Efficacy and Safety of Tirzepatide Once Weekly in Participants Without Type 2 Diabetes Who Have Obesity or Are Overweight With Weight- Related Comorbidities: A Randomized, Double-Blind, Placebo-Controlled Trial (SURMOUNT-1)
Phase: PHASE3
Conditions: Overweight, Obesity
Sponsor: Eli Lilly and Company

Protocol I8F-MC-GPHK(b) 
 
Efficacy and Safety of Tirzepatide Once Weekly in Participants 
without Type 2 Diabetes Who Have Obesity or are Overweight with Weight- 
Related Comorbidities: A Randomized, Double-Blind, Placebo-Controlled Trial 
(SURMOUNT-1) 
 
NCT04184622 
 
Approval Date: 04-Oct-2021 

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Protocol I8F-MC-GPHK(b)
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Title Page
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investigation of tirzepatide (LY3298176), unless such persons are bound by a confidentiality agreement with Eli Lilly and Company 
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Protocol Title: Efficacy and Safety of Tirzepatide Once Weekly in Participants 
without Type 2 Diabetes Who Have Obesity or are Overweight with Weight-
Related Comorbidities: A Randomized, Double-Blind, Placebo-Controlled Trial 
(SURMOUNT-1)
Protocol Number: I8F-MC-GPHK(b)
Compound Number: LY3298176
Study Phase: Phase 3
Short Title: Efficacy and Safety of Tirzepatide Once Weekly Versus Placebo in Participants 
Who are either Obese or Overweight with Weight-Related Comorbidities (SURMOUNT-1)
Acronym: SURMOUNT-1
Sponsor Name: Eli Lilly and Company
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s)
IND: 139721
Approval Date:  Protocol Amendment (b) Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 04-Oct-2021 GMT

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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment (a)
24-Jul-2020
Original Protocol
09-Sep-2019
Overall Rationale for Amendment (b):
The overall rationale for the current GPHK protocol amendment is to update the key study 
objectives and endpoints in Section 3; clarify the definition of incident diabetes, add guidance for
retesting, confirmation, recording, and adjudication of incident diabetes in Section 4.1.2.3; add 
guidance in Sections 6.6.1 and 6.6.3 for study drug dose modification during the additional 
2-year treatment period in participants with perceived excessive weight loss; and to update 
information relevant to statistical analyses in Section 9 to align with recent updates to the SAP.
These and other changes are listed in the below table.
Section # and 
Name
Description of Change
Brief Rationale
1.1. Synopsis
3. Objectives and 
Endpoints
Key secondary objective at 20 weeks was 
modified, changing heading from “by dose” to 
“pooled dose” analysis, and editing objective 
to reflect the pooled 10 mg and 15 mg doses.
Analysis of pooled data 
from participants on 
different tirzepatide doses 
is more appropriate as 
participants randomized to 
the 15-mg dose of 
tirzepatide will not be 
exposed to that dose until 
after Week 20.
1.1. Synopsis
3. Objectives and 
Endpoints 
Key secondary objective at 72 weeks, by dose 
analysis, was modified:
For the body weight objective, added the 
endpoint “≥20% body weight reduction from 
randomization”.
To better inform clinical 
decisions in management 
of people living with 
obesity.
Deleted the objective and associated endpoint
for SF-36v2 acute form Physical Functioning 
domain score for 10 mg and 15 mg separately.
Objective and associated 
endpoint were moved to 
Key secondary at 72 
weeks, pooled dose
analysis.

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Section # and 
Name
Description of Change
Brief Rationale
1.1. Synopsis
3. Objectives and 
Endpoints 
Revised key secondary objective at 72 weeks
from “by dose” to “pooled dose” analysis to 
demonstrate that the pooled 10 mg and 15 mg 
QW tirzepatide is superior to placebo for SF-
36v2 acute form Physical Functioning domain 
score.
To reduce the number of 
key secondary objectives.
1.1. Synopsis
3. Objectives and 
Endpoints 
In the key secondary objective at 72 weeks, 
pooled dose analysis for tirzepatide (all doses 
combined) to demonstrate superiority to 
placebo for lipid parameters, the endpoint was 
modified to replace “LDL” with “non-HDL
cholesterol”, and to replace “total” with 
“HDL” cholesterol.
Emerging science 
indicates assessing HDL-
cholesterol in addition to 
non-HDL cholesterol 
should provide more 
valuable data on CVD risk
in this specific population.
1.1. Synopsis
3. Objectives and 
Endpoints 
Additional secondary objective at 72 weeks, 
pooled dose analysis, the endpoint associated 
with lipid parameters was modified to replace 
“HDL” with “LDL” cholesterol, and to add 
“total cholesterol”.
For consistency and to 
reflect the changes to the 
key secondary objectives.
4.1.1.2.3. 
Additional 2-Year 
Treatment Period 
for Participants 
with Prediabetes 
at Randomization 
(Visits 101 
through 116)
Added wording “unless diabetes had been 
diagnosed prior to the visits”.
For clarity.
4.1.2.2. Oral 
Glucose 
Tolerance Test
Added wording regarding use of OGTT for 
confirming diagnosis of diabetes.
For clarity and 
consistency with new text 
related to confirmation of 
diabetes diagnosis in
Section 4.1.2.3.
4.1.2.3. Definition 
and Management 
of Incident 
Diabetes
Revised definition of incident diabetes and 
added subsections containing clarifying 
information related to “Confirmation of 
diabetes diagnosis” and “Recording of incident 
diabetes events”.
Definition of incident 
diabetes was revised to 
clarify the criteria 
regarding the requirement 
for 2 abnormal test results 
to confirm the diagnosis.

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Section # and 
Name
Description of Change
Brief Rationale
6.6.1. Tirzepatide
Added sentence allowing dose modification for 
management of participants with perceived 
excessive weight loss during the additional 2-
year treatment period for participants with 
prediabetes at randomization.
To support patient 
management and retention 
in the additional 2-year 
treatment period.
6.6.3. 
Management of 
Participants with 
Perceived
Excessive Weight 
Loss During the 
Additional 2-year 
Treatment Period 
for Participants 
with Prediabetes 
at Randomization
Added this subsection containing information
for managing participants with perceived 
excessive weight loss during the additional 2-
year treatment period for participants with
prediabetes at randomization.
Provide clear, detailed
information for managing
and retaining participants
in the additional 2-year 
treatment period.
7.2. Participant 
Discontinuation/
Withdrawal from 
the Study
Added bullet point “Female participants will 
be withdrawn from the study if the participant 
becomes pregnant.”
For clarity in participant 
management.
9.1. Statistical 
Hypotheses
Updated to reflect the changes specified in the 
key secondary objectives and endpoints in 
Section 3.
For consistency.
9.4.3.1. Primary 
Analyses
Updated information on estimands and related 
analyses.
To address and align with 
FDA feedback.
9.4.3.2. Key 
Secondary 
Analyses
Updated to reflect the changes specified in the 
key objectives and endpoints in Section 3.
For consistency.
9.4.4.4.2. Events 
Related to 
Potential Abuse 
Liability
Updated to replace current information with 
“To identify AE terms suggestive of potential 
abuse liability, narrow terms from SMQ of 
Drug abuse and dependence (20000101) will 
be used.”
Based on mechanism of 
action of tirzepatide, 
anticipated gastrointestinal 
adverse events, and low 
likelihood for abuse 
potential/psychoactive 
effects, it is reasonable to 
narrow the list of abuse 
terms used.
10.1.4. 
Committee 
Structure
Added wording pertaining to adjudication of 
incident diabetes events and cross-reference to 
related details in Section 4.1.2.3.
For clarity and 
consistency.

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Section # and 
Name
Description of Change
Brief Rationale
10.4. Appendix 4: 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information
In subsection for “Female Participants who 
become pregnant”, modified final sentence to 
indicate that if a study participant becomes 
pregnant, the participant will discontinue study 
intervention “and” will be withdrawn from the 
study.
For clarity and to align 
with other changes in 
protocol Section 7.2.
10.7. Appendix 7: 
Protocol GPHK 
Standardized 
Protocols for the 
Measurement of 
Height, Weight, 
Waist 
Circumference, 
Vital Signs, 
Electrocardiogra
m, and Oral 
Glucose 
Tolerance Test
Added note in the text stating that placement 
of a venous cannula may not be required when 
a 2-hour OGTT is repeated to confirm the 
diagnosis of diabetes during the study, and 
only samples at 0 and 120 minutes for glucose 
measurement will be collected.
For clarity and to align 
with changes in 
Section 4.1.2.2.
Throughout
Used the term “additional 2-year treatment
period for participants with prediabetes at 
randomization” to replace similar but 
inconsistently used terms when referring to the 
study period following primary outcome at 
Visit 21 (Week 72).
For clarity and 
consistency.
Throughout
Minor, editorial and document formatting 
revisions.
Minor, therefore have not 
been summarized.

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Table of Contents
1.
Protocol Summary......................................................................................................9
1.1.
Synopsis.......................................................................................................................9
1.2.
Schema.......................................................................................................................17
1.3.
Schedule of Activities.................................................................................................18
1.3.1.
Schedule of Activities covering visits to primary study endpoint.................................18
1.3.2.
Schedule of Activities for additional 2-year treatment period for 
participants with prediabetes at randomization............................................................22
2.
Introduction..............................................................................................................29
2.1.
Study Rationale ..........................................................................................................29
2.2.
Background ................................................................................................................30
2.3.
Benefit/Risk Assessment ............................................................................................31
3.
Objectives and Endpoints.........................................................................................32
4.
Study Design .............................................................................................................37
4.1.
Overall Design............................................................................................................37
4.1.1.
Overview of Study Periods .........................................................................................37
4.1.2.
Study Procedures........................................................................................................42
4.2.
Scientific Rationale for Study Design .........................................................................45
4.3.
Justification for Dose..................................................................................................46
4.4.
End of Study Definition..............................................................................................47
5.
Study Population ......................................................................................................48
5.1.
Inclusion Criteria........................................................................................................48
5.2.
Exclusion Criteria.......................................................................................................49
5.3.
Lifestyle Considerations .............................................................................................53
5.3.1.
Meals and Dietary Restrictions ...................................................................................54
5.3.2.
Physical Activity ........................................................................................................55
5.4.
Screen Failures ...........................................................................................................55
6.
Study Intervention....................................................................................................56
6.1.
Study Interventions Administered...............................................................................56
6.1.1.
Medical Devices.........................................................................................................56
6.2.
Preparation/Handling/Storage/Accountability.............................................................57
6.3.
Measures to Minimize Bias:  Randomization and Blinding .........................................57
6.4.
Study Intervention Compliance...................................................................................58
6.5.
Concomitant Therapy .................................................................................................58
6.6.
Dose Modification......................................................................................................59
6.6.1.
Tirzepatide .................................................................................................................59
6.6.2.
Management of Participants with Gastrointestinal Symptoms.....................................59
6.6.3.
Management of Participants with Perceived Excessive Weight 
Loss During the Additional 2-year Treatment Period for 
Participants with Prediabetes at Randomization ..........................................................60
6.7.
Intervention after the End of the Study........................................................................60
6.7.1.
Treatment after Study Completion ..............................................................................60

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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................61
7.1.
Discontinuation of Study Intervention ........................................................................61
7.1.1.
Temporary Study Drug Discontinuation......................................................................63
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................64
7.2.1.
Participant Disposition and Timing of Safety Follow-up for the 
Primary Endpoint (72 Weeks).....................................................................................65
7.2.2.
Participant Disposition and Timing of Safety Follow-up for those 
with Prediabetes at Randomization Continuing in Additional 
2-year Treatment Period .............................................................................................66
7.2.3.
Discontinuation of Inadvertently Enrolled Participants ...............................................67
7.3.
Lost to Follow-up .......................................................................................................67
8.
Study Assessments and Procedures .........................................................................68
8.1.
Efficacy Assessments .................................................................................................68
8.1.1.
Primary Efficacy Assessments....................................................................................68
8.1.2.
Secondary Efficacy Assessments ................................................................................68
8.1.3.
Patient-Reported Outcomes Assessments....................................................................68
8.1.4.
Short Form 36 version 2, acute, 1 week recall version.................................................69
8.1.5.
Impact of Weight on Quality of Life-Lite Clinical Trials Version ...............................69
8.1.6.
EQ-5D-5L ..................................................................................................................69
8.1.7.
Patient Global Impression of Status for Physical Activity ...........................................70
8.2.
Safety Assessments ....................................................................................................70
8.2.1.
Physical Examinations................................................................................................70
8.2.2.
Vital Signs..................................................................................................................70
8.2.3.
Electrocardiograms.....................................................................................................70
8.2.4.
Clinical Safety Laboratory Assessments .....................................................................71
8.2.5.
Safety Monitoring.......................................................................................................72
8.2.6.
Depression, Suicidal Ideation, and Behavior Risk Monitoring.....................................72
8.3.
Adverse Events and Serious Adverse Events ..............................................................73
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information.................................................................................................................75
8.3.2.
Follow-up of AEs and SAEs.......................................................................................75
8.3.3.
Regulatory Reporting Requirements for SAEs............................................................75
8.3.4.
Pregnancy...................................................................................................................76
8.3.5.
Medical Device Incidents (Including Malfunctions)....................................................76
8.3.6.
Complaint Handling ...................................................................................................77
8.4.
Treatment of Overdose ...............................................................................................77
8.5.
Pharmacokinetics........................................................................................................78
8.6.
Pharmacodynamics.....................................................................................................78
8.7.
Genetics .....................................................................................................................78
8.7.1.
Whole Blood Sample(s) for Pharmacogenetic Research..............................................78
8.8.
Biomarkers.................................................................................................................79
8.9.
Health Economics.......................................................................................................79
9.
Statistical Considerations.........................................................................................80
9.1.
Statistical Hypotheses.................................................................................................80

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9.2.
Sample Size Determination.........................................................................................81
9.3.
Populations for Analyses ............................................................................................83
9.4.
Statistical Analyses.....................................................................................................83
9.4.1.
General Statistical Considerations...............................................................................83
9.4.2.
Treatment Group Comparability .................................................................................84
9.4.3.
Efficacy Analyses.......................................................................................................84
9.4.4.
Safety Analyses ..........................................................................................................86
9.4.5.
Pharmacokinetic/Pharmacodynamic Analyses ............................................................88
9.4.6.
Evaluation of Immunogenicity....................................................................................88
9.4.7.
Other Analyses ...........................................................................................................88
9.5.
Interim Analyses.........................................................................................................89
10.
Supporting Documentation and Operational Considerations ................................90
10.1.
Appendix 1:  Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................90
10.1.1.
Regulatory and Ethical Considerations........................................................................90
10.1.2.
Informed Consent Process ..........................................................................................90
10.1.3.
Data Protection...........................................................................................................91
10.1.4.
Committees Structure .................................................................................................91
10.1.5.
Dissemination of Clinical Study Data .........................................................................91
10.1.6.
Data Quality Assurance ..............................................................................................92
10.1.7.
Data Capture System ..................................................................................................92
10.1.8.
Source Documents......................................................................................................93
10.1.9.
Study and Site Closure................................................................................................93
10.1.10. Publication Policy.......................................................................................................93
10.2.
Appendix 2:  Clinical Laboratory Tests.......................................................................94
10.3.
Appendix 3:  Adverse Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting......................................................98
10.3.1.
Special Safety Topics .................................................................................................98
10.4.
Appendix 4:  Contraceptive Guidance and Collection of 
Pregnancy Information .............................................................................................104
10.5.
Appendix 5:  Liver Safety:  Suggested Actions and Follow-Up 
Assessments .............................................................................................................108
10.6.
Appendix 6:  Medical Device Incidents:  Definition and 
Procedures for Recording, Evaluating, Follow-Up, and Reporting ............................109
10.7.
Appendix 7:  Protocol GPHK Standardized Protocols for the 
Measurement of Height, Weight, Waist Circumference, Vital 
Signs, Electrocardiogram, and Oral Glucose Tolerance Test.....................................111
10.8.
Appendix 8:  Suggested Visit Structure.....................................................................114
10.9.
Appendix 9:  Management of Gastrointestinal Symptoms.........................................115
10.10.
Appendix 10:  Provisions for Changes in Study Conduct During 
Exceptional Circumstances.......................................................................................116
10.11.
Appendix 11:  Abbreviations ....................................................................................120
10.12.
Appendix 12: Protocol Amendment History .............................................................125
11.
References...............................................................................................................127

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1.
Protocol Summary
1.1.
Synopsis
Protocol Title:
Efficacy and Safety of Tirzepatide Once Weekly in Participants without Type 2 Diabetes Who 
Have Obesity or are Overweight with Weight-Related Comorbidities: A Randomized, Double-
Blind, Placebo-Controlled Trial (SURMOUNT-1)
Short Title:
Efficacy and Safety of Tirzepatide Once Weekly Versus Placebo in Participants Who are either 
Obese or Overweight with Weight-Related Comorbidities (SURMOUNT-1)
Rationale:
Obesity is a chronic disease and its increasing prevalence is a public health concern associated 
with the rising incidence of type 2 diabetes mellitus (T2DM), increased risk for premature death 
and increased risk for some cancers (Allison et al. 2008; AMA 2013; Council on Science and 
Public Health 2013).  Although loss of 5% to 10% body weight has been shown to reduce 
complications related to obesity and improve quality of life (Mertens and Van Gaal 2000;
Knowler et al. 2002; Jensen et al. 2014; Li et al. 2014; Warkentin et al. 2014), lifestyle therapies 
fail to achieve sustainable weight loss in the majority of patients with obesity (Dombrowski et al. 
2014).  
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® SmPc, 2015).
Preclinical data indicate that GIP also exerts effects on appetite regulation and food intake,
adipose tissue, and on peripheral energy metabolism. Although studies evaluating effects of GIP 
on body weight have yielded equivocal results, GIP receptor (GIPR) activation may play a role 
in body weight regulation and targeting both the GLP-1R and the GIPR simultaneously may
result in additive or synergistic effects of the 2 incretins on body weight (Coskun et al. 2018).
Tirzepatide is a 39-amino acid synthetic peptide dual GIP and GLP-1 receptor agonist. Its 
structure is based on the GIP sequence and includes a C20 fatty diacid moiety. It is administered 
once-weekly (QW) by subcutaneous (SC) injection (Coskun et al. 2018).

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As a dual GIP/GLP-1R agonist, tirzepatide could exceed the efficacy of selective GLP-1R 
agonists by recruiting metabolically active tissues not targeted by selective GLP-1R agonists (for 
example, adipose tissue as indicated by the observation of increased energy utilization) (Baggio 
and Drucker 2007) and has the potential to reach higher efficacy in target tissues, such as insulin-
producing pancreatic beta cells that express both GIPR and GLP-1R, before reaching its 
therapeutic limitation. 
Study I8F-MC-GPHK (GPHK; SURMOUNT-1) is a Phase 3, multicenter, randomized, placebo-
controlled, double-blinded study of the safety and efficacy of 5-mg, 10-mg and 15-mg tirzepatide 
QW, compared with placebo, when used in conjunction with a reduced-calorie diet and increased 
physical activity for weight management, in participants who do not have T2DM, and have 
obesity (BMI ≥30 kg/m2) or are overweight (BMI ≥27 kg/m2) with at least one weight-related 
comorbid condition (for example, hypertension, dyslipidemia, or cardiovascular disease).  All 
participants will be randomized to at least 72 weeks of treatment to study the effects on body
weight reduction. Participants who have prediabetes will be studied for a total of 176 weeks of 
treatment to provide sufficient follow-up time to detect potential differences in progression to 
T2DM.

