A Phase 3b, Randomized Controlled Study to Evaluate the Efficacy and Safety of Tirzepatide Compared to Semaglutide in Adults Who Have Obesity or Overweight With Weight Related Comorbidities
Phase: PHASE3
Conditions: Obesity, Overweight
Sponsor: Eli Lilly and Company

Protocol(c): I8F-MC-GPHJ 
 
 
 
A Phase 3b, Randomized Controlled Study to Evaluate the Efficacy and Safety of Tirzepatide 
Compared to Semaglutide in Adults Who Have Obesity or Overweight with Weight-Related 
Comorbidities (SURMOUNT-5) 
 
 
NCT05822830 
 
 
 
Approval Date: 24-Aug-2023 

CONFIDENTIAL 
I8F-MC-GPHJ(c) 
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Title Page  
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of Tirzepatide (LY3298176), unless such persons are bound by a confidentiality agreement with Eli Lilly and Company 
or its subsidiaries.  
 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: 
A Phase 3b, Randomized Controlled Study to Evaluate the Efficacy and Safety of Tirzepatide 
Compared to Semaglutide in Adults Who Have Obesity or Overweight with Weight-Related 
Comorbidities (SURMOUNT-5) 
Protocol Number: I8F-MC-GPHJ 
Amendment Number: c 
Compound: Tirzepatide (LY3298176) 
Brief Title: 
Efficacy and Safety of Tirzepatide Compared to Semaglutide in Adults Who Have Obesity or 
Overweight (SURMOUNT-5) 
Study Phase: 3b 
Acronym: SURMOUNT-5 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s) 
IND: 139721 
EU Number: 2022-501106-35-00 
Document ID: VV-CLIN-116398 
Approval Date: Protocol Amendment (c) Electronically Signed and Approved by Lilly on date 
provided below. 
 
 
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Medical Monitor Name and Contact Information will be provided separately. 
 
 
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Protocol Amendment Summary of Changes Table  
 
DOCUMENT HISTORY 
Document 
Date 
Amendment (b) 
20-Jun-2023 
Amendment (a) 
29-Jul-2022 
Original Protocol 
23-Jun-2022 
Amendment [c]  
Overall Rationale for the Amendment: 
This amendment reflects updates made in the most recent version of the US Semaglutide 
(Wegovy) package insert. Updates have also been made throughout the protocol to remove the 
safety-follow-up visit (Visit 801). The safety follow-up visit is no longer required given available 
safety information from similar duration of exposure to semaglutide or tirzepatide at all doses 
being studied. Corrections and clarifications have also been added where needed. 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page and 1.1 Synopsis 
Removed “2.4 mg” from 
semaglutide dose in 
protocol title 
To reflect the most recent 
information in the US package 
insert. 
1.1 Synopsis 
Updated “Rationale”, 
“Objectives, Endpoints, 
and Estimands”, and 
“Overall Design” sections 
to reflect the maximum-
tolerated dose of 
semaglutide (1.7 mg or 
2.4 mg) 
To reflect the most recent 
information in the US package 
insert. 
Updated “Overall Design”, 
“Brief Summary”, and 
“Ethical Considerations of 
Benefit/Risk” sections to 
reflect the change in study 
duration from 78 weeks to 
74 weeks and removal of 
safety follow-up period 
The safety follow-up visit (Visit 
801) is no longer required. 
Updated “Ethical 
Considerations of 
Benefit/Risk” section to 
reflect change in duration 
of medical care from 76 
weeks to 72 weeks 
The safety follow-up visit (Visit 
801) is no longer required. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.2 Schema 
Removed Visit 801 
The safety follow-up visit (Visit 
801) is no longer required. 
Updated the semaglutide 
dose to include 1.7 mg as a 
possible maintenance dose 
To reflect the most recent 
information in the US package 
insert. 
1.3 Schedule of Activities 
(SoA) 
 
Removed Visit 801 
The safety follow-up visit (Visit 
801) is no longer required. 
“Site transmits study 
intervention prescription 
for central pharmacy study 
intervention dispensing” 
row:  
Added “as needed” to visit 
detail 
Clarification 
2.1 Study Rationale 
Added information about 
the maximum-tolerated 
dose of semaglutide 
(1.7 mg or 2.4 mg) 
To reflect the most recent 
information in the US package 
insert. 
2.2 Background 
Updated information about 
the semaglutide dose 
To reflect the most recent 
information in the US package 
insert. 
2.3.1 Risk Assessment 
Updated 2.4 mg 
semaglutide to 1.7 mg 
semaglutide 
To reflect the most recent 
information in the US package 
insert. 
2.3.3 Overall Benefit Risk 
Conclusion 
Updated the duration of 
medical care from 76 
weeks to 72 weeks 
The safety follow-up visit (Visit 
801) is no longer required. 
3. Objectives, Endpoints, 
and Estimands 
Added information about 
the maximum-tolerated 
dose of semaglutide 
(1.7 mg or 2.4 mg) 
To reflect the most recent 
information in the US package 
insert. 
Added an additional 
secondary objective for 
mean percent decrease in 
weight loss 
To investigate a scientifically 
relevant question. 
4.1 Overall Design 
Added information about 
the maximum-tolerated 
dose of semaglutide 
(1.7 mg or 2.4 mg) and 
information about the 
To reflect the most recent 
information and the safety follow-
up visit (Visit 801) is no longer 
required. 
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Section # and Name 
Description of Change 
Brief Rationale 
safety-follow up period 
has been removed 
4.1.2.2 Treatment Period 
End of Visit 2 to Visit 8 
Added information about 
the maximum-tolerated 
dose of semaglutide 
(1.7 mg or 2.4 mg) 
To reflect the most recent 
information in the US package 
insert. 
End of Visit 8 to Visit 20 
Added “as needed” to 
transmission of 
prescription for central 
pharmacy study 
intervention dispensing 
Clarification 
Early discontinuation 
visit 
Removed “of treatment” 
from title of section and 
throughout section and 
added reference to Section 
7.1 
Clarification 
4.1.2.3 Safety Follow-Up 
Period 
This section has been 
removed 
The safety follow-up visit (Visit 
801) is no longer required. 
4.2 Scientific Rationale for 
Study Design 
Added information about 
the maximum-tolerated 
dose of semaglutide 
(1.7 mg or 2.4 mg) and 
removed information 
about the safety follow-up 
period 
To reflect the most recent 
information in the US package 
insert and the safety follow-up 
visit (Visit 801) is no longer 
required. 
4.3 Justification for Dose 
Added the word 
“recommended” to 
semaglutide maintenance 
dose of 2.4 mg and added 
information about the 
maximum-tolerated dose 
of semaglutide (1.7 mg or 
2.4 mg) 
To reflect the most recent 
information in the US package 
insert. 
5.2 Exclusion Criteria 
EC 36: removed 2.4 mg 
from dose of Wegovy 
To reflect the most recent 
information in the US package 
insert. 
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Section # and Name 
Description of Change 
Brief Rationale 
5.3.1 Meals and Dietary 
Restrictions 
Revised to allow either 
tirzepatide or semaglutide 
dose to be reduced in case 
a participant reaches BMI 
≤22 kg/m
2 
To reflect the most recent 
information in the US package 
insert. 
6.1 Study Intervention(s) 
Administered 
Updated semaglutide 
dosage level 
To reflect the most recent 
information in the US package 
insert. 
6.5 Dose Modification 
Revised to allow either 
tirzepatide or semaglutide 
dose to be reduced in case 
a participant reaches BMI 
≤22 kg/m2 
To reflect the most recent 
information in the US package 
insert. 
6.5.2 Semaglutide 
Updated information 
regarding semaglutide 
dose escalation phase and 
maintenance dose phase 
To reflect the most recent 
information in the US package 
insert. 
Removed “weight 
maintenance” from 
footnote a in “Tirzepatide 
and Semaglutide 
Temporary Dose 
Adjustment Schedule” 
table 
To reflect the most recent 
information in the US package 
insert. 
6.6 Continued Access to 
Study Intervention after the 
End of the Study 
Removed semaglutide 
dose 
To reflect the most recent 
information in the US package 
insert. 
7.1 Discontinuation of 
Study Intervention 
Removed information 
about the safety follow-up 
visit and added clarifying 
language regarding ED 
visit 
The safety follow-up visit (Visit 
801) is no longer required. 
Removed pregnancy from 
list of clinical 
considerations for 
permanent discontinuation 
from study intervention 
Duplication 
7.2 Participant 
Discontinuation/Withdrawal 
from the Study 
Removed information 
about the safety follow-up 
visit 
The safety follow-up visit (Visit 
801) is no longer required. 
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Section # and Name 
Description of Change 
Brief Rationale 
8.2.4 Clinical Safety 
Laboratory Tests 
Removed “or within 4 
weeks after the last dose of 
study intervention” from 
the requirement to repeat 
abnormal laboratory tests 
The safety follow-up visit (Visit 
801) is no longer required. 
8.3.1 Timing and 
Mechanism for Collecting 
Events 
Removed information 
about the safety follow-up 
visit 
The safety follow-up visit (Visit 
801) is no longer required. 
8.3.3.7 Arrhythmias and 
Cardiac Conduction 
Disorders 
Removed information 
about central reading 
center 
Correction 
9.1 Statistical Hypotheses 
Added information about 
the maximum-tolerated 
dose of semaglutide (1.7 
mg or 2.4 mg) 
To reflect the most recent 
information in the US package 
insert. 
9.2 Analyses Sets 
Safety Analysis Set (SS) 
description: Updated 
“Treatment Period plus 
Safety Follow-up” to 
“study” 
The safety follow-up visit (Visit 
801) is no longer required. 
9.3.2 Primary Endpoint 
Analysis 
Added information about 
maximum-tolerated dose 
of semaglutide 
To reflect the most recent 
information in the US package 
insert. 
9.3.4 Safety Analyses 
Updated “safety follow-
up” to “study 
participation” 
The safety follow-up visit (Visit 
801) is no longer required. 
9.5 Sample Size 
Determination 
Added information about 
maximum-tolerated dose 
of semaglutide 
To reflect the most recent 
information in the US package 
insert. 
10.4.2 Contraception 
Guidance 
Added clarification about 
adding second form of 
contraception in females 
who had bilateral tubal 
ligation 
Clarification 
10.10 Appendix 10: 
Provisions for Changes in 
Study Conduct During 
Exceptional Circumstances 
Adjustments to visit 
windows: 
Removed Visit 801 
The safety follow-up visit (Visit 
801) is no longer required. 
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Section # and Name 
Description of Change 
Brief Rationale 
11. References and 
throughout 
Updated reference and 
citations for Wegovy 
package insert  
To reflect the most recent 
information in the US package 
insert. 
Throughout 
Minor editorial changes 
For clarity 
 
 
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Table of Contents  
1. 
Protocol Summary ........................................................................................................12 
1.1. 
Synopsis ..........................................................................................................................12 
1.2. 
Schema ............................................................................................................................15 
1.3. 
Schedule of Activities (SoA) ..........................................................................................16 
2. 
Introduction ...................................................................................................................24 
2.1. 
Study Rationale ...............................................................................................................24 
2.2. 
Background .....................................................................................................................24 
2.3. 
Benefit/Risk Assessment ................................................................................................25 
2.3.1. 
Risk Assessment .............................................................................................................25 
2.3.2. 
Benefit Assessment .........................................................................................................26 
2.3.3. 
Overall Benefit Risk Conclusion ....................................................................................26 
3. 
Objectives, Endpoints, and Estimands .......................................................................27 
4. 
Study Design ..................................................................................................................30 
4.1. 
Overall Design ................................................................................................................30 
4.1.1. 
Overview of Study Periods .............................................................................................30 
4.1.2. 
Main Study Period ..........................................................................................................30 
4.1.3. 
Study Procedures ............................................................................................................32 
4.2. 
Scientific Rationale for Study Design ............................................................................33 
4.3. 
Justification for Dose ......................................................................................................34 
4.4. 
End of Study Definition ..................................................................................................35 
5. 
Study Population ...........................................................................................................36 
5.1. 
Inclusion Criteria ............................................................................................................36 
5.2. 
Exclusion Criteria ...........................................................................................................38 
5.3. 
Lifestyle Considerations .................................................................................................42 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................42 
5.3.2. 
Monitoring nutritional needs...........................................................................................43 
5.3.3. 
Activity ...........................................................................................................................43 
5.4. 
Screen Failures ................................................................................................................43 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant .....................................44 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................45 
6.1. 
Study Intervention(s) Administered................................................................................45 
6.1.1. 
Medical Devices..............................................................................................................45 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................45 
6.2.1. 
Investigator Site Responsibilities ....................................................................................45 
6.2.2. 
Direct-to-Participant Study Intervention Access ............................................................46 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................46 
6.4. 
Study Intervention Compliance ......................................................................................47 
6.5. 
Dose Modification ..........................................................................................................47 
6.5.1. 
Tirzepatide ......................................................................................................................47 
6.5.2. 
Semaglutide.....................................................................................................................49 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................50 
6.7. 
Treatment of Overdose ...................................................................................................50 
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6.8. 
Concomitant Therapy .....................................................................................................51 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................52 
7.1. 
Discontinuation of Study Intervention ............................................................................52 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................54 
7.1.2. 
QTc Stopping Criteria .....................................................................................................54 
7.1.3. 
Temporary Discontinuation ............................................................................................54 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................55 
7.3. 
Lost to Follow-up............................................................................................................56 
8. 
Study Assessments and Procedures.............................................................................57 
8.1. 
Efficacy Assessments .....................................................................................................57 
8.2. 
Safety Assessments .........................................................................................................58 
8.2.1. 
Physical Examinations ....................................................................................................58 
8.2.2. 
Vital Signs .......................................................................................................................58 
8.2.3. 
Electrocardiograms .........................................................................................................58 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................59 
8.2.5. 
Pregnancy Testing ...........................................................................................................60 
8.2.6. 
Suicidal Ideation and Behavior Risk Monitoring ...........................................................60 
8.2.7. 
Hepatic Safety Monitoring ..............................................................................................60 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................62 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................63 
8.3.2. 
Pregnancy ........................................................................................................................65 
8.3.3. 
Adverse Events of Special Interest .................................................................................66 
8.4. 
Pharmacokinetics ............................................................................................................71 
8.5. 
Pharmacodynamics .........................................................................................................71 
8.6. 
Genetics ..........................................................................................................................71 
8.7. 
Biomarkers ......................................................................................................................72 
8.8. 
Immunogenicity Assessments.........................................................................................72 
8.9. 
Health Economics ...........................................................................................................72 
9. 
Statistical Considerations .............................................................................................73 
9.1. 
Statistical Hypotheses .....................................................................................................73 
9.1.1. 
Multiplicity Adjustment ..................................................................................................73 
9.2. 
Analyses Sets ..................................................................................................................74 
9.3. 
Statistical Analyses .........................................................................................................74 
9.3.1. 
General Considerations ...................................................................................................74 
9.3.2. 
Primary Endpoint Analysis .............................................................................................75 
9.3.3. 
Secondary Endpoints Analysis .......................................................................................76 
9.3.4. 
Safety Analyses ...............................................................................................................77 
9.3.5. 
Subgroup Analysis ..........................................................................................................78 
9.4. 
Interim Analysis ..............................................................................................................78 
9.5. 
Sample Size Determination ............................................................................................78 
10. 
Supporting Documentation and Operational Considerations ..................................79 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................79 
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10.1.1. Regulatory and Ethical Considerations ...........................................................................79 
10.1.2. Financial Disclosure........................................................................................................80 
10.1.3. Informed Consent Process ..............................................................................................80 
10.1.4. Data Protection................................................................................................................80 
10.1.5. Committees Structure......................................................................................................81 
10.1.6. Dissemination of Clinical Study Data.............................................................................81 
10.1.7. Data Quality Assurance ..................................................................................................81 
10.1.8. Source Documents ..........................................................................................................83 
10.1.9. Study and Site Start and Closure ....................................................................................83 
10.1.10. Publication Policy ...........................................................................................................84 
10.1.11. Investigator Information .................................................................................................84 
10.1.12. Sample Retention ............................................................................................................84 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................85 
10.2.1. Appendix 10.2.1. Laboratory Samples to be Obtained at the Time 
of a Systemic Hypersensitivity Event .............................................................................87 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................88 
10.3.1. Definition of AE .............................................................................................................88 
10.3.2. Definition of SAE ...........................................................................................................89 
10.3.3. Definition of Product Complaints ...................................................................................90 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................91 
10.3.5. Reporting of SAEs ..........................................................................................................93 
10.3.6. Regulatory Reporting Requirements ...............................................................................93 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................95 
10.4.1. Definitions.......................................................................................................................95 
10.4.2. Contraception Guidance..................................................................................................96 
10.5. 
Appendix 5: Genetics......................................................................................................99 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-Up 
Assessments ..................................................................................................................100 
10.6.1. Hepatic Evaluation Testing ...........................................................................................100 
10.7. 
Appendix 7: Suggested Visit Structure .........................................................................102 
10.8. 
Appendix 8: Protocol GPHJ Standardized Protocols for the 
Measurement of Height, Weight, Waist Circumference, Vital 
Signs, and Electrocardiogram .......................................................................................103 
10.9. 
Appendix 9: World Health Organization Classification of 
Diabetes and American Diabetes Association Diagnostic Criteria ..............................105 
10.10. 
Appendix 10: Provisions for Changes in Study Conduct During 
Exceptional Circumstances ...........................................................................................106 
10.11. 
Appendix 11: Abbreviations and Definitions ...............................................................110 
10.12. 
Appendix 12: Protocol Amendment History ................................................................115 
11. 
References ....................................................................................................................122 
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1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title: 
A Phase 3b, Randomized Controlled Study to Evaluate the Efficacy and Safety of Tirzepatide 
Compared to Semaglutide in Adults Who Have Obesity or Overweight with Weight-Related 
Comorbidities (SURMOUNT-5) 
Brief Title: 
Efficacy and Safety of Tirzepatide Compared to Semaglutide in Adults Who Have Obesity or 
Overweight (SURMOUNT-5) 
Regulatory Agency Identifier Number(s): 
IND: 139721 
EU Number: 2022-501106-35-00 
Rationale: 
This Phase 3b study will evaluate the efficacy and safety of once-weekly treatment with 
tirzepatide 15 mg or the maximum-tolerated dose of tirzepatide (10 mg or 15 mg) compared with 
semaglutide 2.4 mg or the maximum-tolerated dose of semaglutide (1.7 mg or 2.4 mg) on change 
in body weight in adult participants who have obesity (BMI ≥30 kg/m2) or overweight (BMI 
≥27 kg/m2) with weight-related comorbidities. 
Objectives, Endpoints, and Estimands: 
Objectives 
Endpoints 
Primarya 
 
To demonstrate that tirzepatide at 15 mg or MTD (10 mg 
or 15 mg) is superior to semaglutide at 2.4 mg or MTD 
(1.7 mg or 2.4 mg) for the mean percent decrease in 
weight loss  
Percent change from baseline in body weight at 72 
weeks 
Key Secondarya 
 
To demonstrate that tirzepatide at 15 mg or MTD (10 mg 
or 15 mg) is superior to semaglutide at 2.4 mg or MTD 
(1.7 mg or 2.4 mg) at Week 72 for: 
 
 
Body weight 
Body weight reduction from baseline of: 
 
≥10% 
 
≥15% 
 
≥20%, and 
 
≥25%  
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 
Waist circumference 
Change from baseline in waist circumference (cm)  
Additional Secondary 
 
To compare tirzepatide at 15 mg or MTD (10 mg or 
15 mg) to semaglutide at 2.4 mg or MTD (1.7 mg or 2.4 
mg) at Week 72 for: 
 
 
Body weight  
Change from baseline in body weight (kg) 
Body weight reduction from baseline of ≥30% 
 
