of participants who had resting pulse increases from baseline at 2 
or more consecutive visits of more than 10 bpm and/or 20 bpm 
 counts and percentages of participants who had resting pulse increases from maximum 
baseline ≥20 bpm at any postbaseline visit  
 counts and percentages of participants who had at least 1 resting pulse at any postbaseline 
visit exceeding 100 bpm, and 
 counts and percentages of participants who had at least 1 resting pulse exceeding 
100 bpm occurring at 2 or more consecutive study visits.  
4.6.3.5. 
Electrocardiograms  
Summary statistics by treatment and by nominal visit will be provided for electrocardiogram 
(ECG) parameters (heart rate, PR, QRS, QT, and QT corrected using Fridericia’s correction 
factor [QTcF] [QTcF = QT / RR0.333]). When the QRS is prolonged (for example, a complete 
bundle branch block), QT and QTc should not be used to assess ventricular repolarization. Thus, 
for a particular ECG, the following will be set to missing (for analysis purposes) when QRS is 
≥120 msec: QT and QTcF. 
Change from baseline to postbaseline values for ECG parameters will be summarized for 
participants who have both a baseline and at least 1 postbaseline result. Treatment differences in 
mean change from baseline for heart rate and PR interval will be assessed using the analysis 
model described in Section 4.6. Only planned measurements will be included in the mean change 
analyses.  
The counts and percentages of participants who meet following criteria at any time during the 
entire study period (including the safety follow-up time period) will be summarized by treatment 
group:  
 treatment-emergent ECG abnormalities as listed in Table GPHM.4.6. 
 QT greater than 500 msec  
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 QTcF greater than 480 msec 
 QTcF greater than 500 msec, and 
 treatment-emergent increase from the maximum baseline in QTcF interval of greater than 
30 msec, 60 msec, or 75 msec. Maximum baseline (see Table GPHM.4.1 for details) will 
be the maximum nonmissing observation in the baseline period. The maximum value 
during the treatment period will be analyzed. Scheduled and unscheduled measurements 
will be included.  
Table GPHM.4.6. 
Selected Categorical Limits for ECG Data  
 
Low 
High 
Parameter 
Males 
Females 
Males 
Females 
Heart rate (bpm) 
<50 and decrease 
≥15 
<50 and decrease 
≥15 
>100 and increase 
≥15 
>100 and increase 
≥15 
PR interval (msec) 
<120 
<120 
≥220 
≥220 
QRS interval (msec) 
<60 
<60 
≥120 
≥120 
QTcF (msec) 
<330 
<340 
>450 
>470 
Abbreviations: ECG = electrocardiogram; QTcF = Fridericia’s corrected QT interval. 
 
4.6.3.6. 
Clinical Laboratory Evaluation  
Descriptive summaries at each planned visit, by treatment group, will be provided for the 
baseline and postbaseline values, and change from baseline values. The associated descriptive 
summaries will be presented in SI units and CN units. Limits from the performing laboratory will 
be used to define low and high. 
Observed and change from baseline values for each visit may be displayed in plots for 
participants who have both a baseline and at least 1 postbaseline planned measurement. Baseline 
is defined in Table GPHM.4.1. Unplanned measurements will be excluded from plots. 
A shift table will be provided including unplanned measurements. The shift table will include the 
number and percentage of participants within each baseline category (minimum value is low, 
normal, high, or missing) versus each postbaseline category (minimum value is low, normal, 
high, or missing) by treatment. The Fisher’s exact test will be used to compare percentages of 
participants who shift from normal/high to low between treatments. 
For qualitative laboratory analytes, the number and percentage of participants with normal and 
abnormal values will be summarized by treatment. 
A listing of abnormal findings will be created for laboratory analyte measurements, including 
qualitative measures. The listing will include participant identification, treatment group, 
laboratory collection date, study day, analyte name, and analyte finding. 
The MMRM model, or ANCOVA (if the MMRM model is not applicable), will be used for the 
analysis during the treatment period for the continuous measurements for selected lab tests.  
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4.6.4. 
Patient Narratives  
The following are “notable” events, from start of study drug through the end of study 
participation:  
 deaths 
 SAEs 
 permanent discontinuations of study treatment due to AEs, and 
 pregnancies. 
Patient narratives (participant-level data and descriptive paragraphs) will be provided for 
participants in the enrolled population with at least 1 notable event. 
4.6.5. 
Special Safety Topics  
For AEs of special interest (AESI) or special safety topics, the counts and percentages of 
participants will be summarized by treatment and PT with decreasing frequency. Individual 
participant-level data may be presented. Displays with individual participant-level data may be 
created using various formats, such as a customized listing and/or a customized graphical patient 
profile. Adverse events of special interest are defined in each section of special safety topics, 
where applicable.  
4.6.5.1. 
Exocrine Pancreas Safety  
4.6.5.1.1. Pancreatic Enzyme  
Observed pancreatic enzyme data (p-amylase and lipase) will be summarized by treatment. 
The counts and percentages of participants with maximum postbaseline pancreatic enzyme 
values exceeding the following thresholds will be provided by baseline pancreatic enzyme values 
(≤ upper limit of normal [ULN], > ULN) and postbaseline values (≤1 × ULN, >1 to ≤3 × ULN, 
>3 to ≤5 × ULN, >5 to ≤10 × ULN, and >10 × ULN).  
An MMRM analysis will be used to analyze each pancreatic enzyme with a log-transformed 
(postbaseline measure/baseline measure) response variable and treatment, nominal visit, 
treatment-by-nominal visit interaction as fixed effects. 
4.6.5.1.2. Pancreatitis Events  
The counts and percentages of participants with pancreatitis will be presented for both 
investigator-reported events and subsequently confirmed adjudicated events. Detailed searching 
criteria can be found in Appendix 7 (Section 6.7). 
Treatment-emergent, adjudication-confirmed pancreatitis will be considered as an AESI. Listings 
of participants with adjudicated pancreatitis may be provided if deemed necessary.  
4.6.5.2. 
Gastrointestinal Adverse Events  
4.6.5.2.1. Nausea, Vomiting, and Diarrhea  
Summaries and analyses for the incidence and severity of nausea, vomiting (including 
“vomiting” and “vomiting projectile”), diarrhoea (including “diarrhea” and “diarrhoea”), and the 
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3 events combined will be provided by each treatment group. A summary of the prevalence over 
time for nausea, vomiting, and diarrhea will also be presented. Time to the first onset of nausea, 
vomiting, and diarrhea will be plotted. 
4.6.5.2.2. Severe Gastrointestinal Events  
Severe gastrointestinal (GI) AEs (GI SOC) will be captured with the AE-CRF form, and serious 
cases will be captured with the SAE form. The PTs in the GI SOC from the most recent 
MedDRA version at the time of DBL will be used to identify GI AEs, and only the PTs with 
severe/serious cases will be considered AESI.  
The counts and percentages of participants with severe/serious GI events will be summarized by 
treatment.  
4.6.5.3. 
Hepatobiliary Disorders  
4.6.5.3.1. Hepatic Events  
The counts and percentages of participants with treatment-emergent, potentially drug-related 
hepatic events will be summarized by treatment using MedDRA PTs. Detailed searching criteria 
can be found in Appendix 7 (Section 6.7). Severe/serious hepatic events will be considered AESI 
and summarized separately.  
4.6.5.3.2. Acute Gallbladder Disease  
Events related to acute gallbladder disease will also be summarized by treatment groups by PTs 
with decreasing frequency. Detailed searching criteria can be found in Appendix 7 (Section 6.7). 
Severe/serious acute gallbladder disease will be considered AESI and summarized separately.  
4.6.5.3.3. Liver Enzymes  
Common analyses for laboratory analyte measurements described in Section 4.6.3.6 are 
applicable for the liver-enzyme-related measurements. This section provides additional analyses 
for liver enzymes. 
The counts and percentages of participants with the following elevations in hepatic laboratory 
tests at any time during the treatment period, and during the entire study including the follow-up 
period, will be summarized between treatment groups: 
 The counts and percentages of participants with an alanine aminotransferase (ALT) 
measurement ≥3 times (3×), 5 times (5×), and 10 times (10×) the central lab ULN will be 
summarized for all participants with a postbaseline value and for subsets based on 
various levels of baseline value:  
o participants whose nonmissing maximum baseline value is ≤1 × ULN  
o participants whose maximum baseline is >1 × ULN, and 
o participants whose baseline values are missing.  
 The counts and percentages of participants with an aspartate aminotransferase 
measurement ≥3 ×, 5 ×, and 10 × the central lab ULN will be summarized for all 
participants with a postbaseline value and for subsets based on various levels of baseline 
values, as described above for ALT. 
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 The counts and percentages of participants with a total bilirubin (TBL) measurement 
≥2 × the central lab ULN will be summarized for all participants with a postbaseline 
value and for subsets based on various levels of baseline values:  
o participants whose nonmissing maximum baseline value is ≤1 × ULN 
o participants whose maximum baseline is >1 × ULN, but <2 × ULN 
o participants whose maximum baseline value is ≥2 × ULN, and  
o participants whose baseline values are missing. 
 The counts and percentages of participants with a serum alkaline phosphatase 
measurement ≥2 × the central lab ULN will be summarized for all participants with a 
postbaseline value and for subsets based on various levels of baseline values, as described 
above for TBL. 
Maximum baseline will be the maximum nonmissing observation in the baseline period. The 
maximum postbaseline value will be the maximum nonmissing value from the postbaseline 
period. Planned and unplanned measurements will be included. 
4.6.5.4. 
Hypoglycemia  
The following categories in accordance with the 2020 American Diabetes Association position 
statement on glycemic targets (ADA 2020) will be defined in the database. 
Glucose Alert Value (Level 1) 
 Documented symptomatic hypoglycemia is defined as any time a participant feels that 
he/she is experiencing symptoms and/or signs associated with hypoglycemia and has a 
blood glucose (BG) 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 BG <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 BG <70 mg/dL 
(<3.9 mmol/L). 
Documented Clinically Significant Hypoglycemia (Level 2)  
 Documented symptomatic hypoglycemia is defined as any time a participant feels that 
he/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). 
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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. Plasma glucose (PG) measurements may not 
be available during such an event, but neurological recovery attributable to the restoration 
of PG to normal is considered sufficient evidence that the event was induced by a low PG 
concentration.  
Other Hypoglycemia Categories 
 Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs between 
bedtime and waking. 
To avoid duplicate reporting, all consecutive hypoglycemic events occurring within a 1-hour 
period will be considered to be a single hypoglycemic event.  
Both the incidence (percentage of participants experiencing ≥1 episode) and the rate 
(episodes/participant/year) of Level 2 or Level 3 hypoglycemia, and Level 3 hypoglycemia, will 
be reported.  
If a hypoglycemic event meets the criteria of severe, the event would specifically be collected as 
an SAE. Serious hypoglycemia is defined by pharmacovigilance criteria and will also be 
captured with an SAE form.  
Severe/serious hypoglycemia will be considered AESI. The summaries of severe/serious 
hypoglycemia will be provided by treatment group. A listing of all events of severe/serious 
hypoglycemia may be provided, if deemed necessary. This listing will provide treatment 
allocation and clinical characteristics of the hypoglycemic event. 
4.6.5.5. 
Immunogenicity  
4.6.5.5.1. Definitions of Sample ADA Status  
At a high level, an individual sample is potentially examined multiple times, in a hierarchical 
procedure, to produce a sample anti-drug antibodies (ADA) assay result, potentially multiple 
cross-reactive ADA assay results, and multiple neutralizing antibodies (NAb) assay results. The 
cut points used, the drug tolerance of each assay, and the possible values of titers are operating 
characteristics of the assay. 
Figure GPHM.4.1 details a flow chart that reflects the multitiered testing approach. 
 