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Objectives and Endpoints
Objectives
Endpoints
Primary
at 72 weeks, by dose analysis
To demonstrate that tirzepatide 10 mg QW is superior 
to placebo for:

percent change in body weight AND

percentage of participants with ≥5% body 
weight reduction 
AND/OR
To demonstrate that tirzepatide 15 mg QW is superior 
to placebo for:

percent change in body weight AND 

percentage of participants with ≥5% body 
weight reduction 

mean percent change in body weight from 
randomization

percentage of study participants who achieve ≥5% 
body weight reduction from randomization  
Key secondary (controlled for Type I error)
at 20 weeks, pooled dose analysis
For pooled tirzepatide 10 mg and 15 mg QW doses, to 
demonstrate superiority to placebo for: 

body weight 

mean change in body weight (kg) from 
randomization
Key secondary (controlled for Type I error)
at 72 weeks, by dose analysis
To demonstrate that tirzepatide 5 mg QW is superior 
to placebo for:

percent change in body weight AND 

percentage of participants with ≥5% body 
weight reduction  

mean percent change in body weight from 
randomization 

percentage of study participants who achieve ≥5% 
body weight reduction from randomization  

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Objectives
Endpoints
For tirzepatide 10-mg and/or 15-mg QW doses, to 
demonstrate superiority to placebo for: 

body weight 

percentage of participants who achieve:
o
≥10% body weight reduction from 
randomization
o
≥15% body weight reduction from 
randomization
o
≥20% body weight reduction from 
randomization 

waist circumference 

mean change in waist circumference (cm) from 
randomization
Key secondary (controlled for Type I error)
at 72 weeks, pooled dose analysis
To demonstrate that pooled tirzepatide 10 mg and 15 
mg QW is superior to placebo for:

patient-reported outcomes (SF-36v2 acute 
form Physical Functioning domain score)

mean change in SF-36v2 acute form Physical 
Functioning domain score from randomization
Key secondary (controlled for Type I error)
at 72 weeks, pooled dose analysis
For tirzepatide QW (all doses combined), to 
demonstrate superiority to placebo for: 

lipid parameters 

SBP

insulin 

mean change from randomization in 
o
triglycerides (mg/dL)
o
non-HDL cholesterol (mg/dL)
o
HDL cholesterol (mg/dL)

mean change in SBP (mmHg) from randomization

mean change in fasting insulin (pmol/L) from 
randomization

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Objectives
Endpoints
Key secondary (controlled for Type I error)
at 176 weeks, by dose analysis
For tirzepatide 10-mg and/or 15-mg QW doses, to 
demonstrate superiority to placebo (for participants 
with prediabetes at randomization) for: 

body weight

mean percent change in body weight from 
randomization
Key secondary (controlled for Type I error)
at 176 or 193 weeks, pooled dose analysis
For tirzepatide QW (all doses combined), to 
demonstrate superiority to placebo (for participants 
with prediabetes at randomization) in:

delayed progression to T2DM at 176 weeks

delayed progression to T2DM at 193 weeks

time to onset of T2DM during 176 weeks
treatment period

time to onset of T2DM during entire study 
including safety follow up period
Additional secondary at 72 weeks, by dose analysis
For tirzepatide 5-mg QW dose, to demonstrate 
superiority to placebo for:

body weight

waist circumference

patient-reported outcomes (SF-36v2 Physical 
Functioning)
For tirzepatide 5-mg, 10-mg, and/or 15-mg QW 
doses, to demonstrate superiority to placebo for:

percentage of participants who achieve:
o
≥10% body weight reduction from 
randomization
o
≥15% body weight reduction from 
randomization

mean change in waist circumference (cm) from 
randomization

mean change in SF-36v2 acute form Physical 
Functioning domain score from randomization

body weight  

mean change in body weight (kg) from 
randomization

mean change in BMI (kg/m2) from randomization

glycemic control

mean change in HbA1c (%, mmol/mol) from 
randomization

mean change in fasting glucose (mg/dL) from 
randomization

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Objectives
Endpoints

patient-reported outcomes

mean change in IWQOL-Lite-CT Physical 
Function composite score from randomization
Additional secondary at 72 weeks, pooled dose 
analysis
For tirzepatide QW (all doses combined), to 
demonstrate superiority to placebo for:

DBP

mean change in DBP (mmHg) from 
randomization

lipid parameters 

mean change from randomization in:
o
LDL-cholesterol (mg/dL)
o
total cholesterol (mg/dL)
o
VLDL-cholesterol (mg/dL)
o
free fatty acids (mg/dL)
Additional secondary at 176 weeks, by dose 
analysis
For tirzepatide 5-mg QW dose, to demonstrate 
superiority to placebo (for participants with 
prediabetes at randomization) for:

body weight
For tirzepatide 5 mg, 10 mg and/or 15 mg QW doses, 
to demonstrate superiority to placebo (for participants 
with prediabetes at randomization) for:

body weight

mean percent change in body weight from 
randomization

percentage of study participants who achieve ≥5% 
body weight reduction from randomization  
Additional Secondary at 176 weeks, pooled dose
analysis
For tirzepatide QW (all doses combined), to 
demonstrate superiority to placebo (for participants 
with prediabetes at randomization) for:

Patient-reported outcomes

mean change in SF-36v2 acute form Physical 
Functioning domain score from randomization

mean change in IWQOL-Lite-CT Physical 
Function composite score from randomization

CONFIDENTIAL
Protocol I8F-MC-GPHK(b)
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15
Objectives
Endpoints
Additional Secondary
Pharmacokinetics/Pharmacodynamics

To characterize the population PK of tirzepatide 
and explore the relationships between the 
tirzepatide concentration and efficacy, safety and 
tolerability measures

population PK and PD parameters
Abbreviations: AUC= area under curve: BMI = body mass index; DBP = diastolic blood pressure; 
HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; IWQOL-Lite-CT = Impact of Weight on Quality of 
Life-Lite-Clinical Trials Version; LDL = low-density lipoprotein; PK = pharmacokinetics; QW = once-weekly; 
SF-36v2 = Short Form survey-36 version 2; SBP = systolic blood pressure; T2DM = type 2 diabetes mellitus; 
VLDL = very low-density lipoprotein.

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Protocol I8F-MC-GPHK(b)
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Overall Design:
Study I8F-MC-GPHK is a Phase 3, multicenter, randomized, placebo-controlled, double-blinded 
study of the safety and efficacy of 5-mg, 10-mg, and 15-mg tirzepatide QW compared with
placebo for weight management when used in conjunction with a reduced-calorie diet and 
increased physical activity, in participants who have obesity (BMI ≥30 kg/m2) or are overweight 
(BMI ≥27 kg/m2) with weight-related comorbidities (excluding T2DM).  Eligible participants 
will be stratified based on prediabetes status to either 72 (no prediabetes) or 176 weeks
(prediabetes), follow-up for endpoints of weight loss, and delay of diabetes onset.
Disclosure Statement: This is a parallel group-treatment study with 4 arms that is participant 
and investigator blinded.
Number of Participants:
Approximately 2400 participants will be randomized in a 1:1:1:1 ratio to 5-mg tirzepatide (600 
participants), 10-mg tirzepatide (600 participants), 15-mg tirzepatide (600 participants), and 
placebo (600 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 1:1:1:1 ratio (tirzepatide 5 mg QW, tirzepatide 10 mg 
QW, tirzepatide 15 mg QW, and placebo QW), stratified by country, sex, and prediabetes status.
All participants will undergo a 2-week screening period and a 72-week treatment period
including a 20-week dose escalation.  Participants with prediabetes at randomization who remain 
on study drug during the first 72 weeks will undergo a further 104-week treatment period (total 
treatment duration of 176 weeks).  The safety follow-up period will be 4 weeks (for those 
completing or discontinuing study drug during the first 72 weeks) or 17 weeks (for participants 
completing or discontinuing study drug between Weeks 72 through 176).
Data Monitoring Committee: 
An independent data monitoring committee (DMC) will review unblinded interim-analysis 
results.

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Protocol I8F-MC-GPHK(b)
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17
1.2.
Schema
Abbreviations:  QW= once weekly; T= telephone visit
All participants will be randomized to at least 72 weeks of treatment to study the effects on body weight reduction. 
Participants who have prediabetes will be studied for a total of 176 weeks of treatment to provide sufficient follow-up time to 
detect potential differences in progression to T2DM. The safety follow-up visit will occur after 4 weeks in participants
discontinuing (or completing) the study within the first 72 weeks.  Those discontinuing (or completing) the study after 
72 weeks will undergo safety follow-up after 17 weeks.

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Protocol I8F-MC-GPHK(b)
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18
1.3.
Schedule of Activities
The Schedule of Activities described below should be followed for all participants enrolled in Study GPHK. 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.
1.3.1.
Schedule of Activities covering visits to primary study endpoint
Visit*
1
2 3* 4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 99* ED*
801*
Week of Treatment
-2 -1 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 +7 ±3 +7 ±3 ±3 ±3 ±3 +7 ±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
Telephone Visit
X X
X X
X X
X X
Informed consent
X
Randomization
X
Register study visit in 
IWRS
X X X X X X X X X X X X X X X X X X X X X
X
X
X
Clinical Assessments
Medical history*
X
Physical examination
X
Height
X
Weight*
X
X X X X X X X
X
X
X
X
X
X
X
Waist circumference
X X X X X X X
X
X
X
X
X
X
X
Electrocardiogram*
X
X
X
X
X
X
X
X
Vital signs (3
sitting BP and 
HR)*
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
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
Participant Education and Assessment
Hand out diary, 
instruct in use*
X
X
X
X
X
X
X

CONFIDENTIAL
Protocol I8F-MC-GPHK(b)
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19
Visit*
1
2 3* 4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 99* ED*
801*
Week of Treatment
-2 -1 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 +7 ±3 +7 ±3 ±3 ±3 ±3 +7 ±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
Telephone Visit
X X
X X
X X
X X
Review study 
participant diary, 
including study-
drug compliance* 
X X X X X X X X X X X X X X X X X X
X
Lifestyle Program 
instructions*
X X X X
X
X
X
X
X
X
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
Injection training 
with autoinjector 
demonstration 
device*
X
Dispense study 
drug
X X X X X X X
X
X
X
X*
Observe participant 
administer study 
drug*
X
Participant returns 
study drugs and 
injection supplies
X X X X X X
X
X
X
X
X
Laboratory Tests
Serum pregnancy test*
X
Urine pregnancy test*
X
X
X
X
X
X
X
X
X
Follicle-stimulating 
hormone test*
X

CONFIDENTIAL
Protocol I8F-MC-GPHK(b)
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20
Visit*
1
2 3* 4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 99* ED*
801*
Week of Treatment
-2 -1 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 +7 ±3 +7 ±3 ±3 ±3 ±3 +7 ±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
Telephone Visit
X X
X X
X X
X X
2-hour oral glucose 
tolerance test (includes 
glucose, insulin, c-
peptide at each
timepoint)*
X
X
X
Chemistry panel (include 
Cr for eGFR calculation
and glucose)*
X
X
X
X
X
X
X
X
X
X
Lipid panel
X
X
X
X
X
X
Fasting insulin
X
X
X
X
X
X
X
X
C-peptide
X
X
X
X
X
X
X
X
Free fatty acids
X
X
X
X
X
X
Urinary 
albumin/creatinine 
X*
X
X
X
X
Cystatin-c
X*
X
X
X
X
Calcitonin
X*
X
X
X
X
X
Hematology
X*
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
X
X
Pancreatic amylase, 
lipase
X
X
X
X
X
X
X
Thyroid-stimulating 
hormone 
X*
Immunogenicity 
(includes PK sample)*
X X
X
X
X
X
X
X
TZP PK*
X
X
X
Pharmacogenetic stored 
sample
X

CONFIDENTIAL
Protocol I8F-MC-GPHK(b)
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21
Visit*
1
2 3* 4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 99* ED*
801*
Week of Treatment
-2 -1 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 +7 ±3 +7 ±3 ±3 ±3 ±3 +7 ±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
Telephone Visit
X X
X X
X X
X X
Nonpharmacogenetic 
stored sample
X
X
X
X
X
X
X
Mental Health Questionnaires
PHQ-9*
X
X
X
X
X
X
X
X
X
X
X
C-SSRS 
(Baseline/Screening)
Version)*
X
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
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
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
Patient Reported Outcomes
  PGIS
X
X
X
SF-36, version 2, acute 
form
X
X
X
IWQOL-Lite CT
X
X
X
EQ-5D-5L
X
X
X
                        

CONFIDENTIAL
Protocol I8F-MC-GPHK(b)
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22
1.3.2.
Schedule of Activities for additional 2-year treatment period for participants with prediabetes at 
randomization
Visit*
101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 199*ED*
802*
Week of 
Treatment
78
85
91
98 104 111 117 124 130 137 143 150 156 163 169 176 176
17 wks 
Post 
TxP
Allowable Deviation 
(days)*
±7
±7 ±7
±7
±7
±7 ±7
±7
±7 ±7
±7
±7
±7 ±7
±7
±7
±7
    ±3
Fasting Visit*
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
X
X
Register study visit in IWRS X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Assessments
Weight*
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram*
X
X
X
X
Vital signs (3 sitting 
BP and HR)*
X
X
X
X
X
X
X
X
X
X
Adverse events/Product 
Complaints
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Participant Education and Assessment
Hand out diary, instruct 
in use*
X
X
X
X
X
X
X
Review study 
participant diary, 
including study drug
compliance*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lifestyle Program 
instructions*
X
X
X
X
X
X
X
X
X
Review diet and 
exercise goals*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense study drug
X
X
X
X
X
X
X

CONFIDENTIAL
Protocol I8F-MC-GPHK(b)
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23
Visit*
101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 199*ED*
802*
Week of 
Treatment
78
85
91
98 104 111 117 124 130 137 143 150 156 163 169 176 176
17 wks 
Post 
TxP
Allowable Deviation 
(days)*
±7
±7 ±7
±7
±7
±7 ±7
±7
±7 ±7
±7
±7
±7 ±7
±7
±7
±7
    ±3
Fasting Visit*
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
X
X
Participant returns study 
drugs and injection 
supplies
X
X
X
X
X
X
X
X
X
Laboratory Tests
Urine pregnancy test*
X
X
X
X
X
X
X
X
X
2 hour oral glucose tolerance 
test (includes glucose, 
insulin, c-peptide)*
X
X
X
X
X
Chemistry panel (includes 
Cr for eGFR calculation and 
glucose)*
X
X
X
X
X
X
X
X
X
X
Lipid panel
X
X
X
X
Free fatty acids
X
X
X
X
Urinary 
albumin/creatinine ratio
X
X
X
X
Cystatin-c
X
X
X
X
 Calcitonin
X
X
X
X
Hematology
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
X
X
Pancreatic amylase, lipase
X
X
X
X
Immunogenicity (includes 
PK sample)*
X
X
X
X
X
X
Nonpharmacogenetic 
stored sample
X
X
X
X
Mental Health Questionnaires
PHQ-9*
X
X
X
X
X
X
X
X
X
X
X

CONFIDENTIAL
Protocol I8F-MC-GPHK(b)
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Visit*
101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 199*ED*
802*
Week of 
Treatment
78
85
91
98 104 111 117 124 130 137 143 150 156 163 169 176 176
17 wks 
Post 
TxP
Allowable Deviation 
(days)*
±7
±7 ±7
±7
±7
±7 ±7
±7
±7 ±7
±7
±7
±7 ±7
±7
±7
±7
    ±3
Fasting Visit*
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
X
X
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
Self-Harm Supplement 
Form*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Self-Harm Follow-up 
Form*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PROs
PGIS
X
X
X
SF-36, version 2 acute
X
X
X
IWQOL-Lite -CT
X
X
X
EQ-5D-5L
X
X
X
*Please see table below for corresponding additional information
Abbreviations: BP = blood pressure; Cr= creatinine; C-SSRS = Columbia-Suicide Severity Rating Scale; ED= early 
discontinuation of treatment; eGFR = estimated glomerular filtration rate; HbA1c = hemoglobin A1c; HR = heart rate; 
IWQOL-Lite-CT = Impact of Weight on Quality of Life-Lite Clinical trials; IWRS = interactive web-response system;
PGIS = Patient Global Impression of status for physical activity; PHQ-9 = Patient Health Questionnaire-9; 
PK = pharmacokinetics; SF-36 = Short-Form-36 Health Survey version 2, acute form; TxP = treatment period; 
TZP = tirzepatide

CONFIDENTIAL
Protocol I8F-MC-GPHK(b)
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Additional Information Regarding Activities Described in Schedule of Activities
Activity
Notes
Visit
Fasting Visit
On all office visits, study participants should be reminded to report to the site 
before taking study drug (s) 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. 
Visit 3
Baseline assessments must be completed before processing in the IWRS.
Visit 99
Visit 199
Participants wanting to discontinue the study before Week 72 will be asked to 
return for Visit 99 at 72 weeks ± 7 days after randomization 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 wanting to 
discontinue the study after Week 72 but before Week 176 will be asked to return 
for Visit 199 primarily for the body weight measurement and assessment of 
adverse events.  Refusal to attend should be documented.  

CONFIDENTIAL
Protocol I8F-MC-GPHK(b)
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ED
Participants who are unable or unwilling to continue the study treatment for any 
reason will perform an ED visit.  If the participant is discontinuing during an 
unscheduled visit or a scheduled visit, that visit should be performed as the ED
visit.  
Safety Follow-up Visits
Visit 801
Visit 802
For participants who discontinue or complete the study within the first 72 weeks, 
Visit 801 (safety follow-up visit) should be performed 4 weeks after the last visit 
during the 72-week treatment period. Participants with prediabetes continuing 
to Week 78 should not perform Visit 801.  For participants with prediabetes who
complete the 176 weeks or discontinue after Week 72, Visit 802 should be 
performed 17 weeks after the last visit during the additional 2-year treatment
period for participants with prediabetes at randomization.  
Allowable Deviation (days)
The visit date is determined in relation to the date of the randomization visit
(± the allowed visit window).
Medical History
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).
Weight
Weight measurements should be obtained per the instructions in Section 10.7.  
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.
Electrocardiogram
ECG measurements should be obtained per the instructions in Section 10.7.  
ECGs will be performed in triplicate at Weeks 0 and 36.  All other ECGs will be 
single measurements.  ECGs should be collected at least 30 minutes prior to 
collection of blood samples for laboratory testing, including PK samples.
Vital signs (3 sitting BP and HR)
Vital-sign measurements should be taken before obtaining an ECG tracing and 
before collection of blood samples for laboratory testing, per the instruction in 
Section 10.7.  
Hand out diary, instruct in use
All training should be repeated as needed to ensure participant compliance.
Review study participant diary and study-
drug compliance
Data from diary, as well as study drug compliance, should be reviewed.

CONFIDENTIAL
Protocol I8F-MC-GPHK(b)
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Lifestyle Program instructions
Counselling on diet and exercise, to be performed by a dietician or equivalent 
qualified delegate, to include calculation of individualized energy requirement 
and methods to change dietary composition and amount of physical activity.  
The Lifestyle Program Instruction may be delivered on a separate day from the 
rest of that visit’s study procedures but must occur within the visit window.  
Beginning at Week 8, the Lifestyle Program Instruction may be delivered by 
phone.
Review diet and exercise goals
All training should be repeated as needed to ensure participant compliance.  
Study personnel to provide reinforcement and encouragement for lifestyle 
modifications.
Injection training with Autoinjector 
demonstration device
All training should be repeated as needed to ensure participant compliance
Dispense study drug Visit 72
This applies only to those participants going into the additional 2-year treatment
period for participants with prediabetes at randomization.
Observe participant administer study drug
Participants should administer their first dose of study drug at the end of the
Visit 3, after other study procedures are completed
Serum pregnancy test
A serum pregnancy test will be performed at Visit 1 for women of childbearing 
potential only.
Urine pregnancy test
A urine pregnancy test must be performed at Visit 3 with the result available 
prior to randomization and first injection of study drug(s) for women of 
childbearing potential only. Additional pregnancy tests (beyond those required 
per the Schedule of Activities) 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
Follicle-stimulating hormone test performed at Visit 1 for postmenopausal
women at least 40 years of age with an intact uterus, not on hormone therapy,
and who have had spontaneous amenorrhea for more than 1 year without an 
alternative medical cause. 
2-hour oral glucose tolerance test (includes 
glucose, insulin, c-peptide)
2-hour OGTT testing should be omitted at visits following a protocol-defined 
diabetes diagnosis.

CONFIDENTIAL
Protocol I8F-MC-GPHK(b)
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Abbreviations:  ADA = antidrug antibody; BP = blood pressure; CKD-EPI = Chronic Kidney Disease-Epidemiology; Cr = creatinine; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ED = early discontinuation of treatment; eGFR = estimated 
glomerular filtration rate; HR = heart rate; IWRS = interactive web-response system; OGTT = oral glucose tolerance test; PHQ-9 = Patient 
Health Questionnaire-9; PK = pharmacokinetic; TSH = thyroid-stimulating hormone; TZP = tirzepatide.
Urinary albumin/creatinine ratio
Cystatin-c
Calcitonin
Hematology
Thyroid-stimulating hormone (TSH)
Screening visit assessment will be used to confirm eligibility.  If calcitonin 
results are not available, a final review of eligibility will occur at Visit 3 before 
randomization can proceed.
Chemistry panel (include Cr for eGFR 
calculation)
The CKD-EPI equation will be used by the central lab to estimate and report 
eGFR.
Immunogenicity (includes PK sample)
PK samples for immunogenicity must be taken prior to drug administration at 
these visits. In the event of systemic drug hypersensitivity reactions (immediate
or nonimmediate), additional blood samples will be collected including ADA,
PK, and exploratory biomarker samples.
TZP PK
PK samples will be collected at these visits at time windows of 1 to 24 hours, 24 
to 96 hours, or 120 to 168 hours post dose, as assignedby IWRS at 
randomization. Dependent on the time windows to which a participant is
assigned, they may be required to come to site for PK-specific visits.
PHQ-9
C-SSRS (Baseline/Screening Version)
C-SSRS (Since last Visit Version)
Self-Harm Supplement Form
The C-SSRS, Self-Harm Supplement Form and PHQ-9 should be administered 
after assessment of adverse events. For this study, the C-SSRS is adapted for 
the assessment of the ideation and behavior categories only.  The Intensity of 
Ideation and Lethality of Behavior sections are removed.
Self-Harm Follow-up Form
Self-Harm Follow-up Form is only required if triggered by the Self-Harm 
Supplement Form, per instructions in the form.