BMI 
Change from baseline in BMI (kg/m2) 
To compare tirzepatide at 15 mg to semaglutide at 
2.4 mg for the mean percent decrease in weight loss 
Percent change from baseline in body weight at 72 
weeks 
Abbreviations: BMI = body mass index; MTD = maximum-tolerated dose. 
 a Primary and key secondary endpoints are controlled for multiplicity. 
Overall Design: 
This is a Phase 3b, parallel-design, open-label, randomized active-controlled study to evaluate 
the efficacy and safety of once-weekly treatment with 15 mg or the maximum-tolerated dose 
(MTD) of tirzepatide (10 mg or 15 mg) compared with semaglutide or MTD of semaglutide (1.7 
mg or 2.4 mg) on change in body weight in adult participants who have obesity (BMI ≥30 kg/m2) 
or overweight (BMI ≥27 kg/m2) with weight-related comorbidities. 
The study includes a 2-week screening period and a 72-week treatment period. 
Brief Summary: 
This is a study to compare the weight loss efficacy of tirzepatide to semaglutide in people with 
obesity or overweight, without Type 2 diabetes. The trial will last 74 weeks, including 72 weeks 
on study intervention, and include 20 visits. 
The primary outcome is the change in body weight at 72 weeks. 
Study Population: 
In general, participants may take part in the study if they 
 are 18 years of age or older 
 have a BMI ≥30 kg/m2 or ≥27 kg/m2 and previously diagnosed with at least 1 
weight-related comorbidity (excluding Type 2 diabetes), and 
 have a history of at least 1 self-reported unsuccessful dietary effort to lose body weight. 
In general, participants may not take part in the study if they 
 have Type 1 diabetes or Type 2 diabetes or a history of ketoacidosis or hyperosmolar 
state or coma 
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 have a self-reported change in body weight >5 kg within 3 months prior to screening 
 are women who are pregnant, lactating, or breastfeeding, or 
 have a history or presence of an underlying disease, or surgical, physical, or medical 
condition that, in the opinion of the investigator, would potentially affect participant 
safety within the study or interfere with the interpretation of data. 
Number of Participants: 
Approximately 700 participants will be randomly assigned to tirzepatide and semaglutide in a 
1:1 ratio. With the assumption of a 20% discontinuation rate of study intervention, 
approximately 280 participants will complete 72 weeks of treatment for each treatment group. 
Intervention Groups and Duration: 
Participants who meet entry criteria will be randomly assigned in a 1:1 ratio tirzepatide or 
semaglutide treatment. Tirzepatide and semaglutide will be administered once-weekly. 
The study treatment period is 72 weeks. 
Ethical Considerations of Benefit/Risk: 
The potential benefits from participation in this study, which include frequent expert medical 
care for up to 72 weeks and the chance for achieving body weight reduction, are expected to 
outweigh the described risks, which will be closely monitored and managed through the 
established procedures. 
Data Monitoring Committee: No 
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1.2. Schema  
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1.3. 
Schedule of Activities (SoA)  
The SoA described below should be followed for all participants enrolled in Study I8F-MC-GPHJ (GPHJ). 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 for additional guidance. 
Period I – Screening (Visit 1): Visit 1 procedures may be conducted over more than 1 day as long as all activities are completed 
within the allowable visit tolerance. 
Period II – Treatment period (Visits 2-20): For early discontinuation that occurs before the last visit in treatment period, see the 
activities listed for ED in this table. Participants who are unable or unwilling to continue the study for any reason will perform an ED 
visit. If the participant is discontinuing during an unscheduled visit or a scheduled visit, that visit should be performed as an ED visit 
(See Section 7.1). 
Telephone visits 
Telephone visits may be by telephone or other technology. Gray-shaded columns in the SoA tables represent telephone visits. 
Fasting visits 
On all office visits, study participants should be reminded to report to the site in a fasting condition, after a period of approximately 8 
hours without eating, drinking (except water), or any significant physical activity. If a participant attends a fasting visit in a non-
fasting state, they will be offered to return in fasting state; if they are not able to return, then the samples should be collected as a non-
fasting and this will not be considered a protocol deviation. However, if a participant attends Visits 2, 8, 11, 15, or 20 in the non-
fasting state, these visits must be rescheduled. 
If a participant is adversely affected by the fasting condition, they can be allowed to eat after specific study procedures that need to be 
completed while fasting. See Section 10.7 for a suggested order of activities that occurs at office visits. 
 
 
 
 
 
 
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CONFIDENTIAL 
I8F-MC-GPHJ(c) 
Page 17 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
ED 
Weeks from 
randomization  
-2 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
— 
Visit interval 
tolerance (days) 
-21 to -7  
_ 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
— 
Visit Detail 
F 
F 
F 
F 
F 
F 
F 
F 
T 
T 
F 
T 
T 
F 
F 
T 
F 
T 
T 
F 
F 
F = fasting visit; T = telephone visit (shaded columns) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The informed consent form must be signed before any protocol-specific tests or procedures are performed. 
See Appendix 10.1, Section 10.1.3, for additional details. 
Inclusion and 
exclusion criteria, 
review and confirm 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria should be confirmed prior to drug assignment and administration of first dose of study intervention. 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes ethnicity (where permissible), year of birth, sex, and race. 
Preexisting 
conditions and 
medical history, 
including relevant 
surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All conditions ongoing and relevant past surgical and medical history should be collected. 
Prespecified 
medical history 
(indication and 
history of interest) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Should include, but not limited to, collecting diagnosis of obesity, and obesity-related health problems. 
Prior treatments for 
indication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Include medications used for overweight or obesity. 
Substance use 
(alcohol, tobacco 
use) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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I8F-MC-GPHJ(c) 
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Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
ED 
Weeks from 
randomization  
-2 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
— 
Visit interval 
tolerance (days) 
-21 to -7  
_ 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
— 
Visit Detail 
F 
F 
F 
F 
F 
F 
F 
F 
T 
T 
F 
T 
T 
F 
F 
T 
F 
T 
T 
F 
F 
F = fasting visit; T = telephone visit (shaded columns) 
AE collection begins when the ICF is signed (Section 8.3.1). For AESIs, additional data could be collected (Section 8.3.3). 
Evaluation of 
antihypertensive or 
lipid-lowering 
treatment 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
For participants receiving antihypertensive or lipid-lowering treatment, the investigator should evaluate changes in the 
participant’s treatment intensity within each therapeutic area. The evaluation should be based on whether an overall change from 
randomization until the time of evaluation has occurred. 
Physical Evaluation 
Height  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Weight 
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 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
X 
  
  
X 
X 
  
X 
  
  
X 
X 
Include pulse rate and blood pressure. Measure after participant has been sitting for at least 5 min and before obtaining an ECG 
tracing and before collection of blood samples for laboratory testing. See Section 8.2.2. 
Physical 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 8.2.1 
 
 
 
Symptom-direct 
physical assessment 
 
 
 
 
X (refer to comment below) 
Will be conducted at the discretion of the PI or qualified personnel per local regulations, as indicated based on participant status 
and standard of care for Visits 2-8, 11, 14-15, 17, and 20, ED. If Visits 9, 10, 12, 13, 16, 18, and 19 are performed as telephone 
visits, then the symptom-directed physical assessment will not be done at these visits. 
First day of last 
menstrual cycle in 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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CONFIDENTIAL 
I8F-MC-GPHJ(c) 
Page 19 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
ED 
Weeks from 
randomization  
-2 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
— 
Visit interval 
tolerance (days) 
-21 to -7  
_ 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
— 
Visit Detail 
F 
F 
F 
F 
F 
F 
F 
F 
T 
T 
F 
T 
T 
F 
F 
T 
F 
T 
T 
F 
F 
F = fasting visit; T = telephone visit (shaded columns) 
WOCBP with 
menstrual cycles 
12-lead ECG 
(local) 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Perform prior to collection of blood samples for laboratory testing. Participants should be supine for approximately 5 to 10 min 
before ECG collections and remain supine but awake during the ECG collection. ECGs may be repeated at the investigator’s 
discretion at any visit. See Section 8.2.3. 
Participant Electronic Diary 
Dispense electronic 
diary, instruct to 
use 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary contains the following assessments: exposures and self-reported hypoglycemia. 
Electronic diary 
review 
  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of diary (electronic) 
Electronic diary 
return 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
Participant Paper 3-day Diet and Exercise Log 
Dispense paper log 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
X 
 
 
 
 
Paper log review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Patient-Reported Outcomes (Electronic) 
 
Complete prior to any Clinician Administered Assessments  
Short Form Health 
Survey Version 2 
(SF-36 v2) 
  
X 
  
  
  
  
  
  
  
  
X  
  
  
  
  
  
  
  
  
X 
X 
Patient Global 
Impression of 
Status for Physical 
  
X 
  
  
  
  
  
  
  
  
X  
  
  
  
  
  
  
  
  
X 
X 
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CONFIDENTIAL 
I8F-MC-GPHJ(c) 
Page 20 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
ED 
Weeks from 
randomization  
-2 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
— 
Visit interval 
tolerance (days) 
-21 to -7  
_ 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
— 
Visit Detail 
F 
F 
F 
F 
F 
F 
F 
F 
T 
T 
F 
T 
T 
F 
F 
T 
F 
T 
T 
F 
F 
F = fasting visit; T = telephone visit (shaded columns) 
Activity (PGIS 
Physical Activity) 
Patient Health 
Questionnaire 
(PHQ-9) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
X 
  
  
X 
X 
  
X 
  
  
X 
X 
Clinician-Administered Assessments (Paper) 
C-SSRS 
screening/baseline 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE collection should occur prior to the collection of the C-SSRS. 
C-SSRS since last 
visit 
  
X 
X 
X 
X 
X 
X 
X 
  
  
X 
  
  
X 
X 
  
X 
  
  
X 
X 
AE collection should occur prior to the collection of the C-SSRS. 
Weight history 
questionnaire 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Education 
Lifestyle (diet and 
exercise goals) 
program instruction 
  
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 
Review of 
contraceptive 
measures as 
applicable for 
WOCBP and males 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Laboratory Tests and Sample Collection 
HbA1c 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
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CONFIDENTIAL 
I8F-MC-GPHJ(c) 
Page 21 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
ED 
Weeks from 
randomization  
-2 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
— 
Visit interval 
tolerance (days) 
-21 to -7  
_ 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
— 
Visit Detail 
F 
F 
F 
F 
F 
F 
F 
F 
T 
T 
F 
T 
T 
F 
F 
T 
F 
T 
T 
F 
F 
F = fasting visit; T = telephone visit (shaded columns) 
Hematology  
X 
 
  
  
X 
  
 
X 
  
  
X 
  
  
  
X 
  
  
  
  
X 
X 
Clinical chemistry 
X 
 
  
  
X 
  
 
X 
  
  
X  
  
  
  
X 
  
  
  
  
X 
X 
Lipid panel 
 
X 
  
  
X 
  
 
X 
  
  
X  
  
  
  
 
  
  
  
  
X 
 
 
Serum pregnancy 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For all WOCBP and females with a history of tubal ligation. See Section 8.3.2. 
 
 
 
Urine pregnancy 
(local) 
 
 
 
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
X 
A urine pregnancy test must be performed at Visit 2 with the result available prior to first dose or injection of study intervention 
for all women of childbearing potential only. Additional pregnancy tests (beyond those required per the SoA) should be performed 
at any time during the trial if a menstrual period is missed, there is clinical suspicion of pregnancy, or as required by local law or 
regulation. 
Follicle-
stimulating 
hormone (FSH) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional; performed as needed to confirm postmenopausal status. See Section 10.2. 
Thyroid-
stimulating 
hormone (TSH) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Insulin 
X  
 
  
  
  
  
 
 
  
  
 X 
  
  
  
  
  
  
  
  
X 
 
Cystatin-c 
X 
 
  
  
  
  
 
X 
  
  
  
  
  
  
X 
  
  
  
  
X 
X 
Calcitonin 
X 
 
  
  
 
  
 
X 
  
  
  
  
  
  
X 
  
  
  
  
X 
X 
Pancreatic amylase 
X 
 
  
  
 
  
 
X 
  
  
  
  
  
  
X 
  
  
  
  
X 
X 
Lipase 
X 
 
  
  
 
  
 
X 
  
  
  
  
  
  
X 
  
  
  
  
X 
X 
eGFR 
X 
 
  
  
  
  
 
X 
  
  
  
  
  
  
X 
  
  
  
  
X 
X 
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CONFIDENTIAL 
I8F-MC-GPHJ(c) 
Page 22 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
ED 
Weeks from 
randomization  
-2 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
— 
Visit interval 
tolerance (days) 
-21 to -7  
_ 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
— 
Visit Detail 
F 
F 
F 
F 
F 
F 
F 
F 
T 
T 
F 
T 
T 
F 
F 
T 
F 
T 
T 
F 
F 
F = fasting visit; T = telephone visit (shaded columns) 
Calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method. 
Stored Samples 
Epigenetics sample 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Exploratory 
biomarker samples 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Genetics 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Optional, confirm informed consent before collection. See Section 8.6. 
Randomization and Dosing 
Register visit with 
IWRS 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign treatment 
via IWRS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For Visit 2 - Baseline assessments must be completed before processing in the IWRS. 
Dispense study 
intervention 
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
Site transmits study 
intervention 
prescription for 
central pharmacy 
study intervention 
dispensing as 
needed 
  
 
X 
X 
X 
X 
X 
X 
 X 
 X 
X 
 X 
 X 
X 
X 
X  
X 
 X 
X  
  
  
Study intervention 
injection training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Observe participant 
administer first 
dose of study 
intervention  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
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CONFIDENTIAL 
I8F-MC-GPHJ(c) 
Page 23 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
ED 
Weeks from 
randomization  
-2 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 
72 
— 
Visit interval 
tolerance (days) 
-21 to -7  
_ 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
— 
Visit Detail 
F 
F 
F 
F 
F 
F 
F 
F 
T 
T 
F 
T 
T 
F 
F 
T 
F 
T 
T 
F 
F 
F = fasting visit; T = telephone visit (shaded columns) 
Dispense ancillary 
supplies to 
participant 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Ancillary Supplies may be resupplied as needed from central pharmacy per participant requirements. 
Participant returns 
study intervention  
  
  
X 
X 
X 
X 
X 
X 
  
  
X 
  
  
X 
X 
  
X 
  
  
X 
X 
Assess study 
intervention 
compliance 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE = adverse events, AESI = adverse event of special interest; C-SSRS = Columbia Suicide Severity Rating Scale, ECG = electrocardiogram; 
eGFR = estimated glomerular filtration rate, ICF = informed consent form; IWRS = Interactive Web-Response System; PI = principal investigator. 
 
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CONFIDENTIAL 
I8F-MC-GPHJ(c) 
Page 24 
2. 
Introduction  
Tirzepatide is once-weekly GIP and GLP-1R agonist that integrates the actions of both incretins 
into a single molecule being developed for the once-weekly treatment of T2D and weight 
management. 
2.1. 
Study Rationale  
This Phase 3b study will evaluate the efficacy and safety of once-weekly treatment with 
tirzepatide 15 mg or the maximum-tolerated dose of tirzepatide (10 mg or 15 mg) compared with 
semaglutide 2.4 mg or the maximum-tolerated dose of semaglutide (1.7 mg or 2.4 mg) on change 
in body weight in adult participants who have obesity (BMI ≥30 kg/m2) or overweight (BMI 
≥27 kg/m2) with weight-related comorbidities. 
2.2. 
Background  
Obesity is a chronic disease, and its increasing prevalence is a public health concern associated 
with rising incidence of T2D, 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; 
Warkentin et al. 2014), lifestyle therapies fail to achieve sustainable weight loss in the majority 
of patients with obesity (Dombrowski et al. 2014). Restricted energy intake and voluntary efforts 
to increase energy expenditure through physical activity have been shown to be counteracted by 
adaptive physiological responses that make continued weight loss difficult and predispose to 
weight regain (Pasman et al. 1999; Rosenbaum et al. 2005; Sumithran et al. 2011). Therefore, 
there is increasing recognition that adjunctive therapies are required in addition to lifestyle 
modification for patients with obesity to achieve and maintain sufficient weight loss to improve 
health outcomes. 
The incretin hormones, GIP and 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-1R agonists have been approved for pharmacological treatment of T2D 
(Baggio and Drucker 2007). 
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 (Shah 
and Vella, 2014). The US Food and Drug Administration and the European Medicines Agency 
approved the GLP-1R agonists liraglutide (SAXENDA® package insert, 2014; SAXENDA® 
summary of product characteristics, 2015) and more recently, semaglutide (Wegovy® package 
insert, 2023) for the treatment of overweight and obesity. Semaglutide is a GLP-1R agonist that 
has been shown to achieve a clinically relevant reduction in body weight compared to placebo in 
participants who have obesity or overweight. Once-weekly semaglutide demonstrated 
significantly greater body weight loss compared to once-daily liraglutide at 68 weeks in adults 
with overweight or obesity without diabetes (Rubino et al. 2022). 
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CONFIDENTIAL 
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Page 25 
Preclinical data indicate that GIP also exert 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, GIPR activation may play a role in body weight 
regulation and targeting both the GLP-1R and the GIPR simultaneously could potentially result 
in additive or synergistic effects of the 2 incretins on body weight (Coskun et al. 2018). 
Tirzepatide is a GIP and GLP-1R agonist. Its structure is based on the GIP sequence and includes 
a C20 fatty diacid moiety. It is administered once-weekly by subcutaneous injection (Coskun et 
al. 2018). 
As a GIP/GLP-1R agonist, tirzepatide could exceed the efficacy of currently available selective 
GLP-1R analogs by recruiting metabolically active tissues not targeted by selective GLP-1R 
analogs, for example, adipose tissue as indicated by the observation in preclinical models of 
increased energy utilization (Baggio and Drucker 2007). Tirzepatide also 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 the 
SURPASS program for T2D provide strong evidence that tirzepatide has the potential to be a 
highly efficacious treatment option for both glycemic control in T2D and as a medication for 
chronic weight management. Tirzepatide resulted in clinically important reductions in body 
weight across the T2D disease continuum and showed superiority in weight loss versus all 
comparators (Del Prato et al. 2021; Frías et al. 2021; Ludvik et al. 2021; Rosenstock et al. 2021; 
Dahl et al., 2022). SURPASS 2, which compared tirzepatide 5 mg, 10 mg, and 15 mg to 
semaglutide 1 mg, demonstrated superior weight loss with tirzepatide with mean weight loss of 
7.6 kg, 9.3 kg, 11.2 kg compared to 5.7 kg after 40 weeks of study intervention (Frías et al. 
2021). Tirzepatide has been approved in the US for treatment of T2D (Mounjaro® package insert, 
2022). 
Study GPHJ is a Phase 3b, multicenter, randomized, parallel-arm, open-label, active comparator-
controlled, 72-week study that will investigate the effects of treatment with tirzepatide 15 mg or 
the MTD of tirzepatide (10 mg or 15 mg) compared with semaglutide 2.4 mg or the MTD of 
semaglutide (1.7 mg or 2.4 mg) on change in body weight in adult participants and who have 
obesity (BMI ≥30 kg/m2) or overweight (BMI ≥27 kg/m2) with weight related comorbidities. 
2.3. 
Benefit/Risk Assessment  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of tirzepatide may be found in the Investigator’s Brochure. 
In addition, detailed information about the known and expected benefits and risks of semaglutide 
may be found in the semaglutide package insert (Wegovy® package insert, 2023). 
2.3.1. 
Risk Assessment  
The data from global tirzepatide Phase 3 studies (SURPASS) indicate that the safety and 
tolerability profile of tirzepatide is consistent with the safety profile of other GLP-1R agonists 
(Del Prato et al. 2021; Frías et al. 2021; Ludvik et al., 2021; Rosenstock et al., 2021). 
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CONFIDENTIAL 
I8F-MC-GPHJ(c) 
Page 26 
The most common AEs observed in the tirzepatide clinical trials in healthy participants and 
participants with T2D have been GI effects (Del Prato et al. 2021; Frías et al. 2021; Ludvik et al., 
2021; Rosenstock et al., 2021). Similar GI-related effects have been observed with semaglutide 
(Rubino et al. 2022). For both interventions, GI-related effects will be closely monitored and 
managed through titration to target dose and dose de-escalation (for duration of study if needed). 
If still unable to tolerate the intervention (at least 10 mg tirzepatide or 1.7 mg semaglutide), 
participants will continue to receive a benefit of continued safety monitoring visits for the 
duration of the study. 
Participation in the study may impact mental health status, for example due to changes in body 
weight. Each participant will be regularly monitored for this risk. 
Other safety topics of interest for both interventions include pancreatic safety, cardiovascular 
events, hypoglycemia, hypersensitivity reactions, and thyroid C-cell effects; refer to Section 
8.3.3 for further details. Please refer to the tirzepatide IB Section 6 and the semaglutide package 
insert for more details. These risks are managed through proposed monitoring and exclusion of 
those with relevant risk history. 
Overall, the potential risks to participating in this study are deemed to be monitorable and 
manageable. 
2.3.2. 
Benefit Assessment  
All participants, regardless of intervention, will be monitored and treated at more frequent 
intervals than regular standard of care by experts in the field. Additionally, all participants in this 
study will receive diet and physical activity counseling. 
In global Phase 3 studies, tirzepatide demonstrated superior efficacy on body weight reductions 
and glycemic control as well as an improvement in different measures, which are associated with 
increased risk of longer-term cardiometabolic complications in participants with T2D (Del Prato 
et al. 2021; Frías et al. 2021; Ludvik et al., 2021; Rosenstock et al., 2021). The results indicate 
that clinically meaningful improvements in body weight reduction are anticipated for those 
randomized to and remaining on tirzepatide in this study. 
For those randomized to and remaining on semaglutide, body weight reductions are an 
anticipated benefit as this intervention has been approved for the treatment of overweight and 
obesity (Wegovy® package insert, 2023). 
2.3.3. 
Overall Benefit Risk Conclusion  
The potential benefits from participation in this study, which include frequent expert medical 
care for up to 72 weeks and the chance for achieving body weight reduction, are expected to 
outweigh the described risks, which will be closely monitored and managed through established 
procedures. 
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3. 
Objectives, Endpoints, and Estimands  
Objectives 
Endpoints 
Primarya 
 