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Abbreviations: ADA = anti-drug antibody; CP = cut point; GIPR = glucose-dependent 
insulinotropic polypeptide receptor; GLP-1R = glucagon-like peptide-1 receptor; 
LY = LY3298176 (tirzepatide); NAb = neutralizing antibody; nGIP = native glucose-
dependent insulinotropic polypeptide receptor; nGLP-1 = native glucagon-like peptide-
1.  
Figure GPHM.4.1. 
Flowchart of immunogenicity multitiered testing approach.  
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Table GPHM.4.7 outlines results as reported from Tier 2a of the multitiered testing approach. 
Tier 4 results are reported similarly.  
Table GPHM.4.7. 
Sample Anti-Drug Antibodies (ADA) Assay Results  
Sample Laboratory Result 
Explanation 
Detected 
ADA are detected and confirmed. 
Not Detected 
The raw result as reported from the laboratory indicates not detected. The 
clinical interpretation of such results depends on other factors (see Table 
GPHM.4.8). 
NO TEST, QNS, etc. 
Sample exists but was unevaluable by the assay. 
Abbreviations: ADA = anti-drug antibodies; QNS = quantity not sufficient. 
 
It can be the case that the presence of high concentrations of tirzepatide will affect ADA 
immunoassays, and conversely high levels of ADA may affect the measurement of tirzepatide 
concentration. Thus, a tirzepatide drug concentration, assessed from a sample drawn at the same 
time as the ADA sample, plays a key role in clinical interpretation of a sample when the 
laboratory result is Not Detected (see Table GPHM.4.8). 
Table GPHM.4.8. 
Sample Clinical Anti-Drug Antibodies Interpretation Results  
Sample Clinical Interpretation 
Explanation 
ADA Present 
ADA assay result is Detected. 
ADA Not Present 
ADA assay result is Not Detected, and simultaneous drug concentration is 
at a level that has been demonstrated to not interfere in the ADA detection 
method (that is, drug concentration is below the assay’s drug tolerance 
level). 
 
For participants receiving placebo, drug concentration is not assessed and is 
assumed to be below the assay’s drug tolerance level. 
 
If drug concentration was planned but is not available for a treatment-period 
sample, a Not Detected sample will be declared ADA Not Present.  
ADA Inconclusive 
ADA assay result is Not Detected, but the drug concentration in the sample 
is greater than or equal to the assay’s drug tolerance level, which may cause 
interference in the ADA detection method. 
Abbreviations: ADA = antidrug antibodies. 
 
All ADA-present samples will be evaluated for cross-reactivity to native glucose-dependent 
insulinotropic polypeptide (GIP) (Tier 2b), cross-reactivity to native glucagon-like peptide-1 
(GLP-1) (Tier 2c), NAb tirzepatide on the GIPR receptor (GIPR) (Tier 4a), and NAb LY 
(tirzepatide) on the GLP-1 receptor (GLP-1R) (Tier 4b). If cross-reactive ADA against native 
GIP is detected, the in silico assessment for cross-reactive NAb against native GIP is evaluated. 
If cross-reactive ADA against GLP-1 is detected, the in silico assessment for cross-reactive NAb 
against native GLP-1 is evaluated (Figure GPHM.4.1).  
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Similar terminology to Table GPHM.4.8 applies for each type of cross-reactive and NAb assay. 
Importantly, each of these is a distinct assay and, in general, has different assay operating 
characteristics.  
The following are considered inconclusive for the NAb result: 
 NAb tirzepatide on GIPR - If an NAb result is not detected and pharmacokinetic (PK) 
concentration is greater than or equal to the drug tolerance limit of the NAb tirzepatide on 
the GIPR assay. 
 NAb tirzepatide on GLP-1R - If an NAb result is not detected and PK concentration is 
greater than or equal to the drug tolerance limit of the NAb tirzepatide on the GLP-1R 
assay.  
An in silico method utilizing results from Tiers 2b and 2c, Tiers 4a and 4b, and tirzepatide 
concentrations is used to determine cross-reactive NAb against native GIP and GLP-1. The in 
silico method is outlined in Table GPHM.4.9. 
Table GPHM.4.9. 
In Silico Classification for Cross-Reactive NAb  
In Silico 
Classification 
Cross-Reactive ADA 
Result 
NAb Result 
Circulating 
Tirzepatide 
Level (ng/mL) 
In Silico Cross-
Reactive NAb 
Interpretation 
Cross-Reactive 
Tier 2b: Not Detected 
Tier 4a: Not Detected 
or Detected 
or  
Tier 4a: Detected, NA, 
or Missing 
Any value or 
missing 
Not Present 
NAb to nGIP 
Tier 2b: Detected 
Tier 4a: Not Detected 
< drug tolerance 
limit of the assay 
Not Present 
 