CONFIDENTIAL
Protocol I8F-MC-GPHK(b)
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29
2.
Introduction
Obesity is a chronic disease whose increasing prevalence is a public-health concern associated 
with rising incidence of type 2 diabetes mellitus (T2DM), increased risk for premature death and 
increased risk for some cancers (Allison et al. 2008; AMA 2013; Council on Science and Public 
Health 2013).  Although loss of 5% to 10% body weight has been shown to reduce complications 
related to obesity and improve quality of life (Mertens and Van Gaal 2000; Knowler et al. 2002;
Jensen et al. 2014; Li et al. 2014; Warkentin et al. 2014), lifestyle therapies fail to achieve 
sustainable weight loss in the majority of patients with obesity (Dombrowski et al. 2014).
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 system), 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® SmPc, 2015).
Preclinical data indicate that GIP exerts effects on appetite regulation and food intake, on 
adipose tissue and on peripheral energy metabolism. Although studies evaluating effects of GIP 
on body weight have yielded equivocal results, GIP receptor (GIPR) activation may play a role 
in body weight regulation and targeting both the GLP-1R and the GIPR simultaneously may
result in additive or synergistic effects of the 2 incretins on body weight (Coskun et al. 2018).
Tirzepatide is a 39-amino acid synthetic peptide with agonist activity at both the GIPR and GLP-
1R.  Its structure is based on the GIP sequence and includes a C20 fatty di-acid moiety (Coskun 
et al. 2018).  It is administered once weekly (QW) by subcutaneous (SC) injection. As a dual 
GIP/GLP-1R agonist, tirzepatide could exceed the efficacy of selective GLP-1R agonists by 
recruiting metabolically active tissues not targeted by selective GLP-1R agonists (for example, 
adipose tissue as indicated by the observation of increased energy utilization) (Baggio and 
Drucker 2007) and has the potential to reach higher efficacy in target tissues that express both 
GIPR and GLP1R. 
Study I8F-MC-GPHK (GPHK, SURMOUNT-1) is a Phase 3, multicenter, randomized, placebo-
controlled, double-blinded study, to investigate the safety and efficacy of 5-mg, 10-mg, and 15-
mg tirzepatide QW, compared with placebo, when used in conjunction with a reduced-calorie 
diet and increased physical activity for body weight management in participants who do not have 
T2DM and have obesity (BMI ≥30 kg/m2) or are overweight (BMI ≥27 kg/m2) with at least one 

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weight-related comorbid condition (for example, hypertension, dyslipidemia, or cardiovascular 
disease). All participants will be randomized to at least 72 weeks of treatment to study the 
effects on body weight reduction. Participants who have prediabetes at randomization will be 
studied for a total of 176 weeks of treatment to provide sufficient follow-up time to assess the 
effects of tirzepatide on progression to T2D and on long-term body weight changes.
2.2.
Background
There remains an unmet need in the pharmacologic treatment of obesity for drugs that are safe, 
efficacious and well tolerated.  With the exception of orlistat, a drug that blocks absorption of 
dietary fat, many current obesity treatments work primarily by stimulating regions of the brain to 
promote satiety.  Weight loss induced by GLP-1R agonists appears to be mediated through a 
combination of hormonal inputs to satiety centers (van Bloemendaal et al. 2014) and 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, Marso et al. 2016b, Gerstein et al. 2019).  Tirzepatide, which is both a GLP-1R and 
GIPR agonist, has been associated with significant dose-dependent weight loss at 5-, 10- and 15-
mg doses in Phase 2 studies (Frias et al. 2018).
Dose selection for obesity treatment has been informed by 3 clinical trials: a Phase 1 study, 
Study I8F-MC-GPGA (GPGA), and two Phase 2 studies, Study I8F-MC-GPGB (GPGB) and 
I8F-MC-GPGF (GPGF). 
Phase 1 Study GPGA was a combination of single ascending dose (SAD) and multiple ascending
dose (MAD) studies in healthy subjects and a multiple dose study in patients with T2DM.  A 
total of 142 participants (89 healthy subjects and 53 patients with T2DM) received at least 1 dose 
of treatment.  Doses of tirzepatide ranged from:

0.25 mg to 8 mg in the SAD (with maximum tolerated dose achieved at 5 mg) 

multiple doses from 0.5 mg to 4.5 mg QW and titrated doses up to 10 mg QW for 4 
weeks in healthy subjects

multiple doses at 0.5 mg and 5 mg QW and titrated up to 15 mg QW for 4 weeks in 
patients with T2DM in the MAD
The safety and tolerability and pharmacokinetic/pharmacodynamic (PK/PD) profiles of 
tirzepatide at doses and escalation regimens administered in this Phase 1 study supported further 
development of tirzepatide for QW dosing in patients with T2DM.
Phase 2 studies GPGB and GPGF studies provided initial safety, tolerability and efficacy data in 
the tirzepatide 1-to-15-mg dose range when used in treatment of patients with T2DM.  In the 
dose range of 5 to 15 mg, tirzepatide provided significantly greater reductions in hemoglobin 
A1c (HbA1c) and body weight compared with dulaglutide 1.5 mg QW.  The most common AEs, 
which were also dose dependent, were mild to moderate nausea, vomiting, and diarrhea.  Study 
GPGF showed that adjustments in the tirzepatide dose-escalation algorithm resulted in additional 
reductions in the frequency of GI AEs and reduced the frequency of treatment discontinuations
due to GI AEs. 

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2.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, serious AEs (SAEs) and 
reasonably anticipated AEs of tirzepatide are to be found in the Investigator’s Brochure (IB).

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3.
Objectives and Endpoints
Objectives
Endpoints
Primary
at 72 weeks, by dose analysis
To demonstrate that tirzepatide 10 mg QW is superior 
to placebo for:  

percent change in body weight AND

percentage of participants with ≥5% body 
weight reduction 
AND/OR
To demonstrate that tirzepatide 15 mg QW is superior 
to placebo for:

percent change in body weight AND 

percentage of participants with ≥5% body 
weight reduction  

mean percent change in body weight from 
randomization 

percentage of study participants who achieve ≥5% 
body weight reduction from randomization  
Key Secondary (controlled for Type I error)
at 20 weeks, pooled dose analysis
For pooled tirzepatide 10 mg and 15 mg QW doses, to 
demonstrate superiority to placebo for:
  

body weight 

mean change in body weight (kg) from 
randomization
Key Secondary (controlled for Type I error)
at 72 weeks, by dose analysis
To demonstrate that tirzepatide 5 mg QW is superior 
to placebo for:

percent change in body weight AND

percentage of participants with ≥5% body 
weight reduction

mean percent change in body weight from 
randomization 

percentage of study participants who achieve ≥5% 
body weight reduction from randomization

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Objectives
Endpoints
For tirzepatide 10 mg and/or 15 mg QW doses, to 
demonstrate superiority to placebo for:

body weight 

waist circumference

percentage of participants who achieve:
o
≥10% body weight reduction from 
randomization
o
≥15% body weight reduction from 
randomization
o
≥20% body weight reduction from 
randomization 

mean change in waist circumference (cm) from 
randomization
Key Secondary (controlled for Type I error)
at 72 weeks, pooled dose analysis
To demonstrate that pooled tirzepatide 10 mg and 15
mg QW is superior to placebo for:

patient-reported outcomes (SF-36v2 acute 
form Physical Functioning domain score)

mean change in SF-36v2 acute form Physical 
Functioning domain score from randomization
Key Secondary (controlled for Type I error)
at 72 weeks, pooled dose analysis
For tirzepatide QW (all doses combined), to 
demonstrate superiority to placebo for:

lipid parameters 

SBP

insulin

mean change from randomization in 
o
triglycerides (mg/dL)
o
non-HDL cholesterol (mg/dL)
o
HDL cholesterol (mg/dL)

mean change in SBP (mmHg) from 
randomization

mean change in fasting insulin (pmol/L) from 
randomization
Key Secondary (controlled for Type I error)
at 176 weeks, by dose analysis
For tirzepatide 10 mg and/or 15 mg QW doses, to 
demonstrate superiority to placebo (for participants 
with prediabetes at randomization) for:

body weight

mean percent change in body weight from 
randomization

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Objectives
Endpoints
Key Secondary (controlled for Type I error)
at 176 or 193 weeks, pooled dose analysis
For tirzepatide QW (all doses combined), to 
demonstrate superiority to placebo (for participants 
with prediabetes at randomization) in:

delayed progression to T2DM at 176 weeks

delayed progression to T2DM at 193 weeks

time to onset of T2DM during 176 weeks
treatment period

time to onset of T2DM during entire study 
including safety follow up period
Additional secondary at 72 weeks, by dose analysis
Efficacy
For tirzepatide 5 mg QW dose, to demonstrate 
superiority to placebo at 72 weeks for:

body weight

waist circumference

patient reported outcomes (SF-36v2 Physical 
Functioning)
For tirzepatide 5 mg, 10 mg, and/or 15 mg QW doses, 
to demonstrate superiority to placebo for:

percentage of participants who achieve
o
≥10% body weight reduction from 
randomization
o
≥15% body weight reduction from 
randomization

mean change in waist circumference (cm) from 
randomization

mean change in SF-36 v2 acute form Physical 
Functioning domain score from randomization

body weight  

mean change in body weight (kg) from 
randomization

mean change in BMI (kg/m2) from randomization

glycemic control

mean change in HbA1c (%, mmol/mol) from 
randomization

mean change in fasting glucose (mg/dL) from 
randomization

Patient-reported outcomes

Mean change in IWQOL-Lite-CT Physical 
Function composite score from randomization

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Objectives
Endpoints
Additional secondary at 72 weeks, pooled dose 
analysis
For tirzepatide QW (all doses combined), to 
demonstrate superiority to placebo at 72 weeks for 

DBP

mean change in DBP (mmHg) from 
randomization

lipid parameters 

mean change from randomization in:
o
LDL-cholesterol (mg/dL)
o
total cholesterol (mg/dL)
o
VLDL-cholesterol (mg/dL)
o
Free Fatty acids (mg/dL)
Additional secondary at 176 weeks, by dose analysis
For tirzepatide 5 mg QW dose, to demonstrate 
superiority to placebo (for participants with 
prediabetes at randomization) for:

body weight

mean percent change in body weight from 
randomization
For tirzepatide 5 mg, 10 mg, and/or 15 mg QW doses, 
to demonstrate superiority to placebo (for participants 
with prediabetes at randomization) for:

body weight

percentage of study participants who achieve ≥5% 
body weight reduction from randomization  
Additional Secondary at 176 weeks, pooled dose 
analysis
For tirzepatide QW (all doses combined), to 
demonstrate superiority to placebo (for participants 
with prediabetes at randomization) for:

Patient-reported outcomes

mean change in SF-36v2 acute form Physical 
Functioning domain score from randomization

mean change in IWQOL-Lite-CT Physical 
Function composite score from randomization

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Objectives
Endpoints
Additional Secondary
Pharmacokinetics/Pharmacodynamics

To characterize the population PK of 
tirzepatide and explore the relationships 
between the tirzepatide concentration and
efficacy, safety and tolerability measures 

population PK and PD parameters
Abbreviations: AUC = area under the curve; BMI = body mass index; DBP = diastolic blood pressure; 
HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; IWQOL-Lite-CT = Impact of Weight on Quality of 
Life-Lite-Clinical Trials Version; LDL = low-density lipoprotein; PD = pharmacodynamics; 
PK = pharmacokinetics; QW = once-weekly; SAP = statistical analysis plan; SBP = systolic blood pressure; 
SF-36v2 = Short Form survey-36 version 2, T2DM = type 2 diabetes mellitus; VLDL = very low-density 
lipoprotein.

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4.
Study Design
4.1.
Overall Design
Study GPHK (SURMOUNT-1) is a Phase 3, multicenter, randomized, double-blinded, placebo-
controlled study that will investigate the effects of treatment with tirzepatide 5 mg, 10 mg, and 
15 mg QW compared with placebo on weight loss in study participants without T2DM who are 
either obese (BMI ≥30 kg/m2) or overweight (≥27 kg/m2 ) with at least one weight-related 
comorbid condition (for example, hypertension, dyslipidemia, or cardiovascular disease).  The 
coprimary endpoints will be mean percent change in weight and percentage of participants 
reaching ≥5% total body weight loss, measured from randomization to Week 72.
Study participants will be randomized in a 1:1:1:1 ratio (tirzepatide 5 mg QW, tirzepatide 10 mg 
QW, tirzepatide 15 mg QW, and placebo).  An upper limit of 70% enrollment of women will be 
used to ensure a sufficiently large sample of men.
All participants will undergo a 2-week screening period and a 72-week treatment period
including a 20-week dose escalation.  Participants who have prediabetes will be studied for a 
total of 176 weeks of treatment to provide sufficient follow-up time to detect potential 
differences in progression to T2DM. 
The safety follow-up period will be 4 weeks (for participants completing or discontinuing study 
drug during the first 72 weeks) or 17 weeks (for participants completing or discontinuing study 
drug between Weeks 72 through 176).
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 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 and classify glycemic 
status (Section 4.1.2.1).  The participant must sign the informed consent form (ICF) before the 
study procedures are performed, as outlined in the Schedule of Activities, 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 have 
no glycemic assessments suggestive of T2DM (Section 4.1.2.1) and meet all other applicable 

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inclusion criteria and none of the applicable exclusion criteria (Sections 5.1 and 5.2) at Visit 1 
will continue to Visit 2. 
Visit 2
Participants should arrive to the clinic in the fasting state (approximately 8 hours without eating, 
drinking [except water], or any significant physical activity).  At Visit 2, the screening laboratory 
results will be reviewed.  For those participants without glycemic evidence of T2DM 
(Section 4.1.2.1), and meeting all other eligibility requirements, a 2-hour oral glucose tolerance 
test (OGTT) will be performed.  The 2-hour OGTT consists of assessment of glucose, insulin, 
and c-peptide at time 0, 30, 60, 90, and 120 minutes (Sections 4.1.2.2 and 10.7). If calcitonin 
results are not available, Visit 2 can proceed. A final review of eligibility will occur at Visit 3 
before randomization can proceed.
The mental health questionnaires (Columbia-Suicide Severity Rating Scale [C-SSRS] and Self-
Harm Form) should be completed after the assessment for AEs.
4.1.1.2.2. Treatment Period
Randomization (Visit 3)
At Visit 3, eligible participants will perform all required baseline study procedures (including the 
collection of all baseline laboratory measures and questionnaires) prior to randomization and 
prior to taking the first dose of study drug.  Participants should arrive to the clinic in the fasting 
state (after a period of approximately 8 hours without eating, drinking [except water], or any 
significant physical activity). Patient-reported outcomes (PROs) questionnaires should be 
administered as early as possible, as per Suggested Visit Structure (Section 10.8). Preferred 
administration order is: Patient Global Impression of status for physical activity (PGIS), Short 
Form survey-36 version 2 (SF-36v2) acute form, Impact of Weight on Quality of Life-Lite-
Clinical Trials Version (IWQOL-Lite-CT), and EQ-5D-5L. The mental health questionnaires 
(Patient Health Questionnaire-9 [PHQ-9], C-SSRS, and Self-Harm Form) should be completed 
after the assessment for AEs.
Participants will receive an initial consultation with a qualified dietician, according to local 
standards, to set lifestyle goals for caloric intake and physical activity (Sections 5.3.1 and 5.3.2).  
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 treatment period including a 20-week dose escalation.  
Participants will be provided diaries and be trained to record key study information, as 
appropriate.  
Treatment Period (End of Visit 3 to Visit 21):
During the treatment period, office visits will occur monthly through 24 weeks and then every 12 
weeks thereafter, to 72 weeks. The participant should be fasting for all office visits.  Telephone 
visits will occur at 4-week intervals between the office visits starting at Week 28.  

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Office visit procedures should be conducted according to the Schedule of Activities (Section 
1.3), and will include:

weight, waist circumference, and vital signs measurements 

review of participant diary information (to include reinforcement and compliance 
assessments for study drug administration and lifestyle goals)

administration of questionnaires 

laboratory testing 

drug dispensing

collect AEs, product complaints and concomitant medications  
Mental Health Questionnaires should be completed after the assessment of AEs.  
Dietician consultations continue at Weeks 4, 8, 12, and then every 12 weeks thereafter, to 
Week 72.  Study drug and injection supplies will be returned per the Schedule of Activities 
(Section 1.3) and according to local requirements.  New supplies will be dispensed as needed.
Study drug dose escalation is double-blinded and will be managed via the interactive web-
response system (IWRS).  The starting dose is 2.5 mg QW (or matching placebo) for 4 weeks, 
then the dose is increased by 2.5 mg (or matching placebo) every 4 weeks: 2.5 to 5 mg for those 
randomized to 5 mg, 2.5 to 5 to 7.5 to 10 mg for those randomized to 10 mg, and continuing to 
12.5 to 15 mg for those randomized to 15 mg.  The dose is then maintained up to 72 weeks. 
At each of the 8 scheduled telephone visits, procedures will include:

reinforcement and compliance assessments for study drug administration and lifestyle 
goals,

listing of concomitant medications

AE and Product Complaints (PCs) assessment (see Schedule of Activities
Section 1.3.1)

administration of questionnaires  
Participants should be instructed to contact the investigative site for assistance as soon as 
possible if they experience any difficulties administering their study medication.  Participants
should also be advised about the appropriate course of action in the event that study drug is not 
taken at the required time (late/missing doses).
Study participants will be permitted to use concomitant medications that they require during the 
study, except certain excluded medications (see Section 5.2) that may interfere with the 
assessment of efficacy and safety characteristics of the study treatments.  
For those participants without glycemic evidence of T2DM (Section 4.1.2.1), a 2-hour oral 
OGTT will be performed at Visit 21.  
Visit 99
Visit 99 is only applicable to participants who discontinue the study treatment prematurely 
(before Week 72).  Participants will be asked to return for Visit 99 at 72 weeks ± 7 days after 

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randomization.  This visit is critical to ensure complete data collection for the primary weight-
loss endpoint.  
Participants should attend this visit in the fasting state.  Procedures to be completed are

measurement of weight 

listing of concomitant medications

assessment of AEs

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.
4.1.1.2.3. Additional 2-Year Treatment Period for Participants with Prediabetes at 
Randomization (Visits 101 through 116)
Participants classified as having prediabetes at randomization and who remain on study drug 
through Week 72, will continue follow-up for an additional 104 weeks (total study duration 176 
weeks). Subsequent visits will occur approximately every 1.5 months, alternating between 
telephone and office visits. 
Office visit procedures should be conducted according to the Schedule of Activities
(Section 1.3), and will include:

weight, waist circumference, and vital signs measurements 

review of participant diary information (to include reinforcement and compliance 
assessments for drug administration and lifestyle goals)

administration of questionnaires 

laboratory testing

drug dispensing

collection of AEs, product complaints, and concomitant medications
Patient-reported outcomes questionnaires should be administered as early as possible, as per 
Suggested Visit Structure (Section 10.8). Mental Health Questionnaires should be completed 
after the assessment of AEs.  
Dietician consultations continue approximately every 3 months after Visit 21 to Visit 116.  At 
Visits 108 and 116, participants will undergo 2 hour OGTTs, unless diabetes had been diagnosed
prior to the visits (Sections 4.1.2.2 and 10.7).  Study drug and injection supplies will be returned 
per the Schedule of Activities (Section 1.3) and according to local requirements.  New supplies 
will be dispensed as needed.
At each of the 8 scheduled telephone visits, procedures will include:

reinforcement and compliance assessments for study drug administration and lifestyle 
goals

listing of concomitant medications

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
AE and PC assessment (see Schedule of Activities [Section 1.3]) 

administration of questionnaires
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).
Visit 199
Visit 199 is only applicable to participants who discontinue the study treatment prematurely 
(between Week 72 and Week 176).  Participants will be asked to return for Visit 199 at 176 
weeks ± 7 days after randomization.  This visit is critical to ensure complete data collection for 
the weight-loss and progression-to-diabetes endpoints.  
Participants should attend this visit in the fasting state.  Procedures to be completed are:

measurement of weight

measurement of waist circumference

listing of concomitant medications

assessment of AEs

completion of the mental health questionnaires (after the AE assessment)

2-hour OGTT
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 treatment for any reason will perform an
early discontinuation of treatment (ED) visit.  If the participant is discontinuing during an 
unscheduled visit, that visit should be performed as the ED visit.  If the participant is 
discontinuing during a scheduled visit, that visit should be performed as an ED visit.  Procedures 
should be completed according to the Schedule of Activities (Section 1.3).  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 for AEs (see Section 7.2). 
4.1.1.2.5. Safety Follow-up Period
Visit 801 or Visit 802
All participants are required to complete a safety follow-up visit (Visit 801 or Visit 802), 
according to the Schedule of Activities (Section 1.3). Participants discontinuing the study early 
and performing an ED visit will also be asked to perform the safety follow-up visit. During the 
safety follow-up period, participants will not receive study drug.  Participants are also required to 
return any remaining study diaries to the study site at the end of this period.