To demonstrate that tirzepatide at 15 mg or MTD (10 mg 
or 15 mg) is superior to semaglutide at 2.4 mg or MTD 
(1.7 mg or 2.4 mg) for the mean percent decrease in 
weight loss  
Percent change from baseline in body weight at 72 
weeks 
Key Secondarya 
 
To demonstrate that tirzepatide at 15 mg or MTD (10 mg 
or 15 mg) is superior to semaglutide at 2.4 mg or MTD 
(1.7 mg or 2.4 mg) at Week 72 for: 
 
 
Body weight 
Body weight reduction from baseline of 
 
≥10% 
 
≥15% 
 
≥20%, and 
 
≥25% 
 
Waist circumference 
Change from baseline in waist circumference (cm)  
Additional Secondary 
 
To compare tirzepatide at 15 mg or MTD (10 mg or 
15 mg) to semaglutide at 2.4 mg or MTD (1.7 mg or 2.4 
mg) at Week 72 for: 
 
 
Body weight  
Change from baseline in body weight (kg) 
Body weight reduction from baseline of ≥30% 
 
BMI 
Change from baseline in BMI (kg/m2) 
To compare tirzepatide at 15 mg to semaglutide at 2.4 
mg for the mean percent decrease in weight loss 
Percent change from baseline in body weight at 72 
weeks 
Tertiary 
 
To compare tirzepatide at 15 mg or MTD (10 mg or 
15 mg) to semaglutide at 2.4 mg or MTD (1.7 mg or 2.4 
mg) at Week 72 for 
 
 
Lipid parameters 
Change from baseline in 
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 
triglycerides (mg/dL) 
 
VLDL (mg/dL) 
 
non-HDL cholesterol (mg/dL)  
 
Insulin 
Change from baseline in fasting insulin (pmol/L)  
 
HbA1c 
Change from baseline in HbA1c (%) 
Abbreviations: BMI = body mass index; HDL = high-density lipoprotein; MTD = maximum-tolerated dose; SF36 
physical function = Short Form 36 physical function; VLDL = very low-density lipoprotein. 
a Primary and key secondary endpoints are controlled for multiplicity. 
Primary estimand 
The primary estimand evaluated in this study is a modified treatment-regimen estimand. This 
estimand aims at reflecting how participants with obesity or overweight with at least 1 weight-
related comorbid condition are treated in clinical practice and takes into account both tolerability 
and efficacy. 
This modified treatment-regimen estimand answers the following question of interest for the 
primary objective: What is the treatment difference in mean percent change from baseline in 
body weight after 72 weeks of treatment as an adjunct to a reduced-calorie diet and increased 
physical activity in participants with obesity or overweight with at least 1 weight-related 
comorbid condition. Under this estimand framework, participants will be included regardless of 
treatment discontinuation for any reason and regardless of initiation of other anti-obesity 
medication (except for non-study tirzepatide or semaglutide). This estimand also assumes that 
participants who had bariatric surgery or another weight loss procedure did not get any benefit or 
might have worsened from their randomized study treatment. 
The modified treatment-regimen estimand is described by the following attributes: 
 Population: Participants who have obesity (BMI ≥30 kg/m2) or overweight (BMI 
≥27 kg/m2) with at least 1 weight-related comorbid condition, but without Type 2 
diabetes. Further details can be found in Section 5. 
 Endpoint: Percent change from baseline to Week 72 in body weight. 
 Treatment condition: The randomized treatment as an adjunct to a reduced-calorie diet 
and increased physical activity regardless of adherence to treatment with or without other 
anti-obesity medications, except for non-study tirzepatide, or semaglutide. Further details 
on study treatment and concomitant therapy can be found in Section 6. 
 Intercurrent events: Intercurrent events of interest: “treatment discontinuation for any 
reason” and “initiation of other anti-obesity medication except for non-study tirzepatide 
or semaglutide” are addressed by the treatment condition. Bariatric surgery or other 
weight loss procedures will be addressed by the hypothetical strategy. It will be assumed 
that patients who undergo any of these procedures did not get any benefits or might have 
worsened from their randomized study treatment. 
 Population-level summary: Difference in mean percent change between treatment 
conditions. 
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Secondary estimand 
The secondary estimand evaluated in this study is the efficacy estimand. This estimand focuses 
on the treatment effect if participants who underwent randomization continued to receive the 
study treatment without taking other anti-obesity therapies such as weight management drugs, 
bariatric surgery, or weight loss procedure. This estimand will be used in publications to inform 
prescribers or physicians and may be submitted to other regulatory agencies outside the United 
States. 
The efficacy estimand answers the following question of interest for the primary objective: What 
is the treatment difference in percent change in body weight from baseline after Week 72 of 
treatment as an adjunct to a reduced-calorie diet and increased physical activity in participants 
with obesity or overweight with at least 1 weight-related comorbid condition assuming that 
participants had stayed on treatment and not taken other anti-obesity therapies (that is, other 
weight management drugs, bariatric surgery, or other weight management procedures)? 
The efficacy estimand is described by the following attributes. 
 Population: Participants who have obesity (BMI ≥30 kg/m2) or overweight (BMI 
≥27 kg/m2) with at least 1 weight-related comorbid condition, but without Type 2 
diabetes. Further details can be found in Section 5. 
 Endpoint: Percent change from baseline to Week 72 in body weight. 
 Treatment condition: The randomized treatment as an adjunct to a reduced-calorie diet 
and increased physical activity. Further details on study treatment can be found in Section 
6. 
 Intercurrent events: “Treatment discontinuation for any reason” and “Initiation of other 
anti-obesity therapies such as weight management drugs, bariatric surgery or other weight 
management procedures” will be addressed using the hypothetical strategy: 
o Had participants stayed on treatment. 
o Had participants not taken other weight management drugs or bariatric surgery or 
weight loss procedure. 
 Population-level summary: Difference in mean changes between treatment conditions. 
Both the efficacy and treatment-regimen estimands will be evaluated for the primary and all key 
secondary objectives. The population, treatment condition, intercurrent events, and population-
level summary specified above for each estimand for the primary objective will also apply to the 
key secondary objectives. The endpoint for each key secondary objective is defined in the table 
above. 
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4. 
Study Design  
4.1. 
Overall Design  
Study GPHJ is a Phase 3b, multicenter, randomized, parallel-arm, open-label, comparator-
controlled, 72-week trial that will investigate the efficacy and safety of 15 mg or MTD 
tirzepatide (10 mg or 15 mg) compared with 2.4 mg or MTD semaglutide (1.7 mg or 2.4 mg) in 
study participants who have obesity (BMI ≥30 kg/m2) or overweight (BMI ≥27 kg/m2).  
Study GPHJ will consist of 2 periods: a 2-week screening period and a 72-week open-label 
tirzepatide and semaglutide treatment period (including a 20-week dose escalation period for 
tirzepatide and a 16-week dose escalation period for semaglutide). The study participants will be 
randomly assigned in a 1:1 ratio to tirzepatide 15 mg or MTD (10 mg or 15 mg) or semaglutide 
2.4 mg or MTD (1.7 mg or 2.4 mg) at the end of the screening period. An upper limit of 
70% enrollment of women will be used to ensure a sufficient enrollment of men. 
4.1.1. 
Overview of Study Periods  
Visit structure for fasting office visits 
On all designated fasting office visits, study participants are required to report to the site in a 
fasting condition, after a period of approximately 8 hours without eating, drinking (except 
water), or performing any significant physical activity. If a participant is adversely affected by 
the fasting condition, they are allowed to eat; however, specific study procedures need to be 
completed while fasting. 
4.1.2. 
Main Study Period  
4.1.2.1. 
Screening Period  
Visit 1 
The purpose of screening procedures at Visit 1 is to establish initial eligibility and to obtain 
blood samples for laboratory assessments needed to confirm eligibility. The participant must sign 
the ICF before the study procedures are performed, as outlined in the SoA, Section 1.3. Since 
some screening procedures need to be completed in the fasting state (at least 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. The Mental Health Questionnaires 
should be completed after the assessment for AEs. The preferred administration order is 
1. Patient Health Questionnaires 
2. C-SSRS screening/baseline 
4.1.2.2. 
Treatment Period  
Visit 2 
At Visit 2, eligible participants will perform all required baseline study procedures, including the 
collection of all baseline laboratory measures and questionnaires, prior to enrollment and prior to 
taking the first dose of study intervention. Participants will be provided diaries and be trained to 
record key study information, as appropriate. 
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Patient-reported outcomes questionnaires should be administered as early as possible. Preferred 
administration order is 
1. SF-36 v2 acute form 
2. PGIS Physical Activity 
The Mental Health Questionnaires (PHQ-9 and C-SSRS Since Last Visit) should be completed 
after the assessment for AEs. 
Participants will receive an initial consultation with a qualified delegate, according to local 
standards, to set lifestyle goals for diet and physical activity (Section 5.3). 
End of Visit 2 to Visit 8 
At the end of Visit 2, for participants that meet all the entry criteria are enrolled in this study and 
randomized, study site personnel will demonstrate use of molecule-specific device using the 
provided instructions for use and observe the study participant inject the first dose of study 
intervention. The date and time of the first dose of study intervention will be recorded in the e-
diary. 
After study enrollment, participants will undergo either a 20-week tirzepatide or a 16-week 
semaglutide dose escalation as indicated in the SoA. 
Patient-reported outcomes questionnaires should be administered as early as possible. Preferred 
administration order is the same as described for Visit 2. Mental Health Questionnaires should be 
completed after the assessment of AEs. 
Study intervention and injection supplies will be returned per the SoA and according to local 
requirements. New supplies will be dispensed as needed. 
The starting dose of tirzepatide is 2.5 mg for 4 weeks, then the dose is increased by 2.5 mg every 
4 weeks (2.5 to 5 to 7.5 to 10 to 12.5 to 15 mg) up to 15 mg or MTD (10 mg or 15 mg) (see 
Section 6.5.1). 
The starting dose of semaglutide is 0.25 mg for 4 weeks, then the dose is increased every 
4 weeks (0.25 to 0.5 to 1.0 to 1.7 to 2.4 mg) up to the 2.4 mg dose but with the dosing flexibility 
for 1.7 mg if unable to tolerate 2.4 mg (see Section 6.5.2). 
End of Visit 8 to Visit 20 
Office and telephone visits should occur as indicated in the SoA (Section 1.3). 
Office visit procedures should be conducted according to the SoA (Section 1.3) and will include 
 weight, waist circumference, and vital signs measurements 
 laboratory testing 
 administration of PRO questionnaires, collection of AEs, product complaints, and 
concomitant medications 
 Mental Health Questionnaires 
 review of participant electronic diary information and diet and exercise log (to include 
reinforcement and compliance assessments for study intervention administration and 
lifestyle goals), and 
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 transmission of prescription for central pharmacy study intervention dispensing, as 
needed. 
Patient-reported outcomes questionnaires should be administered as early as possible. Preferred 
administration order is the same as Visit 2. 
Mental Health Questionnaires should be completed after the assessment of AEs. 
Lifestyle consultations continue as indicated in the SoA. Study intervention and injection 
supplies will be returned per the SoA and according to local requirements. New supplies will be 
dispensed as needed. 
At each of the 7 scheduled telephone visits, procedures will include 
 collection of AEs, product complaints, and concomitant medications 
 review first day of last menstrual cycle in applicable WOCBP 
 review of electronic diary and diet and exercise log 
 reinforcement and compliance assessments for study intervention administration and 
lifestyle goals, and 
 transmission of prescription for central pharmacy study intervention dispensing, as 
needed. 
At any treatment period, 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 intervention is not taken at the required time (late/missing doses). 
Early discontinuation visit 
Participants unable or unwilling to continue the study for any reason will perform an early 
discontinuation visit. Procedures should be completed according to the SoA. Patient-reported 
outcomes questionnaires should be administered as early as possible. Administration of Mental 
Health Questionnaires should be after the assessment for AEs (see Section 7.1). 
4.1.3. 
Study Procedures  
Participants will perform study procedures listed in the SoA (Section 1.3). Study participants will 
be permitted to use concomitant medications that they require during the study, except certain 
excluded medications (Section 5.2) that may interfere with the assessment of efficacy and safety 
characteristics of the study treatments. 
Study governance considerations are described in detail in Section 10.1. 
4.1.3.1. 
Management of Participants with Gastrointestinal Symptoms  
Participants who report significant GI symptoms (for example, nausea, vomiting, or diarrhea) at 
any time during the study should follow the steps outlined in the table below (see also Section 
5.3.2). 
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Step 1 
Be counseled on dietary behaviors that may help mitigate nausea and vomiting, 
for example, eating smaller meals, splitting 3 daily meals into 4 or more smaller 
ones, and stopping eating when they feel full 
Step 2 
If symptoms persist, the participant should be prescribed, at the investigator’s 
discretion, symptomatic medication, for example, antiemetic or antidiarrheal 
medication 
Step 3 
A temporary interruption of study intervention for 1 dose is permitted. Study 
intervention should be resumed immediately, either alone, or in combination 
with symptomatic medication, which can also be utilized to manage symptoms. 
A single-dose interruption is not recommended in participants that have missed 
any of the last 3 weekly doses 
Step 4 
If significant GI symptoms develop after randomization and persist despite the 
above measures, for example, dietary counseling, symptomatic medication, and 
interruption of study intervention for 1 dose, the investigator should contact 
Lilly medical monitor to consider dose de-escalation with subsequent re-
escalation 
4.1.3.2. 
Management of Incident Diabetes  
Participants who develop diabetes (Section 10.9) 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 an electronic diary to record hypoglycemic episodes. 
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 DPP-4 inhibitors 
and GLP-1R agonists, which are prohibited in the study. Monitoring for hypoglycemia includes 
capture of events as defined in Section 8.3.3.1. Diagnosis date of diabetes will be captured in the 
AE CRF. 
4.2. 
Scientific Rationale for Study Design  
Tirzepatide is an agonist at both the GIPR and GLP-1R. Its structure is based on the GIP 
sequence and includes a C20 fatty diacid moiety (Coskun et al. 2018). It is administered once-
weekly by injection. 
As a 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 such as 
semaglutide, which is approved for chronic weight management (Wegovy® package insert, 
2023). Tirzepatide demonstrated superior weight loss in SURPASS 2, which evaluated efficacy 
and safety of tirzepatide compared to semaglutide 1 mg in people with T2D (Frías et al. 2021). 
Tirzepatide has been approved in the US for treatment of T2D (Mounjaro® package insert, 2022). 
Semaglutide 2.4 mg or MTD (1.7 mg or 2.4 mg) will be provided consistent with FDA-approved 
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USPI (Wegovy® package insert, 2023), while tirzepatide intended dose will be 15 mg or MTD 
(10 mg or 15 mg). 
Higher weight loss efficacy with next generation anti-obesity medications is expected to be 
paradigm shifting for obesity care. It has been proposed that higher efficacy anti-obesity 
medications will allow individualized treat-to-target approach in weight management that was 
not achievable with historical anti-obesity medications (Garvey 2022). Defining characteristics 
of individual anti-obesity medications will support shared decision making with the treat-to-
target approach. The current trial will determine the differences in weight loss efficacy for what 
are expected to be the 2 leading next generation anti-obesity medications. The weight loss 
efficacy, the primary objective, is essential to the individualized treat-to-target approach. The 
study will also determine if cardiovascular risk factors are differently impacted by tirzepatide 
and semaglutide. Also, of relevance is the additional secondary outcome to determine physical 
function, an important predictor of long-term outcomes including mortality (Tice et al. 2006; St. 
John et al. 2016). 
All participants, regardless of treatment assignment, will receive lifestyle modification 
counseling consistent with current guidelines for weight management (Jensen et al. 2013). 
Specifically, participants will consult with a dietitian, or equivalent qualified delegate, 
throughout the study to achieve at least a 500 kcal/day energy deficit through a combination of 
caloric restriction and increased physical activity (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 15 mg or MTD (10 mg or 15 mg).  
An upper limit of 70% enrollment of women will be used to ensure a sufficiently large sample of 
men. 
In this study, collection of demographic information includes race and ethnicity. The scientific 
rationale is based on the need to assess variable response in safety and/or efficacy based on race 
or ethnicity. This question can be answered only if all the relevant data are collected. 
4.3. 
Justification for Dose  
Tirzepatide dose of 15 mg administered SC is the intended dose to be evaluated in this study 
with the option of lower maintenance dose of 10 mg if participant does not tolerate 15 mg. 
These doses and associated escalation scheme for tirzepatide were consistent with the design of 
the ongoing studies (GPHM, GPHN) for chronic weight management indication. 
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. 
Similar to the GLP-1R agonist class, most of the tirzepatide AEs were dose-dependent and 
GI-related, consisting mainly of nausea, vomiting, and diarrhea. In general, these events were 
mild, or moderate in severity, with few severe episodes, and transient. 
Tirzepatide doses 15 mg or MTD (10 mg or 15 mg) were selected based principally on the 
following criteria 
 each dose provides robust weight loss relative to placebo 
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 the percent of participants achieving ≥10% weight loss is higher with 15 mg than 10 mg, 
and 
 safety and tolerability were supported by Phase 3 results in T2DM. 
Semaglutide recommended maintenance dose of 2.4 mg or MTD (1.7 mg or 2.4 mg) and 
associated escalation scheme were selected in accordance with the approved Wegovy® label 
(Wegovy® package insert, 2023). 
The proposed tirzepatide maintenance dose of 15 mg or MTD (10 mg or 15 mg) using a dose 
escalation regimen is expected to safely maximize the potential for weight loss with tolerable GI 
profile.  
4.4. 
End of Study Definition  
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA for the last participant in the trial globally. 
A participant is considered to have completed the study if the participant has completed all 
periods of the study, including the last visit or the last scheduled procedure shown in the SoA. 
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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: 
Age 
1. Participants must be ≥18 years of age or of an acceptable age to provide informed 
consent according to local regulations, whichever is older 
Weight 
2. Have a BMI of 
 ≥30 kg/m2 or 
 ≥27 kg/m2 and previously diagnosed with at least 1 of the following 
weight-related comorbidities: 
o hypertension: treated or with systolic blood pressure ≥130 mmHg 
or diastolic blood pressure ≥80 mmHg 
o dyslipidemia: treated or with LDL ≥160 mg/dL (4.1 mmol/L) or 
triglycerides ≥150 mg/dL (1.7 mmol/L), or 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, and 
o cardiovascular disease, for example, ischemic cardiovascular 
disease, New York Heart Association Functional Classification 
Class I-III heart failure 
3. Have a history of at least 1 self-reported unsuccessful dietary effort to lose body 
weight 
4. In the investigator’s opinion, are well motivated, capable, and willing to 
 learn how to self-inject study intervention, as required for this protocol (visually 
impaired persons who are not able to perform the injections must have the 
assistance of a sighted individual trained to inject the study intervention; persons 
with physical limitations who are not able to perform the injections must have the 
assistance of an individual trained to inject the study intervention) 
 inject study intervention (or receive an injection from a trained individual if 
visually impaired or with physical limitations), and 
 follow study procedures for the duration of the study, including, but not limited 
to, following lifestyle advice (for example, dietary restrictions and exercise plan), 
maintaining a study diary, and completing required questionnaires 
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o for visual impaired participants, they must have the assistance of a 
sighted individual for maintaining 3-day diet and exercise log be 
completed prior to each counseling visit 
Sex and contraceptive/barrier requirements 
5.  Male and/or female 
Contraceptive use by participants should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. For the contraception 
requirements of this protocol, see Section 10.4. 
 Male participants 
o 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 intervention plus 90 days, corresponding to 4 months after the last 
injection. 
 Female participants 
o Female participants not of childbearing potential may participate and include 
those who are 
▪ infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy), congenital anomaly such as Mullerian agenesis; or 
▪ postmenopausal – defined as either: 
➢ A woman at least 40 years of age up to 55 years with an intact 
uterus, not on hormone therapy, who has cessation of menses for 
at least 12 consecutive months without an alternative medical 
cause, AND an FSH ≥ 40 mIU/mL; women in this category must 
test negative in pregnancy test prior to study entry 
or 
➢ A woman 55 years of age 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 HRT 
o 
Female participants of childbearing potential (not surgically sterilized and 
between menarche and 1-year postmenopausal) and who are NOT completely 
abstinent as their preferred and usual lifestyle, or NOT in a same-sex 
relationship as their preferred and usual lifestyle, must do the following: 
▪ test negative for pregnancy at Visit 1 based on a serum pregnancy test 
▪ agree to use 2 forms of effective contraception, where at least 1 form is 
highly effective (less than 1% failure rate) for the duration of the trial 
plus 30 days thereafter, and 
▪ not be breastfeeding 
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Informed Consent 
6. Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
Diabetes Related 
7. Have T1D or T2D, history of ketoacidosis, or hyperosmolar state or coma 
8. Have at least 1 laboratory value suggestive of diabetes during screening including 1 or 
more of HbA1c ≥6.5% (≥48 mmol/mol), fasting glucose ≥126 mg/dL (≥7.0 mmol/L), or 
random glucose ≥200 mg/dL (≥11.1 mmol/L) 
Obesity Related 
9. Have a self-reported change in body weight >5 kg within 3 months prior to screening 
10. Have a prior or planned surgical treatment for obesity, excluding liposuction or 
abdominoplasty if performed >1 year prior to screening 
11. Have or plan to have endoscopic and/or device-based therapy for obesity or have had 
device removal within the last 6 months prior to screening 
Examples: 
 mucosal ablation 
 gastric artery embolization 
 intragastric balloon 
 duodenal-jejunal endoluminal liner 
Other Medical 
12. Have renal impairment measured as eGFR <30 mL/min/1.73 m2, calculated by Chronic 
Kidney Disease Epidemiology as determined by central laboratory during screening 
13. Have a known clinically significant gastric emptying abnormality (for example, severe 
gastroparesis or gastric outlet obstruction) or chronically take drugs that directly affect GI 
motility 
14. Have a history of chronic or acute pancreatitis 
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15. Have TSH outside of the range of 0.4 to 6.0 mIU/L at the screening visit 
Note: Participants receiving treatment for hypothyroidism may be included, provided 
their thyroid hormone replacement dose has been stable for at least 3 months and their 
TSH at screening falls within the range indicated above. 
Note: Participants with a history of subclinical hypothyroidism but a TSH at screening 
within the range indicated above may be included if, in the investigator’s opinion, the 
participant is unlikely to require initiation of thyroid hormone replacement during the 
course of the study. 
16. 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 
17. Have a history of significant active or unstable MDD or other severe psychiatric disorder, 
for example, schizophrenia, bipolar disorder, or other serious mood or anxiety disorder, 
within the last 2 years 
Note: Participants with MDD or generalized anxiety disorder whose disease state is 
considered stable for the past 2 years and expected to remain stable throughout the course 
of the study, in the opinion of the investigator, may be considered for inclusion if they are 
not on excluded medications. 
18. Have a PHQ-9 score of 15 or more on or before Visit 2 
19. Are, in the judgment of the investigator, actively suicidal, and therefore deemed to be at 
significant risk for suicide 
20. On the C-SSRS on or before Visit 2 
 have answered “yes” to either Question 4 or Question 5 on the “Suicidal Ideation” 
portion of the C-SSRS or 
 have answered “yes” to any of the suicide-related behaviors on the “Suicidal 
Behavior” portion of the C-SSRS, and 
 the ideation or behavior occurred within the past month. 
21. Have uncontrolled hypertension (systolic blood pressure above or equal to 160 mmHg 
and/or diastolic blood pressure above or equal to 100 mmHg) 
22. Have any of the following cardiovascular conditions within 3 months prior to Visit 3 
 acute myocardial infarction 
 cerebrovascular accident (stroke) 
 unstable angina, and 
 hospitalization due to CHF 
23. Have New York Heart Association Functional Classification Class IV CHF 
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24. Have acute or chronic hepatitis, signs and symptoms of any other liver disease other than 
NAFLD, or any of the following, as determined by the central laboratory during 
screening: 
 ALT level >3.0x ULN for the reference range 
 ALP level >1.5x ULN for the reference range, or 
 TBL level >1.5x ULN for the reference range (except for cases of known 
Gilbert’s Syndrome) 
Note: Participants with NAFLD are eligible to participate in this trial if their ALT level is 
≤3.0x ULN for the reference range 
25. Have a serum calcitonin level (at Visit 1) of 
 ≥20 ng/L, if eGFR ≥60 mL/min/1.73 m2, and 
 ≥35 ng/L, if eGFR <60 mL/min/1.73 m2 
26. Have a family or personal history of medullary thyroid carcinoma or multiple endocrine 
neoplasia syndrome Type 2 
27. 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 
28. Have any other condition not listed in this section, for example, hypersensitivity or 
intolerance, that is a contraindication to GLP-1R agonists 
29. 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 
30. Have a history of use of marijuana or tetrahydrocannabinol-containing products within 3 
months of enrollment or unwillingness to abstain from marijuana or 
tetrahydrocannabinol-containing products use during the trial. 
Note: If a participant has used cannabidiol oil during the past 3 months but agrees to 
refrain from use for the duration of the study, the participant can be enrolled. 
31. Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or awaiting an 
organ transplant 
32. Have any hematological condition that may interfere with HbA1c measurement, for 
example, hemolytic anemias and sickle cell disease 
Prior/concomitant therapy 
33. Have used a GLP-1R agonist within 3 months of screening 
34. 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 
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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) during the course of the study 
35. 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 antipsychotics, and mood stabilizers 
Examples: 
 