Tier 2b: Detected 
Tier 4a: Not Detected 
≥ drug tolerance 
limit of the assay 
Inconclusive 
 
Tier 2b: Detected 
Tier 4a: Detected 
< drug tolerance 
limit of the assay 
Present 
 
Tier 2b: Detected 
Tier 4a: Detected 
≥ drug tolerance 
limit of the assay 
Present 
Cross-Reactive  
Tier 2c: Not Detected 
Tier 4b: Not Detected 
or Detected 
or  
Tier 4b: Detected, NA, 
or Missing 
Any value or 
missing 
Not Present 
NAb to nGLP-1 
Tier 2c: Detected 
Tier 4b: Not Detected 
< drug tolerance 
limit of the assay 
Not Present 
 
Tier 2c: Detected 
Tier 4b: Not Detected 
≥ drug tolerance 
limit of the assay 
Inconclusive 
 
Tier 2c: Detected 
Tier 4b: Detected 
< drug tolerance 
limit of the assay 
Present 
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In Silico 
Classification 
Cross-Reactive ADA 
Result 
NAb Result 
Circulating 
Tirzepatide 
Level (ng/mL) 
In Silico Cross-
Reactive NAb 
Interpretation 
 
Tier 2c: Detected 
Tier 4b: Detected 
≥ drug tolerance 
limit of the assay 
Present 
Abbreviations: ADA = anti-drug antibodies; NA = not applicable; NAb = neutralizing antibody; nGIP = native 
glucose-dependent insulinotropic polypeptide; nGLP-1 = native glucagon-like peptide-1; Tier 2b = cross-reactive 
ADA to nGIP; Tier 2c = cross-reactive ADA to nGLP-1; Tier 4a = NAb LY (tirzepatide) on GIPR; Tier 4b = 
NAb LY (tirzepatide) on GLP-1R. 
 
Note that, in the case of an ADA Inconclusive sample, each of the NAb and Cross-Reactive NAb 
assay results are taken to be Inconclusive. 
Note also that any reference to an assay cut point and/or drug tolerance is population specific and 
is subject to modification to study-specific parameters per regulatory guidance. 
4.6.5.5.2. Definitions of Immunogenicity Assessment Periods  
Immunogenicity Baseline Observations 
The baseline period for immunogenicity assessment for each participant includes all observations 
prior to the first dose of study treatment. In instances where multiple baseline observations are 
collected, to determine participant ADA status, the last nonmissing immunogenicity assessment 
prior to first administration of study drug is used to determine treatment-emergent status (see 
below).  
Immunogenicity Postbaseline Period Observations 
Postbaseline period observations for each participant include all observations after the first 
administration of study drug. There are 2 different periods:  
 The planned treatment period is defined as from the first dose of treatment to end of the 
treatment period. 
 The entire postbaseline period is defined as from the first dose of treatment to the end of 
the safety follow-up visit or the date of study withdrawal.  
4.6.5.5.3. Definitions of Participant ADA Status  
Participants Evaluable for Treatment-Emergent ADA (TE ADA) 
A participant is evaluable for TE ADA if the participant has a nonmissing baseline ADA result 
and at least 1 nonmissing postbaseline ADA result. 
TE-ADA-Unevaluable Participants 
A TE ADA-unevaluable participant is any participant who does not meet the evaluable criteria. 
Baseline ADA Present (preexisting antibody) 
Anti-drug antibodies are detected in a sample collected up to the first dose date and time. 
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Baseline ADA Not Present 
Anti-drug antibodies are not detected, and the corresponding PK concentrations are missing or 
are below the drug tolerance limit in a sample collected up to the first dose date and time. 
Treatment-Emergent ADA-Positive (TE ADA+) Participants 
A participant who is evaluable for TE ADA is TE ADA+ if either of the following holds:  
 The participant has baseline status of ADA Not Present and at least 1 postbaseline status 
of ADA Present with titer ≥2 × the minimum required dilution (MRD) of the ADA assay. 
 The participant has baseline and postbaseline status of ADA Present, with the 
postbaseline titer being 2 dilutions (4-fold) greater than the baseline titer. That is, the 
participant has a baseline status of ADA Present, with a titer of 1:baseline, and at least 
1 postbaseline status of ADA Present, with a titer of 1:postbaseline, with 
postbaseline divided by baseline ≥4.  
As shown in Figure GPHM.4.1, a titer is expected when an ADA assay result is Detected. On 
occasion, the corresponding assay cannot be performed, in which case a titer value will be 
imputed for the purpose of TE ADA determination. A baseline sample with detected ADA and 
no titer is imputed to be the MRD (1:10), and a postbaseline sample with ADA detected and no 
titer is imputed to be 1 dilution above the MRD (1:20). 
Treatment-Emergent ADA-Inconclusive Participants 
A participant who is evaluable for TE ADA is TE ADA Inconclusive if ≥20% of the participant’s 
postbaseline samples are ADA Inconclusive and all remaining postbaseline samples are ADA 
Not Present. 
Treatment-Emergent ADA-Negative (TE ADA-) Participants 
A participant who is evaluable for TE ADA is TE ADA- when the participant is not TE ADA+ 
and the participant is not TE ADA Inconclusive.  
For each NAb assay, the following are defined: 
 NAb-positive (NAb+) participant - A participant who is TE ADA+ and has an NAb 
positive sample in the postbaseline period. 
 NAb-Inconclusive participant - A participant who is TE ADA+, is not NAb+, and all 
samples that have TE ADA+ titer have an NAb Inconclusive sample result. 
 NAb-negative (NAb-) participant - A participant is NAb- when the participant is neither 
NAb+ nor NAb Inconclusive. 
Unless specified otherwise, the above-mentioned definitions of NAb are applicable to all NAb 
analyses, including cross-reactive NAb analyses and cross-reactive antibodies. 
4.6.5.5.4. Analyses to be Performed  
The count and proportion of participants who are TE ADA+ will be tabulated by treatment 
group, where proportions are relative to the number of participants who are TE ADA evaluable, 
as defined above. The tabulation will include the number and proportion of participants with 
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ADA Present at baseline and the number and proportion of TE-ADA+ participants exhibiting 
each type of cross-reactive antibody and NAb. This analysis will be performed for the following 
periods: 
 the planned treatment period, and 
 the entire postbaseline period, including safety follow-up.  
The in silico classification for cross-reactive NAb will be summarized.  
A summary will be provided of the count and percentage of tirzepatide-treated participants 
experiencing a specific TEAE (see Table GPHM.4.10) by participant TE-ADA status (TE 
ADA+, TE ADA-, or TE ADA Inconclusive).  
Table GPHM.4.10. Adverse Events for Analysis with Immunogenicity Results  
TEAE Category 
Criteria 
Hypersensitivity reactions 
Anaphylaxis SMQ (narrow or algorithm) 
Hypersensitivity SMQ (narrow) 
Angioedema SMQ (narrow) 
Severe Cutaneous Adverse Reaction SMQ (narrow) 
Vasculitis SMQ (narrow) 
Injection site reactions 
Injection site reaction HLT  
Infusion site reaction HLT  
Administration site reaction HLT 
Abbreviations: HLT = High-Level Term; MedDRA = Medical Dictionary for Regulatory Activities; 
SMQ = Standardized MedDRA Query; TEAE = treatment-emergent adverse event. 
 