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For participants who discontinue or complete the study within the first 72 weeks, Visit 801 
(safety follow-up visit) should be performed 4 weeks after the last treatment visit (Visit 21 or 99) 
or 4 weeks after the ED visit for those who decline to return for Visit 99.  Participants with 
prediabetes continuing to Week 78 should not perform Visit 801.   
For those participants without glycemic evidence of T2DM (Section 4.1.2.1), a 2-hour oral 
OGTT will be performed at Visit 802.  
4.1.2.
Study Procedures
Participants will perform study procedures listed in the Schedule of Activities (Section 1.3).
Participants will be permitted to use concomitant medications that they require during the study, 
except certain medications that may interfere with the assessment of efficacy and safety 
characteristics of the study treatments (Section 5.2).
Study governance considerations are described in detail in Section 10.1 (Appendix 1).
4.1.2.1.
Definition of Prediabetes
The duration of treatment in Study GPHK (SURMOUNT-1) is determined by glycemic status at 
randomization, categorized into those with prediabetes or normoglycemia (participants with 
T2DM are excluded), as defined by the 2019 American Diabetes Association Standards of 
Medical Care in Diabetes (American Diabetes Association 2019b).  The following populations 
are defined:
Normoglycemia
Prediabetes
Diabetes
Fasting glucose
Obtained alone or at time = 0 
during an OGTT
<100 mg/dL
(<5.6 mmol/L)
100-125 mg/dL
(5.6-6.9 mmol/L)
≥126 mg/dL
(≥7.0 mmol/L)
2H glucose
Obtained at time = 120 min 
during an OGTT
<140 mg/dL
(<7.8 mmol/L)
140-mg-199 mg/dL
(7.8-11.0 mmol/L)
≥200 mg/dL
(≥11.1 mmol/L)
HbA1c
<5.7%
(<39 mmol/mol)
5.7%-6.4%
(39-47 mmol/mol)
≥6.5%
(≥48 mmol/mol)
Abbreviations:  H = hour; HbA1c = hemoglobin A1c; OGTT = 2-hour oral glucose tolerance test.
Screening to determine randomization glycemic status will occur in 2 visits:
Screening Visit 1
Participants will have a fasting glucose (FG) and HbA1c test.  Results of these tests determine 
eligibility to proceed to Screening Visit 2.

FG ≥126 mg/dL (7.0 mmol/L) OR HbA1c ≥6.5% (48 mmol/mol) suggests DM.  
These participants are excluded from the study and should be referred to their 
primary care physician for further work-up to confirm the diagnosis.  

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
All participants otherwise eligible and without FG or HbA1c values suggestive of 
diabetes will proceed to Screening Visit 2
Screening Visit 2
All participants attending Screening Visit 2 will undergo a 2-hour OGTT test.  These results, in 
combination with those obtained from Screening Visit 1, will be used to determine study 
eligibility and randomization glycemic status.

2-hour OGTT results:  FG ≥126 mg/dL (≥7.0 mmol/L) OR 2-hour OGTT ≥200 
mg/dL (≥11.1 mmol/L) suggests diabetes mellitus.  These participants are excluded
from the study and should be referred to their primary care physician for further 
work-up to confirm the diagnosis.  
Glycemic Classification
All participants without laboratory tests suggestive of diabetes will be classified as having either 
normoglycemia or prediabetes.  In keeping with American Diabetes Association guidelines
(American Diabetes Association 2019b), at least 2 abnormal tests are required to diagnose 
prediabetes.  For example:

Both 0 AND 2-hour values during the 2-hour OGTT values are in the prediabetes
range.

FG at Screening Visit 1 AND Visit 2 are in the prediabetes range.

FG at Screening Visit 1 AND 2-hour values during 2-hour OGTT are in the 
prediabetes range.

HbA1c AND 1 of either the FG or 2-hour OGTT values are in the prediabetes range.
4.1.2.2.
Oral Glucose Tolerance Test
Participants should attend visits requiring a 2-hour OGTT in the fasting state.  Samples will be 
collected at 0, 30, 60, 90, and 120 minutes during the 2-hour OGTT, unless the OGTT is 
repeated to confirm the diagnosis of diabetes.  For glycemic classification, the values at time = 0 
min (FG) and 120 minutes (2-hour OGTT) will be used. If a 2-hour OGTT is repeated to confirm
the diagnosis of diabetes (see Section 4.1.2.3), only samples at 0 and 120 minutes for glucose 
measurement will be collected.
Two-hour OGTTs should be performed per the Schedule of Activities (Section 1.3) and as 
described in Section 10.7, until such time as a protocol-defined diagnosis of diabetes is 
confirmed (see Section 4.1.2.3).  Two-hour OGTT testing should be omitted at visits following a 
protocol-defined diabetes diagnosis.
4.1.2.3.
Definition and Management of Incident Diabetes
Definition of incident diabetes
Incident diabetes is defined when any 1 of the following occur after randomization (American 
Diabetes Association 2019b):

unequivocal hyperglycemia (random glucose ≥200 mg/dL) with signs or symptoms of 
hyperglycemia

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
any 2 of the following criteria are observed at the same visit, or 1 abnormal value is 
observed and subsequently confirmed:
o
HbA1c ≥6.5% (48 mmol/mol)
o
FG or 0-hour serum glucose from 2-hour OGTT ≥126 mg/dL (7.0 mmol/L)
o
2-hour glucose ≥200 mg/dL (11.1 mmol/L) by a 2-hour OGTT

initiation of any medication for the treatment of diabetes
Confirmation of diabetes diagnosis 
In the event 1 abnormal value is observed (HbA1c ≥6.5% [48 mmol/mol]) OR fasting glucose 
(or 0-hour serum glucose from 2-hour OGTT) ≥126 mg/dL (7.0 mmol/L) OR 2-hour glucose 
from 2-hour OGTT ≥200 mg/dL (11.1 mmol/L)* after randomization, the abnormal test should 
be repeated within 4 weeks to confirm diagnosis of diabetes and to ensure that diabetes 
management is initiated without delay.
*If the abnormal value observed is 2-hour glucose from the OGTT ≥200 mg/dL (11.1 mmol/L),
the 2-hour OGTT should be repeated within 4 weeks (only samples at 0 and 120 minutes for 
glucose measurement will be collected).
The diagnosis of diabetes is confirmed if any of the following occur:
•
HbA1c ≥6.5% (48 mmol/mol) is observed at 2 measurements any time during the study.
•
2-hour glucose ≥200 mg/dL (11.1 mmol/L) during an OGTT is observed at 2
measurements any time during the study.
•
FG value ≥126 mg/dL (7.0 mmol/L) is observed at a consecutive FG measurement (either 
at a scheduled or an unscheduled visit) following an isolated FG (or 0-hour serum 
glucose from 2-hour OGTT) value ≥126 mg/dL (7.0 mmol/L).
o
If diabetes diagnosis has not been confirmed at the consecutive FG measurement, 
another FG (or 0-hour serum glucose result from 2-hour OGTT) result ≥126 
mg/dL (7.0 mmol/L) observed during the study will be considered as a new 
finding requiring confirmation.
Note: Once diabetes has been confirmed, repeating any future abnormal test within 4 weeks is 
no longer required.
Recording of incident diabetes events
•
Diabetes diagnosis and the onset date as assessed by investigator will be recorded in the 
AE eCRF and the dedicated endpoint eCRF. 
•
If the diagnosis of diabetes is based on laboratory results, the date of the first abnormal 
HbA1c or glucose value within the diabetes range should be indicated as the date of 
diagnosis, unless, in the investigator’s opinion, a different date is more appropriate. If the 
diagnosis is based on initiation of any medication for the treatment of diabetes, the 
investigator should indicate the most probable date of diagnosis in the eCRFs.

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•
All reported or suspected cases of incident diabetes will be adjudicated by an independent 
clinical endpoint committee (adjudication committee). 
•
Decisions of the adjudication committee regarding diabetes diagnosis and the onset date 
will be recorded in the dedicated adjudication eCRF.
Management of incident diabetes
Participants who develop diabetes during the study will be

provided and trained to use a glucometer 

educated on the signs and symptoms of hypoglycemia and its treatment, and 

provided a diary to record hypoglycemic episodes per Section 10.3.1.1.  
Participants will be referred to their usual care provider and provided with a letter showing the 
study results indicative of diabetes.  The decision to further evaluate, to initiate 
antihyperglycemic therapy, and the choice of antihyperglycemic medication will be at the 
discretion of the participant’s usual care provider, with the exception of use of dipeptidyl-
peptidase-4 (DPP-4) inhibitors and open-label GLP-1R agonists, which are prohibited in the
study.  Monitoring for hypoglycemia includes capture of events as defined in Section 10.3
(Appendix 3).
4.2.
Scientific Rationale for Study Design
Tirzepatide is a 39-amino acid synthetic peptide with agonist activity at both the GIPR and GLP-
1R.  Its structure is based on the GIP sequence and includes a C20 fatty di-acid moiety (Coskun 
et al. 2018).  It is administered QW by SC injection. 
As a dual GIP/GLP-1R agonist, tirzepatide could exceed the efficacy of selective GLP-1R 
agonists by recruiting metabolically active tissues not targeted by selective GLP-1R agonists (for 
example, adipose tissue as indicated by the observation of increased energy utilization) (Baggio 
and Drucker 2007) and has the potential to reach higher efficacy in target tissues, such as insulin-
producing pancreatic beta cells that express both GIPR and GLP-1R, before reaching its 
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.  Although GI AEs were more common at 
the 15-mg arm of tirzepatide, this dose demonstrated the highest efficacy in terms of weight loss. 
This suggests that tirzepatide has the potential to become a medication for chronic weight 
management. An optimized dose escalation regimen, proposed in the Study GPHK
(SURMOUNT-1) to improve tolerability (and supported by a dose-escalation algorithm from 
study GPGF), should enable a use of higher doses to maximize effects on body weight. Study 
GPHK (SURMOUNT-1) is designed to determine the comparative benefits and risks of 

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tirzepatide 5 mg, 10 mg or 15 mg QW versus placebo in participants who have obesity or are 
overweight.  A double-blind design was selected to minimize participant and investigator bias in 
assessments for efficacy, safety, and study drug tolerability.
A placebo comparator was selected for this trial in accordance with regulatory guidance (FDA 
2007; EMA 2016).  In addition, all participants, regardless of treatment assignment, will receive 
lifestyle modification counselling consistent with current guidelines for weight management 
(Jensen et al. 2013).  Specifically, participants will consult with a dietician, or equivalent 
qualified delegate, throughout the study to achieve at least a 500 kcal/day energy deficit through 
a combination of caloric restriction and increased physical activity (Section 5.3.1).  The planned 
duration of treatment for the primary endpoint at 72 weeks allows for at least a 52-week 
treatment period at the dose achieved following dose escalation to either 5, 10, or 15 mg. This 
duration is considered appropriate to assess the full effects and benefit/risk of each maintenance 
dose of tirzepatide compared with placebo on body weight and is consistent with regulatory 
guidelines (FDA 2007; EMA 2016). 
The effects of drug cessation will be assessed in the 4-week and in the 12-week safety follow-
up/observational periods
Another objective of the study is to evaluate the effect of tirzepatide on the risk of new-onset 
diabetes. Obesity is associated with an increased risk of developing T2DM and diabetes 
prevention is of a great importance in obese subjects to protect them from complications of the 
disease. Several studies have shown that interventions leading to weight loss may help prevent 
diabetes (Adams et al. 2017, le Roux et al. 2017).
To obtain additional information regarding the rate of conversion to diabetes on tirzepatide, 
participants with prediabetes diagnosed at the beginning of the study (being at increased risk of 
diabetes), will be treated and observed for an additional 2 years. Based on available literature, 
the 3 years of treatment with tirzepatide should be sufficient to demonstrate the risk reduction of 
developing T2DM compared to placebo. This additional treatment period would also permit 
collecting data on the durability of weight changes with long-term therapy and safety of long-
term tirzepatide treatment.
To minimize the potential confounding effect of changes to concomitant medications, 
participants will be permitted to use concomitant medications that do not interfere with the 
assessment of efficacy or safety characteristics of the study treatments.
4.3.
Justification for Dose
Tirzepatide doses of 5 mg, 10 mg, and 15 mg QW will be evaluated in this study. These doses 
and associated escalation schemes were selected based on assessment of safety, efficacy (weight 
loss), and GI tolerability data, followed by exposure-response modeling of data in patients in 
Phase 1 and 2 studies that predicted weight loss in obese and overweight patients without T2DM.
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 
the last scheduled procedure shown in the Schedule of Activities (Section 1.3.1 or 1.3.2 based on 
randomization glycemic status), 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

≥30 kg/m2 or

≥27 kg/m2 and previously diagnosed with at least one of the following weight 
related comorbidities:
o
hypertension: treated or with systolic blood pressure (SBP) ≥130 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 Class I-III heart 
failure)
2. Have a history of at least one self-reported unsuccessful dietary effort to lose 
body weight
3. In the investigator’s opinion, are well-motivated, capable, and willing to 

learn how to self-inject study drug, as required for this protocol (visually impaired 
persons who are not able to perform the injections must have the assistance of a 
sighted individual trained to inject study drug; persons with physical limitations who 
are not able to perform the injections must have the assistance of an individual trained 
to inject study drug) 

inject study drug (or receive an injection from a trained individual if visually 
impaired or with physical limitations)

follow study procedures for the duration of the study, including, but not limited to: 
follow lifestyle advice (for example, dietary restrictions and exercise plan), maintain 
a study diary, and complete required questionnaires

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Participant Characteristics
4. Are 18 years or older
a.
male participants:

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), congenital anomaly such as
Mullerian agenesis 
o
postmenopausal, defined as either

a woman at least 40 years of age with an intact uterus, not 
on hormone therapy, who has cessation of menses for at 
least 1 year without an alternative medical cause, AND a 
follicle-stimulating hormone ≥40 mIU/mL; women in this 
category must test negative in pregnancy test prior to study 
entry
or

a woman 55 or older not on hormone therapy, who has had 
at least 12 months of spontaneous amenorrhea 
or

a woman at least 55 years of age with a diagnosis of 
menopause prior to starting hormone replacement therapy

Female participants of child-bearing potential (not surgically sterilized and 
between menarche and 1-year postmenopausal) must:
o
test negative for pregnancy at Visit 1 based on a serum pregnancy 
test
and
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 and for 30 days thereafter 
o
not be breastfeeding
Informed Consent
5.
Have given written informed consent to participate in this study in accordance 
with local regulations and the ethical review board (ERB) governing the study 
site 
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:

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Medical Conditions
Diabetes-related
6. Have type 1 diabetes mellitus (T1DM) or T2DM, history of ketoacidosis, or hyperosmolar 
state/coma
7. Have laboratory evidence diagnostic of diabetes mellitus during screening, including 1 or 
more of: HbA1c ≥6.5% (≥48 mmol/mol), FG ≥126 mg/dL (≥7.0 mmol/L), random glucose 
or 2-hour glucose measurement from a 2-hour OGTT ≥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 (for example, mucosal ablation, gastric artery 
embolization, intragastric balloon and duodenal-jejunal bypass sleeve)
Other medical
11. Have renal impairment measured as estimated glomerular filtration rate (eGFR) 
<30 mL/min/1.73 m2, calculated by Chronic Kidney Disease-Epidemiology as determined 
by central laboratory during screening
12. Have a known clinically significant gastric emptying abnormality (for example, severe 
diabetic gastroparesis or gastric outlet obstruction) or chronically take drugs that directly 
affect GI motility
13. Have had a history of chronic or acute pancreatitis
14. Have thyroid-stimulating hormone (TSH) outside of the range of 0.4 to 6.0 mIU/L at 
screening visit
Note: Patients receiving treatment for hypothyroidism may be included, provided their 
thyroid hormone replacement dose has been stable for at least 3 months.
Note: TSH values above the normal range can, in some patients, suggest subclinical 
hypothyroidism.  If, in the investigator’s opinion, the participant has subclinical 
hypothyroidism and may require initiation of thyroid hormone replacement during the 
course of the study, the patient should be excluded from the study. 
15. Have obesity induced by other endocrinologic disorders (for example, Cushing Syndrome) 
or diagnosed monogenetic or syndromic forms of obesity (for example, Melanocortin 4 
Receptor deficiency or Prader Willi Syndrome)
16. Have a history of significant active or unstable Major Depressive Disorder (MDD) or other 
severe psychiatric disorder (for example, schizophrenia, bipolar disorder, or other serious 
mood or anxiety disorder) within the last 2 years

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Note: Patients with MDD or generalized anxiety disorder whose disease state is considered 
stable and expected to remain stable throughout the course of the study, in the opinion of the 
investigator, may be considered for inclusion if they are not on excluded medications
17. Have any lifetime history of a suicide attempt
18. Have a Patient Health Questionnaire-9 (PHQ-9) score of 15 or more at Visit 1 or 3, prior to 
randomization
19. On the C-SSRS at Visits 1, 2, or 3, prior to randomization: 

a “yes” answer to either Question 4 (Active Suicidal Ideation with Some Intent to 
Act, Without Specific Plan) 
or

a “yes” answer to Question 5 (Active Suicidal Ideation with Specific Plan and 
Intent) on the "Suicidal Ideation" portion of the C-SSRS 
or 

a “yes” answer to any of the suicide-related behaviors (Actual Attempt, Interrupted 
Attempt, Aborted Attempt, Preparatory Act or Behavior) on the "Suicidal Behavior" 
portion of the C-SSRS
and

the ideation or behavior occurred within the past month
20. Have uncontrolled hypertension (SBP above or equal to 160 mmHg and/or diastolic blood 
pressure above or equal to 100 mmHg)
21. Have any of the following cardiovascular conditions within 3 months prior to 
randomization: acute myocardial infarction (MI), cerebrovascular accident (stroke), 
unstable angina, or hospitalization due to congestive heart failure (CHF)
22. Have NYHA Functional Classification IV CHF
23. Have acute or chronic hepatitis, signs and symptoms of any other liver disease other than 
nonalcoholic fatty liver disease, or any of the following, as determined by the central 
laboratory during screening:

alanine aminotransferase (ALT) level >3.0X the upper limit of normal 
(ULN) for the reference range
or

alkaline phosphatase (ALP) level >1.5X the ULN for the reference range
or

total bilirubin (TBL) level >1.2X the ULN for the reference range
(except for cases of known Gilbert’s Syndrome)
Note: Participants with nonalcoholic fatty liver disease are eligible to participate in this trial
if their ALT level is ≤3.0X the ULN for the reference range  
24. Have a calcitonin level (at Visit 1) of:

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o
≥20 ng/L at Visit 1, if eGFR ≥60 mL/min/1.73 m2
o
≥35 ng/L at Visit 1, if eGFR <60 mL/min/1.73 m2
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 within 3 months of enrollment and unwillingness to 
abstain from marijuana use during the trial. Participants should also refrain from use of 
cannabidiol oil for the duration of the study 
30. Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or 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, intraocular, intranasal, intra-
articular, or inhaled preparations) or have evidence of a significant, active autoimmune 
abnormality (for example, lupus or rheumatoid arthritis) that has required (within the last 
3 months) or is likely to require, in the opinion of the investigator, concurrent treatment with 
systemic glucocorticoids (excluding topical, intraocular, intranasal, intra-articular or inhaled 
preparations) in the next 12 months
33. Have current or history of (within 3 months prior to randomization) treatment with 
medications that may cause significant weight gain, including but not limited to: tricyclic 
antidepressants, atypical antipsychotic and mood stabilizers for example:

imipramine

amitriptyline

mirtazapine

paroxetine

phenelzine

chlorpromazine

thioridazine

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
clozapine

olanzapine

valproic acid and its derivatives

lithium
Note: Selective serotonin reuptake inhibitors other than paroxetine are permitted.
34. Have taken within 3 months prior to randomization, medications (prescribed or over-the-
counter) or alternative remedies intended to promote weight loss.  Examples include, but are 
not limited to

Saxenda® (liraglutide 3.0 mg)

Xenical®/Alli® (orlistat)

Meridia® (sibutramine)

Acutrim® (phenylpropanolamine)

Sanorex® (mazindol)

Adipex® (phentermine)

BELVIQ® (lorcaserin)

Qsymia® (phentermine/topiramate combination)

Contrave® (naltrexone/bupropion)
Note: Use of metformin or any other glucose-lowering medication, whether prescribed 
for polycystic ovary syndrome or diabetes prevention is not permitted.
35. Have started implantable or injectable contraceptives (such as Depo-Provera®) within 18 
months prior to screening
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
Other Exclusions
38. Are investigator site personnel directly affiliated with this study and/or their immediate 
family. Immediate family is defined as a spouse, legal partner, parent, child, or sibling, 
whether biological or legally adopted.
39. Are Eli Lilly and Company (Lilly) employees
5.3.
Lifestyle Considerations
Per the Schedule of Activities (Section 1.3), participants will consult with a dietician, or 
equivalent qualified delegate, according to local standards, to receive lifestyle management 
counseling at Weeks 0, 4, 8 and 12 during dose escalation and then at Week 24 and every 12 

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weeks thereafter through 72 weeks.  Participants in the additional 2-year treatment period for 
participants with prediabetes at randomization will continue to receive lifestyle management 
counseling at 3-month intervals as defined in the Schedule of Activities (Section 1.3).
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
At Visit 3 and subsequent visits, study participants will receive diet counselling by a 
dietician/nutritionist, or equivalent qualified delegate, according to local standard. Dietary 
counseling will consist of advice on healthy food choices and focus on calorie restriction using a 
hypocaloric diet with macronutrient composition of:

maximum 30% of energy from fat 

approximately 20% of energy from protein

approximately 50% of energy from carbohydrates

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 a 3-day diet and exercise diary be completed 
prior to each counseling visit. During each visit, the participant’s diet is reviewed and advice to 
maximize adherence is provided if needed.
The hypocaloric diet is continued after randomization and throughout the treatment period. If a 
BMI ≤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 (TEE) is calculated by multiplying the estimated Basal Metabolic Rate 
(BMR) (see table below) with a Physical Activity Level 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

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>60 years
9.082 X actual weight in kg + 658.5
Abbreviations:  BMR = basal metabolic rate; WHO = World Health Organization.
*Revised WHO equations (adapted from: FAO/WHO/UNU 2004).
5.3.2.
Physical Activity
At Visit 3 and all subsequent visits, participants will be advised to increase their physical activity 
to at least 150 minutes per week.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to the study intervention. A minimal set of screen-failure 
information should be collected to ensure transparent reporting of screen-failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.