imipramine 
 
amitriptyline 
 
mirtazapine 
 
paroxetine 
 
phenelzine 
 
chlorpromazine 
 
thioridazine 
 
clozapine 
 
olanzapine 
 
valproic acid (and its derivatives), and 
 
lithium 
Note: Selective serotonin reuptake inhibitors other than paroxetine are permitted. 
36.  Have taken, within 3 months prior to Visit 2, medications (prescribed or over-the-
counter) or alternative remedies that promote weight loss 
Examples include, but are not limited to 
 
Saxenda® (liraglutide injection 3.0 mg) 
 
Xenical®/Alli® (orlistat) 
 
Meridia® (sibutramine) 
 
Acutrim® (phenylpropanolamine) 
 
Sanorex® (mazindol) 
 
Apidex® (phentermine) 
 
Belviq® (lorcaserin) 
 
Bontril® (phendimetrazine) 
 
Qsymia® (phentermine/topiramate combination) 
 
Contrave® (naltrexone/bupropion) 
 
Wegovy® (semaglutide injection), and 
 
Plenity® (Oral Superabsorbent Hydrogel) 
Note: Use of metformin or any other glucose-lowering medication, whether prescribed 
for polycystic ovary syndrome or diabetes prevention, is not permitted. 
Prior/concurrent clinical study experience 
37. Are currently enrolled in any other clinical study involving an IP or any other type of 
medical research judged not to be scientifically or medically compatible with this study 
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38. Within the last 30 days of Visit 2, 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 
39. Have previously completed or withdrawn from this study or any other study investigating 
tirzepatide after receiving at least 1 dose of IP 
Other exclusions 
40. Are investigator site personnel directly affiliated with this study and/or their immediate 
families. Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological, or legally adopted 
41. Are Eli Lilly and Company employees 
5.3. 
Lifestyle Considerations  
Per the SoA (Section 1.3), participants will consult with a dietitian, 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 weeks thereafter through 72 
weeks. 
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 2 and subsequent visits, study participants will receive diet counseling by a 
dietitian/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, and 
 an energy deficit of approximately 500 kcal/day compared to the participant’s estimated 
total energy expenditure. 
To encourage adherence, it is recommended that a 3-day diet and exercise log 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/m
2 is reached, the recommended energy intake should be recalculated with no kcal 
deficit for the remainder of the trial. 
Additionally, if a BMI ≤22 kg/m
2 is reached in participants receiving study intervention, the site 
physician should contact Lilly medical monitor for consideration of a single dose reduction for 
remainder of trial (for example, 15 mg to 10 mg or 10 mg to 5 mg for tirzepatide or 2.4 mg to 1.7 
mg for semaglutide).  
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Total energy expenditure is calculated by multiplying the estimated 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/daya 
Sex 
Age 
BMR (kcal/day) 
Men
 
18-30 years 
15.057 × actual weight in kg + 692.2 
31-60 years 
11.472 × actual weight in kg + 873.1 
>60 years 
11.711 × actual weight in kg + 587.7 
Women 
18-30 years 
14.818 × actual weight in kg + 486.6 
31-60 years 
8.126 × actual weight in kg + 845.6 
>60 years 
9.082 × actual weight in kg + 658.5 
Abbreviations: BMR = basal metabolic rate; WHO = World Health Organization. 
a Revised WHO equations (adapted from: FAO/WHO/UNU 2004). 
5.3.2. 
Monitoring nutritional needs  
Tirzepatide and semaglutide are next generation anti-obesity medications with potential for 
superior weight loss compared to established anti-obesity medications. Caloric restriction is a 
standard component of weight loss interventions, and there is potential that a small portion of 
participants will have significantly reduced caloric intake. 
Medical staff should consider clinical monitoring (via history and physical and laboratory 
assessment as needed) of the participant’s nutritional and hydration status if report of 
significantly reduced caloric intake (for example, below 800-1200 kcal). By recognizing early 
signs of poor intake and dehydration, preventive actions can be taken to reduce the risk of 
potential complications. 
5.3.3. 
Activity  
Participants will abstain from strenuous exercise for 8 hours before each blood collection for 
clinical laboratory tests. 
At Visit 2 and all subsequent visits, participants will be advised to increase their physical activity 
to at least 150 minutes per week. 
5.4. 
Screen Failures  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
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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. 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant  
This section is not applicable to this study. All entry criteria must be met within the specified 
intervals in the SoA. 
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6. 
Study Intervention(s) and Concomitant Therapy  
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to or used by a study participant 
according to the study protocol. 
6.1. 
Study Intervention(s) Administered  
This table lists the interventions used in this clinical study 
Intervention Name 
Tirzepatide 
Semaglutide 
Dosage Level(s) 
15 mg or the MTD (10 mg or 
15 mg) 
2.4 mg or the MTD (1.7 mg 
or 2.4 mg) 
Route of Administration 
Subcutaneous injection 
Subcutaneous injection 
Abbreviation: MTD = maximum-tolerated dose. 
Packaging and labeling 
Study interventions will be supplied by the sponsor or its designee in accordance with current 
Good Manufacturing Practice. Study interventions will be labeled as appropriate for country 
requirements. 
6.1.1. 
Medical Devices  
The products provided for use in the study are tirzepatide locally marketed autoinjector or 
investigational autoinjector pending the marketing status of tirzepatide and semaglutide locally 
marketed pen, for example, prefilled and single-dose pen. Any medical device-related AEs, 
including those resulting from malfunctions of the devices, must be detected, documented, and 
reported by the investigator throughout the study. 
6.2. 
Preparation, Handling, Storage, and Accountability  
6.2.1. 
Investigator Site Responsibilities  
Lilly or its designee is supplying study intervention to the investigator for Visit 2 dispensing. 
The investigator or designee must confirm appropriate storage 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. Only authorized study 
personnel may supply, prepare, or administer 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 study personnel. 
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The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and final 
disposition records. 
Further guidance and information for the final disposition of unused study interventions are 
provided in the study training materials. 
6.2.2. 
Direct-to-Participant Study Intervention Access  
Lilly or its designee is supplying study intervention to a central licensed pharmacy that will 
dispense study intervention direct-to-participant beginning at Visit 3 for at-home dosing.   
Investigator responsibilities 
Upon receipt, the investigator must confirm that appropriate storage conditions have been 
maintained during transit for all study intervention received and that any discrepancies are 
reported and resolved before use of the study intervention. 
Investigators are responsible for accountability of study intervention that they store and dispense 
at the site.  
The investigator is responsible for ensuring the study intervention is used in accordance with the 
approved protocol and that each participant follows the instructions for use properly.  
Investigators are responsible for dose adjustment decisions and documentation that they report 
within the case report form, as applicable.  
Treatment compliance of trial participants falls under the investigator’s responsibility and does 
not change with the direct-to-participant supply method. If needed, the central licensed pharmacy 
will supply records to support any investigator determinations related to treatment compliance or 
PCs. 
Licensed pharmacy responsibilities 
Upon receipt, the licensed pharmacy must confirm that appropriate storage conditions have been 
maintained during transit for all study intervention received and that any discrepancies are 
reported and resolved before dispensing the study intervention. 
Proper storage, handling, and disposition of study intervention stored and dispensed by the 
central licensed pharmacy shall be the responsibility of the central licensed pharmacy contracted 
by Lilly.  
To ensure appropriate preparation, handling, and storage for at-home dosing, participants will be 
provided instructions for receipt, storage, and handling when study intervention is supplied by 
the central licensed pharmacy.  
Participants will return any unused study intervention as instructed for the purpose of dosing 
compliance. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding  
This is an open-label study. 
All participants will be centrally assigned to randomized study intervention using an IWRS. 
Before the study is initiated, the log-in information and directions for the IWRS will be provided 
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to each site. The site will record the intervention assignment if required. Potential bias will be 
reduced by central randomization, and the randomization will be stratified by prediabetes status 
(yes, no), baseline BMI (<35 kg/m2, ≥35 kg/m2), and sex (female, male). 
6.4. 
Study Intervention Compliance  
Participant compliance with study intervention will be assessed at each visit. 
Study intervention compliance will be determined by the following: 
 Study intervention 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 intervention 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 intervention. Similarly, a participant will be considered significantly 
noncompliant if he or she is judged by the investigator to have intentionally or repeatedly taken 
more than the prescribed amount of medication (more than 125%). 
In addition to the assessment of a participant’s compliance with the study intervention 
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. 
Dose Modification  
Dose modification is permitted for management of intolerable GI symptoms only (Section 
4.1.3.1). The only additional modification of dose is if a BMI ≤22 kg/m
2 is reached in 
participants receiving study intervention (Section 5.3.1). 
Interventions to optimize study intervention tolerance and adherence may be employed 
throughout the study and include, but are not limited to, brief temporary interruptions (Section 
7.1.3) and use of additional medications to manage GI symptoms, for example, nausea, vomiting, 
and diarrhea. If study intervention is interrupted, the participant will continue to follow the 
lifestyle program (see Section 5.3). 
6.5.1. 
Tirzepatide  
Tirzepatide is administered 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. 
Dose escalation phase 
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The starting dose of tirzepatide is 2.5 mg for 4 weeks, then the dose is increased by 2.5 mg every 
4 weeks (2.5 to 5 to 7.5 to 10 to 12.5 to 15 mg) to intended maintenance dose of 15 mg but with 
dosing flexibility for 10 mg if unable to tolerate 15 mg. 
During dose escalation of tirzepatide, participants unable to tolerate 2.5 mg despite measures 
taken as described in Section 4.1.3.1 will be discontinued from the study intervention but remain 
in the study for continued follow-up. For participants unable to tolerate any dose escalation 
between 5 mg and 15 mg inclusive, despite measures taken as described in Section 4.1.3.1, the 
investigator should contact Lilly medical monitor to consider dose de-escalation to next lower 
dose with subsequent re-escalation in an open-label fashion to reach the 15 mg or 10 mg dose as 
described below: 
 5 mg to 2.5 mg for 4 weeks, then the dose is increased by 2.5 mg every 4 weeks up to 
MTD (either 10 mg or 15 mg) 
 7.5 mg to 5 mg for 4 weeks, then the dose is increased by 2.5 mg every 4 weeks up to 
MTD (either 10 mg or 15 mg) 
 10 mg to 7.5 mg for 4 weeks, then the dose is increased by 2.5 mg every 4 weeks up to 
MTD (either 10 mg or 15 mg) 
 12.5 mg to 10 mg for 4 weeks, then the dose is increased by 2.5 mg every 4 weeks up to 
MTD (either 10 mg or 15 mg), and 
 15 mg to 12.5 mg for 4 weeks, then the dose is increased by 2.5 mg every 4 weeks up to 
MTD (either 10 mg or 15 mg). 
A maximum of 2 cycles of temporary dose adjustment to mitigate gastrointestinal intolerance are 
permitted during the study, with only 1 attempt at a dose less than the maintenance dose, 15 mg 
or 10 mg. Consecutive attempts with temporary dose adjustment from the same dose will not be 
allowed. 
If a dose adjustment occurs, then additional visits at 4-week intervals will be scheduled to allow 
for the dose escalation. 
This table below provides guidance if a participant does not tolerate a tirzepatide dose. 
Tirzepatide Dose Adjustment 
If a participant tolerates… 
but after the de-escalation/re-
escalation attempt(s) does not 
tolerate 
then participant continues with their 
MTD/maintenance dose as… 
15 mg 
- 
15 mg 
12.5 mg 
15 mg  
10 mg 
10 mg 
12.5 or 15 mg 
10 mg 
5 mg 
7.5 or 10 mg 
Participant will be discontinued from study 
intervention but remains in the study for 
continued follow-up 
Abbreviation: MTD = maximum-tolerated dose. 
Maintenance dose phase 
It is expected most temporary dose adjustments to mitigate gastrointestinal intolerance will occur 
during dose escalation to reach maintenance dose, tirzepatide MTD (10 mg or 15 mg). After this 
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time, if the participant has experienced 1 or no temporary dose adjustments, 1 additional de-
escalation from maintenance dose for 4 weeks, with subsequent re-escalation to maintenance 
dose, can occur to mitigate gastrointestinal intolerance if the participant has received at least 4 
consecutive doses of maintenance dose weekly. 
Participants unable to tolerate the 10 mg or 15 mg despite 2 attempts with temporary dose 
adjustment will be discontinued from the study intervention but remain in the study for continued 
follow-up. 
6.5.2. 
Semaglutide  
Semaglutide is administered once-weekly by SC injection. There are no restrictions on the time 
of day each weekly dose of semaglutide is given, but it is advisable to administer the SC 
injections on the same day of the week. 
Dose escalation phase 
The starting dose of semaglutide is 0.25 mg for 4 weeks, then the dose is increased every 
4 weeks (0.25 mg to 0.5 mg to 1.0 mg to 1.7 mg to 2.4 mg) to recommended maintenance dose 
of 2.4 mg. If after attempting 2.4 mg and unable to tolerate 2.4 mg, there is dosing flexibility for 
1.7 mg as the maintenance dose (Section 1.2). For participants unable to tolerate any dose 
escalation, despite the recommended measures described in Section 4.1.3.1, the investigator 
should contact Lilly medical monitor to consider temporary dose adjustment to mitigate 
gastrointestinal intolerance in an open-label fashion to reach 2.4 mg. 
If difficulty tolerating the dose despite the recommended measures described in Section 4.1.3.1 
 for the initial dose, 0.25 mg, a delay in dose escalation for 4 weeks before escalation (a 
total of 8 weeks with 0.25 mg), and 
 for doses 0.5 mg to 2.4 mg, a de-escalation to next lower dose for 4 weeks with re-
escalation can occur. 
A maximum of 2 cycles of temporary dose adjustment to mitigate gastrointestinal intolerance are 
permitted during the study, with only 1 attempt at a dose less than the recommended 
maintenance dose, 2.4 mg (see the Tirzepatide and Semaglutide Temporary Dose Adjustment 
Schedule table below). Consecutive attempts with temporary dose adjustment from the same 
dose will not be allowed. 
If a dose adjustment occurs, then additional visits at 4-week intervals will be scheduled to allow 
for the dose escalation 
Maintenance dose phase 
It is expected most temporary dose adjustments to mitigate gastrointestinal intolerance will occur 
during dose escalation to reach the recommended maintenance dose, 2.4 mg. After this time, if 
the participant has experienced 1 or no temporary dose adjustments, 1 additional de-escalation 
from 2.4 mg to 1.7 mg for 4 weeks with subsequent re-escalation to 2.4 mg can occur to mitigate 
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gastrointestinal intolerance if the participant has received at least 4 consecutive doses of 
semaglutide 2.4 mg weekly. 
Participants unable to tolerate the 2.4 mg despite 2 attempts with temporary dose adjustment will 
be allowed to remain on 1.7 mg in consultation with Lilly medical monitor. Any participant who 
is unable to tolerate at least 1.7 mg despite above measures will be discontinued from the study 
intervention but remain in the study for continued follow-up. 
The table below provides a summary to timing for temporary dose adjustment to mitigate 
gastrointestinal intolerance, which can occur after mitigation strategies and discussion with Lilly 
medical monitor. 
Tirzepatide and Semaglutide Temporary Dose Adjustment Schedule 
Maximum 2 attempts allowed 
during trial 
Tirzepatide 
Semaglutide 
Dose escalation phase (initial dose) 
 