A listing will be provided for all participants who had ADA Present at any time (including 
baseline) or had any specific TEAE (see Table GPHM.4.10). This listing includes a time course 
of ADA (clinical interpretation result plus flags for samples meeting TE ADA+ criteria and for 
samples with cross-reactive antibodies and NAb present) along with the TEAE.  
Cases of TE ADA that are associated with AEs of either severe/serious hypersensitivity or 
severe/serious injection site reaction (ISR) will be classified as AESI.  
Additional immunogenicity analyses, as determined later, may be presented. The relationship 
between antibody titers, the PK parameters, and pharmacodynamic (PD) response to tirzepatide 
may also be assessed.  
4.6.5.6. 
Hypersensitivity Reactions  
Two main analyses are performed in support of assessment of potential immediate 
hypersensitivity, including anaphylaxis, as well as potential nonimmediate hypersensitivity.  
Time Period A of potential immediate hypersensitivity includes all TEAEs occurring from start 
of study drug administration up to 24 hours after end of study drug administration. For events 
without the hypersensitivity eCRF, only date (no time) information is collected. If such events 
occurred on the same date as the study drug injection date, they will be included in Time Period 
A. 
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Time Period B of potential nonimmediate hypersensitivity includes all TEAEs occurring more 
than 24 hours after the end of study drug administration but prior to subsequent drug 
administration. 
The counts and percentages of participants who experienced a hypersensitivity TEAE will be 
summarized by PT with decreasing frequency by treatment.  
Analyses for both time periods are based on the following: 
 narrow and algorithm terms in the Anaphylactic reaction Standardized MedDRA Query 
(SMQ) (20000021) (note that the Anaphylactic reaction SMQ algorithm will only be 
summarized for Time Period A) 
 narrow terms in the Angioedema SMQ (20000024) 
 narrow terms in the Severe cutaneous adverse reactions SMQ (20000020) 
 narrow terms in the Hypersensitivity SMQ (20000214), and 
 narrow terms in the Vasculitis SMQ (20000174). 
For the Anaphylactic reaction SMQ, each term is classified by scope (narrow, broad) and by 
category (A, B, C, D). All narrow terms are Category A, and all broad terms are Category B, C, 
or D. In addition to the usual narrow and broad searches, the SMQ defines an algorithm to 
further refine the cases of interest. For Time Period A analysis, the Anaphylactic reaction SMQ 
algorithm will be included. The algorithm is based upon events that occur within Time Period A.  
The counts and percentages of participants who experienced a TEAE for the following will be 
analyzed for each of the 2 time periods:  
 any narrow term from any one of the 5 SMQs indicated above (that is, combined search 
across the narrow scope of all 5 SMQs), and 
 any narrow term within each SMQ, separately (that is, narrow SMQ search) 
o for Time Period A analysis, any term from the Anaphylactic reaction SMQ 
algorithm. 
Within queries, individual PTs that satisfied the queries will be summarized. For Time Period A 
analysis, the Anaphylactic reaction SMQ algorithm will be summarized. Also, a single event 
may satisfy multiple SMQs, in which case, the event contributes to every applicable SMQ.  
4.6.5.6.1. Serious Hypersensitivity Reactions  
The severe/serious cases of hypersensitivity will be considered AESI. A summary with 
severe/serious hypersensitivity reactions may be provided, if deemed necessary.  
4.6.5.7. 
Injection Site Reaction  
Injection site reactions, incidence and rates, and related information reported via the “Injection 
Site Reactions” eCRF will be summarized by treatment. Information to be summarized includes 
the location of the reaction, timing of the reaction relative to study drug administration, and 
characteristics of the ISR: erythema, induration, pain, pruritis, and edema.  
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Patient-based analysis and event-based analysis may be provided if necessary. The patient-based 
analysis summarizes all ISR questionnaire forms for an individual participant with a single 
statistic, typically an extreme value. This analysis allows each participant to contribute only once 
for each parameter, at the expense of a focus on the most extreme events. By contrast, the event-
based analysis summarizes all ISR questionnaire forms received, without regard to individual 
participants. This provides characteristics of ISR events as a proportion of all events for which 
questionnaire responses were provided, at the expense of some potential bias due to differential 
contribution of individual participants to the analysis. 
The counts and percentages of participants with treatment-emergent ISRs will be summarized by 
treatment using MedDRA PTs. Detailed searching criteria can be found in Appendix 7 (Section 
6.7).  
The PT will be summarized in decreasing order of incidence for tirzepatide-treated participants. 
4.6.5.7.1. Severe/Serious Injection Site Reactions  
The severe/serious treatment-emergent ISRs, based on the TEAE search criteria specified in 
Appendix 6.7 (Section 6.7), will be considered AESI. The counts and percentages of participants 
with severe/serious ISRs will be summarized by treatment. A listing of participants with 
treatment-emergent severe/serious ISRs may be provided, if deemed necessary. 
4.6.5.8. 
Major Adverse Cardiovascular Events  
The following positively adjudicated major adverse cardiovascular events (MACE) will be 
considered AESI:  
 death due to cardiovascular AEs 
 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.  
The counts and percentages of participants with positively adjudicated MACE may be 
summarized by treatment.  
A listing of participants reporting MACE events, either reported by the investigator or identified 
by the CEC, may be provided.  
In addition, MACE reported by the investigator may be summarized, although a MACE reported 
by the investigator and not positively adjudicated is not considered an AESI. 
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4.6.5.9. 
Major Depressive Disorder/Suicidal Ideation  
The severe/serious major depressive disorder/suicidal ideation or behavior will be captured as 
AESI. Adverse events will be searched using MedDRA PTs. Detailed searching criteria can be 
found in Appendix 7 (Section 6.7).  
The counts and percentages of participants with TEAEs will be summarized by treatment group 
using MedDRA PT nested within SMQ. Events will be ordered by decreasing frequency nested 
within SMQ. A listing of participants with major depressive disorder/suicidal ideation or 
behavior may be provided if deemed necessary. 
In addition to spontaneously reported AEs assessed by the investigator, suicidal ideation and 
behavior and depression will be assessed through the use of the Columbia-Suicide Severity 
Rating Scale (C-SSRS) and the Patient Health Questionnaire (PHQ-9), respectively. 
4.6.5.9.1. Patient Health Questionnaire  
Total scores for the PHQ-9 range from 0 to 27 with total scores being categorized as follows:  
 None (not depressed) - 0 to 4. 
 Mild - 5 to 9. 
 Moderate - 10 to 14. 
 Moderately Severe - 15 to 19. 
 Severe - 20 to 27. 
Shift tables will be provided showing the counts and percentages of participants within each 
baseline category (maximum value) versus each postbaseline category (maximum value) by 
treatment. 
Additionally, the following 3 outcomes of interest will be compared between treatments (based 
on the maximum value during baseline and postbaseline): 
 Any increase in depression category (that is, worsening of depression) - Includes 
participants in the none, mild, moderate, or moderately severe categories during baseline 
with at least 1 postbaseline measurement. 
 