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6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol.
6.1.
Study Interventions Administered
ARM Name
Tirzepatide 5 mg
Tirzepatide 10 mg
Tirzepatide 15 mg
Placebo
Dose
5 mg QW
10 mg QW
15 mg QW
N/A
Route of 
Administration
SC
SC
SC
SC
Sourcing
Provided centrally by the Sponsor and dispensed via IWRS
Packaging and 
Labeling
Study 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 service; N/A = not available; 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 subcutaneously 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 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 medical-device incidents, including those resulting 
from malfunctions of the device, must be detected, documented, and reported by the investigator 
throughout the study (see Section 10.6).

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6.2.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.

Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply study intervention. 

All study intervention must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff.  

The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention (includes study drug and autoinjector or single-dose 
pen) accountability, reconciliation, and record maintenance (for example, receipt, 
reconciliation, and final disposition of records).

Study site staff must regularly assess whether the participant is correctly administering 
the assigned study drug and storing study drug according to the provided instructions.
6.3.
Measures to Minimize Bias:  Randomization and Blinding
This is a double-blind study.
Participants who meet all criteria for enrollment will be randomized to one of the study treatment 
groups at Visit 3.  Assignment to treatment groups will be determined by a computer-generated,
random sequence using an IWRS.  Participants will be randomized in a 1:1:1:1 ratio to receive
tirzepatide 5 mg, tirzepatide 10 mg, tirzepatide 15 mg, or placebo.  
The randomization will be stratified by prediabetes status, country, and sex (female, male). 
Investigators, site staff, clinical monitors and participants will remain blinded to the treatment 
assignments until the study is complete. To preserve the blinding of the study, a limited number 
of individuals from the Sponsor will be unblinded to treatment assignments as needed for the 
interim analysis and for the primary endpoint (Week 72) database lock (see Section 9.5).
Emergency unblinding may be performed through the IWRS.  This option may be used ONLY if 
the participant’s wellbeing 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 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 intervention will be assessed at each visit. Compliance will be 
assessed by direct questioning and counting of unused study drug and/or empty cartons returned.
Study drug compliance will be determined by the following: 

Study drug administration data will be recorded by the participant and reviewed 
by the investigator at each study visit.

The participants will be instructed to return any unused study drug and/or empty 
cartons at the next visit to the study site for the purpose of performing drug 
accountability.
Treatment compliance for each visit interval is defined as taking at least 75% of the required 
doses of study drug.  Similarly, a participant will be considered significantly noncompliant if he 
or she is judged by the investigator to have intentionally or repeatedly taken more than the 
prescribed amount of medication (more than 125%).  
In addition to the assessment of a participant’s compliance with study drug administration, other 
aspects of compliance with the study treatments will be assessed at each visit based on the 
participant’s adherence to the visit schedule, completion of study diaries, and any other 
parameters the investigator considers necessary.
Participants considered to be poorly compliant with their medication and/or the study procedures 
will receive additional training and instruction, as required, and will be reminded of the 
importance of complying with the protocol.
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) 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 DPP-4 inhibitors or GLP-1R agonists (Section 4.1.2.3).  Initiation of 
metformin for the treatment of diabetes is permitted, but metformin should not be initiated 
during the study for the treatment of other metabolic conditions (for example, polycystic ovary 
syndrome, diabetes prevention).
Investigative-site staff will inform participants that they must consult with the investigator or a 
designated site staff member upon being prescribed any new medications during the study.  This 
may not be possible when initiated for treatment of medical emergencies, in which case, the 
participant will inform the investigator or a designated site staff member as soon as possible.  
Nonstudy medications taken by participants who are screened but not randomized will not be 
reported to Lilly unless an SAE or AE occurs that the investigator believes may have been 
caused by a study procedure.

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6.6.
Dose Modification
6.6.1.
Tirzepatide
Tirzepatide is given once weekly 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.  
Study drug dose modification is not permitted, except for:

management of intolerable GI symptoms during the entire course of the study (see 
Section 6.6.2) and, 

management of participants with perceived excessive weight loss during the additional 
2-year treatment period for participants with prediabetes at randomization only (see 
Section 6.6.3).
Only 1 dose reduction per participant will be permitted during the entire course of the study. All 
dose adjustments will be managed through IWRS.  
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 counselled on dietary behaviors that may 
help mitigate nausea and vomiting, (for example, eating smaller meals, splitting 3 daily meals 
into 4 or more smaller ones, and stopping eating when they feel full).  If symptoms persist, the 
participant should be prescribed, at the investigator’s discretion, symptomatic medication (for 
example, antiemetic or antidiarrheal medication). A temporary interruption of study drug for 1 
dose is permitted, provided the participant has taken the last 3 weekly doses.  Study treatment 
should be resumed at the assigned dose immediately, either alone or in combination with 
symptomatic medication, which can also be utilized to manage symptoms (Section 10.9).  
Management of study drug after interruptions >1 dose is discussed in Section 7.1.1.
If intolerable GI symptoms (for example, nausea, vomiting, or diarrhea) persist despite the above 
measures, the investigator should contact Lilly to consider reinitiating study drug at the next-
lowest maintenance dose in a blinded fashion (for example, 15 mg reduced to 10 mg, 10 mg 
reduced to 5 mg, or 5 mg reduced to placebo) (Section 10.9).
If intolerable GI symptoms persist despite symptomatic treatment, temporary drug interruption, 
and resumption at a lower dose of study drug, the participant should be discontinued from study 
drug.  All participants who discontinue study drug should continue to attend scheduled study 
visits. 

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6.6.3.
Management of Participants with Perceived Excessive Weight Loss During the 
Additional 2-year Treatment Period for Participants with Prediabetes at 
Randomization
As indicated in Section 5.3.1, if BMI ≤22 kg/m2 is reached any time during the study, the 
recommended energy intake should be recalculated. From Visit 101 onwards, in the participants 
who have reached BMI ≤22 kg/m2, if weight loss continues despite above measures and/or there 
are concerns related to degree of weight loss that may lead to discontinuation from study drug, 
the investigator should contact the Sponsor CRP to consider a study drug dose reduction in a 
blinded fashion (see Section 6.6.2 for details regarding study drug dose reduction).
6.7.
Intervention after the End of the Study
6.7.1.
Treatment after Study Completion
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
Possible reasons leading to permanent discontinuation of IP:

participant decision
o
the participant requests to discontinue IP.

clinical considerations
o
initiation of open-label GLP-1R agonist or DPP-4 inhibitor, if participants will 
not or cannot discontinue them
o
intolerable GI symptoms despite management as described in Section 6.6.2
o
BMI ≤18.5 kg/m2 is reached at any time during the treatment period 
Note: The investigator should contact the Sponsor CRP to discuss whether it 
is medically appropriate for the participant to continue study treatment. 
o
diagnosis of T1DM
o
diagnosis of MTC after randomization
o
significant elevation of calcitonin (Section 10.3.1.4)
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) 
after randomization
o
development of any significant study drug-related hypersensitivity reaction
o
onset of pregnancy in a female participant 
o
occurrence of any other treatment-emergent AE (TEAE), SAE, or clinically 
significant finding for which the investigator believes that permanent study
drug discontinuation is the appropriate measure to be taken
o
inadvertent enrollment if continued treatment with study drug would not be 
medically appropriate (Section 7.2.3)
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 subject should be discontinued from 
study drug.  If a participant’s psychiatric disorder can be adequately 
treated with psycho- and/or pharmacotherapy, then the subject, at the 
discretion of the Investigator (in agreement with the MHP), may be 
continued in the trial on randomized therapy.  
o
in addition, study drug may be discontinued if participants:

answered “yes” to either Question 4 (Active Suicidal Ideation with 
Some Intent to Act, Without Specific Plan) on the "Suicidal Ideation" 
portion of the C-SSRS
or

answered “yes” to Question 5 (Active Suicidal Ideation with Specific 
Plan and Intent) on the "Suicidal Ideation" portion of the C-SSRS 
or 

answered “yes” 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 IP due to a hepatic event or liver test 
abnormality should have additional hepatic safety data collected via eCRF.
o
Discontinuation of the IP 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 ≥300U/L, whichever occurs first, if 
baseline ALT≥2X ULN

ALT or AST >5X ULN for more than 2 weeks

ALT or AST >3X ULN and total bilirubin level (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%)

alkaline phosphatase (ALP) >3X ULN

ALP >2.5X ULN and TBL >2X ULN

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
ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, 
right-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)
Participants who stop study drug permanently should continue to attend all scheduled study visits
to collect all planned efficacy and safety measurements. Participants who are unwilling to attend 
all scheduled visits and stop the study prior to 72 weeks, should return for a final weight 
measurement (Visit 99).  If participants are unwilling to attend Visit 99, their refusal to attend 
should be documented in the patient medical record.  Participants with prediabetes who stop 
study drug after 72 weeks should return for a final assessment of weight and glycemic status 
(Visit 199).  Refusal to attend should be documented in the patient medical record.
Participants discontinuing from the IP prematurely for any reason should complete AE and other 
follow-up procedures per Section 1.3 (Schedule of Activities), Section 8.3 (Adverse Events and 
Serious Adverse Events), and Section 8.2 (Safety Assessments) of the protocol.
7.1.1.
Temporary Study Drug 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 medication 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.
Abbreviations:  AE = adverse event; GI = gastrointestinal; IWRS = interactive web response service.
Investigators should inform Lilly 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.

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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. 
Participants will be withdrawn from the study in the following circumstances:

enrollment in any other clinical study involving an IP or enrollment in any other type 
of medical research judged not to be scientifically or medically compatible with this 
study

participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

participant requests to be withdrawn from the study and clearly indicates that there 
will be no further contact of any kind with the site

Female participants will be withdrawn from the study if the participant becomes 
pregnant.
Participants who agree to provide information relevant to any trial endpoint at the end of the 
study are not considered to have discontinued from the study.
Participants discontinuing from the study prematurely for any reason should complete AE and 
other safety follow-up per Section 1.3 (Schedule of Activities), Section 8.3 (Adverse Events and 
Serious Adverse Events), and Section 8.2 (Safety Assessments) of this protocol.

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7.2.1.
Participant Disposition and Timing of Safety Follow-up for the Primary Endpoint (72 Weeks)
Abbreviations:  ED = early discontinuation of treatment; Pt = participant; wks = weeks.

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7.2.2.
Participant Disposition and Timing of Safety Follow-up for those with Prediabetes at Randomization
Continuing in Additional 2-year Treatment Period
Abbreviations:  ED = early discontinuation of treatment; wks = weeks.
Note: Participants with prediabetes at randomization who discontinue study drug on or before Week 72 are not eligible to continue in additional 
2-year treatment period after Visit 21 (Week 72) and should proceed to V801.

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7.2.3.
Discontinuation of Inadvertently Enrolled Participants
If the Sponsor or investigator identify a participant who did not meet enrollment criteria and was 
inadvertently enrolled, the investigator and the Sponsor CRP must agree whether continuing the 
study treatment is medically appropriate.  Continuation of inadvertently enrolled participants in 
the study, with or without study drug treatment, requires documented approval from the Sponsor 
CRP. Safety follow up is as outlined in Section 1.3 (Schedule of Activities), Section 8.3
(Adverse Events and Serious Adverse Events), 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 are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site.
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those 
who did not get IP.  Public sources may be searched for vital status information.  If vital status is 
determined, this will be documented, and the participant will not be considered lost to follow-up.
Eli Lilly and Company personnel will not be involved in any attempts to collect vital status 
information.
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.9.

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8.
Study Assessments and Procedures

Section 10.2 (Appendix 2) lists the laboratory tests that will be performed for this 
study.  Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples.

Unless otherwise stated in the subsections below, all samples collected for specified 
laboratory tests will be destroyed within 60 days of receipt of confirmed test results.
Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
8.1.
Efficacy Assessments
8.1.1.
Primary Efficacy Assessments
The primary efficacy assessment in this study is the body weight.  Body weight measurements 
will be collected at specific clinic visits as summarized in the Schedule of Activities (Section 
1.3).  Methods for measuring body weight are described in Section 10.7 (Appendix 7).
8.1.2.
Secondary Efficacy Assessments
The following secondary efficacy assessments will also be collected according to the Schedule of 
Activities:

waist circumference (measuring method is described in Section 10.7 [Appendix 7]).

fasting insulin (measured through central lab)

onset of T2DM (definition is described Section 4.1.2.3)

HbA1c (%, mmol/mol) (measured through central lab)

fasting glucose (measured through central lab)

BMI (derived using body weight in kilograms divided by the square of height in 
meters) 

blood pressure

lipids
8.1.3.
Patient-Reported Outcomes Assessments
The self-reported questionnaires will be translated into the native language of the region, 
linguistically validated and administered according to the Schedule of Activities (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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8.1.4.
Short Form 36 version 2, acute, 1 week recall version
The SF-36v2 acute, 1-week recall version is a 36-item, generic, patient-administered measure 
designed to assess the following 8 domains:

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).  
8.1.5.
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, 2018). 
8.1.6.
EQ-5D-5L
Generic health-related quality of life will be assessed using the EQ-5D-5L (EQ-5D; EuroQoL 
Group 2015).  The EQ-5D-5L is a standardized 5-item instrument for use as a measure of health 
outcome.  It provides a simple descriptive profile and a single index value for health status that 
can be used in the clinical and economic evaluation of health care as well as population health 
surveys.  The EQ-5D-5L comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression).  The 5L version, introduced in 2005, scores each 
dimension at 5 levels (no problems, slight problems, moderate problems, severe problems, 
unable to perform/extreme problems), for a total of 3125 possible health states.  In addition to the 
health profile, a single health-state index value can be derived based on a formula that attaches 
weights to each of the levels in each dimension. This index value ranges between ˂0 (where 0 is 

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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 on a vertical graduated (0 to 100) scale.  In conjunction with the health-
state data, it provides a composite picture of the respondent’s health status.  
The EQ-5D-5L is used worldwide and is available in more than 170 different languages.  Details 
on the instrument, and scoring, organizing, and presenting the data collected can be found in the 
EQ-5D-5L User Guide (EuroQoL Group 2015).
8.1.7.
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 patient-rated assessment of current health limitation and is rated on a 5-point scale 
ranging from “1- not at all limited” to “5- extremely limited.”
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities 
(Section 1.3).
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 a 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 should be measured according to the Schedule of Activities 
(Section 1.3) and Section 10.7.
Any clinically significant findings from vital-signs measurement that result in a diagnosis and 
that occur after the participant receives the first dose of study treatment should be reported to 
Lilly or its designee as an AE via the eCRF.
8.2.3.
Electrocardiograms
For each participant, 12-Lead electrocardiograms (ECGs) should be collected according to the 
Schedule of Activities (Section 1.3) and Section 10.7.  
Electrocardiograms will initially be interpreted by a qualified physician (the investigator or 
qualified designee) at the site as soon after the time of ECG collection as possible, and ideally 
while the participant is still present, for immediate subject management, should any clinically 
relevant findings be identified. Any clinically significant findings from ECGs that result in a 
diagnosis and that occur after the participant receives the first dose of the investigational 
treatment should be reported to Lilly or its designee as an AE via the eCRF.

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All digital ECGs will be obtained using centrally provided ECG machines and will be 
electronically transmitted to a designated central ECG laboratory. ECGs will be performed in 
triplicate at Weeks 0 and 36.  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 (HR) may be used for data analysis and report-writing 
purposes, unless a cardiologist overreading of the ECGs is conducted prior to completion of the 
final study report (in which case, the overread data would be used).
8.2.4.
Clinical Safety Laboratory Assessments

For each participant, laboratory tests detailed in (Section 10.2) should be conducted 
according to the Schedule of Activities (Section 1.3). 

With the exception of laboratory test results that may unblind the study, Lilly or its 
designee will provide the investigator with the results of laboratory tests analyzed by 
a central vendor, if a central vendor is used for the clinical trial.  

Any clinically significant findings from laboratory tests that result in a diagnosis and 
that occur after the participant receives the first dose of IP should be reported to Lilly 
or its designee as an AE via eCRF.
8.2.4.1.
Immunogenicity Assessment
Where local regulations and ERBs allow, blood samples for immunogenicity testing will be 
collected to determine antibody production against tirzepatide as specified in the Schedule of 
Activities (Section 1.3).
At the visits and times specified in the Schedule of Activities (Section 1.3), venous blood 
samples will be collected to determine antibody production against tirzepatide.  To interpret the 
results of immunogenicity, a PK sample will be collected at the same time points as the 
immunogenicity sample.  All samples for immunogenicity should be taken predose when 
applicable and possible.  In the event of systemic drug-hypersensitivity reactions (immediate or 
nonimmediate), additional samples will be collected (including antidrug antibodies [ADAs], PK,
and exploratory biomarker samples) as close to the onset of the event as possible, at the 
resolution of the event, and 30 days following the event.  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.  Immunogenicity will be assessed by a validated 
assay designed to detect ADAs in the presence of tirzepatide at a laboratory approved by the 
Sponsor. Antibodies may be further characterized and/or evaluated for their ability to neutralize 
the activity of tirzepatide. Sample collected at Visit 801 or Visit 802 will assess immunogenicity 
at washout of tirzepatide (5 half-lives post end of treatment).
Samples with tirzepatide ADA detected will be titered and evaluated for their ability to neutralize 
the activity of assigned treatment (tirzepatide-neutralizing antibodies). Samples with tirzepatide 
ADA detected will also be tested for cross-reactive binding to native GIP and GLP-1, and if such 
is detected, then for neutralizing antibodies against native GIP and GLP-1, respectively.
Treatment-emergent ADAs are defined in Section 9.4.6.  

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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. 
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
If a study participant experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated 
TBL ≥2X ULN, liver testing (Section 10.5) should be repeated within 3 to 5 days including 
ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to 
confirm the abnormality and to determine if it is increasing or decreasing.  If the abnormality 
persists or worsens, clinical and laboratory monitoring should be initiated by the investigator and 
in consultation with the study medical monitor.  Monitoring of ALT, AST, TBL, and ALP 
should continue until levels normalize or return to approximate baseline levels. 
Additional safety data should be collected via the eCRF if 1 or more of the following conditions 
occur:

elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2X ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests

participant discontinued from treatment due to a hepatic event or abnormality of liver 
tests

hepatic event considered to be an SAE
8.2.6.
Depression, Suicidal Ideation, and Behavior Risk Monitoring
Overweight and obese patients 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, and 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 study medication in subjects 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 8.3.1.1).