If unable to tolerate 2.5 mg 
despite mitigation will 
discontinue study intervention, 
remain in study 
If unable to tolerate 0.25 mg despite 
mitigation, delay dose escalation by 4 
weeks 
Dose escalation phase 
(de-escalation to next lower dose 
for 4 weeks then re-escalation) 
One attempt when dose 5 mg to 
15 mg 
One attempt when dose 0.5 mg to 
2.4 mg 
Dose maintenance phasea 
(de-escalation to next lower dose 
for 4 weeks then re-escalation) 
One-time attempt to maintain 
15 mg/10 mg (see previous table) 
One-time attempt to maintain the 
recommended maintenance dose 
2.4 mg 
a After receiving 4 consecutive weeks of dose. 
6.6. 
Continued Access to Study Intervention after the End of the Study  
Tirzepatide will not be made available to participants after conclusion of the study. Semaglutide 
is a marketed drug for chronic weight management in adults with obesity or overweight and is 
currently available with a prescription. 
6.7. 
Treatment of Overdose  
Study intervention overdose, defined as taking more than the assigned dose of tirzepatide in less 
than 72 hours or semaglutide in less than 48 hours, will be reported as an AE. In the event of an 
overdose, refer to the IB for tirzepatide or the semaglutide label (Wegovy® package insert, 
2023). 
In the event of an overdose, the investigator should 
● contact the medical monitor immediately 
● evaluate the participant to determine, in consultation with the medical monitor, 
whether study intervention should be interrupted or whether the dose should be 
reduced, and 
● closely monitor the participant for any AE/SAE and laboratory abnormalities until 
study intervention no longer has a clinical effect or can no longer be detected 
systemically (at least 35 days). 
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6.8. 
Concomitant Therapy  
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. 
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. 
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. If newly initiated 
concomitant medication could impact efficacy and safety, clinical site staff should discuss with 
participant and non-study prescribing physician possible alternative options. 
Participants who develop diabetes during the study may initiate medication for glucose control, 
with the exception of DPP-4 inhibitors or GLP-1R agonists. Initiation of metformin for the 
treatment of diabetes is permitted, but metformin should not be initiated during the study for the 
treatment of other metabolic conditions, for example, polycystic ovary syndrome and diabetes 
prevention. 
Non-study 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. 
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements, or other specific categories of interest, that the participant is 
receiving at the time of randomization to treatment or receives during the study must be recorded 
along with 
 reason for use, and 
 dates of administration, including start and end dates. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 
7.1. 
Discontinuation of Study Intervention  
When necessary, a participant may be permanently discontinued from study intervention. If so, 
the participant will remain in the study to complete procedures for the remaining study visits, as 
shown in the SoA. If study intervention is discontinued, the participant will continue to follow 
the lifestyle program (see Section 5.3). 
If a participant who discontinues study treatment prematurely declines to complete the remaining 
scheduled study visits, efforts should be made to have the visits converted to telephone visits. 
Participants should be encouraged to come back for the “last treatment visit” (Visit 20) for final 
collection of primary and key secondary efficacy endpoints and to complete the end-of-treatment 
phase procedures. 
 
If a participant who discontinues the treatment prematurely declines to complete the remaining 
scheduled study visits (onsite or by telephone), then the participant should be scheduled for the 
early discontinuation (ED) procedures indicated in the SoA. 
A participant should be permanently discontinued from study intervention if 
 participant decision 
o the participant requests to discontinue study intervention 
 clinical considerations 
o initiation of open-label GLP-1R agonist or DPP-4 inhibitor, if participants will 
not, or cannot discontinue them 
o initiation of additional approved prescription anti-obesity medication, if 
participants will not, or cannot discontinue them 
o has bariatric surgery or weight loss procedure 
o any female participant who becomes pregnant while participating in the study 
(see Section 8.3.2) 
o BMI ≤18.5 kg/m
2 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 significant GI symptoms despite management (Section 4.1.3.1) 
Note: The investigator should contact the Sponsor CRP to discuss 
whether it is medically appropriate for the participant to continue study 
treatment. 
o significant elevation of calcitonin 
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o occurrence of any other TEAE, SAE, or clinically significant finding for 
which the investigator believes that permanent study intervention 
discontinuation is the appropriate measure to be taken 
o diagnosis of 
▪ T1D 
▪ thyroid C-cell hyperplasia, MTC, or MEN-2 after randomization, and 
▪ acute or chronic pancreatitis 
o 
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 
in the opinion of the investigator, the participant should permanently 
discontinue the study intervention for safety reasons 
 Suicidal ideation and behavior 
o 
PHQ-9 score ≥15 
Participants should be referred to a Mental Health Professional to assist in 
deciding whether the subject should be discontinued from study 
intervention. 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 Mental Health 
Professional), may be continued in the trial on randomized therapy 
o 
Study intervention may be discontinued if participants 
▪ answered “yes” to Question 4 or Question 5 on the “Suicidal Ideation” 
portion of the C-SSRS, or 
▪ answered “yes” to any of the suicide-related behaviors on the Suicidal 
Behavior portion of the C-SSRS. 
A psychiatrist or appropriately trained professional may assist in the decision to 
discontinue the participant. 
 Hypersensitivity reactions 
o 
If the investigator determines that a systemic hypersensitivity reaction has 
occurred related to study intervention administration, the participant may 
be permanently discontinued from the study intervention, and the 
sponsor’s designated medical monitor should be notified. If the 
investigator is uncertain about whether a systemic hypersensitivity 
reaction has occurred and whether discontinuation of study intervention is 
warranted, the investigator may consult the sponsor. 
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7.1.1. 
Liver Chemistry Stopping Criteria  
Interrupting study drug based on elevated liver tests 
The study drug should be interrupted and close hepatic monitoring initiated (see Section 8.2.7) 
if 1 or more of these conditions occur: 
Elevation 
Exception 
ALT or AST >8x ULN 
 
ALT or AST >5x ULN for more than 2 weeks 
 
ALT or AST >3x ULN and either TBL >2x ULN or INR >1.5  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL>2x ULN 
ALT or AST >3x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain, or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >3x ULN, when the source of increased ALP is the liver 
 
ALP >2.5x ULN and TBL > 2x ULN 
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL>2x ULN 
ALP >2.5x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain, or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009, and 
other consensus guidelines, with minor modifications 
Resuming study drug after elevated liver tests 
Resumption of the study drug can be considered only in consultation with the Lilly-designated 
medical monitor and only if the liver test results return-to-baseline and if a self-limited non-drug 
etiology is identified. Otherwise, the study drug should be discontinued. 
7.1.2. 
QTc Stopping Criteria  
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QT interval corrected using Fridericia’s formula [QTcF] after enrollment), the 
investigator or qualified designee will determine if the participant can continue in the study and 
if any change in participant management is needed. This review of the ECG printed at the time of 
collection must be documented. Any new clinically relevant finding should be reported as an AE. 
7.1.3. 
Temporary Discontinuation  
In certain situations, the investigator may need to temporarily interrupt study intervention. If 
study intervention is interrupted, the participant will continue to follow the lifestyle program (see 
Section 5.3).Every effort should be made by the investigator to maintain participants on study 
intervention and to restart study intervention after any temporary interruption, as soon as it is 
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safe to do so. This may require an additional unscheduled visit to address in a timely manner. 
Distribution of study intervention at the correct dose will be per protocol as detailed below. 
If study intervention 
interruption is… 
then… 
2 consecutive doses or less  
participant restarts study intervention at last administered dose, 
as per escalation schedule. 
3 consecutive doses or more  
participant restarts study intervention (at 5 mg for tirzepatide 
and 0.25 mg for semaglutide) and repeats dose escalation 
scheme. 
due to an AE 
the event is to be documented and followed according to the 
procedures in Section 10.3 of this protocol. 
due to intolerable persistent 
GI AE 
participants should be treated as suggested in Section 4.1.3.1. 
Investigators should inform Lilly medical monitor that study intervention has been temporarily 
interrupted. The data related to temporary interruption of study treatment will be documented. 
Missed dose 
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. 
If a dose of semaglutide is missed, the participant should take it as soon as possible unless it is 
within 48 hours of the next dose, in which case, that dose should be skipped and the next dose 
should be taken at the appropriate time. 
7.2. 
Participant Discontinuation/Withdrawal from the Study  
To minimize the amount of missing data and to enable assessment of study objectives and 
estimands 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 intervention 
 start of another anti-obesity medication 
 adherence to visit schedule 
 missing assessments 
 study intervention discontinuation due to AE 
 development of comorbidities, and 
 development of clinical outcomes. 
Discontinuation is expected to be uncommon. 
The circumstances listed above are not valid reasons for discontinuation from the study. 
A participant may withdraw from the study 
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● at any time at the participant’s own request 
● at the request of the participant’s designee, for example, legal guardian 
● at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons, or 
● if enrolled in any other clinical study involving an investigational product, or 
enrolled in any other type of medical research judged not to be scientifically or 
medically compatible with this study. 
A participant will withdraw from the study: 
 if a female participant becomes pregnant, or 
 if participant undergoes bariatric surgery or a weight-loss procedure, for example, gastric 
balloon placement, during the study. 
Participation in the study can be stopped for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and good clinical practice. Participants who agree to 
provide information relevant to any trial endpoint at the end of the study are not considered to 
have discontinued from the study. 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an ED visit, as shown in the SoA. If the participant has not already discontinued the study 
intervention, the participant will be permanently discontinued from the study intervention at the 
time of the decision to discontinue the study. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, the participant may request destruction of any samples taken and not 
tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow-up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designee are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site. 
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8. 
Study Assessments and Procedures  
● Study procedures and their timing are summarized in the SoA. 
● Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
● Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
● All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 
8.1. 
Efficacy Assessments  
Primary 
The primary efficacy measure is percent body weight change. Body weight measurements will 
be collected at specific clinic visits as summarized in the SoA. Methods for measuring body 
weight are described in Section 10.8. 
Secondary 
The following secondary efficacy measures will be collected at the times shown in the SoA: 
 body weight 
 BMI (derived using body weight in kilograms divided by the square of height in meters), 
and 
 waist circumference (see Section 10.8). 
Patient-reported outcomes: 
 36-item Short Form Health Survey, Version 2, acute (1-week recall version) 
The SF-36 v2 acute 1-week recall version is a 36-item, generic, participant-administered 
measure designed to assess the following 8 domains: 
o Physical Functioning 
o Role-Physical 
o Bodily Pain 
o General Health 
o Vitality 
o Social Functioning 
o Role-Emotional, and 
o 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 
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component summary scores: Physical Component Summary and Mental Component 
Summary. Items are answered on Likert scales of varying lengths (3-point, 5-point, 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 of 10; higher 
scores indicate better levels of function and/or better health (Maruish 2011). 
 Patient Global Impression of Status for Physical Activity 
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.” The recall is during the past 
week. Impaired physical function at baseline will be defined as a PGIS response at baseline 
of 
o moderately limited 
o very much limited, or 
o extremely limited. 
See Section 3 for specific efficacy endpoints. 
8.2. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations  
For each participant, measurements including height, weight, and waist circumference should be 
conducted according to SoA, and following the study-specific recommendations included in 
Section 10.8. 
A complete physical examination will include, at a minimum, assessments of 
1. cardiovascular 
2. respiratory 
3. GI 
4. neurological systems 
5. thyroid examination 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.2. 
Vital Signs  
For each participant, vital sign measurements should be conducted according to the SoA and 
following the study-specific recommendations included in Section 10.8. 
Any clinically significant findings from vital sign measurement that result in a diagnosis and that 
occur after the participant receives the first dose of study intervention should be reported to Lilly 
or its designee as an AE via CRF. 
8.2.3. 
Electrocardiograms  
For each participant, a single 12-lead digital ECG will be collected according to the SoA. 
Electrocardiograms must be recorded before collecting any blood samples. Participant must be 
supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake 
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during ECG collection. Electrocardiograms may be obtained at additional times, when deemed 
clinically necessary. All ECGs recorded should be stored at the investigational site. 
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while 
the participant is still present, to determine whether the participant meets entry criteria at the 
relevant visit(s) and for immediate participant management, should any clinically relevant 
findings be identified. 
If a clinically significant finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the participant can 
continue in the study. The investigator, or qualified designee, is responsible for determining if 
any change in participant management is needed and must document his or her review of the 
ECG printed at the time of collection. Any new clinically relevant finding should be reported as 
an adverse event. 
8.2.4. 
Clinical Safety Laboratory Tests  
● See Section 10.2 for the list of clinical laboratory tests to be performed and the 
SoA for the timing and frequency. 
● The investigator must review the laboratory results, document this review, and 
report any clinically relevant changes occurring during the study as an AE. The 
laboratory results must be retained with source documents unless a Source 
Document Agreement or comparable document cites an electronic location that 
accommodates the expected retention duration. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, 
unless judged by the investigator to be more severe than expected for the 
participant’s condition. 
● All laboratory tests with values considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to 
normal or baseline or are no longer considered clinically significant by the 
investigator or medical monitor. 
○ If such values do not return to normal or baseline within a period of time 
judged reasonable by the investigator, the etiology should be identified and 
the sponsor notified. 
○ All protocol-required laboratory assessments, as defined in Appendix 2, must 
be conducted in accordance with the SoA, standard collection requirements, 
and laboratory manual. 
● If laboratory values from non-protocol-specified laboratory assessments 
performed at an investigator-designated local laboratory require a change in 
participant management or are considered clinically significant by the 
investigator, for example, SAE or AE or dose modification, then report the 
information as an AE. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. If repeated testing supports technical issue with a safety laboratory, the investigator is 
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recommended to contact the sponsor. An alignment to medical interpretation between the 
investigator and sponsor can occur to allow for potential additional testing as needed to satisfy 
prioritizing safety and limiting interruption of study intervention if appropriate. 
8.2.5. 
Pregnancy Testing  
Pregnancy testing will occur as outlined in the SoA. 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected as outlined in Sections 8.3.1 and 8.3.2. 
WOCBP should be offered home urine pregnancy tests and instructed to test if any concern for 
pregnancy, for example, late menstrual cycle and new symptoms. WOCBP are recommended to 
notify site staff of positive home testing and to hold next dose of study intervention until 
additional testing. Positive test should be confirmed with on-site clinical serum testing. 
Study intervention should not be administered after positive home urine test unless that test is 
confirmed (at least 2 serum tests separated by 14 days) false positive. 
8.2.6. 
Suicidal Ideation and Behavior Risk Monitoring  
Patients with obesity or overweight may occasionally develop suicidal ideation or behavior. 
The C-SSRS and PHQ-9 will be performed for baseline assessment of suicidal ideation and 
behavior and monitoring for intervention emergent suicidal ideation and behavior. 
Participants should be monitored appropriately and observed closely for SIB or any other 
unusual changes in behavior, especially at the beginning and end of the course of intervention, or 
at the time of dose changes, either increases, or decreases. Participants who experience signs of 
SIB should undergo a risk assessment. All factors contributing to SIB should be evaluated, and 
consideration should be given to discontinuation of the study intervention. 
8.2.6.1. 
C-SSRS  
Columbia Suicide Severity Rating Scale is a scale that captures the occurrence, severity, and 
frequency of suicidal ideation and behavior during the assessment period via a questionnaire. 
The scale was developed by the National Institute of Mental Health trial group (TASA) for the 
purpose of being counterpart to the Columbia Classification Algorithm of Suicide Assessment 
categorization of suicidal events. (The Columbia Lighthouse Project, Version 2.0) 
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. 
8.2.6.2. 
PHQ-9  
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). 
8.2.7. 
Hepatic Safety Monitoring  
Close hepatic monitoring 
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Laboratory tests (Appendix 2), including ALT, AST, ALP, TBL, D. Bil, GGT, CK, and CBC 
should be repeated within 48 to 72 hours to confirm the abnormality and to determine if it is 
increasing or decreasing, if 1 or more of these conditions occur: 
If a participant with baseline results 
of...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN 
ALP <1.5x ULN 
ALP ≥2x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN, except for patients with Gilbert’s 
syndrome 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥1.5x baseline, except for patients with Gilbert’s 
syndrome 
 
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal, and dietary supplements, history of alcohol 
drinking, and other substance abuse. 
Initially, monitoring of symptoms, and hepatic biochemical tests should be done at a frequency 
of 1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical 
tests. Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if 
the participant’s clinical condition and laboratory results stabilize. Monitoring of ALT, AST, 
ALP, and TBL should continue until levels normalize or return to approximate baseline levels. 
Comprehensive hepatic evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 1 
or more of these conditions occur: 
If a participant with baseline 
results of...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN with hepatic signs/symptomsa, or 
ALT or AST ≥5x ULN 
ALP <1.5x ULN 
ALP ≥3x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN, except for patients with Gilbert’s syndrome 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline with hepatic signs/symptomsa, or 
ALT or AST ≥3x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥2x baseline, except for patients with Gilbert’s syndrome 
a Hepatic signs or symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
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At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for PT-INR; tests for viral hepatitis A, B, C, E; tests for 
autoimmune hepatitis; and an abdominal imaging study, for example, ultrasound or CT scan (see 
Section 10.6.1). 
Based on the patient’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus, 
cytomegalovirus, Epstein-Barr virus, acetaminophen levels, acetaminophen protein adducts, 
urine toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl glucuronide, and 
blood phosphatidylethanol. Based on the circumstances and the investigator’s assessment of the 
participant’s clinical condition, the investigator should consider referring the participant for a 
hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy. 
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study 
Additional hepatic safety data collection in hepatic safety CRF should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
1. Elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5x ULN) 
 In participants with baseline ALT ≥1.5x ULN, the threshold is ALT ≥3x baseline 
on 2 or more consecutive tests 
2. Elevated TBL to ≥ 2x ULN (if baseline TBL <1.5x ULN) (except for cases of known 
Gilbert’s syndrome) 
 In participants with baseline TBL ≥1.5x ULN, the threshold should be TBL ≥2x 
baseline 
3. Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5x ULN) 
 In participants with baseline ALP ≥1.5x ULN, the threshold is ALP ≥2x baseline 
on 2 or more consecutive blood tests 
4. Hepatic event considered to be an SAE 
5. Discontinuation of study drug due to a hepatic event 
Note: the interval between the 2 consecutive blood tests should be at least 2 days. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in Appendix 10.3: 
 AEs 
 SAEs, and 
 PCs. 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
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are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study intervention (see Section 7). 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits or contacts. All SAEs and AEs of special interest, as defined in Section 8.3.3, 
will be followed until resolution, stabilization, the event is otherwise explained, or the participant 
is lost to follow-up (as defined in Section 7.3). For product complaints, the investigator is 
responsible for ensuring that follow-up includes any supplemental investigations as indicated to 
elucidate the nature, and/or causality. Further information on follow-up procedures is provided in 
Appendix 10.3. 
8.3.1. 
Timing and Mechanism for Collecting Events  
This table describes the timing, deadlines, and mechanism for collecting events. 
Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
Adverse Event 
AE 
Signing of 
the ICF  
Participation 
in study has 
ended 
As soon as possible 
upon site awareness 
AE CRF 
N/A 
Serious Adverse Event 
SAE and SAE 
updates – prior 
to start of study 
intervention and 
deemed 
reasonably 
possibly related 
to study 
procedures 
Signing of 
the ICF 
Start of 
intervention 
Within 24 hours of 
awareness 
SAE CRF  
SAE paper 
form 
SAE and SAE 
updates – after 
start of study 
intervention 
Start of 
intervention 
Participation 
in study has 
ended 
Within 24 hours of 
awareness 
SAE CRF  
SAE paper 
form 
SAEa – after 
participant’s 
study 
participation has 
ended and the 
investigator 
becomes aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
Pregnancy 
Pregnancy in 
female 
participants and 
female partners 
of male 
participants 
After the 
start of study 
intervention 
Four months 
after the last 
injection for 
female 
partners of 
male 
participants 
and 2 months 
after the last 
injection for 
female 
participants  
Within 24 hours (see 
Section 8.3.2) 
Pregnancy paper 
form  
Pregnancy 
paper form 
Product Complaints 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 24 hours of 
awareness 
Product complaint 
form 
N/A 
PC not 
associated with 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
Product complaint 
form 
N/A 
Updated PC 
information 
— 
— 
As soon as possible 
upon site awareness 
Originally 
completed product 
complaint form with 
all changes signed 
and dated by the 
investigator 
N/A 
PC (if 
investigator 
becomes aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
Product complaint 
form 
 