Increase from no or mild depression to moderate, moderately severe or Severe 
depression - Includes participants in the none or mild depression category during baseline 
with at least 1 postbaseline measurement. 
 Increase from mild or moderate depression to moderately severe or severe 
depression - includes participants in the mild or moderate depression category during 
baseline and at least 1 postbaseline measurement. 
4.6.5.9.2. Suicidal Ideation and Behavior Solicited Through C-SSRS  
Suicide-related thoughts and behaviors occurring during the entire study period, based on the 
C-SSRS, will be summarized by treatment group. In particular, for each of the following suicide-
related events, the counts and percentages of participants with the event will be summarized by 
treatment group: 
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 died by suicide 
 nonfatal suicide attempt 
 interrupted attempt 
 aborted attempt 
 preparatory acts or behavior 
 active suicidal ideation with a specific plan and intent 
 active suicidal ideation with some intent to act without a specific plan 
 active suicidal ideation with any methods (no plan) without an intent to act 
 nonspecific active suicidal thoughts 
 wish to be dead, and 
 nonsuicidal, self-injurious behavior. 
In addition, the counts and percentages of participants who experienced at least 1 of the 
composite measures will be presented. The participants with at least 1 postbaseline C-SSRS 
assessment are included. The composite measure is determined at each assessment by the “yes” 
or “no” responses in C-SSRS categories by the study participant:  
 Category 1 - Wish to be Dead. 
 Category 2 - Non-Specific Active Suicidal Thoughts. 
 Category 3 - Active Suicidal Ideation with Any Methods (Not Plan) without Intent to 
Act. 
 Category 4 - Active Suicidal Ideation with Some Intent to Act, without Specific Plan. 
 Category 5 - Active Suicidal Ideation with Specific Plan and Intent. 
 Category 6 - Preparatory Acts or Behavior. 
 Category 7 - Aborted Attempt. 
 Category 8 - Interrupted Attempt. 
 Category 9 - Actual Attempt (non-fatal). 
 Category 10 - Completed Suicide. 
Composite endpoints of suicidal ideation and suicidal behavior based on the above categories are 
defined below: 
 Suicidal ideation - A “yes” answer at any time during study to any 1 of the 5 suicidal 
ideation questions (Categories 1 through 5) on the C-SSRS. 
 Suicidal behavior - A “yes” answer at any time during study to any 1 of the 5 suicidal 
behavior questions (Categories 6 through 10) on the C-SSRS.  
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 Suicidal ideation or behavior - A “yes” answer at any time during study to any 1 of the 
10 suicidal ideation and behavior questions (Categories 1 through 10) on the C-SSRS.  
A listing containing data for each participant with suicidal ideation, suicidal behavior, or 
nonsuicidal self-injurious behavior during the study by treatment and visit may be provided. Data 
from all visits are displayed, regardless of a “yes” or “no” answer, for participants with any “yes” 
answer for suicidal ideation, suicidal behavior, or self-injurious behavior without suicidal intent. 
4.6.5.10. Malignancy  
Malignancy will be considered as an AESI. The counts and percentages of participants with 
treatment-emergent malignancy will be summarized by treatment and PT ordered by decreasing 
frequency. Detailed searching criteria can be found in Appendix 7 (Section 6.7). 
4.6.5.11. Renal Safety  
Laboratory measures related to renal safety will be analyzed as specified for laboratory 
measurements in Section 4.6.3.6. 
Additionally, 2 shift tables examining renal function will be created. A minimum-to-minimum 
shift table of estimated glomerular filtration rate (eGFR) will be estimated by the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation with units of mL/min/1.73m2, 
using categories of <30, ≥30 to <45, ≥45 to <60, ≥60, and ≥90 mL/min/1.73m2. A max-to-max 
shift table of urine albumin-to-creatinine ratio (UACR) will be created, using the categories of 
UACR<30 mg/g, 30 mg/g ≤UACR≤300 mg/g, and UACR>300 mg/g (respectively, these 
represent normal, microalbuminuria, and macroalbuminuria).  
Mixed model for repeated measure analyses for eGFR and UACR will be provided. Log 
transformation will be performed for UACR.  
4.6.5.11.1. Acute Renal Events  
Acute renal events, including those associated with chronic renal failure exacerbation, will also 
be captured.  
Severe/serious renal events from the SMQ search below will be considered AESI.  
The counts and percentages of participants with acute renal events will be summarized by 
treatment by using MedDRA PTs contained in any of the following SMQs: 
 Acute renal failure:  
o narrow terms in the Acute renal failure SMQ (20000003) 
 Chronic kidney disease: 
o narrow terms in the Chronic kidney disease SMQ (20000213).  
In addition, a listing of participants with treatment-emergent acute renal events may be provided, 
if deemed necessary. 
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4.6.5.11.2. Dehydration  
Dehydration events will be captured in the following SMQ and summarized. Severe/serious 
dehydration events will be considered AESI:  
 narrow terms in the Dehydration SMQ (20000232).  
The counts and percentages of participants with dehydration will be summarized by treatment 
and PT and ordered by decreasing frequency. A listing of participants with treatment-emergent 
dehydration events may be provided, if deemed necessary. 
4.6.5.12. Thyroid Safety Monitoring  
4.6.5.12.1. Calcitonin  
The number and proportion of participants with a maximum postbaseline calcitonin value in the 
following thresholds will be provided by treatment and baseline calcitonin value 
(≤20 ng/L, >20 ng/L to ≤35 ng/L, >35 ng/L) and postbaseline value (≤20 ng/L, >20 ng/L to 
≤35 ng/L, >35 ng/L to ≤50 ng/L, >50 ng/L to ≤100 ng/L, and >100 ng/L). 
4.6.5.12.2. C-Cell Hyperplasia and Thyroid Malignancies  
Thyroid malignancies and C-cell hyperplasia will be considered AESI. Detailed searching 
criteria can be found in Appendix 6.7 (Section 6.7). 
The counts and percentages of participants with treatment-emergent thyroid C-cell hyperplasia 
and malignancies will be summarized by treatment and PT ordered with decreasing frequency. In 
addition, a listing of participants with treatment-emergent thyroid C-cell hyperplasia and 
neoplasms may be provided if deemed necessary.  
4.6.5.13. Treatment-Emergent Arrhythmias and Cardiac Conduction Disorders  
The treatment-emergent arrhythmias and cardiac conduction disorders events will be identified 
using MedDRA PTs. Detailed searching criteria can be found in Appendix 7 (Section 6.7).  
The counts and percentages of participants with treatment-emergent arrhythmias and cardiac 
conduction disorders will be summarized by treatment and PT nested within SMQ. The PT will 
be ordered with decreasing frequency within SMQ. A listing of participants with treatment-
emergent arrhythmias and cardiac conduction disorders may be provided if deemed necessary.  
4.6.5.14. Severe/serious treatment-emergent arrhythmias and cardiac conduction 
disorders will be considered AESI and summarized separately. Treatment of 
Overdose  
Overdose is defined as taking more than 15 mg of tirzepatide in less than 72 hours. Overdosing 
of tirzepatide will be summarized by treatment group, and a listing of participants with 
tirzepatide overdosing will be provided. 
In addition, a listing of participants reporting AEs related to overdosing of tirzepatide may be 
provided. 
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4.6.5.15. Abuse Potential  
To identify AE terms suggestive of abuse liability potential, narrow terms from the Drug abuse 
and dependence SMQ (20000101) will be used. Counts and percentages of participants will be 
summarized by treatment group with decreasing frequency. 
4.7. 
Other Analyses  
4.7.1. 
Health Outcomes  
The patient-reported outcome questionnaires will be analyzed using the mITT population on the 
EAS, unless specified otherwise. 
Item-level missingness is dealt with as per the instrument developers’ instruction. 
Additional psychometric analyses may be performed by the Value Evidence Outcomes group at 
Lilly and documented in a separate analysis plan. 
4.7.1.1. 
Patient Global Impression of Status for Physical Activity  
The counts and percentages of participants for Patient Global Impression of Status for Physical 
Activity (PGIS) response categories will be summarized by nominal visit and by treatment. A 
shift table from baseline to postbaseline of 5 PGIS response categories at each postbaseline visit 
by treatment will be created.  
4.7.1.2. 
Short-Form-36 Health Survey Version 2, Acute Form  
Per copyright owner, the QualityMetric Health Outcomes™ Scoring Software 4.5 will be used to 
derive the following domain and component scores: 
 Mental Component Summary (MCS) 
 Physical Component Summary (PCS) 
 Physical Functioning (PF) domain  
 Role-Physical domain (RP) 
 Bodily Pain (BP) domain 
 General Health domain (GH) 
 Vitality domain (VT) 
 Social Functioning domain (SF) 
 Role-Emotional domain (RE), and 