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8.3.
Adverse Events and Serious Adverse Events
Please refer to Section 10.3 Appendix 3 Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.
Investigators are responsible for monitoring the safety of participants who have entered this 
study and for alerting Lilly or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the participant.
The investigator is responsible for the appropriate medical care of participants during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the IP or the study, 
or that caused the participant to discontinue the IP before completing the study.  The participant 
should be followed until the event resolves, stabilizes with appropriate diagnostic evaluation, or 
is reasonably explained.  The frequency of follow-up evaluations of the AE is left to the 
discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed, study site personnel will record via eCRF the occurrence and nature of 
each participant’s preexisting conditions, including clinically significant signs and symptoms of 
the disease under treatment in the study.  In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs. Investigators should record their assessment of the 
potential relatedness of each AE to protocol procedure and IP via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the IP, 
study device, and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a participant’s IP is discontinued as a result of an AE, study-site personnel must report this to 
Lilly or its designee via eCRF, clarifying if possible, the circumstances leading to any dosage 
modifications or discontinuations of treatment.
Serious Adverse Events
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization 

a life-threatening experience (that is, immediate risk of dying)

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
persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the participant or may require 
intervention to prevent 1 of the other outcomes listed in the definition above.  
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse.

when a condition related to the drug delivery system necessitates medical or surgical 
intervention to preclude either permanent impairment of a body function or 
permanent damage to a body structure, the serious outcome of “required intervention” 
will be assigned.
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  The SAE reporting to the Sponsor begins after the participant has signed the ICF and 
has received IP.  However, if an SAE occurs after signing the ICF, but prior to receiving IP, the 
SAE should be reported to the Sponsor per SAE-reporting requirements and timelines (see 
Section 8.3.1) if it is considered reasonably possibly related to study procedure.
Study-site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 24-
hour notification requirement refers to the initial SAE information and all follow-up SAE 
information. Participants with a serious hepatic AE should have additional data collected using 
the eCRF.
Pregnancy (during maternal or paternal exposure to IP) does not meet the definition of an AE.  
However, to fulfill regulatory requirements any pregnancy should be reported following the SAE 
process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the participant disposition case report form [CRF] has 
been completed).  However, if the investigator learns of any SAE, including a death, at any time 
after a subject has been discharged from the study, and he or she considers the event reasonably 
possibly related to the study treatment or study participation, the investigator must promptly 
notify Lilly.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to IP or procedure.  United States 21 CFR 
312.32, European Union Clinical Trial Directive 2001/20/EC, and the associated detailed 
guidance or national regulatory requirements in participating countries require the reporting of 
SUSARs.  Lilly has procedures that will be followed for the identification, recording, and 
expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidance.

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8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All AE data will be collected from the signing of the ICF until the time points specified in the 
Schedule of Activities (Section 1.3).
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.1.1.
Adverse Event Monitoring with a Systematic Questionnaire
Before administering the C-SSRS or the PHQ-9, study site personnel will question the 
participant about any change in the preexisting condition(s) and the occurrence and nature of any 
AEs.
Nonserious AEs obtained through the questionnaire are recorded and analyzed separately.  Only 
serious AEs elicited through the C-SSRS or PHQ-9 are to be recorded as AEs via the eCRF and 
reported to Lilly or its designee within 24 hours as SAEs. For this study, the C-SSRS is adapted
for the assessment of the ideation and behavior categories only.  The Intensity of Ideation and 
Lethality of Behavior sections are removed.
The C-SSRS is a scale that captures the occurrence, severity, and frequency of suicidal ideation 
and/or behavior during the assessment period.  The scale includes suggested questions to solicit 
the type of information needed to determine if suicidal ideation and/or behavior occurred.  The 
tool was developed by the National Institute of Mental Health trial group for the purpose of 
being a counterpart to the Columbia Classification Algorithm of Suicide Assessment 
categorization of suicidal events.  
The PHQ-9 is a validated self-report screening tool that assesses the presence and intensity of 
depressive symptoms.  The PHQ-9, which incorporates the 9 Diagnostic and Statistical Manual-
IV depression criteria as “0” (not at all) to “3” (nearly every day), was developed for use in 
primary care settings (Kroenke et al. 2001).  
8.3.2.
Follow-up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the participant is lost to follow-up (as defined in Section 1.3). 
8.3.3.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the Sponsor of a 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, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

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
Investigator safety reports must be prepared for SUSARs according to local 
regulatory requirements and sponsor policy and forwarded to investigators as 
necessary.

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.
8.3.4.
Pregnancy

Details of all pregnancies in female participants and female partners of male 
participants will be collected after the start of study intervention and the participant 
will be followed to determine the outcome of the pregnancy for mother and neonate.  

If a pregnancy is reported, the investigator should inform the Sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Section 
10.4 (Appendix 4).

Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, and ectopic pregnancy) are considered SAEs.
8.3.5.
Medical Device Incidents (Including Malfunctions)
Medical devices are being used in this study for the purposes of administering tirzepatide. In 
order to fulfill regulatory reporting obligations worldwide, the investigator is responsible for the 
detection and documentation of events meeting the definitions of incident or malfunction that 
occur during the study with such devices.
The definition of a medical device incident can be found in Section 10.6 (Appendix 6).
Note: Incidents fulfilling the definition of an AE/SAE will also follow the processes outlined in 
Section 8.3.2.
8.3.5.1.
Time Period for Detecting Medical Device Incidents

Medical device incidents, or malfunctions of the device that result in an incident, will 
be detected, documented, and reported to the Sponsor during all periods of the study 
in which the medical device is used.

If the investigator learns of any incident at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to a 
medical device used during the study, the investigator will promptly notify the 
Sponsor through the complaints process.
The method of documenting medical device incidents is provided in Section 10.6 (Appendix 6).
8.3.5.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE will be followed and reported in the 
same manner as other AEs (see Section 8.3.2). This applies to all participants, 
including those who discontinue study intervention.

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
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident.

New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator.
8.3.5.3.
Prompt Reporting of Medical Device Incidents and Malfunctions to Sponsor

Medical device incidents or malfunctions will be reported to the Sponsor within a 
business day or as determined for the study, after the investigator determines that the 
event or issue meets the protocol definition of a medical device incident or 
malfunction.

Medical device incidents or malfunctions that result in an SAE will be reported to the 
Sponsor within 24 hours, in the same manner as other (S)AEs.  

Malfunctions will be reported via the Product Complaint Form and sent to the 
Sponsor per training and per instructions provided on the Product Complaint Form.

The same individual at the site will be the contact for the receipt of medical device 
reports and SAE.
8.3.5.4.
Regulatory Reporting Requirements for Medical Device Incidents

The investigator will promptly report to the Sponsor all incidents occurring with any 
medical device provided for use in the study in order for the Sponsor to fulfill the 
legal responsibility to notify appropriate regulatory authorities and other entities 
about certain safety information relating to medical devices being used in clinical 
studies.

The investigator, or responsible person according to local requirements (for example;
the head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC.
8.3.6.
Complaint Handling
Lilly collects product complaints on all IPs (drugs/medical devices, inclusive of packaging, 
labeling, instructions for use, or other component) used in clinical studies, inclusive of 
comparators, in order to ensure the safety of study participants, monitor product quality, and 
facilitate process and product improvements.
Participants will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational drug or medical device, so that the situation can be 
assessed.
Investigators will provide complete and timely reports to the Sponsor as instructed for the study, 
and per the Product Complaint Form.
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.

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8.5.
Pharmacokinetics
Pharmacokinetic samples will be collected from all randomized participants.
Plasma tirzepatide concentrations will only be determined from blood samples obtained from 
participants receiving tirzepatide treatment. Blood samples for PK assessment will be collected 
at Weeks 8, 16, and 36 following tirzepatide treatment per the Schedule of Activities or at ED
(Section 1.3).  At each visit prior to a PK assessment, each participant will be assigned via IWRS 
to one of the sampling PK time windows of 1 to 24 hours, 24 to 96 hours, or 120 to 168 hours 
postdose.  In addition, plasma tirzepatide concentration will be determined on immunogenicity 
visits up to and including Week 176.  
The date and time of the most recent tirzepatide SC injection administered prior to collecting the 
PK sample must be recorded on the eCRF from the study diaries.
The date and time at which each sample was drawn must be recorded on the laboratory accession 
page. 
Concentrations of tirzepatide will be assayed using a validated liquid chromatography mass 
spectrometry method.
Bioanalytical samples collected to measure tirzepatide concentration will be retained for a 
maximum of 1 year following last participant visit for the study. 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.
8.6.
Pharmacodynamics
Samples to assess the PD properties of tirzepatide are included in the efficacy measures and not 
applicable in this section.
8.7.
Genetics
8.7.1.
Whole Blood Sample(s) for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in the 
Schedule of Activities (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 patient only by the investigator site personnel.  
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 
ERBs/ 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.

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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 will be collected at the times specified in the 
Schedule of Activities (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/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.
8.9.
Health Economics
Health Economics and Medical Resource Utilization Parameters are not evaluated in this study.

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9.
Statistical Considerations
9.1.
Statistical Hypotheses
The alternative hypotheses for the primary objective are the following: 

H10,1: QW tirzepatide 10 mg is superior to placebo for percent change in body weight 
from randomization AND percentage of participants who achieve ≥5% body weight 
reduction at 72 weeks.

H15,1: QW tirzepatide 15 mg is superior to placebo for percent change in body weight 
from randomization AND percentage of participants who achieve ≥5% body weight 
reduction at 72 weeks
The above two hypotheses will be tested in parallel, each at a 2-sided significance level of 0.025.
The alternative hypotheses for the key secondary objective controlling for type 1 error rate are 
the following: 

H15,2 and H10,2:  superiority of tirzepatide 10 mg and/or 15 mg versus placebo for 
percentage of participants who achieve ≥10% body weight reduction from randomization 
at 72 weeks 

H15,3 and H10,3:  superiority of tirzepatide 10 mg and/or 15 mg versus placebo for 
percentage of participants who achieve ≥15% body weight reduction from randomization 
at 72 weeks

H15,4 and H10,4:  superiority of tirzepatide 10 mg and/or 15 mg versus placebo for 
percentage of participants who achieve ≥20% body weight reduction from randomization 
at 72 weeks

H15,5 and H10,5:  superiority of tirzepatide 10 mg and/or 15 mg versus placebo for change 
from randomization in waist circumference (cm) at 72 weeks

H1015,6:  superiority of pooled tirzepatide 10 mg and 15 mg versus placebo for change in 
body weight (kg) from randomization at 20 weeks 

H5,1:  superiority of tirzepatide 5 mg versus placebo for percent change in body weight 
from randomization and percentage of participants who achieve ≥5% body weight 
reduction at 72 weeks

Hp,7: superiority of tirzepatide (all doses combined) versus placebo for change in systolic 
blood pressure (SBP) (mmHg) from randomization at 72 weeks

Hp,8: superiority of tirzepatide (all doses combined) versus placebo for change in 
triglycerides (mg/dL) from randomization at 72 weeks

Hp,9: superiority of tirzepatide (all doses combined) versus placebo for change in non-
high-density lipoprotein cholesterol (non-HDL-cholesterol) (mg/dL) from randomization 
at 72 weeks

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
Hp,10:  superiority of tirzepatide (all doses combined) versus placebo for change in high-
density lipoprotein cholesterol (HDL-cholesterol) (mg/dL) from randomization at 72 
weeks

Hp,11:  superiority of tirzepatide (all doses combined) versus placebo for change in fasting 
insulin (pmol/L) from randomization at 72 weeks

H1015,12:  superiority of pooled tirzepatide 10 mg and 15 mg versus placebo for change in 
SF-36v2 acute form Physical Functioning domain score from randomization at 72 weeks.

H15,13 and H10,13: superiority of tirzepatide 10 mg and/or 15 mg versus placebo for change 
in percent body weight from randomization at 176 weeks (for participants with 
prediabetes at randomization).

Hp,14 and Hp,15:  superiority of tirzepatide (all doses combined) versus placebo for 
delaying the onset of type 2 diabetes mellitus (T2DM) during 176 weeks or 193 weeks 
(for participants with prediabetes at randomization).
The details of family-wise type I error rate control strategy and methods for the aforementioned 
hypotheses will be provided in the statistical analysis plan (SAP).
9.2.
Sample Size Determination
Approximately 3429 participants will be screened to achieve 2400 randomly assigned to study 
intervention (600 participants per intervention group).
The sample size determination assumes that evaluation of superiority of 10-mg tirzepatide and 
tirzepatide 15 mg to placebo will be conducted in parallel, each at a 2-sided significance level of 
0.025 using a 2-sample t-test.  Additionally, a difference of at least 11% mean body weight 
percentage reduction from randomization at 72 weeks for 10-mg tirzepatide and/or tirzepatide 
15 mg compared with placebo, a common SD of 10%, and a dropout rate of 25% are assumed for 
statistical power calculations.  Under the assumptions above, randomizing 2400 participants in a 
1:1:1:1 ratio to tirzepatide 5 mg (600), tirzepatide 10 mg (600), tirzepatide 15 mg (600), and 
placebo (600) provides more than 90% power to demonstrate superiority of tirzepatide 10 mg 
and/or 15 mg to placebo. 
The chosen sample size and randomization ratio also provides >90% power to establish 
superiority of 10-mg tirzepatide and 15-mg tirzepatide doses to placebo in term of percentage of 
participants achieving at least 5% body weight reduction at 72 weeks, conducted in parallel using 
a Fisher’s exact test, each at a 2-sided significance level of 0.025, assuming 25% placebo-treated 
participants and 90% tirzepatide-treated participants achieving the goal and a dropout rate of 
25%.  
In addition, assuming that approximately 60% of the randomized population will have 
prediabetes, the study sample size will also provide more than 90% power to demonstrate 
superiority of tirzepatide (all doses combined) over placebo in terms of delaying the onset of
diabetes for participants with prediabetes at study entry.  It is based on the following
assumptions: 1.6% (corresponding to annual hazard rate of 0.54%) of participants randomized to
tirzepatide and 6% of participants randomized to placebo (corresponding to annual hazard rate of 

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2.1%) will progress to diabetes during the 3-year period; 49% of participants will drop out 
(corresponding to annual drop-out rate of 22%) during the same period; and the test will be 
conducted at a 2-sided significance level of 0.05.

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9.3.
Populations for Analyses
For purposes of analysis, the following analysis sets are defined:
Analysis Set
Description
Entered Participants
all participants who sign informed consent
Randomized Participants
all participants who are randomly assigned a study treatment
Modified Intent-to-Treat (mITT) 
all randomly assigned participants who are exposed to at least 1 dose of study 
drug; participants will be included in the treatment group they were randomized 
to
Efficacy Analysis Set (EAS)
data obtained during treatment period from mITT, excluding data after 
discontinuation of study drug (last dose date + 7 days)
Full analysis set (FAS)
data obtained during treatment period from mITT, regardless of adherence to 
study drug.
Safety Analysis Set (SS)
data obtained during the treatment period plus safety follow-up period from 
mITT, regardless of adherence to study drug
9.4.
Statistical Analyses
9.4.1.
General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.  Any change to 
the data analysis methods described in the protocol will require an amendment ONLY if it 
changes a principal feature of the protocol.  Any other change to the data analysis methods 
described in the protocol, and the justification for making the change, will be described in the 
SAP or the Clinical Study Report (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 will be calculated at 95%, 2-sided.  In statistical summaries and 
analyses, data will be analyzed as randomized.
Unless specified otherwise, efficacy and safety will be assessed using the modified intention-to-
treat (mITT) population.  Baseline will be defined as the last available non-missing measurement 
during Visit 1 to Visit 3.  Unless specified otherwise, safety assessments will be guided by an 
estimand comparing safety of tirzepatide doses with placebo irrespective of adherence to study 
drug. Thus, safety analysis will be conducted using safety analysis set (SS).  
Summary statistics for continuous measures will include sample size, mean, SD, median, 
minimum, and maximum.  The analysis model to make comparisons among treatment groups
relative to continuous measurements assessed over time will include a mixed model for repeated 
measures (MMRM), with terms of treatment, visit, and treatment-by-visit interaction,
stratification factors, and baseline measurement as a covariate.  
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. 

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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, randomized, and receiving at least 
1 dose of study drug will be presented by treatment groups.  Of the participants in the mITT 
population, frequency counts and percentages of participants who completed the study, 
prematurely discontinued the study (and/or study drug), including reason for premature 
discontinuation, will be presented by treatment groups.  
A Kaplan-Meier analysis of time from randomization to premature discontinuation from study by 
treatment group will be provided.
9.4.2.2.
Participant Characteristics
Demographics and other baseline characteristics (including years of education) will be 
summarized by treatment group for all randomized participants.
9.4.2.3.
Concomitant Therapy 
Concomitant medications, including previous therapy, will be summarized by treatment arm for 
SS.  
9.4.2.4.
Treatment Compliance 
Frequency counts and percentages of participants compliant to study drug will be summarized by 
treatment groups and visits for full analysis set (FAS).
9.4.3.
Efficacy Analyses
9.4.3.1.
Primary Analyses
There will be 2 estimands of interest in comparing efficacy of tirzepatide doses with placebo. 

For objectives controlled for Type 1 error at 72 weeks:
1) The “efficacy” estimand, defined as the average treatment effect of tirzepatide 
relative to placebo at 72 weeks, as an adjunct to a reduced-calorie diet and increased 
physical activity, in the randomized participants had they remained on their 
randomized treatment for the entire planned 72 weeks treatment duration.
2) The “hybrid” estimand, defined as the average treatment effect of tirzepatide relative 
to placebo at 72 weeks, as an adjunct to a reduced-calorie diet and increased physical
activity, for the randomized participants regardless of the adherence to study drug.  

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
For objectives controlled for Type 1 error assessed after 72 weeks: 
1) The “efficacy” estimand, defined as the treatment effect of tirzepatide relative to 
placebo at 176/193 weeks, as an adjunct to a reduced-calorie diet and increased 
physical activity, in the randomized participants with prediabetes at randomization 
had they remained on their randomized treatment for the entire planned 176 weeks 
treatment duration.  
2) The “hybrid” estimand, defined as the average treatment effect of tirzepatide relative 
to placebo at 176/193 weeks, as an adjunct to a reduced-calorie diet and increased 
physical activity, for the randomized participants with prediabetes at randomization 
regardless of the adherence to study drug.  
For the Food and Drug Administration, the primary efficacy analysis will be guided by the 
hybrid estimand and 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 will include terms of treatment, 
stratification factors, and baseline body weight as a covariate.  Missing data at the 72-week visit
will be imputed and analysis will be conducted with multiple imputations (see details in the 
SAP). Since the mean percent change in body weight and percentage of participants with ≥5% 
body weight reduction objectives need to be achieved at the same time, no multiplicity 
adjustment is planned for these 2 tests. 
For all other purposes, the primary efficacy analysis will be guided by the “efficacy” estimand 
and conducted using the efficacy analysis set (EAS).  The primary analysis model will be an
MMRM for body weight percent change over time and logistic regression for percentage of 
participants achieving at least 5% body weight reduction over time. Details of the statistical 
modeling will be provided in the SAP.
9.4.3.2.
Key Secondary Analyses

superiority of pooled tirzepatide 10 mg and 15 mg to placebo for change in body 
weight (kg) from randomization at 20 weeks visit

superiority of QW tirzepatide 5 mg to placebo for percent change in body weight 
from randomization AND percentage of participants who achieve ≥5% body weight 
reduction at 72 weeks visit

superiority of each tirzepatide dose (10 mg and 15 mg) to placebo for the percentage
of study participants who achieve ≥10% body weight reduction at 72 weeks visit

superiority of each tirzepatide dose (10 mg and 15 mg) to placebo for the percentage
of study participants who achieve ≥15% body weight reduction at 72 weeks visit

superiority of each tirzepatide dose (10 mg and 15 mg) to placebo for the percentage 
of study participants who achieve ≥20% body weight reduction at 72 weeks visit

superiority of each tirzepatide dose (10 mg and 15 mg) to placebo for change from 
randomization in waist circumference (cm) at 72 weeks visit

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
superiority of pooled tirzepatide 10 mg and 15 mg to placebo for change from 
randomization in SF-36v2 acute form physical functioning domain score at 72 weeks 
visit

superiority of tirzepatide (all doses combined) to placebo for change from 
randomization in triglycerides (mg/dL) at 72 weeks visit

superiority of tirzepatide (all doses combined) to placebo for change from 
randomization in non-HDL-cholesterol (mg/dL) at 72 weeks visit 

superiority of tirzepatide (all doses combined) to placebo for change from 
randomization in HDL-cholesterol (mg/dL) at 72 weeks visit

superiority of tirzepatide (all doses combined) to placebo for change from 
randomization in SBP (mmHg) at 72 weeks visit

superiority of tirzepatide (all doses combined) to placebo for change from 
randomization in fasting insulin (pmol/L) at 72 weeks visit

superiority of each tirzepatide dose (10 mg and 15 mg) to placebo for change from 
randomization in percent change of body weight at 176 weeks visit (for participants 
with prediabetes at randomization)

superiority of tirzepatide (all doses combined) to placebo in delaying the onset of 
diabetes during 176 weeks treatment period (for participants with prediabetes at 
randomization)

superiority of tirzepatide (all doses combined) to placebo in delaying the onset of 
diabetes during 193 weeks study period (for participants with prediabetes at 
randomization)
Additional details, including analysis methods for key secondary endpoints and the strategy for 
controlling overall type 1 error rate at a 2-sided alpha of 0.05 of primary and key secondary 
endpoint evaluation, will be provided in the SAP.
9.4.4.
Safety Analyses
Unless specified otherwise, safety assessments will be guided by an estimand comparing safety 
of tirzepatide doses with placebo irrespective of adherence to study drug. Thus, safety analysis 
will be conducted using SS.  
9.4.4.1.
Study Drug Exposure
Exposure to each study treatment 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 
percentages of participants experiencing events will be reported for each treatment group, and 
Fisher’s exact test will be used to compare the treatment groups.