a Serious adverse events should not be reported unless the investigator deems them to be possibly related to study 
treatment or study participation. 
8.3.1.1. 
Adverse Event Monitoring with a Systematic Questionnaire  
Nonleading AE collection should occur prior to the collection of the C-SSRS. 
If a suicide-related event is discovered during the C-SSRS but was not captured during the 
nonleading AE collection, sites should not change the AE form. 
If an AE is serious or leads to discontinuation, it needs to be included on the AE form and the 
process for reporting SAEs is followed. 
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8.3.2. 
Pregnancy  
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. This applies only to male participants who receive study 
intervention. 
● After learning of a pregnancy in the female partner of a study participant, the 
investigator 
o will obtain a consent to release information from the pregnant female partner 
directly, and 
o within 24 hours after obtaining this consent will record pregnancy information 
on the appropriate form and submit it to the sponsor. 
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 gestational age, fetal status (presence or absence of 
anomalies), or indication for the procedure. 
Female participants who become pregnant 
● The investigator will collect pregnancy information on any female participant 
who becomes pregnant while participating in this study. The initial information 
will be recorded on the appropriate form and submitted to the sponsor within 24 
hours of learning of a participant’s pregnancy. 
● The 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 gestational age, 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 for medical reasons will be 
reported as an AE or SAE. 
● A spontaneous abortion (occurring at <20 weeks gestational age) or still birth 
(occurring at ≥20 weeks gestational age) is always considered to be an SAE and 
will be reported as such. 
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● Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
protocol Section 8.3.1. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
● Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention and be withdrawn from the study. If the 
participant is discontinued from the study, follow the standard discontinuation 
process and continue directly to the follow-up phase. The follow-up on the 
pregnancy outcome should continue independent of intervention or study 
discontinuation. 
8.3.3. 
Adverse Events of Special Interest  
The following are adverse events of special interest and will be adjudicated by an independent 
clinical endpoint committee: 
 pancreatitis 
 major adverse cardiovascular events, and 
 deaths. 
The following are additional adverse events of special interest for this program that will not be 
adjudicated by an external committee: 
 hypoglycemia (Levels 2 and 3) 
 thyroid malignancies and C-cell hyperplasia 
 arrhythmias and cardiac conductive disorders 
 hypersensitivity events 
 injection site reactions 
 hepatobiliary disorders 
 severe GI AEs 
 antidrug antibodies 
 acute renal events, and 
 Major depressive disorder, suicidal ideation, or suicidal behaviors. 
Sites should collect additional details and data regarding these safety topics, as instructed on the 
applicable CRFs, and detailed below. 
8.3.3.1. 
Hypoglycemia  
All participants will be trained by authorized study personnel about signs and symptoms of 
hypoglycemia and how to treat hypoglycemia. Glucose meters will be required to be provided to 
participants with incident T2D during the course of the trial; investigators should use the 
following classification of hypoglycemia: 
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Level 2 hypoglycemia 
Glucose <54 mg/dL (3.0 mmol/L): Level 2 hypoglycemia is also referred to as documented 
or blood glucose-confirmed hypoglycemia with glucose <54 mg/dL (3.0 mmol/L). This 
glucose threshold is clinically relevant regardless of the presence or absence of symptoms of 
hypoglycemia. 
Level 3 hypoglycemia 
Severe hypoglycemia: A severe event characterized by altered mental and/or physical status 
requiring assistance for treatment of hypoglycemia. For example, participants had altered 
mental status, and could not assist in their own care, or were semiconscious or unconscious, 
or experienced coma with or without seizures, and the assistance of another person was 
needed to actively administer carbohydrate, glucagon, or other resuscitative actions. Glucose 
measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of glucose concentration to normal is considered sufficient 
evidence that the event was induced by a low glucose concentration. 
 The determination of a hypoglycemic event as an episode of severe hypoglycemia, as 
defined above, is made by the investigator based on the medical need of the 
participant to have required assistance and is not predicated on the report of a 
participant simply having received assistance. 
 If a hypoglycemic event meets the criteria of severe hypoglycemia, the investigator 
must record the event as serious on the AE CRF and report it to Lilly as an SAE. 
Nocturnal hypoglycemia 
Nocturnal hypoglycemia is a hypoglycemia event, including severe hypoglycemia, that 
occurs at night and presumably during sleep. 
8.3.3.2. 
Pancreatitis  
Diagnosis of acute pancreatitis 
Acute pancreatitis is an AE of interest in all studies with tirzepatide or semaglutide, including 
this study. The diagnosis of acute pancreatitis requires 2 of the following 3 features (Banks 2006; 
Koizumi 2006): 
 abdominal pain, characteristic of acute pancreatitis (that is, epigastric pain radiating to the 
back, often associated with nausea, and vomiting) 
 serum amylase (total, pancreatic, or both) and/or lipase ≥3x ULN, and 
 characteristic findings of acute pancreatitis on CT scan or MRI. 
If acute pancreatitis is suspected, the investigator should 
 obtain appropriate laboratory tests, including pancreatic amylase (p-amylase) and lipase 
 perform imaging studies, such as abdominal CT scan with or without contrast, or 
abdominal MRI, and 
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 evaluate for possible causes of acute pancreatitis, including alcohol use, gallstone or gall 
bladder disease, hypertriglyceridemia, and concomitant medications. 
Discontinuation for acute pancreatitis 
If acute pancreatitis is diagnosed, the participant must discontinue use of the investigational 
products, but will continue in the study. 
Case adjudication and data entry 
An independent clinical endpoint committee will adjudicate all suspected cases of acute 
pancreatitis. 
Asymptomatic elevation of serum amylase and/or lipase 
Serial measures of pancreatic enzymes have limited clinical value for predicting episodes of 
acute pancreatitis in asymptomatic patients (Nauck et al. 2016; Steinberg et al. 2017 a, 2017b). 
Therefore, further diagnostic follow-up of cases of asymptomatic elevation of pancreatic 
enzymes (lipase and/or p-amylase ≥3x ULN) is not mandated but may be performed based on the 
investigator’s clinical judgment and assessment of the participant’s overall clinical condition. 
8.3.3.3. 
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 
intervention stopped and should continue follow-up with an endocrinologist. 
The assessment of thyroid safety during the trial will include reporting of any case of thyroid 
malignancy (including MTC, papillary carcinoma, and others) and measurements of calcitonin. 
These data will be captured in specific CRFs. The purpose of calcitonin measurements is to 
assess the potential of study intervention to affect thyroid C-cell function, which may indicate 
development of C-cell hyperplasia and neoplasms. 
8.3.3.4. 
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 CRF. 
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Calcitonin measurements in participants with eGFR ≥60 mL/min/1.73 m2 
A significant increase in calcitonin for participants with eGFR ≥60 mL/min/1.73 m2 is defined 
below. If a participant’s laboratory results meet these criteria, these clinically significant 
laboratory results should be recorded as an AE. 
 Serum calcitonin value ≥20 ng/L and <35 ng/L AND ≥50% increase from the screening 
value. These participants will be asked to repeat the measurement within 1 month. If this 
repeat value is increasing (≥10% increase), the study intervention 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 event on the thyroid. 
 Serum calcitonin value ≥35 ng/L AND ≥50% over the screening value. In these 
participants, study intervention should be stopped, and the participant recommended to 
immediately undergo additional endocrine assessments and longer-term follow-up by an 
endocrinologist. 
Calcitonin measurement in participants with eGFR <60 mL/min/1.73 m2 
A significant increase in calcitonin for participants with eGFR <60 mL/min/1.73 m2 is defined as 
a serum calcitonin value ≥35 ng/L AND ≥50% over the screening value. If a participant’s labs 
meet these criteria, these clinically significant labs should be recorded as an AE. 
In these participants, study intervention 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. 
8.3.3.5. 
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. 
8.3.3.6. 
Deaths  
All deaths will be adjudicated by a committee of physicians external to Lilly. This committee 
will be blinded to treatment assignment. 
8.3.3.7. 
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. Additional diagnostic 
tests to determine exact diagnosis should be performed, as needed. The specific diagnosis will be 
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recorded as an AE. Events that meet criteria for serious conditions as described in Section 10.3 
must be reported as SAEs. 
8.3.3.8. 
Hypersensitivity Reactions  
Many drugs, including oral agents, and biologic agents, carry the risk of systemic 
hypersensitivity reactions. If such a reaction occurs, additional data should be provided to the 
sponsor in the designated CRFs. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study intervention. It is recommended that 
participants who experience a systemic hypersensitivity reaction be treated per national and 
international guidelines. 
In the case of a suspected systemic hypersensitivity event, additional blood samples should be 
collected as described in Section 10.2. Laboratory results are provided to the sponsor via the 
central laboratory. 
8.3.3.9. 
Injection Site Reactions  
Symptoms and signs of a local injection site reaction may include erythema, induration, pain, 
pruritus, and edema. 
If an ISR is reported by a participant or site staff for tirzepatide or semaglutide, the ISR CRF will 
be used to capture additional information about this reaction, for example 
 injection site pain 
 degree and area of erythema 
 induration 
 pruritis, and 
 edema. 
At the time of AE occurrence in the tirzepatide group only, samples will be collected for 
measurement of tirzepatide antidrug antibodies and tirzepatide concentration. 
8.3.3.10. Hepatobiliary Disorders  
All events of treatment-emergent biliary colic, cholecystitis, or other suspected events related to 
gallbladder disease should be evaluated and additional diagnostic tests performed, as needed. In 
cases of elevated liver markers, hepatic monitoring should be initiated as outlined in 
Section 8.2.7. 
8.3.3.11. 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 CRF/AE form. For 
detailed information concerning the management of GI AEs, please refer to Section 4.1.3.1 
8.3.3.12. 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 study intervention, 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. 
8.3.3.13. Major Depressive Disorder, Suicidal Ideation, or Suicidal Behavior Monitoring  
Participants will be monitored for Major Depressive Disorder and suicidal ideation or suicidal 
behaviors through AE collection and by using the C-SSRS and the PHQ-9. Participants will be 
referred to a Mental Health Professional 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 have answered “yes” to either Question 4 or Question 5 on the “Suicidal Ideation” 
portion of the C-SSRS or 
o have answered “yes” to any of the suicide-related behaviors on the “suicidal 
behavior” portion of the C-SSRS, and 
o the ideation or behavior occurred within the past month. 
8.4. 
Pharmacokinetics  
Pharmacokinetics are not evaluated in this study. 
8.5. 
Pharmacodynamics  
Pharmacodynamics are not evaluated in this study. 
8.6. 
Genetics  
A whole blood sample will be collected for genetic analysis as specified in the SoA (Section 1.3) 
where local regulations allow. The genetic sample collection will be discussed during informed 
consent and participants will designate if they agree to this optional sample collection in the 
informed consent document. The sample should only be collected if the participant has provided 
a signed ICF.  
The sample collection is scheduled for Visit 11 but if this sample is missed it can be collected at 
another visit, and does not require fasting. 
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/or 
semaglutide and to investigate genetic variants thought to play a role in obesity and obesity-
related diseases. Assessment of variable response may include evaluation of AEs or differences 
in efficacy. 
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the investigator site personnel. 
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Samples will be retained at a facility selected by Lilly or its designee for a maximum of 7 years 
after the last participant visit for the study, or for a shorter period if local regulations and/or 
Ethical Review Boards/Institutional Review Boards 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 becomes commercially available. 
Molecular technologies are expected to improve during the 7-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. 
Sample retention is described in Section 10.1.12. 
8.7. 
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 DNA, proteins, lipids, and other 
cellular elements. 
Serum, plasma (exploratory biomarker) and whole blood (epigenetic) samples for biomarker research 
will be collected at the times specified in the SoA (Section 1.3) where local regulations allow. 
Samples will be used for research on the drug target, disease process, variable response to tirzepatide, 
and/or semaglutide, 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 7 years after the 
last participant visit for the study, or for a shorter period if local regulations and Ethical Review 
Boards 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 becomes commercially available for chronic 
weight management. 
Sample retention is described in Section 10.1.12. 
8.8. 
Immunogenicity Assessments  
Exploratory biomarker samples collected during the study may be used to perform any 
immunogenicity-related assessments as deemed appropriate.  
8.9. 
Health Economics  
Health economics parameters are not evaluated in this study. 
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9. 
Statistical Considerations  
The statistical analysis plan will be developed and approved prior to first participant first visit, 
and it will include a more technical and detailed description of the statistical analyses described 
in this section. This section is a summary of the planned statistical analyses of the most 
important endpoints, including primary, and key secondary endpoints. 
9.1. 
Statistical Hypotheses  
The null hypothesis corresponding to the primary objective of this study is as follows: 
 H1,0: tirzepatide at 15 mg or MTD (10 mg or 15 mg) is not superior to semaglutide at 
2.4 mg or MTD (1.7 mg or 2.4 mg) with respect to mean percent change in body weight 
from baseline at Week 72 
The null hypotheses corresponding to the key secondary objectives is as follows: 
 H2,0: tirzepatide at 15 mg or MTD (10 mg or 15 mg) is not superior to semaglutide at 
2.4 mg or MTD (1.7 mg or 2.4 mg) for the percentage of participants who achieve ≥10% 
body weight reduction from baseline at Week 72 
 H3,0: tirzepatide at 15 mg or MTD (10 mg or 15 mg) is not superior to semaglutide at 
2.4 mg or MTD (1.7 mg or 2.4 mg)  for the percentage of participants who achieve ≥15% 
body weight reduction from baseline at Week 72 
 H4,0: tirzepatide at 15 mg or MTD (10 mg or 15 mg) is not superior to semaglutide at 
2.4 mg or MTD (1.7 mg or 2.4 mg) for the percentage of participants who achieve ≥20% 
body weight reduction from baseline at Week 72 
 H5,0: tirzepatide at 15 mg or MTD (10 mg or 15 mg) is not superior to semaglutide at 
2.4 mg or MTD (1.7 mg or 2.4 mg) for the percentage of participants who achieve ≥25% 
body weight reduction from baseline at Week 72 
 H6,0: tirzepatide at 15 mg or MTD (10 mg or 15 mg) is not superior to semaglutide at 
2.4 mg or MTD (1.7 mg or 2.4 mg) with respect to change in waist circumference (cm) 
from baseline at Week 72 
Operationally, the hypotheses will be evaluated by 2-sided tests. 
9.1.1. 
Multiplicity Adjustment  
The primary and the key secondary objectives will be evaluated using both the treatment regimen 
and the efficacy estimands. Since the purpose for each estimand is different, multiplicity 
adjustment will be conducted for each estimand separately. 
A prespecified graphical scheme (Bretz et al. 2009, 2011) will be implemented to control the 
family-wise error rate at a 1-sided alpha level of 0.025 for testing the null hypotheses stated in 
Section 9.1. More specifically, multiple testing adjusted p-values described by Bretz et al. (2009) 
will be calculated, and any hypothesis tests with a multiple testing adjusted 1-sided p-value of 
less than 0.025 will be considered statistically significant. This graphical approach is a closed 
testing procedure; hence, it strongly controls the family-wise error rate across all endpoints 
(Bretz et al. 2009, 2011; Alosh et al. 2014). 
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The testing scheme will be fully detailed in the statistical analysis plan. Unless otherwise 
specified, there will be no adjustment for multiple comparisons for any other analyses outside the 
primary and key secondary endpoints. The testing scheme will be finalized before the first 
participant visit. 
9.2. 
Analyses Sets  
This table defines the analysis populations and datasets for the purposes of analysis based on the 
estimands defined in Section 3. 
9.3. 
Statistical Analyses  
9.3.1. 
General Considerations  
Statistical analysis of this study will be the responsibility of Lilly or its designee. 
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the SAP or CSR. Additional exploratory analyses of the data will be conducted as deemed 
appropriate. 
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05/1-sided alpha 
level of 0.025, unless otherwise stated, and all CIs will be given at a 2-sided (95%) level. In 
statistical summaries and analyses, all data will be analyzed by randomized treatment 
Population/Analysis Set 
Description 
Screened population 
All participants who signed informed consent. 
Randomized population 
All participants who are randomly assigned to a treatment 
arm. 
Modified intent-to-treat population (mITT) 
All randomly assigned participants who are exposed to at 
least 1 dose of study intervention. Participants will be 
analyzed according to the treatment they were randomly 
assigned to regardless of the treatment actually received.  
Efficacy Analysis Set (EAS): This analysis set will 
be used to estimate the efficacy estimand 
Data obtained during the Treatment Period from the mITT 
population excluding participants who were inadvertently 
enrolled, excluding data after permanent discontinuation of 
treatment or initiation of other anti-obesity medication, 
bariatric surgery, or other weight management procedures. 
Full Analysis Set (FAS): This analysis set will be 
used to estimate the modified treatment-regimen 
estimand  
Data obtained during the Treatment Period from the mITT 
population excluding participants who were inadvertently 
enrolled, regardless of adherence to treatment and 
regardless of initiation of other anti-obesity medication 
except for non-study tirzepatide/semaglutide, bariatric 
surgery, or other weight management procedures. 
Safety Analysis Set (SS): This analysis will be used 
to assess the safety of study treatment 
Data obtained during the study from the mITT population, 
regardless of adherence to treatment and regardless of 
initiation of other anti-obesity medication or bariatric 
surgery. 
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assignment. Participants will be analyzed according to the treatment they were randomly 
assigned to, regardless of the treatment actually received. 
Baseline is defined as the last non-missing measurement recorded on or before the randomization 
visit, prior to first dose of treatment, unless otherwise specified. 
Efficacy analyses will use the efficacy analysis set to evaluate the efficacy estimand and the full 
analysis set to evaluate the modified treatment-regimen estimand. Safety will be assessed using 
Safety Analysis Set. Selected safety analyses may be conducted after excluding data after 
starting another anti-obesity medication, bariatric surgery, or other weight management 
procedures. 
Summary statistics for continuous measures may include sample size, mean, standard deviation, 
median, minimum, and maximum. The analysis model to make comparisons between treatment 
groups relative to continuous measurements assessed over time will be an MMRM with terms for 
 treatment 
 visit 
 treatment-by-visit interaction 
 prediabetes status at randomization (yes/no) 
 sex (female/male),  
 baseline BMI category (<35 kg/m2, ≥35 kg/m2), and 
 baseline measurement as a covariate. 
The Kaplan-Meier method will be used for estimation of cumulative event-free survival rates 
over time, and Cox proportional hazards regression analysis will be used to compare hazard rates 
among treatments. 
Summary statistics for categorical measures, including categorized continuous measures, will 
include sample size, frequency, and percentages. Fisher’s exact test will be used to examine the 
treatment difference in categorical outcomes. Logistic regression may be used to examine the 
treatment difference in binary efficacy outcomes. The negative binomial regression model will 
be used for the treatment comparison of discrete count measures if deemed appropriate. 
Other statistical methods may be used, as appropriate, and details will be documented in the 
SAP. 
Handling of missing, unused, and spurious data is addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. Adjustments to 
the planned analyses are described in the final CSR. 
9.3.2. 
Primary Endpoint Analysis  
The primary endpoint for this study is percentage change from baseline in body weight to the 72-
week visit (Visit 20). This endpoint will be used to evaluate the primary objective of the study 
for both the modified treatment-regimen and the efficacy estimands (Section 3). The null 
hypothesis corresponding to the primary objective is specified in Section 9.1. 
The primary efficacy analysis will be guided by the modified treatment-regimen estimand and 
conducted using the Full Analysis Set. This assessment will analyze mean percent change in 
body weight obtained at the 72-week visit using an ANCOVA. Model will include terms of 
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treatment, prediabetes status at randomization, sex, and baseline BMI category, and baseline 
body weight as a covariate. For the purpose of the treatment-regimen estimand, missing body 
weight for participants who had bariatric surgery during the study will be imputed using the 
worst value (for example, highest body weight value) from baseline until the last observed value 
before bariatric surgery or another weight loss procedure. Missing body weight values at the 72-
week visit in patients who discontinued study intervention early and did not have bariatric 
surgery or another weight loss procedure will be imputed based on observed data in the same 
treatment group from participants who had their efficacy assessed after early discontinuation of 
study intervention. This analysis will be conducted with multiple imputations, and statistical 
inference over multiple imputations will be guided by the method proposed by Rubin (1987). 
The primary objective based on the efficacy estimand defined in Section 3 will be evaluated 
using the Efficacy Analysis Set dataset (Section 9.2). The primary analysis model for body 
weight percent change over time will be an MMRM. The response variable of MMRM will be 
the mean percent change in body weight from baseline values obtained at each scheduled post 
baseline visit. The independent variables of the analysis model are treatment group (tirzepatide 
15 mg or MTD, and semaglutide 2.4 mg or MTD), visit, and treatment-by-visit interaction, 
prediabetes status at randomization, sex, and baseline BMI category, and baseline body weight as 
a covariate. An unstructured covariance structure will model relationship of within-patient errors. 
If the analysis fails to converge, the following variance-covariance matrices will be used (in 
order) until convergence is achieved: heterogeneous compound symmetry, compound symmetry, 
and first-order autoregressive. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. 
9.3.3. 
Secondary Endpoints Analysis  
The endpoints corresponding to the secondary study objective subject to Type 1 error rate control 
are specified in Section 3 under “Key Secondary” (Controlled for Type 1 error) endpoints. 
The null hypotheses corresponding to the key secondary objectives can be found in Section 9.1. 
Key secondary objectives will be evaluated based on the modified treatment-regimen and the 
efficacy estimands, similar to the primary objective. 
Change from baseline in waist circumference at the 72-week visit will be conducted in a manner 
similar to the primary efficacy analyses (Section 9.3.2). 
Body weight reductions from baseline of ≥10%, ≥15%, ≥20%, and ≥25% at Week 72 will be 
analyzed. 
Missing body weight measurement at Week 72 will be imputed as follows: 
 For the modified treatment-regimen estimand, the same imputation methods described in 
Section 9.3.2 will be applied. 
 For the efficacy estimand, missing body weight in participants who discontinue study 
intervention drug early, or initiate other anti-obesity medications (AOMs) will be 
imputed by multiple imputation based on missing at random (MAR) assumption using the 
EAS. 
Dichotomized data (Yes or No) will then be derived based on the continuous imputed values for 
each weight loss category. 
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A logistic regression model with terms of treatment group, baseline BMI category, sex, and 
prediabetes status at randomization as fixed effects, and baseline body weight as a covariate will 
be used. The marginal mean for each treatment group will be calculated based on g-computation 
(FDA guidance, May 2023), and then the benefit difference (the difference in the proportions) 
and relative benefit (the ratio of the proportions) will the calculated. The standard errors for these 
quantities will be estimated using the delta-method (Ge et al. 2011). Two-sided 95% CI and p-
values will be derived. 
Endpoints for additional secondary objectives are described in Section 3 and will be evaluated 
based on the efficacy estimand. 
Additional details will be provided in the SAP. 
9.3.4. 
Safety Analyses  
Safety assessments will be conducted using the Safety Analysis Set (see Section 9.2) irrespective 
of adherence to study intervention and initiation of anti-obesity medication or bariatric surgery, 
unless indicated otherwise. 
Adverse events will be coded from the actual term using the Medical Dictionary for Regulatory 
Activities and reported with preferred terms and system organ class. Selected notable AEs of 
interest may be reported using high-level terms or Standardized Medical Dictionary for 
Regulatory Activities Queries. Summary statistics will be provided for incidence of TEAEs, 
SAEs, and study discontinuation due to AEs, study intervention discontinuation due to AEs, or 
deaths from the time of first dose through the end of study participation. 
Counts and proportions of participants experiencing AEs will be reported for each treatment 
group, and Fisher’s exact test will be used to compare the treatment groups. 
9.3.4.1. 
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 (see Section 8.3.3). Summaries and analyses for incidence of AESIs will 
be provided by treatment. The details of analysis of AESI will be provided in the SAP. 
9.3.4.2. 
Major Depressive Disorder, Suicidal Ideation and Suicidal Behavior  
In addition to the summary of TEAEs, suicidal ideation and suicidal 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. 
9.3.4.3. 
Gastrointestinal Events  
Summaries and analyses for incidence and severity of nausea, vomiting, and diarrhea will be 
provided by each treatment. 
9.3.4.4. 
Events Related to Potential Abuse Liability  
To identify AE terms suggestive of potential abuse liability, narrow terms from Standardized 
MedDRA Queries of Drug abuse and dependence (20000101) will be used. Summaries and 
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analyses for incidence of potential abuse liability terms will be provided by treatment. The 
details will be provided in the SAP. 
9.3.4.5. 
Central Laboratory Measures, Vital Signs, and Electrocardiograms  
Values and change from baseline to postbaseline values of central laboratory measures and vital 
signs will be summarized at each scheduled visit. The analysis model to make comparisons 
between treatment arms relative to continuous change from baseline values assessed over time 
will be an MMRM, with terms: treatment, visit, and treatment-by-visit interaction, stratifying 
factors, and baseline measurement as covariates. An unstructured covariance structure will 
model relationship of within-participant errors. 
9.3.5. 
Subgroup Analysis  
Details of the subgroup analyses will be shown in the SAP. The following subgroup variables 
will be considered, but not limited to: 
 age group: < 65 years, ≥ 65 years 
 sex: female, male 
 baseline BMI: <35, ≥35 kg/m2 
 race: white vs black vs other 
 ethnicity: Hispanic vs not Hispanic, and 
 glycemic status at randomization (normoglycemia vs prediabetes). 
9.4. 
Interim Analysis  
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended. Final analysis 
will be performed when all participants complete the study. 
9.5. 
Sample Size Determination  
Approximately 700 participants (350/group) will be randomly assigned in a 1:1 ratio to each 
study arm. 
For the treatment-regimen estimand, this sample size provides approximately 90% power to 
show that tirzepatide 15 mg or MTD is superior to semaglutide 2.4 mg or MTD in the mean 
percent change from baseline at Week 72 using the following assumptions: 
 a 2-sample t-test with a 2-sided significance level of 0.05 
 a study intervention discontinuation rate of 20% resulting in a common SD of 12%, and 
 a 3% treatment difference. 
For the efficacy estimand, this sample size also provides at least 90% power to show that 
tirzepatide 15 mg or MTD is superior to semaglutide 2.4 mg or MTD in the mean percent change 
from baseline at Week 72 using the following assumptions: 
 a 2-sample t-test with a 2-sided significance level of 0.05 
 a common SD of 10% 
 a 3% treatment difference, and 
 study intervention discontinuation rate of 20%. 
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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: 
○ consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences International Ethical Guidelines 
○ applicable ICH GCP Guidelines, and 
○ applicable laws and regulations. 
● The protocol, protocol amendments, ICF, Investigator 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. 
● Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
● The investigator will be responsible for the following: 
○ providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
○ notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
○ providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 Code of Federal Regulations, ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations, and 
o reporting significant issues related to participant safety, participant rights, or data 
integrity 
● Investigator sites are compensated for participation in the study as detailed in the 
Clinical Trial Agreement. 
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10.1.2. 
Financial Disclosure  
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process  
● The investigator or the investigator’s representative will explain the nature of the 
study, including the risks, and benefits, to the participant, or the participant’s 
legally authorized representative and answer all questions regarding the study. 
● Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representatives will be required to sign a statement of 
informed consent that meets the requirements of 21 Code of Federal Regulations 
50, local regulations, ICH guidelines, privacy, and data protection requirements, 
where applicable, and the IRB/IEC or study center. 
● The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
● Participants must be reconsented to the most current version of the ICF(s) during 
their participation in the study. 
● A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative and is kept on file. 
10.1.4. 
Data Protection  
● Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets, or tissue samples that are transferred to the sponsor will contain 
the identifier only; participant names or any information which would make the 
participant identifiable will not be transferred. 
● The participant must be informed that the participant’s personal study-related data 
will be used by the sponsor in accordance with local data protection law. The 
level of disclosure must also be explained to the participant who will be required 
to give consent for their data to be used as described in the informed consent. 
● The participant must be informed that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
● The sponsor has processes in place to ensure data protection, information security, 
and data integrity. These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach. 
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10.1.5. 
Committees Structure  
Prospective adjudication of major adverse cardiovascular events, pancreatic AEs, and deaths will 
be performed for this study.  
10.1.6. 
Dissemination of Clinical Study Data  
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete dataset 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, trial not yet unblinded), the summary of results 
will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
Data 
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of pharmacokinetic or genetic data. 
Data are available to request 6 months after the indication studied has been approved in the US 
and EU and after primary publication acceptance, whichever is later. No expiration date of data 
requests is currently set once data are made available. 
Access is provided after a proposal has been approved by an independent review committee 
identified for this purpose and after receipt of a signed data-sharing agreement. 
Data and documents, including the study protocol, statistical analysis plan, clinical study report, 
and blank, or annotated case report forms, will be provided in a secure data-sharing environment 
for up to 2 years per proposal. 
For details on submitting a request, see the instructions provided at www.vivli.org. 
10.1.7. 
Data Quality Assurance  
● All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically, for example, 
laboratory data. The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
● The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 
● The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 
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● QTLs will be predefined to identify systematic issues that can impact participant 
safety and/or reliability of study results. These predefined parameters will be 
monitored during the study, and important excursions from the QTLs and 
remedial actions taken will be summarized in the clinical study report. 
● Monitoring details describing strategy (for example, risk-based initiatives in 
operations and quality such as risk management and mitigation strategies and 
analytical risk-based monitoring), methods, responsibilities, and requirements, 
including handling of noncompliance issues and monitoring techniques are 
provided in the Monitoring Plan. 
● The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
● The sponsor assumes accountability for actions delegated to other individuals, for 
example, contract research organizations. 
● Study monitors will perform ongoing source data verification to confirm that data 
transcribed into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
● Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the period outlined in the Clinical 
Trial Agreement unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without 
the written approval of the sponsor. No records may be transferred to another 
location or party without written notification to the sponsor. 
● In addition, sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study 
may be audited by sponsor or its representatives, and/or regulatory agencies at 
any time. Investigators will be given notice before an audit occurs. 
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
An EDC will be used in this study for the collection of CRF data. The investigator maintains a 
separate source for the data entered by the investigator or designee into the sponsor-provided 
EDC system. The investigator is responsible for the identification of any data to be considered 
source and for the confirmation that data reported are accurate and complete by signing the CRF. 
Additionally, COA data (clinician-focused outcome instrument) for suicidality assessments and 
weight history questionnaire will be collected by the authorized study personnel, via a paper 
source document and will be transcribed by the authorized study personnel into the EDC system. 
Additionally, COA data (participant-focused outcome instrument) will be directly recorded by 
the participant, into an instrument, for example, hand-held smart phone, or tablet. The COA data 
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will serve as the source documentation, and the investigator does not maintain a separate written 
or electronic record of these data. 
Data collected via the sponsor-provided data capture system(s) will be stored at third parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system(s). Prior to decommissioning, the investigator will receive, or access 
an archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system, and reports/electronic transfers will be provided to the 
investigator for review and retention. Data will subsequently be transferred from the central 
vendor to the sponsor data warehouse. 
Data from complaint forms submitted to the sponsor 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 participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
● Data reported on or entered in the CRF and are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available. 
● Definition of what constitutes source data can be found in 10.1.7. 
10.1.9. 
Study and Site Start and Closure  
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and is considered the first act of recruitment and 
will be the study start date. 
Study or site termination 
The sponsor or sponsor’s designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected, and a study site closure visit has been performed. 
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
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Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination 
● discontinuation of further study intervention development 
For site termination 
● failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
● inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator, and 
● total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10. 
Publication Policy  
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal. 
10.1.11. 
Investigator Information  
Researchers with appropriate education, training, and experience, as determined by the sponsor, 
will participate as investigators in this clinical trial. 
10.1.12. 
Sample Retention  
Sample retention 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 
LY3298176 or after LY3298176 become(s) commercially available. 
Sample Type 
Custodian 
Maximum Retention Period after Last Patient Visita 
Genetics 
Sponsor or designee 
7 years 
Exploratory biomarkers  
Sponsor or designee 
7 years 
Tirzepatide antidrug 
antibodies (ADA)b 
Sponsor or designee 
15 years 
Abbreviation: ADA = antidrug antibody 
a Sample retention periods may differ dependent upon local regulations. 
b Sample collection only for hypersensitivity and injection site reactions. 
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests  
The tests detailed in the table below will be performed by the central laboratory unless 
designated as local in the SoA and in the table below. 
 