 Mental Health domain (MH). 
For each above domain and component summary score parameter, the raw scores will be 
transformed into the domain scores (t-scores), and the following analyses for the actual value and 
change from baseline value will be conducted:  
 descriptive summaries by treatment group, and 
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 analysis described in Table GPHM.4.3 and Table GPHM.4.4.  
The empirical cumulative distribution function (eCDF) curves of the change from baseline to 72 
weeks in Short Form-36 Version 2 Health Survey acute form (SF-36v2) PF domain scores will 
be provided by treatment group. 
If data allow, analysis for SF-36v2 PF domain scores described in Table GPHM.4.3 will be 
conducted to evaluate the treatment effect in participants who have limitations in PF at baseline, 
which are defined as PGIS responses at baseline of “moderately limited,” “very much limited,” 
or “extremely limited.”  
4.7.1.3. 
Impact of Weight on Quality of Life-Lite Clinical Trials  
The following parameters will be included from the Impact of Weight on Quality of Life-Lite-
Clinical Trials Version (IWQOL-Lite-CT): 
 IWQOL Lite CT total score (all items: items 1 through 20) 
 PF composite score (5 items: items 1 through 3, 16, 17) 
 Physical composite score (7 items: item 1 through 5, 16, 17), and 
 Psychosocial composite score (13 items: item 6 through 15, 18, 19, 20). 
The IWQOL-Lite-CT total and composite scores range from 0 to 100, with higher scores 
reflecting better levels of functioning. 
The IWQOL-Lite-CT scores are computed according to the IWQOL-Lite scoring rules (Kolotkin 
et al. 2002) as follows: 
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For total and each composite score, the following analyses for the actual value and change from 
baseline value will be conducted:  
 descriptive summaries by treatment group, and 
 ANCOVA analysis described in Table GPHM.4.3 and Table GPHM.4.4.  
If data allow, IWQOL-Lite-CT PF composite score analysis described in Table GPHM.4.3 will 
be conducted to evaluate the treatment effect in participants who have limitations in PF at 
baseline (as defined in Section 4.7.1.2).  
4.7.1.4. 
EQ-5D-5L  
For the utility score and the Visual Analog Scale (VAS) scores, the following analyses of the 
actual value and change from baseline value will be conducted: 
 descriptive summaries by treatment group, and 
 analyses described in Table GPHM.4.4.  
4.7.2. 
Subgroup Analyses  
Efficacy subgroup analyses will be guided by the treatment-regimen estimand in the FAS and the 
efficacy estimand in the EAS.  
Subgroup analyses may be done by country to support local regulatory registrations. 
4.7.2.1. 
Subgroup Analysis of Body Weight Change  
Subgroup analyses by the following baseline characteristics will be provided:  
 age (<65, ≥65 years) 
 sex (female and male)  
 race 
 ethnicity 
 BMI at randomization (<30, ≥30 and <35, ≥35 and <40, ≥40 kg/m2) 
 region of enrollment (US, outside of US), and 
 percentage of body weight reduction at the end of lead-in (<10% and ≥10%). 
The outcome measures for the subgroup analyses will include 
 percent change in body weight from randomization at 72 weeks, and 
 proportion of participants achieving at least 5% body weight reduction from 
randomization to 72 weeks. 
For the percent change in body weight from randomization at 72 weeks, for each subgroup 
analyses aforementioned, the following analyses will be conducted. 
Treatment Regimen Estimand 
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 Conduct the ANCOVA model on the subgroup only with terms of treatment group, 
country/pooled country, and sex as fixed effects and baseline body weight as a covariate. 
Missing body weight measurements at 72 weeks will be imputed using the imputation 
method described in Section 4.3.2.3.  
 Full ANCOVA model - Treatment group, subgroup, treatment-by-subgroup-interaction, 
country/pooled country, and sex as fixed effects and baseline body weight as a covariate. 
Missing body weight measurements at 72 weeks will be imputed using the imputation 
method described in Section 4.3.2.3. 
Efficacy Estimand 
 Conduct the MMRM model on the subgroup only with terms of treatment group, visit, 
treatment-by-visit-interaction, country/pooled country, and sex as fixed effects, and 
baseline body weight as a covariate. The variance-covariance structure for within-patient 
errors will be same as Section 4.3.2.2.  
 Full MMRM model - Treatment group, visit, subgroup, treatment-by-visit-interaction, 
treatment-by-subgroup-interaction, subgroup-by-visit-interaction, treatment-visit-
subgroup-interaction, country/pooled country, and sex as fixed effects and baseline body 
weight as a covariate. The variance-covariance structure for within-patient errors will be 
same as Section 4.3.2.2. 
For the percentage of participants achieving at least 5% body weight reduction at 72 weeks, for 
each subgroup analyses aforementioned, the following analyses will be conducted.  
Treatment Regimen Estimand 
 Conduct the logistic regression model on the subgroup only with terms of treatment 
group, country/pooled country, and sex as fixed effects and baseline body weight as a 
covariate. Missing body weight measurements at 72 weeks will be imputed using the 
imputation method described in Section 4.3.2.3, then the continuous measurements will 
be dichotomized into status of achieving at least 5% body weight reduction (Yes or No). 
 Full logistic regression model - Treatment group, subgroup, treatment-by-subgroup-
interaction, country/pooled country, and sex as fixed effects and baseline body weight as 
a covariate. Missing body weight measurement at 72 weeks will be imputed using the 
imputation method described in Section 4.3.2.3, then the continuous measurements will 
be dichotomized into status of achieving at least 5% body weight reduction (Yes or No). 
Efficacy Estimand 
 Conduct the logistic regression model on the subgroup with terms of treatment group, 
country/pooled country, and sex as fixed effects and baseline body weight as covariate. 
Missing body weight measurement at 72 weeks will be imputed by the predicted value 
from the MMRM model on the subgroup aforementioned, then the continuous 
measurements will be dichotomized into status of achieving at least 5% body weight 
reduction (Yes or No).  
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 Conduct the logistic regression model with terms of treatment group, subgroup, 
treatment-by-subgroup-interaction, country/pooled country, and sex as fixed effects and 
baseline body weight as a covariate. Missing body weight measurement at 72 weeks will 
be imputed by the predicted value from the full MMRM model aforementioned, then the 
continuous measurements will be dichotomized into status of achieving at least 5% body 
weight reduction (Yes or No). 
4.8. 
Interim Analyses  
Not applicable. 
4.9. 
Changes to Protocol-Planned Analyses  
To provide data on efficacy of the investigational product that would be valuable to better inform 
clinical decisions in management of people living with obesity, protocol-planned objectives are 
changed as below. 
Key Secondary Objectives 
 added the key secondary objective, “QW tirzepatide MTD is superior to placebo for 
proportion of participants who achieve ≥20% body weight reduction from randomization 
to 72 weeks” 
Additional Secondary Objectives 
 added the additional secondary objective, “Compare QW tirzepatide MTD with placebo 
for mean change in Non-HDL-cholesterol (mg/dL) from randomization to 72 weeks” 
Subgroup Analysis for Primary Analysis 
 added the subgroup variable, “region of enrollment (US, outside of US)” for both 
outcome measures 
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5. 
Sample Size Determination  
Approximately 1100 participants will be screened, and 800 participants will be enrolled into the 
12-week lead-in period in order to achieve approximately 600 participants randomly assigned to 
study drug intervention (300 participants per treatment group). 
The sample size determination assumes that evaluation of superiority of tirzepatide MTD (10 mg 
or 15 mg) to placebo will be conducted at a 2-sided significance level of 0.05 using a 2-sample t-
test. Additionally, a difference of at least 12% in mean body weight percentage reduction from 
randomization at 72 weeks for tirzepatide MTD compared to placebo, a common SD of 10%, 
and a dropout rate of 25% are assumed for statistical power calculations. Under the assumptions 
above, randomizing 600 participants in a 1:1 ratio to MTD (300 participants) and placebo (300 
participants) provides more than 90% power to demonstrate superiority of tirzepatide MTD to 
placebo. 
The chosen sample size and randomization ratio also provides >90% power to establish 
superiority of tirzepatide MTD to placebo in terms of proportion of participants achieving at least 
5% body weight reduction from randomization at 72 weeks, based on a Chi-square test at a 2-
sided significance level of 0.05, assuming 20% of placebo-treated participants and 46% of 
tirzepatide-treated participants achieve the goal and a dropout rate of 25%.  
 