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The percentage of participants experiencing TEAE, SAE, discontinuation due to AE will be 
summarized by treatment group.
9.4.4.3.
Adverse Event of Special Interest
This section includes areas of interest whether due to observed safety findings, potential findings 
based on drug class, and 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 MI, 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 incidence of AESIs will be provided by treatment. The details of 
analysis of AESI will be provided in the SAP.
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
To identify AE terms suggestive of potential abuse liability, narrow terms from SMQ of Drug 
abuse and dependence (20000101) will be used.  
Summaries and analyses for incidence of potential abuse liability terms will be provided by
treatment. The details will be provided in the SAP.

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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 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 postrandomization values of central laboratory 
measures, vital signs, and selected ECG parameters will be summarized at each scheduled visit.  
Change from randomization to postrandomization value will be summarized for participants who 
have both a randomization and at least 1 postrandomization result.  
The percentages of participants with treatment-emergent (TE) abnormal, high, or low measures 
(including laboratory, vital, and ECG parameters) 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
Tirzepatide concentration data will be analyzed using a population PK approach using nonlinear 
mixed-effects modeling techniques implemented on the NONMEM® software.  The 
relationships between tirzepatide dose and/or concentration and selected efficacy, tolerability, 
and safety endpoints will be characterized. Additionally, the impact of intrinsic and extrinsic 
participant factors such as age, weight, gender, and renal function on tirzepatide PK and/or PD 
parameters may be examined.  If ADA titers are detected from immunogenicity testing, then the 
impact of immunogenicity titers on tirzepatide PK or any relevant PD parameters may also be 
examined.
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 with baseline if ADAs were detected at baseline (treatment-boosted ADA).  
Details of the analyses will be provided in the SAP.
9.4.7.
Other Analyses
9.4.7.1.
Subgroup Analyses for Primary Outcome
Details of the subgroup analyses will be shown in the SAP.  
The following subgroup variables will be considered (but not limited to):

age (<65 years and ≥65 years)

sex (female and male)

baseline BMI (<30, ≥30 and <35, ≥35 and <40, ≥40 kg/m2)

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
race 

ethnicity 

glycemic status at randomization (normoglycemia vs prediabetes) 
The outcome measures for the subgroup analyses will include:

percent change in body weight from randomization at 72 weeks

percentage of participants achieving at least 5% body weight reduction at 72 weeks
9.5.
Interim Analyses 
Based on the projected enrollment, 3 interim analyses are planned.  Changes in the number of 
interim analyses and the timing of conducting the interim analyses due to the change of 
enrollment rate will not require an amendment.  
The first unblinded safety interim analysis will occur approximately 6 months after 
approximately 400 participants are randomized in the study to monitor the safety of the 
participants in the study.  
The second interim analysis is the 36-week interim analysis to monitor the safety of the 
participants in the study with a special focus to assess the effect of 5-, 10-, and 15-mg doses of 
tirzepatide compared to placebo on HR.  The timing of the 36-week interim analysis will be 
triggered by the completion of a 24-hour ambulatory monitoring sub-study; specifically, after 
approximately 576 randomized participants in GPHK who agree to perform ambulatory 
monitoring have either completed 36 weeks of treatment or discontinued earlier. An independent
data monitoring committee (DMC) will have the responsibility to review unblinded interim 
analysis results.  A statistical analysis center independent from the Sponsor will perform the data 
analysis for the DMC.  
The third unblinded safety interim analysis will occur approximately 6 months after the 36-week 
interim analysis to monitor the safety of the participants in the study.    
Following the third interim analysis specified above, the primary database lock will occur after 
all randomized participants complete the 72-week treatment period or discontinue the study 
early.  The primary objective of the study will be assessed following the primary database lock.  
The final database lock will occur after participants classified with prediabetes have completed a 
176-week treatment period and the safety follow-up visit or discontinued the study early.  
A limited number of individuals will have access to the unblinded data from the interim and/or 
primary database lock prior to the final database lock (after all randomized participants complete 
the entire study). Information that may unblind the study after the interim or primary database 
lock will not be communicated to study sites or blinded study team prior to final database lock, 
unless it is deemed necessary for participant safety.  Details will be specified in the 
blinding/unblinding plan and in the DMC charter.  
  

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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 The International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical 
Practice (GCP) Guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, investigator’s brochure, 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.

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the ERB annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by ERB procedures
o
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
10.1.2.
Informed Consent Process

The investigator or his or her representative will explain the nature of the study, 
including risks and benefits, to the study 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 study participant was entered into the trial and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.

Study participants must be reconsented to the most current version of the ICF(s) 
during their participation in the trial.

A copy of the ICF(s) must be provided to the study participant or the study 
participant’s legally authorized representative.
10.1.3.
Data Protection

Study participants will be assigned a unique identifier by the investigator. Any study 
participant records, datasets, or tissue samples that are transferred to the Sponsor will 
contain the identifier only; study participant names or any information which would 
make the study participant identifiable will not be transferred.

The study participant must be informed that his/her personal trial-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 study participant.

The study 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.
10.1.4.
Committees Structure
Prospective adjudication of incident diabetes events as well as major adverse cardiovascular 
events and pancreatic AEs will be performed by the independent adjudication committees for 
this study.  
More details on adjudication of incident diabetes events can be found in Section 4.1.2.3.
Section 10.3 Appendix 3 outlines additional information on pancreatic and cardiovascular 
adjudication committees. 
An independent DMC for the interim analysis (Section 9.5) will include members with no 
conflict of financial interest.
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. 

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All CSRs, amendments, and addenda will be submitted to external regulatory authorities, 
external partners (as applicable), and sites. 
The publication policy for Study I8F-MC-GPHK (SURMOUNT-1) is outlined in Section 10.1.10
and further described in the Clinical Trial Agreement.
10.1.6.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will

provide instructional material to the study sites, as appropriate

provide sponsor start-up training to instruct the investigators and study coordinators.
This training will provide instruction on the protocol, the completion of the eCRFs, 
and study procedures

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax, and

review and verify data reported to detect potential errors.
In addition, Lilly or its representatives will periodically check a sample of the participant data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the Sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
10.1.7.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the Sponsor. 
An electronic data capture (EDC) system will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the eCRF.
Additionally, clinical outcome assessment data (scales, self-reported diary data) will be collected 
by the subject/investigator site personnel via a paper source document and will be transcribed by 
the investigator site personnel into the EDC system.
Data collected via the sponsor-provided data capture systems will be stored at third parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture systems. Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.

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Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and electronic transfers will be provided to the investigator 
for review and retention. Data will subsequently be transferred from the central vendor to the 
Lilly data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
10.1.8.
Source Documents

Source documents provide evidence for the existence of the study 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 trial. Also, current medical records must be available.
10.1.9.
Study and Site Closure
10.1.9.1.
Discontinuation of Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.
10.1.9.2.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
10.1.10.
Publication Policy

The Sponsor will comply with the requirements for publication of study results. 

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

The publication policy for Study I8F-MC-GPHK (SURMOUNT-1) is described in the 
Clinical Trial Agreement.

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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed below will be performed by the central laboratory unless otherwise 
stated.

Local laboratory results are only required in the event that the central laboratory results 
are not available in time for response evaluation.  If a local sample is required, it is 
important that the sample for central analysis is obtained at the same 
time. Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be entered into the eCRF.

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.

Refer to Section 5.1 (Inclusion Criteria) for screening pregnancy criteria.  
Investigators must document their review of each laboratory safety report.
Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded.

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Clinical Laboratory Tests
Hematologya
Clinical Chemistrya
Hemoglobin
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Bicarbonate
Mean cell volume
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils, segmented
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Uric acid
Platelets
Calcium
Glucose, fasting
Urine Chemistriesa
Albumin
Albumin
Creatinine
Total Cholesterol
Triglycerides
Creatine kinase (CK)
Nonpharmacogenetic Stored Samples
Serum
EDTA plasma
P800 plasma
Hormones (females)
Pregnancy Test a, serum and/or urineb
Follicle-stimulating hormone (FSH)d
Pharmacokinetics samplesa,e,f,g
Pharmacogenetics Sample
Whole blood (EDTA)
Calculations
eGFR (calculated by CKD-EPI equation)a,c
UACR (urine albumin mg/dL/creatinine g/dL=UACR 
mg/g)
Pancreas (exocrine) a
Pancreatic amylase
Oral Glucose Tolerance Test (glucose, insuline, 
c-peptidee)
Lipase
Cystatin-Ca
HbA1ca
Immunogenicitya,e,g
Anti-tirzepatide antibodies
Endocrinea
Anti-tirzepatide antibody neutralization
Calcitonin
Thyroid-stimulating hormone (TSH)
Lipid Panela
LDL-C
Insuline
C-peptidee
HDL-C
VLDL-C
  
Free Fatty Acidse

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Abbreviations: ADA = antidrug antibody; ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST =
aspartate aminotransferase; BUN = blood urea nitrogen; CK = creatinine kinase, CKD-EPI = Chronic Kidney 
Disease-Epidemiology; eGFR = estimated glomerular filtration rate; EDTA = ethylenediaminetetraacetic acid; 
FSH = follicle-stimulating hormone; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; IWRS = 
interactive web-response system; LDL = low-density lipoprotein; PK = pharmacokinetics; RBC = red blood 
cells; TSH = thyroid-stimulating hormone; UACR = urine albumin/creatinine ration; VLDL = very low-density 
lipoprotein; WBC = white blood cells.
a
All tests will be performed by a Lilly-designated central laboratory, unless otherwise noted.
b
A serum pregnancy test will be performed at Visit 1 for women of childbearing potential only.
A urine pregnancy test must be performed at Visit 3 with the result available prior to randomization and first 
injection of study drug(s) for women of childbearing potential only. Additional pregnancy tests (beyond those 
required per the Schedule of Activities [Section 1.3]) 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.
c
Estimated glomerular filtration rate will be calculated by the central laboratory at all visits and included in lab
result reports.
d
Follicle-stimulating hormone test performed at Visit 1 for postmenopausal women at least 40 years of age with 
an intact uterus, not on hormone therapy, and who have had spontaneous amenorrhea for more than 1 year 
without an alternative medical cause.
e
Results will not be provided to the investigative sites.
f
PK samples will be collected at these visits at time windows of 1 to 24 hours, 24 to 96 hours, or 120 to 168 hours
postdose, as assigned by IWRS. Dependent on the time-windows to which a participant gets assigned, they may 
be required to come to site for PK-specific visits.
g
In the event of systemic drug hypersensitivity reactions (immediate or nonimmediate), additional blood samples 
will be collected including ADA, PK, and exploratory biomarker samples. PK samples for immunogenicity must 
be taken prior to drug administration.

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Selected tests may be obtained in the event of anaphylaxis or systemic allergic/hypersensitivity 
reactions.
Hypersensitivity Testsa
Anti-LY antibodies (immunogenicity)
Tryptaseb
LY concentration (PK)
N-methylhistamineb
Drug Specific IgEb
Basophil Activation Testb
Complements
Cytokine Panel
Abbreviations:  LY = LY3298176; IgE = immunoglobulin E; PK = pharmacokinetics.
a
Assayed by Lilly-designated laboratory.
b
Will be performed if a validated assay is available.

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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting
Please refer to Section 8.3 Adverse Events and Serious Adverse Events.
10.3.1.
Special Safety Topics
10.3.1.1.
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, at the investigator’s discretion, be given glucometers to assist 
in the evaluation of reported symptoms consistent with hypoglycemia. Participants receiving 
glucometers will be provided a diary to record relevant information (for example, glucose values, 
symptoms).
Hypoglycemic episodes will be recorded on a specific eCRF and should not be recorded as AEs 
unless the event meets serious criteria. If a hypoglycemic event meets severe criteria (see 
definition below), it should be recorded as serious on the AE and SAE eCRFs, and reported to 
Lilly as an SAE.
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the plasma Glucose values in this section 
refer to values determined by a laboratory or International Federation of Clinical Chemistry and 
Laboratory Medicine blood-equivalent glucose meters and strips) in accordance with the 2019
American Diabetes Association position statement on glycemic targets (American Diabetes 
Association 2019a):
Glucose Alert Value (Level 1):

Documented symptomatic hypoglycemia is defined as any time a patient feels that 
he or she is experiencing symptoms and/or signs associated with hypoglycemia and 
has a 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).

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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).  
10.3.1.2.
Pancreatitis 
Acute pancreatitis is defined as an AE of interest in all trials with tirzepatide, including this trial.  
Acute pancreatitis is an acute inflammatory process of the pancreas that may also involve 
peripancreatic tissues and/or remote organ systems (Banks and Freeman 2006).  The diagnosis of 
acute pancreatitis requires 2 of the following 3 features:

abdominal pain, characteristic of acute pancreatitis (generally located in the 
epigastrium and radiates to the back in approximately half the cases) (Banks and 
Freeman 2006; Koizumi et al. 2006); the pain is often associated with nausea and 
vomiting);

serum amylase (total and/or pancreatic) and/or lipase ≥3X ULN

characteristic findings of acute pancreatitis on computed tomography (CT) scan or 
magnetic resonance imaging (MRI).
If acute pancreatitis is suspected, appropriate laboratory tests (including levels of pancreatic 
amylase and lipase) should be obtained via the central laboratory (and locally, if needed).  
Imaging studies, such as abdominal CT scan with or without contrast, MRI, or gallbladder 
ultrasound, should be performed. Abdominal ultrasound may be used as an alternative method 
only if CT and MRI cannot be performed. If laboratory values and/or abdominal imaging 
support the diagnosis of acute pancreatitis, the participant must discontinue therapy with 

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tirzepatide, but will continue in the study. A review of the participant’s concomitant medications 
should be conducted to assess any potential causal relationship with pancreatitis.
Each AE of pancreatitis must be reported.  If typical signs and/or symptoms of pancreatitis are 
present and confirmed by laboratory values (lipase or amylase [total and/or pancreatic]) and 
imaging studies, the event must be reported as an SAE.  For a potential case that does not meet 
all of these criteria, it is up to the investigator to determine the seriousness of the case (AE or 
SAE) and the relatedness of the event to study drug(s).
Each participant will have measurements of p-amylase and lipase (assessed at the central 
laboratory) as shown on the Schedule of Activities (Section 1.3) to assess the effects of the 
investigational doses of tirzepatide on pancreatic enzyme levels.  Serial measurements of 
pancreatic enzymes have limited clinical value for predicting episodes of acute pancreatitis in 
asymptomatic participants (Nauck et al. 2017; Steinberg et al. 2017a, 2017b).  Thus, further 
diagnostic follow-up of cases of asymptomatic pancreatic hyperenzymemia (lipase and/or 
pancreatic amylase ≥3X ULN) is not mandated but may be performed based on the investigator’s 
clinical judgment and assessment of the participant’s overall clinical condition. Only cases of 
pancreatic hyperenzymemia that undergo additional diagnostic follow-up and/or are 
accompanied by symptoms suggestive of pancreatitis will be submitted for adjudication.
All suspected cases of acute or chronic pancreatitis will be adjudicated by an independent 
clinical endpoint committee. In addition, AEs of severe or serious abdominal pain of unknown 
etiology will also be submitted to the adjudication committee to assess for possible pancreatitis 
or other pancreatic disease. Relevant data from participants with acute or chronic pancreatitis 
and those with severe or serious abdominal pain will be entered into a specifically designed 
eCRF page. The adjudication committee representative will enter the results of adjudication in a 
corresponding eCRF page.
10.3.1.3.
Thyroid Malignancies and C-Cell Hyperplasia 
Individuals with personal or family history of MTC and/or MEN-2 will be excluded from the 
study.  Participants who are diagnosed with MTC and/or MEN-2 during the study will have 
study drug stopped and should continue follow-up with an endocrinologist.
The assessment of thyroid safety during the trial will include reporting of any case of thyroid 
malignancy (including MTC and papillary carcinoma) and measurements of calcitonin. This 
data will be captured in specific eCRFs.  The purpose of calcitonin measurements is to assess the 
potential of tirzepatide to affect thyroid C-cell function, which may indicate development of 
C-cell hyperplasia and neoplasms. 
10.3.1.4. Calcitonin Measurements
If an increased calcitonin value (see definitions below) is observed in a participant who has been 
administered a medication that is known to increase serum calcitonin, then this medication 
should be stopped and calcitonin levels should be measured after an appropriate washout period.
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/1.73m2

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A significant increase in calcitonin for participants with eGFR ≥60 mL/min is defined below.  If 
a participant’s laboratory results meet these criteria, these clinically significant laboratory results
should be recorded as an AE.  

calcitonin value ≥20 ng/L and <35 ng/L AND ≥50% increase from the screening 
value.  These participants will be asked to repeat the measurement within 1 month.  If 
this repeat value is increasing (≥10% increase), study drug should be stopped, and the 
participant encouraged to undergo additional endocrine assessment and longer-term 
follow-up by an endocrinologist to exclude any serious adverse effect on the thyroid.

calcitonin value ≥35 ng/L AND ≥50% over the screening value.  In these participants, 
study drug should be stopped, and the participant recommended to immediately 
undergo additional endocrine assessments and longer-term follow-up by an 
endocrinologist.  
Calcitonin Measurement in Participants with eGFR <60 mL/min/1.73m2
A significant increase in calcitonin for participants with eGFR <60 mL/min/1.73m2 is defined as 
a calcitonin value ≥35 ng/L AND ≥50% over the screening value.  If a participant’s labs meet 
these criteria, these clinically significant labs should be recorded as an AE.  
In these participants, study drug should be discontinued (after first confirming the value) and the 
participant recommended to immediately undergo additional endocrine assessments and 
longer-term follow-up by an endocrinologist to exclude any serious adverse effect on the thyroid.
10.3.1.5.
Major Adverse Cardiovascular Events
Deaths and nonfatal cardiovascular AEs will be adjudicated by a committee of physicians 
external to Lilly with cardiology expertise.  This committee will be blinded to treatment 
assignment.  The nonfatal cardiovascular AEs to be adjudicated include

myocardial infarction

hospitalization for unstable angina

hospitalization for heart failure

coronary interventions (such as coronary artery bypass graft or percutaneous coronary 
intervention), and 

cerebrovascular events, including cerebrovascular accident (stroke) and transient 
ischemic attack.
10.3.1.6. Supraventricular Arrhythmias and Cardiac Conduction Disorders
Treatment-emergent cardiac conduction disorders will be further evaluated. Participants who 
develop any event from these groups of disorders should undergo an ECG, which should be 
submitted to the central reading center. The specific diagnosis will be recorded as an AE.  
Events that meet criteria for serious conditions as described in Section 8.3 must be reported as 
SAEs. 

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10.3.1.7. Hypersensitivity Events
All allergic or hypersensitivity reactions will be reported by the investigator as either AEs, or if 
any serious criterion is met, as SAEs.
In the event of suspected drug hypersensitivity reactions (immediate or nonimmediate) in 
subjects who experience moderate-to-severe injection reactions as assessed by the investigator, 
unscheduled blood samples will be collected for PK and ADA analyses at the following time 
points:  

as close as possible to the onset of the event

at the resolution of the event

30 (±3) days following the event.  
Additionally, unscheduled serum samples for immune safety laboratory testing (including, but 
not limited to β tryptase, total IgE, complement, and cytokine panel testing) should also be 
collected at approximately 60 to 120 minutes and 4 to 6 weeks after the onset of the event in 
these participants.  
Additional data, such as type of reaction and treatment received, will be collected on any AEs or 
SAEs that the investigator deems related to study drug(s) via the eCRF created for this purpose.  
Study drug(s) should be temporarily interrupted in any individual suspected of having a severe or 
serious allergic reaction to study drug(s).  Study drug(s) may be restarted when/if it is safe to do 
so, in the opinion of the investigator.  
10.3.1.8.
Injection Site Reactions
Injection site reactions will be collected on the eCRF separate from the hypersensitivity reaction 
eCRF. At the time of AE occurrence, samples will be collected for measurement of tirzepatide
ADA and tirzepatide concentration.
10.3.1.9.
Antidrug Antibodies
The occurrence of ADA formation will be assessed as outlined in Section 8.7.
10.3.1.10. 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 7.
10.3.1.11. 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.
10.3.1.12. Acute Renal Events
Renal safety will be assessed based on repeated renal functional assessment as well as 
assessment of AEs suggestive of acute or worsening of chronic renal failure. Gastrointestinal

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AEs have been reported with tirzepatide, including nausea, diarrhea, and vomiting. This is 
consistent with other 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.
10.3.1.13.
Depression, Suicidal Ideation, or Behavior Monitoring
Participants will be monitored for depression and suicidal ideation or behavior through AE
collection and by using the 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 either Question 4 (Active Suicidal Ideation with 
Some Intent to Act, Without Specific Plan) 
o
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 
o
or 
o
A “yes” answer to any of the suicide-related behaviors (actual attempt, 
interrupted attempt, aborted attempt, preparatory act, or behavior) on 
the “Suicidal Behavior” portion of the C-SSRS.