 In circumstances where the sponsor approves local laboratory testing in lieu of 
central laboratory testing, in the table below, the local laboratory must be 
qualified in accordance with applicable local regulations. 
 Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
 Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
 Investigators must document their review of the laboratory safety results.  
 In the event that the site needs to collect laboratories for urgent medical 
evaluation, local laboratories should be completed as necessary. It is requested 
that simultaneous samples are collected for laboratories to be analyzed by the 
central laboratory if possible. 
 
Clinical Laboratory Tests  
Comments  
Hematology 
Assayed by Lilly-designated laboratory. 
Hemoglobin 
Hematocrit 
 
Erythrocyte count (RBCs - red blood cells) 
Mean cell volume  
Mean cell hemoglobin 
Mean cell hemoglobin concentration  
Leukocytes (WBCs - white blood cells)  
Differential 
  Neutrophils, segmented 
  Lymphocytes 
  Monocytes 
  Eosinophils 
  Basophils 
Platelets 
 
Cell morphology (RBCs and WBCs) 
Clinical Chemistry 
Assayed by Lilly-designated laboratory. 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total bilirubin 
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Direct bilirubin 
 
Alkaline phosphatase (ALP) 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Gamma-glutamyl transferase (GGT) 
Blood urea nitrogen (BUN) 
Creatinine  
Creatine kinase (CK) 
Uric acid 
Total protein 
Albumin 
Calcium 
Phosphorus 
Glucose 
Lipid Panel 
 
High-density lipoprotein (HDL-C) 
Generated by Lilly-designated laboratory. 
Low-density lipoprotein (LDL-C) 
Generated by Lilly-designated laboratory.  
If triglycerides are >400; LDL will be measured. 
Very low-density lipoprotein (VLDL-C) 
Cholesterol 
Assayed by Lilly-designated laboratory. 
Triglycerides 
Assayed by Lilly-designated laboratory. 
Hormones (female) 
Serum pregnancy  
Assayed by Lilly-designated laboratory.  
Urine pregnancy 
Assayed and evaluated locally.  
Follicle-stimulating hormone (FSH)  
Assayed by Lilly-designated laboratory.  
Calculations 
Generated by Lilly-designated laboratory. 
eGFR (CKD-EPI) calculated using creatinine 
Results will not be provided to the investigative sites. 
eGFR (CKD-EPI) calculated using cystatin-C 
Results will not be provided to the investigative sites. 
eGFR (CKD-EPI) calculated using creatinine and 
cystatin-C 
 
Additional Testing 
Assayed by Lilly-designated laboratory.  
HbA1c 
Thyroid-stimulating hormone (TSH) 
Insulin 
Cystatin-C 
Calcitonin 
Pancreatic amylase 
Lipase 
Stored Samples 
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigative sites. 
Genetics sample (whole blood) 
Exploratory biomarker samples 
 
  Serum 
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  Whole blood (epigenetic sample) 
 
  Plasma (EDTA) 
  Plasma (P800) 
Abbreviations: CKD-EPI = Chronic kidney disease epidemiology; EDTA = ethylenediaminetetraacetic acid; eGFR 
= estimated glomerular filtration rate. 
10.2.1. 
Appendix 10.2.1. Laboratory Samples to be Obtained at the Time of a Systemic 
Hypersensitivity Event  
Purpose of collecting samples after a systemic hypersensitivity event 
The samples listed in this appendix are not collected for acute study participant management. 
The sponsor will use the laboratory tests results from these samples to characterize 
hypersensitivity events across the clinical development program. 
When to collect samples after a systemic hypersensitivity event occurs 
Collect the samples listed below if a systemic hypersensitivity event is suspected. The timing 
should be as designated in the table, assuming the participant has been stabilized. 
Obtain follow-up predose samples at the next regularly scheduled laboratory sample collection, 
ideally prior to the next dose after the event, to assess post-event return-to-baseline values. 
Timing 
Preferred 
Sample 
Typea 
Laboratory Testb 
Collect from 30 min to 4 hr after 
the start of the event. 
● 
Note: The optimal collection 
time is from 1 to 2 hr after the 
start of event. 
Serum 
Total tryptase 
Serum 
Complements (C3) 
Plasma 
Complements (C3a and C5a) 
Serum 
Cytokine panels (IL-6, IL‐1β, IL‐10, or any cytokine 
panel that includes these 3 cytokines) 
Collect only if not already collected 
on the same day as the event. 
● 
Note: If collecting, collect up 
to 12 hr after the start of the 
event. 
Serum 
LY3298176 ADA 
Plasma 
LY3298176 concentration 
Abbreviations: ADA = antidrug antibodies; C = complement component; IL = interleukin. 
a Sample type may be different depending on local requirements. 
b All samples for hypersensitivity testing will be assayed by Lilly-designated laboratory. Results will not be provided 
to the study site. If samples are not collected or are collected outside the specified period, this will not be 
considered a protocol deviation. 
What information to record 
Record the date and time when the samples are collected. 
Allowed additional testing for participant management 
The investigator may perform additional tests locally, if clinically indicated, for acute study 
participant management. 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting  
 The definitions and procedures detailed in this appendix are in accordance with ISO 
14155. 
 Both the investigator and the sponsor will comply with all local medical device-reporting 
requirements. 
 The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices provided for use in the study. See Section 6.1.1 for the list of 
sponsor medical devices. 
10.3.1. 
Definition of AE  
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.  
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical 
sequelae. 
 Lack of efficacy or failure of expected pharmacological action per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE.  
 
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Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 The disease or disorder being studied or expected progression, signs, or symptoms of 
the disease or disorder being studied, unless more severe than expected for the 
participant’s condition. 
 Medical or surgical procedure, for example, endoscopy and appendectomy: the 
condition that leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets 1 or 
more of the criteria listed: 
a. Results in death 
b. Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to hospital or 
emergency ward (usually involving at least an overnight stay) for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When 
in doubt as to whether hospitalization occurred or was necessary, the AE should be 
considered serious. 
 Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
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d. Results in persistent disability or incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma, for example, sprained ankle, which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly or birth defect 
 Abnormal pregnancy outcomes, for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, and ectopic pregnancy, are considered SAEs. 
f. 
Other situations: 
 Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the participant or may require medical or surgical intervention to 
prevent 1 of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.  
g. Resulted in medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function.  
10.3.3. 
Definition of Product Complaints  
Product Complaint 
 A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, 
or performance of a study intervention. When the ability to use the study intervention 
safely is impacted, the following are also product complaints: 
o deficiencies in labeling information, and 
o use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 Product complaints related to study interventions used in clinical trials are collected to 
ensure the safety of participants, monitor quality, and to facilitate process and product 
improvements. 
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 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed. 
 An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE. 
 
10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints  
AE, SAE, and Product Complaint Recording 
 When an AE/SAE/product complaint occurs, it is the responsibility of the investigator 
to review all documentation, for example, hospital progress notes, laboratory reports, 
and diagnostics reports, related to the event. 
 The investigator will then record all relevant AE/SAE/product complaint information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice. AE/SAE information is reported on the appropriate CRF page, and 
product complaint information is reported on the Product Complaint Form. 
Note: An event may meet the definition of both a product complaint and an AE/SAE. 
In such cases, it should be reported as both a product complaint and as an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Sponsor or designee in lieu of completion of the CRF page for AE/SAE and 
the Product Complaint Form for product complaints. 
 There may be instances when copies of medical records for certain cases are requested 
by Sponsor or designee. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to Sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.  
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories: 
 Mild: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
 Moderate: A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the research 
participant. 
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 Severe: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. 
An AE that is assessed as severe should not be confused with an SAE. Severe is a 
category utilized for rating the intensity of an event, and both AEs and SAEs can be 
assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated 
 The investigator will also consult the IB and/or Product Information, for marketed 
products, in their assessment 
 For each AE/SAE, the investigator must document in the medical notes that he or she 
has reviewed the AE/SAE and has provided an assessment of causality 
 There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to Sponsor or designee. However, it 
is very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to Sponsor or designee. 
 The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-Up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
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 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Sponsor or designee with a copy of any 
post-mortem findings including histopathology. 
10.3.5. 
Reporting of SAEs  
SAE Reporting via an Electronic Data Collection Tool 
 The primary mechanism for reporting an SAE will be the electronic data collection 
tool. 
 If the electronic system is unavailable, then the site will use the SAE paper form (see 
next section) to report the event within 24 hours. 
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on an SAE paper form (see next 
section) or to the SAE coordinator by telephone. 
 Contacts for SAE reporting can be found in the study training materials. 
 