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6. 
Supporting Documentation  
6.1. 
Appendix 1: Demographic and Baseline Characteristics  
6.1.1. 
Patient Characteristics  
A listing of participant demographics for all randomized participants will be provided. All 
demographic and baseline clinical characteristics will be summarized by study treatment for all 
randomized participants. Baseline demographic and clinical characteristics of special interest 
include but are not limited to age (years), sex (female, male), race, ethnicity, height (cm), weight 
(kg), BMI (kg/m2), waist circumference (cm), age group (<65 years, ≥65 years), BMI group 
(<30, ≥30 and <35, ≥35 and <40, ≥40 kg/m2), country, and weight-related comorbidities. 
6.1.2. 
Historical Illnesses and Preexisting Conditions  
The count and percentages of participants with historical illnesses and preexisting conditions will 
be summarized by treatment group using MedDRA PTs nested within SOC. The SOCs will be in 
alphabetical order. Conditions (that is, PTs) will be ordered by decreasing frequency within 
SOC. This will be summarized for all randomized participants.  
6.1.3. 
Concomitant Therapy  
Concomitant medications will be summarized by PTs by treatment group by decreasing 
frequency for the SS group. The following postbaseline period will be considered:  
 up to 72 weeks plus the safety follow-up (Visit 801) for all randomized participants. 
Additionally, concomitant medications of interest (as defined below) will be summarized by 
treatment for the SS. 
Concomitant medications of interest include the following: 
 baseline antihypertensive therapy, by type/class 
 baseline lipid lowering therapy, by type/class 
 changes to baseline medication postrandomization 
o antihypertensive therapy, and 
o lipid lowering therapy. 
 utilization after randomization of 
o medicines that cause weight gain, 
o antihyperglycemic medication for the treatment of diabetes for participants who 
develop T2DM during the study (antihyperglycemic medication for the treatment 
of prediabetes is not allowed per protocol) 
o antidiarrheal medication, and 
o antiemetic medication. 
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The analysis of concomitant medication for the lead-in period is provided in Appendix 4 (Section 
6.4). 
6.2. 
Appendix 2: Treatment Compliance  
A summary of participants who prematurely discontinued study treatment (including 
discontinuation reason) will be provided by study treatment. A time-to-event analysis of 
premature study treatment discontinuation will also be conducted.  
The analyses related to compliance during the 72-week treatment period will be conducted for all 
randomized participants.  
If data warrant, the counts and percentages of participants who follow the planned escalation 
scheme, have dose interruption, or have dose de-escalation/re-escalation will be summarized for 
the tirzepatide treatment group. In addition, the proportion of participants receiving 2.5 mg, 
5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg may be presented by visit during the dose escalation 
period. 
Treatment compliance will be defined as taking at least 75% of the scheduled study treatment 
doses. Compliance over the double-blind treatment period will be calculated using the number of 
doses administered (regardless of the actual dose in mg administered), divided by the total 
number of doses expected to be administered × 100 over the double-blind treatment period, 
respectively. Treatment compliance will be summarized descriptively over the double-blind 
treatment period by treatment using the mITT population. 
6.3. 
Appendix 3: Important Protocol Deviations  
Important protocol deviations are identified in the Trial Issues Management Plan (TIMP). A 
listing and a summary of important protocol deviations by treatment will be provided at the end 
of the study for all randomized participants. 
6.4. 
Appendix 4: Analyses for the Intensive Lifestyle Modification Lead-
in Period  
6.4.1. 
General Consideration  
Unless specified otherwise, all analyses for the lead-in period will be based on all enrolled 
participants.  
Table GPHM.6.1. 
Baseline and Postbaseline Definitions in Lead-in Period  
Population 
Analysis Type 
Baseline  
Postbaseline  
All enrolled 
participants 
1.1) Treatment-
emergent adverse 
events 
The baseline period is defined 
as the start of screening and 
ends prior to the intensive 
lifestyle modification program 
(typically at Week -12). 
Starts after the first visit of the 
intensive lifestyle modification 
program and ends prior to the first dose 
of study treatment.  
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Population 
Analysis Type 
Baseline  
Postbaseline  
All enrolled 
participants 
1.2) Treatment-
emergent abnormal 
labs, vital signs, and 
ECGs. 
Baseline will include all 
scheduled and unscheduled 
measurements during the 
baseline period as defined 
above (1.1). 
Postbaseline will be defined as above 
(1.1). All scheduled and unscheduled 
measurements will be included. 
All enrolled 
participants 
1.3) Change from 
last baseline to 
Week xx and to last 
postbaseline for 
labs, vital signs, and 
ECGs. 
The last scheduled and 
unscheduled nonmissing 
assessment recorded during the 
baseline period defined above 
(1.1) 
Postbaseline will be defined as above 
(1.1). Only scheduled visits will be 
included. The early discontinuation 
visits are considered scheduled visits. 
All enrolled 
participants 
Other outcomes 
(efficacy, PROs, 
questionnaires, etc.) 
Baseline is defined as the last 
nonmissing data collected 
prior to or at study entry 
(Week -12). 
Postbaseline is defined as data collected 
after the study entry (Week -12) and 
prior to or at randomization (Week 0)  
Abbreviations: ECG = electrocardiogram; PRO = patient-reported outcome. 
6.4.2. 
Patient Characteristics  
A summary table will be generated for participant demographics and baseline disease 
characteristics for the enrolled population. Variables to be included (but not limited to) are age, 
sex, race, ethnicity, weight, BMI, waist circumference, age groups, and BMI groups.  
6.4.3. 
Disposition  
Summaries of study disposition will be provided for the intensive lifestyle modification lead-in 
period. A listing may also be provided if necessary. 
The lead-in period completion status is defined at the end of 12-week intensive lifestyle 
modification lead-in period (when all enrolled participants complete or discontinue the lead-in 
period). Participants with a nonmissing body weight measurement at Week 0 (Visit 10) will be 
considered as completers; otherwise, they will be considered as noncompleters. 
6.4.4. 
Medical History, Preexisting Conditions, and Concomitant Medications  
Medical history, preexisting conditions, and concomitant medications will be summarized by 
PTs by decreasing frequency for all enrolled participants.  
6.4.5. 
Adverse Events  
For the intensive lifestyle modification lead-in period, a TEAE is defined as an event, based 
upon an MedDRA LLT, that first occurred or worsened in severity after baseline of the lead-in 
period.  
Treatment-emergent AEs, common TEAEs, deaths, SAEs, and significant AEs will be 
summarized for all enrolled participants in a similar way to Section 4.6.2 without treatment 
comparison.  
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6.4.6. 
Additional Safety Assessments  
Vital signs, ECG parameters and clinical laboratory results will be summarized for all enrolled 
participants using categorical analysis in a similar way to Section 4.6.3 without treatment 
comparison.  
6.4.7. 
Important Protocol Deviations  
Important protocol deviations are identified in the TIMP. A summary of important protocol 
deviations may be provided at the end of the 12-week intervention (for all enrolled participants), 
if deemed necessary. 
6.5. 
Appendix 5: Clinical Trial Registry Analyses  
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following: 
 Summary tables of AEs for the lead-in period and the double-blind period, provided as 
datasets that will be converted to XML files. For the lead-in period, SAEs and ‘other’ 
nonserious AEs are summarized by MedDRA PT. For the double-blind period, they are 
summarized by treatment group and MedDRA PT. 
o An AE is considered ‘Serious’ whether or not it is a TEAE. 
o An AE is considered in the ‘Other’ category if it is both a TEAE and is not 
serious. For each SAE and ‘Other’ AE, for each term and treatment group, the 
following are provided: 
- the number of participants at risk of an event 
- the number of participants who experienced each event term, and 