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10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
If fertility is unclear (for example; amenorrhea in 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: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Article III. Postmenopausal female

A postmenopausal state is defined as either
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 a follicle-stimulating hormone (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. 

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, 
symptothermal, and postovulation methods), declaration of abstinence just for the duration of a 
trial, and withdrawal are not acceptable methods of contraception.

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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 (usual 
lifestyle). In these situations, men are not required to use contraception. 
Men should refrain from sperm donation for the duration of the study and for 5 half-lives of 
study drug plus 90 days after the last dose of study drug, corresponding to 4 months after the last 
injection. 
Collection of Pregnancy Information
Male participants with partners who become pregnant

The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. 

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
Sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure. 
Female Participants who become pregnant

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant’s pregnancy. 

The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported 
as such. Any poststudy pregnancy-related SAE considered reasonably related to the 
study intervention by the investigator will be reported to the Sponsor as described in 
Section 8.3.2. 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.

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
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and be withdrawn from the study.

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10.5.
Appendix 5: Liver Safety: Suggested Actions and Follow-Up 
Assessments
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Antinuclear antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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10.6.
Appendix 6: Medical Device Incidents: Definition and Procedures 
for Recording, Evaluating, Follow-Up, and Reporting
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study.
Medical Device Incident Definition

A medical device incident is any malfunction or deterioration in the characteristics 
and/or performance of a device as well as any inadequacy in the labeling or the 
instructions for use which, directly or indirectly, might lead to or might have led to a 
serious injury, death of a participant/user/other person, or to a serious deterioration 
in his/her state of health.

Not all incidents lead to death or serious deterioration in health. The nonoccurrence of 
such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:

An incident associated with a device happened.

AND

The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:

Life-threatening illness

Permanent impairment of body function or permanent damage to body structure

Condition necessitating medical or surgical intervention to prevent one of the above

Fetal distress, fetal death, or any congenital abnormality or birth defects
Examples of Incidents

A participant, user, caregiver, or health care professional is injured as a result of a 
medical device failure or its misuse.

A participant’s study intervention is interrupted or compromised by a medical 
device failure.

A misdiagnosis due to a medical device failure leads to inappropriate treatment.

A participant’s health deteriorates due to a medical device failure.

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Documenting Medical Device Incidents
Medical Device Incident Documenting

Any medical device incident occurring during the study will be documented in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form of the eCRF.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
eCRF page will be completed as described in Section 8.3.

A product complaint must be submitted describing the issue or deficiency that may 
have led to the incident or AE.

The eCRF will be completed as thoroughly as possible and signed by the 
investigator before transmittal to the Sponsor or designee.

It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by the Sponsor) at the time of the initial 
AE or SAE report and describes any corrective or remedial actions taken to prevent 
recurrence of the incident.

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10.7.
Appendix 7: Protocol GPHK Standardized Protocols for the 
Measurement of Height, Weight, Waist Circumference, 
Vital Signs, Electrocardiogram, and Oral Glucose 
Tolerance Test
The following information has been adapted from standardized physical measurement protocols 
for the World Health Organization’s STEPwise approach to Surveillance (STEPS) (WHO 2008) 
(Available at:
https://www.who.int/ncds/surveillance/steps/Section%204%20Step%202%20Physical%20Measu
rements.pdf) Accessed January 17, 2019.
Measuring Height
Step 1.Ask the participant to remove their footwear and any headgear (light headgear worn for 
religious reasons can remain, but this should be worn by the participant at every clinic visit when 
their height is measured).
Step 2.Ask the participant to stand on the calibrated height measuring board (stadiometer) or 
against a wall with their feet together and their knees straight with their heels against the 
backboard, the stadiometer, or the wall.
Step 3.Ask the participant to look straight ahead without tilting their head up.
Step 4.Ask the participant to breathe in and stand tall. Measure and record the participant’s 
height in centimeters (cm) to 1 decimal place.
Measuring Weight

Body weight measurements should be done in a consistent manner using a calibrated 
electronic scale capable of measuring weight in kilograms (kg) to 1 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 kg.

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Measuring Waist Circumference

Waist circumference should be measured in the horizontal plane and at the midpoint 
between the lower margin of the last palpable rib and the top of the iliac crest.

Measurements should be taken at the end of a normal expiration using a 
nonstretchable measuring tape.  The tape should lie flat against the skin without 
compressing the soft tissue.

The waist circumference should be measured twice, rounded to the nearest 0.5 cm.
The measuring tape should be removed between the 2 measurements. Both 
measurements will be recorded in the eCRF. If the difference between the 2
measurements exceeds 1 cm, this set of measurements should be discarded and the 2
measurements repeated.
Step 1.Ask the participant to wear light clothing (if available, patient gowns could also be used).
Step 2.Ask the participant to stand with their feet close together, arms at their side, body weight 
evenly distributed.
Step 3.Ask the participant to relax and measure the participant’s waist circumference.
Vital Sign Measurements (blood pressure and heart rate)

Vital sign measurements (blood pressure and heart rate, measured by pulse) should be 
taken before obtaining an ECG tracing and before collection of blood samples for 
laboratory testing

The participant should sit quietly for 5 minutes before vital signs measurements are 
taken

For each parameter, 3 measurements will be taken using the same arm, preferably the 
nondominant arm

The recordings should be taken at least 1 minute apart. Each measurement of sitting 
pulse and BP needs to be recorded in the 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.

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
Electrocardiograms should be collected at least 30 minutes prior to collection of 
blood samples for laboratory testing, including PK samples.

Triplicate ECGs (obtained at Week 0 and Week 36) should be obtained 
approximately 1 minute apart, with all 3 tracings to be obtained within approximately 
5 minutes.  Measurements that deviate substantially from previous readings should be 
repeated immediately.
2-Hour Oral Glucose Tolerance Test

Participants should maintain adequate carbohydrate intake for 3 days prior to the 
scheduled 2-hour OGTT.

In the 24 hours preceding the test, patients should refrain from drinking any alcohol 
or performing any extreme physical activity.

Participants should fast for approximately 8 hours before the administration of the test 
and should not eat until the test is complete.

Placement of a venous cannula, preferably in an antecubital vein, is recommended to 
simplify collection of multiple blood samples for glucose, insulin, and C-peptide at 
time 0, 30, 60, 90, and 120 minutes.
Note: Placement of a venous cannula may not be required when a 2-hour OGTT is repeated to 
confirm the diagnosis of diabetes (see Section 4.1.2.3), and only samples at 0 and 120 minutes 
for glucose measurement will be collected.

Immediately after collection of the time 0 sample, a 75-gram glucose dose will be 
given orally, using a commercial product approved for this use (and in a total volume 
of not more than 350 mL).

The participant should consume the glucose load within 5 minutes.

The patient should remain minimally active for the duration of the test.

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10.8.
Appendix 8:  Suggested Visit Structure
Abbreviations:  AEs = adverse events; ECG = electrocardiogram; OGTT = 2-hour oral glucose tolerance test; PK = 
pharmacokinetics; PRO = patient-reported outcomes; SOA = schedule of activities.

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

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10.10.
Appendix 10:  Provisions for Changes in Study Conduct During 
Exceptional Circumstances
There may be times of exceptional circumstances, such as pandemics or natural disasters, which 
may cause disruptions to the conduct of the study. Possible disruptions are limitations in the 
ability to conduct study procedures or ability to have on-site visits occur by participants.
To mitigate the risk of participants missing visits, to allow participants to safely continue in the 
study, and to maintain the data integrity of the study in the case of an exceptional circumstance, 
sites may implement changes to the conduct of the study on a case-by-case basis following 
Sponsor’s written approval (if permitted by local regulations). Good clinical practice compliance 
and minimization of risks to study integrity are important considerations. Ensuring the safety of 
study participants is the prevailing consideration.
Additional written guidance will be provided by the Sponsor in the event written approval is 
granted for changes in study conduct.
The following changes in study conduct captured in this Appendix will not be considered 
protocol deviations. Missing data will be captured as protocol deviation(s).
1. Remote visit (telephone/telemedicine)
Telephone or IT-assisted virtual visits (telemedicine) to complete appropriate assessments are 
acceptable. The study site should capture the visit location and method with a specific 
explanation for any data missing because of missed in-person site visits in source document 
and eCRF. Examples of assessments to be completed in this manner include AEs and product 
complaints, concomitant medications, review study participant diary (including study drug 
compliance), review diet and exercise goals, C-SSRS (Since Last Visit Version), Self-Harm 
Supplement Form, Self-Harm Follow-up Form (if applicable), and PHQ-9.
2. Mobile home health visit
Mobile visits may be performed at participants’ homes when participants cannot travel to the 
site due to exceptional circumstances. These will be performed by a qualified home nursing 
service provider or trained site personnel, following Sponsor written approval (if permitted 
by local regulations). Procedures performed may include, but are not limited to, weight 
measurement, taking blood samples, conducting physical assessments, administering PROs, 
and collecting health information. Please note that requirements related to the reporting of 
SAEs remain unchanged. Every effort should be made for the participant to return to on-site
visits as soon as reasonably possible, while ensuring the safety of the participant and 
investigational site staff. 
Additional consent from the participant will be obtained for those who participate in home 
health services.
3. Investigational product and ancillary supplies (including participant diaries)
In cases when a participant is unable to come to site to receive trial supplies during normal 
on-site visit, the site should work with the Sponsor to determine appropriate actions to 
receive trial supplies. This may include a participant coming to the site to receive trial 
supplies only from site staff without full completion of a visit, a participant-approved 

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designee coming to the site to receive trial supplies on a participant’s behalf, or delivery to a 
participant’s home.
The following requirements must be met:

Sponsor approves the alternative method of delivery, taking local regulatory 
requirements into consideration

participant consents verbally to alternate method of delivery  

site/Sponsor confirms the participant’s receipt of the trial supplies

site/Sponsor confirm appropriate ethics review board notification

alternate delivery of investigational product 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 

when delivering supplies to a participant’s home:
o
participant consent must include provision of any personal information
o
investigator/Sponsor should ensure oversight of the shipping process to ensure
accountability and product quality (i.e., storage conditions and intact 
packaging upon receipt)

additional instructions should be provided to the participant on how to return any 
unused or completed trial supplies
4. Local laboratory option
In exceptional circumstances, to ensure participant safety and with the Sponsor's prior written 
approval, local laboratory testing may be conducted in lieu of central laboratory testing. The 
local laboratory must be qualified in accordance with local regulations. Clinically significant 
laboratory findings must be recorded as an adverse event in the AE eCRF. 
5. Screening period guidance 
To ensure safety of study participants, laboratory values and other eligibility assessments 
taken at Visit 1 are valid for a maximum of 90 days. Therefore, the following rules will be 
applied for participants who are paused in an active, non-randomized status due to 
exceptional circumstances:   

Paused for less than 90 days from Visit 1 to Visit 3: the participant will proceed to the 
next study visit per the schedule of activities in the protocol and Visit 3 
(randomization visit) must be conducted within 90 days from Visit 1. 
o
The site should proceed with the next visit if eligibility criteria are confirmed 
and document the reason for delay in the eCRF.
o
Due to the pause in screening, sites should also reconfirm each participant’s 
consent and document in the source documentation.

Paused for more than 90 days from Visit 1 to Visit 3: The participant must be 
discontinued from the study and rescreened. The screening procedures per the 
schedule of activities in the protocol should be followed (starting at Visit 1) to ensure 
participant eligibility by randomization visit (Visit 3). Before rescreening, the 

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participant must sign a new ICF and receive a new identification number through 
IWRS.
6. Increasing visit window(s) for primary and secondary endpoint visits

Participants should complete primary endpoint visit (Visit 21 or 99) and the final 
study endpoint visit (Visit 116 or 199) as per original schedule whenever possible and 
safe to do so, at the investigator’s discretion. However, in order to maximize the 
ability for such on-site visits, minimize missing data, and preserve the intended 
conduct of the study, the visit windows may be brought forward no sooner than 
14 days or extended up to 28 days, upon specific guidance from the Sponsor.

For the following 2 secondary endpoint visits, Visit 8 (the key secondary endpoint 
visit) and Visit 12 (the 36-week interim analysis endpoint visit), the visit windows 
may be brought forward no sooner than 7 days or extended up to 7 days, upon 
specific guidance from the Sponsor.

For participants requiring the visit windows to be extended, additional study drug
may need to be provided to avoid study drug interruption and maintain overall 
integrity of the trial. Additional consent from the participant per local regulations will 
be obtained for those participants who will be dispensed additional study drug during 
the extended treatment period.
7. Documentation
a. Changes to study conduct
Changes to study conduct will be documented as the following:

Sites will need to identify and document the details of how all participants, visits,
methods, and activities conducted were affected by exceptional circumstances. All 
dispensing/shipment records of IP and relevant communications, including delegation, 
should be filed with site trial records.

The site should document the participant’s verbal consent for having remote visits
and remote dispensing of IP, ancillaries, and diaries, prior to implementation of these 
activities.

Source document(s) that are generated at participant’s home should be part of the 
investigator’s source documentation and should be transferred to the site in a secure 
and timely manner. 
b. Missing data and other protocol deviations 
The study site should capture specific explanation for any missing data and other protocol 
deviations in source documents and eCRF. While protocol deviations may be 
unavoidable in an exceptional circumstance, documentation of deviations and missing 
data will be important for data analysis and reporting.
8. Informing ethical review boards (ERBs)

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The Sponsor and study investigators will notify ERBs as early as possible to 
communicate implementation of changes in study conduct due to exceptional
circumstances. To protect the safety of study participants, urgent changes may be 
implemented before such communications are made, but all changes will be reported as 
early as possible following implementation.

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10.11. Appendix 11:  Abbreviations
Term
Definition
ADA
antidrug antibodies
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
AESI
adverse events (AEs) of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BG
blood glucose
BMI
body mass index
BMR
basal metabolic rate
BP
blood pressure
CHF
congestive heart failure
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, good clinical practice (GCP), and applicable regulatory 
requirements.
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form
CRP
clinical research physician: Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer.
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale
CT
computed tomography

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CVD
cardiovascular disease
DMC
data monitoring committee
DPP-4
dipeptidyl-peptidase-4
EAS
efficacy analysis set
ECG
electrocardiogram
ED
early discontinuation of treatment
EDC
electronic data capture
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
FAS
full analysis set
FG
fasting glucose
FSH
follicle-stimulating hormone
GCP
good clinical practice
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
GPGA
Study I8F-MC-GPGA
GPGB
Study I8F-MC-GPGB
GPGF
Study I8F-MC-GPGF
GPHK (SURMOUNT-1)
Study I8F-MC-GPHK
HbA1c
hemoglobin A1c

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HDL
high-density lipoprotein
HR
heart rate
HRT
hormonal replacement therapy
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.
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
INR
international normalized ratio
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 
ITT
intention to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IWQOL-Lite-CT
Impact of Weight on Quality of Life-Lite-Clinical trials
IWRS
interactive web-response system
LDL
low-density lipoprotein
Lilly
Eli Lilly and Company
MAD
multiple ascending dose
MDD
Major Depressive Disorder
MedDRA
Medical Dictionary for Regulatory Activities
MEN
multiple endocrine neoplasia

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MHP
mental health professional
MI
myocardial infarction
mITT
modified intention-to-treat
MMRM
mixed-model for repeated measures
MRI
magnetic resonance imaging
MTC
medullary thyroid carcinoma
NYHA
New York Heart Association
OGTT
oral glucose tolerance test
PC
Product Complaints
PGIS
Patient Global Impression of status for physical activity
PHQ-9
Patient Health Questionnaire-9
PK/PD
pharmacokinetics/pharmacodynamics
PROs/ePRO
patient-reported outcomes
QW
once weekly
SAD
single ascending dose
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SD
standard deviation
SF-36v2
Short-Form-36 Health Survey (SF-36), version 2
SMQ
standardized MedDRA queries
SS
safety analysis set
SUSARs
suspected unexpected serious adverse reactions
T1DM
type 1 diabetes mellitus

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T2DM
type 2 diabetes mellitus
TBL
total bilirubin level
TE
treatment emergent
TEAE
treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
TEE
total energy exposure
TSH
thyroid-stimulating hormone
ULN
upper limit of normal

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10.12.
Appendix 12: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Amendment a: (24-July-2020)
Overall Rationale for the Amendment
The GPHK clinical protocol has been amended to extend the safety follow-up period in order to 
better characterize the glycemic status of study participants.  The overall changes and rationale 
for the changes made to this protocol are described in the following table. Note that minor edits 
have been made throughout the protocol, which are not captured in the amendment summary 
table.
Section # and Name
Description of Change
Brief Rationale
1.2 Schema 
1.3.2 Schedule of 
Activities
Figure updated to reflect the 
extended safety follow-up period 
and Schedule of Activities 
changed Visit 802 to 17 weeks 
posttreatment period 
The safety follow-up period has 
been extended to 17 weeks to 
address regulatory feedback 
from Type C advice meeting 
with FDA (26 June 2019).
9.5 Interim Analysis
Two more interim analyses were 
added and text revised 
Additional interim analyses were 
requested by an external DMC to 
perform unblinded safety 
reviews semi-annually.
Details pertaining to the timing 
of interim analyses was added.
1.1 Synopsis
3 Objectives and 
Endpoint
9.1 Statistical 
Hypothesis
9.4.3.2 Key Secondary 
Analyses
A key secondary objective was 
added (time to onset of T2DM 
during the entire study) with the 
associated endpoint and statistical 
hypothesis 
An additional key secondary 
objective was added per FDA 
request from Type C advice 
meeting with FDA (26 June 
2019).
10.10 Appendix 10
An appendix describing mitigation 
for extenuating circumstances was 
added as Section 10.10  Appendix 
10
The Abbreviation Appendix 10 is 
now Appendix 11
Language was added to address 
extenuating circumstances due to 
unforeseen widespread 
emergencies (such as pandemics 
or natural disasters).
9.4.3.1 Primary 
A sentence related to selection of 
variance-covariance structure in 
The details will be provided in 

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Section # and Name
Description of Change
Brief Rationale
Analysis
case of nonconvergence was 
deleted
the Statistical Analysis Plan.
1.3 Schedule of 
Activities
Allowable deviation (days) for 
Visit 21 was changed from 
+7 days to ±7 days
This change allows more 
flexibility for participants to 
schedule the primary study 
endpoint visit.  
1.3 Schedule of 
Activities
Added measurement of waist 
circumference to Visit 199 
The measurement was added to 
obtain 3 year waist 
circumference data for 
participants who discontinue the 
study treatment early but come 
to the 3-year endpoint visit. 
4.1.1.2.3 Continued 
Follow-up for 
Participants with 
Prediabetes (Visits 101 
through 116)
Measurement of waist 
circumference added to list of visit 
procedures
The text was added to align with 
changes in the Schedule of 
Activities regarding 
measurement of waist 
circumference at Visit 199.
1.3 Schedule of 
Activities
Added an activity entitled “register 
study visit in IWRS”
The activity was added to the 
SOA to ensure all visits are 
registered.  This allows 
monitoring of study activities 
using real-time IWRS reports.
10.4 Appendix 4 
Contraceptive 
Guidance and 
Collection of 
Pregnancy Information
Added text “more than 18 months”
The sentence was revised to 
maintain consistency with the 
text from the exclusion criteria.
10.4 Appendix 4 
Contraceptive 
Guidance and 
Collection of 
Pregnancy Information
Note regarding follicle stimulating 
hormone levels used to confirm a 
postmenopausal state in women
has been deleted 
The note could lead to 
misinterpretation of inclusion 
criterion 4.

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11.
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Leo Document ID = 8dd79a8d-d134-4b80-afb3-6ce848a2570c
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Approval Date & Time: 01-Oct-2021 16:14:59 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 04-Oct-2021 15:48:26 GMT
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