- the number of events experienced. 
o For each SAE, these additional terms are provided for EudraCT: 
- the total number of occurrences causally related to treatment 
- the total number of deaths, and 
- the total number of deaths causally related to treatment.  
A demographic table including the following age ranges is required by EudraCT:  
 18 to 65 years 
 65 to 85 years, and  
 85 years and over. 
6.6. 
Appendix 6: Exceptional Circumstances Impact  
This section lists additional statistical analyses that may be performed at final database lock to 
assess the impact of exceptional circumstances if the data warrants.  
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6.6.1. 
General Considerations  
Percentage and count of randomized participants who followed the exceptional circumstances 
mitigation plan may be summarized by treatment group. This includes, but is not limited to, 
participants rescreened, procedures conducted via remote visit or mobile home health visit, visits 
occurred using the extended visit windows, alternative way of investigator product 
shipment/dispensing, use of a local lab, and so on.  
Percentage and count of randomized participants who completely missed at least 1 study visit 
due to exceptional circumstances may also be summarized. 
Similar summaries during the intensive lifestyle modification lead-in period may also be 
provided for all enrolled participants. 
6.6.2. 
Exposure  
A listing of randomized participants who had the study drug temporarily interrupted due to 
exceptional circumstances may be provided.  
6.6.3. 
Protocol Deviations  
Percentage and count of randomized participants having important protocol deviations related to 
exceptional circumstances will be summarized by treatment.  
Percentage and count of randomized participants with protocol deviation and mitigation related 
to exceptional circumstances may also be summarized by treatment.  
A listing of all randomized participants who had protocol deviation and mitigation due to 
exceptional circumstances may be provided.  
Similar summaries during the intensive lifestyle modification lead-in period may also be 
provided for all enrolled participants. 
6.6.4. 
Patient Disposition  
A summary table for all randomized participants that discontinue the study or study treatment 
due to exceptional circumstances will be provided by treatment. A similar summary during the 
intensive lifestyle modification lead-in period may also be provided for all enrolled participants. 
A listing of enrolled participants who discontinued the study or study treatment due to 
exceptional circumstances will be provided with information to indicate if a participant is 
randomized (along with randomized treatment) and if events occur postrandomization.  
6.6.5. 
Adverse Events  
A listing of all enrolled participants who had COVID-19 infection, including deaths due to 
COVID-19, will be provided with information to indicate if a participant is randomized (along 
with randomized treatment), and if events occur post-randomization.  
6.6.6. 
Major Depressive Disorder/Suicidal Ideation  
The counts and percentages of participants with TEAEs for major depression may be 
summarized by treatment group using MedDRA PT nested within SMQ by subgroup impacted 
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by exceptional circumstances (that is, participants without impact versus with impact) for the SS 
group.  
The suicidal ideation and behavior solicited through C-SSRS may be summarized by treatment 
group by subgroup impacted by exceptional circumstances (that is, participants without impact 
vs with impact) for the SS group.  
Similar summaries during the intensive lifestyle modification lead-in period may also be 
provided for all enrolled participants. 
6.6.7. 
Local Laboratory Measurements  
Local laboratory measurements due to exceptional circumstances will not be brought into the 
Lilly database at the time of primary database lock and final database lock per data collection 
system in Study GPHM, even though the local laboratory is one of the options in exceptional 
circumstances. Therefore, this section is not applicable for analysis purposes. 
6.6.8. 
Missing Data Due to Exceptional Circumstances  
For the primary endpoints and key secondary endpoints, missing data due to exceptional 
circumstances will be handled as described in Section 4.3.2.3.  
6.7. 
Appendix 7: Searching Criteria for Special Safety Topics  
Pancreatitis Events  
Determination of investigator-reported events will be through the Acute pancreatitis SMQ 
(20000022, narrow scope) and a Pancreatitis Chronic PT search of the AE database, while 
adjudication-confirmed pancreatitis events are found from adjudication forms.  
Malignancies 
The malignancy events will be identified using the MedDRA PT contained in the Malignant 
tumours SMQ (20000194) narrow scope or Tumours of unspecified malignancy SMQ 
(20000195) narrow scope. 
Arrhythmias and Cardiac Conduction Disorders 
The cardiovascular events will include clinically relevant rhythm and conduction disorders. The 
treatment-emergent arrhythmias and cardiac conduction disorders events will be identified using 
the MedDRA PT contained in any of the following SMQs: 
1) Arrhythmias 
 For symptoms - Arrhythmia related investigations, signs and symptoms SMQ 
(20000051), narrow and broad terms. 
 For supraventricular arrhythmias - Cardiac arrhythmia SMQ, under the 
tachyarrhythmia sub-SMQ. 
o Supraventricular tachyarrhythmia SMQ (20000057), broad and narrow 
terms 
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o Tachyarrhythmia terms, nonspecific SMQ (20000164), narrow terms only, 
and 
o Ventricular tachyarrhythmia SMQ (20000058), narrow terms only. 
2) Cardiac Conduction Disorders  
 Conduction defects SMQ (20000056), narrow terms only, and 
 Cardiac conduction disorders High-Level Term (HLT; 10000032), all PTs. 
Injection Site Reactions 
Treatment-emergent ISRs will be identified using the MedDRA PT in any of the following  
 MedDRA HLT of Injection site reaction  
 HLT of Administration site reaction, and 
 HLT of Infusion site reactions. 
Acute Gallbladder Disease 
All events of TEAE biliary colic, cholecystitis, or other suspected events related to gallbladder 
disease will be identified by PTs under following SMQs: 
 narrow PTs in the Gallbladder related disorders SMQ (20000124) 
 narrow PTs in the Biliary tract disorders SMQ (20000125), and 
 narrow PTs in the Gallstone related disorders SMQ (20000127). 
Hepatic Events 
Treatment-emergent, potentially drug-related hepatic events will be identified using MedDRA 
PTs contained in any of the following SMQs: 
 broad and narrow terms in the Liver related investigations, signs and symptoms 
SMQ (20000008) 
 broad and narrow terms in the Cholestasis and jaundice of hepatic origin SMQ 
(20000009) 
 broad and narrow terms in the Hepatitis non-infections SMQ (20000010) 
 broad and narrow terms in the Hepatic failure, fibrosis and cirrhosis and other 
liver damage SMQ (20000013), and  
 narrow terms in the Liver-related coagulation and bleeding disturbances SMQ 
(20000015). 
Major Depressive Disorder/Suicidal Ideation 
Adverse events will be searched using MedDRA PTs from the Depression and suicide/self-injury 
SMQ as defined in MedDRA (SMQs: 20000037 [Suicide/self-injury] and 20000167 [Depression 
(excl suicide and self-injury)]).  
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7. 
References  
[ADA] American Diabetes Association. Glycemic targets: standards of medical care in diabetes-
2020. Diabetes Care. 2020(suppl 1): S66–S76. https://doi.org/10.2337/dc20-S006  
[ICH] International Council for Harmonisation. Addendum on estimands and sensitivity analysis 
in clinical trials. To the guideline principles for clinical trials E9(R1): guidance for industry. 
November 2019. Accessed August 31, 2022. https://www.gmp-
compliance.org/files/guidemgr/E9-R1_Step4_Guideline_2019_1203.pdf 
Ge M, Durham LK, Meyer DR. Covariate-adjusted difference in proportions from clinical trials 
using logistic regression and weighted risk differences. Drug Inf J. 2011;45(4):481-493. 
https://doi.org/10.1177/009286151104500409 
Kolotkin RL, Crosby RD, Williams GR. Health‐related quality of life varies among obese 
subgroups. Obes Res. 2002;10(8):748-756. https://doi.org/10.1038/oby.2002.102 
Qu Y, Dai B. Return-to-baseline multiple imputation for missing values in clinical trials. Pharm 
Stat. 2022;21:641-653. https://doi.org/10.1002/pst.2191 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons Inc.; 1987. 
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