SAE Reporting via Paper Form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the SAE coordinator. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in the study training materials. 
10.3.6. 
Regulatory Reporting Requirements  
SAE Regulatory Reporting 
 
Prompt notification by the investigator to the sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities toward the safety of 
participants and the safety of a study intervention under clinical investigation 
are met. 
● The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/IEC, and investigators. 
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● An investigator who receives an investigator safety report describing an SAE or 
other specific safety information, for example, summary or listing of SAEs, 
from the sponsor will review and then file it along with the IB and will notify 
the IRB/IEC, if appropriate according to local requirements. 
 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions  
Word/Phrase 
Definition 
WOCBP 
Adult females are considered WOCBP unless they are WNOCBP. 
WNOCBP 
Females are considered WNOCBP if they 
 have a congenital anomaly such as Mullerian agenesis 
 are infertile due to surgical sterilization, or 
 are postmenopausal. 
Examples of surgical sterilization include total hysterectomy, 
bilateral salpingo-oophorectomy, bilateral salpingectomy, or 
bilateral oophorectomy. 
Postmenopausal state 
The postmenopausal state is defined as a woman 
 at any age at least 6 weeks post-surgical bilateral 
oophorectomy with or without hysterectomy, confirmed by 
operative note 
 aged at least 40 years and up to 55 years with an intact 
uterus, not on hormone therapya who has had cessation of 
menses for at least 12 consecutive months without an 
alternative medical cause, AND with an FSH >40 mIU/mL 
 55 years or older not on hormone therapy, who has had at 
least 12 months of spontaneous amenorrhea, or 
 aged at least 55 years with a diagnosis of menopause prior 
to starting hormone replacement therapy. 
a Women should not be taking medications during amenorrhea such as oral 
contraceptives, hormones, gonadotropin-releasing hormone, anti-estrogens, 
Selective Estrogen Receptor Modulators, or chemotherapy that could induce 
transient amenorrhea. 
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10.4.2. 
Contraception Guidance  
Guidance for women 
WOCBP and WNOCBP may participate in this trial. 
WOCBP who are completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship as their preferred and usual lifestyle: 
Must… 
Must not… 
agree to either 
remain abstinent or 
stay in a same-sex 
relationship without 
sexual relationships 
with males 
 use periodic abstinence methods 
o calendar 
o ovulation 
o symptothermal, or 
o post-ovulation 
 declare abstinence just for the duration of a trial, or 
 use the withdrawal method 
 
WOCBP who are NOT completely abstinent as their preferred and usual lifestyle, or NOT in a 
same-sex relationship as their preferred and usual lifestyle, must do the following: 
Topic 
Condition 
Pregnancy testing 
Have a negative serum test result at screening followed by a negative 
urine result within 24 hours prior to treatment exposure. See the 
protocol SoA for subsequent pregnancy testing requirements. 
Contraception 
Agree to use 2 forms of effective contraception, where at least 1 form 
must be highly effective. 
These forms of contraception must be used during the study and for at 
least the duration of the trial and 30 days after the last dose of the study 
intervention. 
Note: Females who had bilateral tubal ligation should use a  
second form of contraception. 
 
Examples of different forms of contraception 
Methods 
Examples 
Highly effective 
contraception (less 
than 1% failure rate) 
 female sterilization, for example, bilateral tubal ligation 
 combination oral contraceptive pill 
 progestin-only contraceptive pill (mini-pill) 
 implanted contraceptives 
 injectable contraceptives 
 contraceptive patch (only women <198 pounds or 90 kg) 
 total abstinence 
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 vasectomy (if only sexual partner) 
 fallopian tube implants (if confirmed by 
hysterosalpingogram) 
 combined contraceptive vaginal ring, or 
 intrauterine devices 
Effective 
contraception 
 male or female condoms with spermicide 
 diaphragms with spermicide or cervical sponges, or 
 barrier method with use of a spermicide 
o condom with spermicide 
o diaphragm with spermicide, or 
o female condom with spermicide 
Note: The barrier method must include use of a spermicide (that is, 
condom with spermicide, diaphragm with spermicide, or female 
condom with spermicide) to be considered effective. 
Ineffective forms of 
contraception whether 
used alone or in any 
combination 
 spermicide alone 
 periodic abstinence 
 fertility awareness (calendar method, temperature method, 
cervical mucus, or symptothermal) 
 withdrawal 
 postcoital douche, or 
 lactational amenorrhea 
 
Guidance for men 
Topic 
Guidance 
For all men 
should refrain from sperm donation for the 
duration of the study and for 5 half-lives plus 90 
days 
Contraception for men with partners of 
childbearing potential 
 
either remain abstinent (if this is their 
preferred and usual lifestyle), or 
 
must use condoms during intercourse for 
the duration of the study, and 
 
for 5 half-lives plus 90 days 
Contraception for men in exclusively same-sex 
relationships, as their preferred, and usual lifestyle 
Are not required to use contraception 
 
Examples of highly effective, effective, and unacceptable methods of contraception 
Methods 
Examples 
Highly effective contraception 
 
combination oral contraceptive pill and 
mini-pill 
 
implanted contraceptives 
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 
injectable contraceptives 
 
contraceptive patch (only women <198 
pounds or 90 kg) 
 
total abstinence 
 
vasectomy (if only sexual partner) 
 
fallopian tube implants (if confirmed by 
hysterosalpingogram) 
 
combined contraceptive vaginal ring, or 
 
intrauterine devices 
Effective contraception  
 
male or female condoms with spermicide 
 
diaphragms with spermicide or cervical 
sponges 
 
barrier method with use of a spermicide 
o condom with spermicide 
o diaphragm with spermicide, or 
o female condom with spermicide 
Note: The barrier method must include use of a 
spermicide (i.e., condom with spermicide, 
diaphragm with spermicide, and female condom 
with spermicide) to be considered effective. 
Ineffective forms of contraception 
 
spermicide alone 
 
immunocontraceptives 
 
periodic abstinence 
 
fertility awareness (calendar method, 
temperature method, combination of 
above 2, cervical mucus, symptothermal) 
 
withdrawal 
 
post coital douche 
 
lactational amenorrhea 
 
 
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10.5. 
Appendix 5: Genetics  
Use/Analysis of DNA 
● Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity, and progression of disease. Variable response to 
study intervention may be due to genetic determinants that impact drug 
absorption, distribution, metabolism, and excretion; mechanism of action of the 
drug; disease etiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and IRB/IEC allow, a blood sample will be 
collected for DNA analysis from consenting participants. 
● DNA samples will be used for research related to study intervention or obesity 
and related diseases. They may also be used to develop tests or assays, including 
diagnostic tests related to study intervention and/or interventions of this drug class 
and obesity. Genetic research may consist of the analysis of 1 or more candidate 
genes or the analysis of genetic markers throughout the genome or analysis of the 
entire genome (as appropriate). 
● The samples may be analyzed as part of a multi-study assessment of genetic 
factors involved in the response to study intervention or study interventions of this 
class to understand study disease or related conditions. 
● The results of genetic analyses may be reported in the CSR or in a separate study 
summary. 
● The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
● The samples will be retained while research on study intervention or study 
interventions of this class or indication continues but no longer than the sample 
retention limits described in Section 10.1.12, or other period as per local 
requirements. 
 
 
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10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-Up 
Assessments  
10.6.1. 
Hepatic Evaluation Testing  
See Section 8.2.7 for guidance on appropriate test selection. 
The Lilly-designated central laboratory should complete the analysis of all selected testing 
except for testing listed in the investigator-designated local laboratory table. The central 
laboratory will report results if a validated test or calculation is available. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
Tests assayed by Lilly-designated central laboratory 
Hepatic Hematology Panel 
Hepatitis A virus (HAV) testing: 
Hemoglobin 
HAV total antibody 
Hematocrit 
HAV IgM antibody 
Erythrocytes (RBCs - red blood cells) 
Hepatis B virus (HBV) testing: 
Leukocytes (WBCs - white blood cells) 
Hepatitis B surface antigen (HBsAg) 
Differential: 
Hepatitis B surface antibody (anti-HBs) 
  Neutrophils, segmented 
Hepatitis B core total antibody (anti-HBc) 
  Lymphocytes 
Hepatitis B core IgM antibody 
  Monocytes 
Hepatitis B core IgG antibody 
  Basophils 
HBV DNAa 
  Eosinophils 
Hepatis C virus (HCV) testing: 
Platelets 
HCV antibody 
Cell morphology (RBC and WBC) 
HCV RNAa 
Hepatic Clinical Chemistry Panel 
Hepatitis D virus (HDV) testing: 
Total bilirubin 
HDV antibody 
Direct bilirubin 
Hepatitis E virus (HEV) testing: 
Alkaline phosphatase (ALP) 
HEV IgG antibody 
Alanine aminotransferase (ALT) 
HEV IgM antibody 
Aspartate aminotransferase (AST) 
HEV RNAa 
Gamma-glutamyl transferase (GGT) 
Anti-nuclear antibody (ANA) 
Creatine kinase (CK) 
Anti-smooth muscle antibody (ASMA)b 
Hepatic Coagulation Panel 
Anti-actin antibodyc 
Prothrombin time, INR (PT-INR) 
Immunoglobulin IgA (quantitative) 
Urine Chemistry 
Immunoglobulin IgG (quantitative) 
Drug screen 
Immunoglobulin IgM (quantitative) 
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Haptoglobin 
 
 
Tests assayed ONLY by investigator-designated local laboratory 
Acetaminophen 
Epstein-Barr virus (EBV) testing: 
Acetaminophen protein adducts 
EBV antibody 
Alkaline phosphatase isoenzymes 
EBV DNAa 
Ceruloplasmin 
Cytomegalovirus (CMV) testing: 
Copper 
CMV antibody 
Ethyl alcohol (EtOH) 
CMV DNAa 
 
Herpes simplex virus (HSV) testing: 
 
HSV (Type 1 and 2) antibody 
 
HSV (Type 1 and 2) DNAa 
 
Liver kidney microsomal Type 1 (LKM-1) antibody 
Phosphatidylethanol (PEth) 
Microbiology 
Urine Chemistry 
Culture: 
Ethyl glucuronide (EtG) 
Blood 
 
Urine 
a Reflex or confirmation dependent on regulatory requirements, testing availability, or both. 
 b Not required if anti-actin antibody is tested. 
c Not required if anti-smooth muscle antibody (ASMA) is tested. 
 
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10.7. 
Appendix 7: Suggested Visit Structure  
 
Abbreviations: AE = adverse event, con meds = concomitant medicines; CRF = case report form; ECG = 
electrocardiogram; IWRS = interactive web response system; PRO = patient-reported outcomes. 
 
 
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10.8. 
Appendix 8: Protocol GPHJ Standardized Protocols for the 
Measurement of Height, Weight, Waist Circumference, Vital Signs, 
and Electrocardiogram  
The following information has been adapted from standardized physical measurement protocols 
for the World Health Organization’s STEPwise approach to Surveillance (STEPS) (WHO 2017). 
 
Measuring height 
Step 1. Ask the participant to remove their footwear and any headgear (light headgear worn for 
religious reasons can remain, but this should be worn by the participant at every clinic 
visit when their height is measured). 
Step 2. Ask the participant to stand on the calibrated height measuring board (stadiometer) or 
against a wall with their feet together and their knees straight with their heels against the 
backboard, the stadiometer, or the wall. 
Step 3. Ask the participant to look straight ahead without tilting their head up. 
Step 4. Ask the participant to breathe in and stand tall. Measure and record the participant’s 
height in centimeters 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 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 will be measured in fasting state at all visits. 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 
to the nearest one-tenth kilogram. 
Measuring waist circumference 
 Waist circumference should be measured in the horizontal plane and at the midpoint 
between the lower margin of the last palpable rib and the top of the iliac crest. 
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 Measurements should be taken at the end of a normal expiration using a non-stretchable 
measuring tape. The tape should lie flat against the skin without compressing the soft 
tissue. 
 
The waist circumference should be measured twice, rounded to the nearest 0.5 cm. The 
measuring tape should be removed between the 2 measurements. Both measurements will 
be recorded in the CRF. 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). Measurement should be completed over light clothing or gown. If this is not 
possible or is impairing accuracy, then measurement can be completed directly over 
skin. The same approach should be used for each time waist circumference is measured 
in the study. 
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 (BP 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 CRF 
 Blood pressure must be taken with an automated BP instrument 
 If BP and pulse measurements are taken separately, pulse should be taken prior to BP. 
Note: In the event pulse measurement cannot be taken via an automated BP instrument, the 
preferred location for measurement of pulse is the radial artery. 
 
Electrocardiogram 
 All digital ECGs will be obtained using local ECG machines. 
 12-lead ECGs should be obtained after the participant has rested in a supine position for 5 
to 10 minutes. 
 Electrocardiograms should be collected prior to collection of blood samples for 
laboratory testing. 
 
 
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10.9. 
Appendix 9: World Health Organization Classification of Diabetes 
and American Diabetes Association Diagnostic Criteria  
Type 1 Diabetes: Type 1 diabetes is judged to be present when the classical symptoms of 
diabetes (thirst, polyuria, wasting and stupor, or coma) are associated with readily detectable 
concentrations of glucose and ketone bodies in the blood and urine. Insulin treatment is 
necessary not only to control hyperglycemia but also to prevent spontaneous ketosis and death. 
Type 2 Diabetes: Type 2 diabetes, although often asymptomatic, may also present with classical 
hyperglycemic symptoms (thirst, polyuria, and weight loss), but despite hyperglycemia, ketone 
bodies are present in only low concentrations in the blood and urine. Coma is rare in Type 2 
diabetes but may result from extreme hyperglycemia and hyperosmolarity; lactic acidosis or 
ketoacidosis can also occur in fulminating illness, for example, severe infection or mesenteric 
artery thrombosis, due to an acute increase in insulin requirements, but spontaneous ketosis does 
not occur. Some patients with Type 2 diabetes later progress to a state of absolute insulin 
deficiency (Alberti and Zimmet 1998). For this study, the diagnosis of prediabetes and T2D will 
be consistent with ADA recommendations. The T2D diagnosis requires classic symptoms of 
hyperglycemia with a random plasma glucose ≥ 200 mg/dL or 2 abnormal tests from the same 
sample or in 2 separate test samples. 
ADA Criteria for the diagnosis of diabetes 
 FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 
hours. OR 
 2-hour PG ≥200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as 
described by WHO, using a glucose load containing the equivalent of 75 g anhydrous 
glucose dissolved in water. OR 
 A1C ≥6.5% (48 mmol/mol). The test should be performed in a laboratory using a method 
that is NGSP certified and standardized to the DCCT assay. OR 
 
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random 
plasma glucose ≥200 mg/dL (11.1 mmol/L). 
(ADA, 2022) 
Abbreviations: DCCT = Diabetes Control, and Complications Trial; FPG = fasting plasma glucose; OGTT = oral 
glucose tolerance test; WHO = World Health Organization; 2-h PG = 2-h plasma glucose. 
 
 
ADA Criteria for the diagnosis of prediabetes 
 FPG 100 mg/dL to 125 mg/dL OR 
 2-hour PG during 75 gm OGTT 140 mg/dL to 199 mg/dL OR 
 HbA1c 5.7-6.4%. 
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10.10. 
Appendix 10: Provisions for Changes in Study Conduct During 
Exceptional Circumstances  
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations. 
After approval by local Ethical Review Boards, regulatory bodies, and any other relevant local 
authorities, implementation of these exceptional circumstance changes will not typically require 
additional notification to these groups, unless they have specific requirements in which 
notification is required, for example, upon implementation, and suspension of changes. All 
approvals and notifications must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with GCP, enabling 
participants to continue safely in the study and maintaining the integrity of the study. 
Informed consent 
Additional consent from the participant will be obtained, if required, for: 
 participation in remote visits, as defined in Section “Remote Visits” 
 a change in the method of study intervention administration 
 dispensation of additional study intervention during an extended treatment period 
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities. 
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 
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Remote visits 
Types of remote visits 
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments. Assessments to be completed in this manner include, but are 
not limited to 
 adverse events 
 concomitant medications 
 review of study participant diary (including study intervention compliance) 
 review diet and exercise goal log 
 review home weight 
 C-SSRS (Since Last Visit Version), and 
 PHQ-9. 
Other alternative locations: Laboratory draws may be done at an alternate location in 
exceptional circumstances. 
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and product complaints remain unchanged. 
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing. However, central 
laboratory testing must be retained for lipid samples. The local laboratory must be qualified in 
accordance with applicable local regulations. 
Study intervention and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the sponsor to determine appropriate actions. These actions may 
include 
 asking the participant to go to the site and receive study supplies from site staff 
without completion of a full study visit 
 asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf, and 
 arranging delivery of study supplies. 
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These requirements must be met before action is taken: 
 Alternate delivery of study intervention should be performed in a manner that ensures 
product integrity. The existing protocol requirements for product accountability 
remain unchanged, including verification of participant’s receipt of study supplies. 
 When delivering supplies to a location other than the study site, for example, 
participant’s home, the investigator, sponsor, or both should ensure oversight of the 
shipping process to ensure accountability and product quality, that is, storage 
conditions maintained, and intact packaging upon receipt. 
 Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
Screening period guidance 
To ensure safety of study participants, laboratory values, and other eligibility assessments taken 
at screening visit are valid for a maximum of 90 days. The following rules will be applied for 
active, nonrandomized participants whose participation in the study must be paused due to 
exceptional circumstances: 
 If screening is paused for less than 90 days from screening visits to randomization 
visit: the participant will proceed to the next study visit per the usual SoA, provided 
that randomization visit must be conducted within 90 days from first screening visit. 
o The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay. 
o Due to the pause in screening, sites should also reconfirm the impacted 
participant’s consent and document this confirmation in the source 
documentation. 
 If screening is paused for more than 90 days from screening visits to randomization 
visit: The participant must be discontinued because of screening interruption due to 
an exceptional circumstance. This is documented as a screen failure in the CRF. The 
participant can reconsent and be rescreened as a new participant. The screening 
procedures per the usual SoA should be followed, starting at screening visit to ensure 
participant eligibility by randomization visit. 
 
Adjustments to visit windows 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA. To maximize the possibility that these visits can be conducted as 
on-site visits, the windows for visits may be adjusted, upon further guidance from the sponsor. 
This minimizes missing data and preserves the intended conduct of the study. 
 
This table describes the allowed adjustments to visit windows. 
Visit Number 
Tolerance 
Visit 1 
(screening) 
No change 
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Visit 2 
Within 90 days after Visit 1 
Visit 3 through 7 
Within 7 days before or after the intended date 
Visit 8 through 20 Within 14 days before or after the intended date 
Visit 20 
Within 14 days before the intended date, or up to 28 days after the 
intended date 
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study. 
Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visits types, and conducted 
activities were affected by exceptional circumstances. Dispensing or shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
Source documents at alternate locations 
Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner. 
 
 
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10.11. 
Appendix 11: Abbreviations and Definitions  
Term 
Definition 
abuse 
use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
ADA 
antidrug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BMR 
basal metabolic rate 
CHF 
congestive heart failure 
CI 
confidence interval 
CK  
creatine kinase 
COA 
clinical outcome assessment 
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 
CRF 
case report form; a printed, optical, or electronic document designed to record all of 
the protocol-required information to be reported to the sponsor for each trial 
participant 
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 
computerized tomography  
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D. Bil 
direct bilirubin 
DCCT 
Diabetes Control and Complications Trial 
DPP-4 
dipeptidyl peptidase-4 
ECG 
electrocardiogram 
ED 
early discontinuation 
EDC 
electronic data capture system 
eGFR 
estimated glomerular filtration rate 
enroll 
the act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment 
enter 
participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives 
FPG 
fasting plasma glucose 
FSH 
follicle-stimulating hormone 
GCP 
good clinical practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
GIP 
glucose-dependent insulinotropic polypeptide 
GIPR 
GIP receptor 
GLP-1 
glucagon-like peptide-1 
GLP-1R 
glucagon-like peptide-1 receptor 
HbA1c 
hemoglobin A1c 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
Investigational Medicinal Product (see also “investigational product”) 
A medicinal product which is being tested or used as a reference, including as a 
placebo, in a clinical trial. 
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informed consent 
A process by which a participant voluntarily confirms their willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the participant’s decision to participate. Informed consent is documented by 
means of a written, signed, and dated informed consent form. 
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. See also “IMP.” 
IP 
investigational product 
IRB/IEC 
Institutional Review Board/Institutional Ethics Committee 
ISR 
injection site reaction 
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 participant (that is, 
the planned treatment regimen) rather than the actual treatment given. It has the 
consequence that participant 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. 
IWRS 
interactive web-response system 
LDL 
low-density lipoprotein 
MDD 
major depressive disorder 
medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication errors generally involve a failure to uphold 1 or more 
of the 5 “rights” of medication use: the right participant, the right drug, the right dose, 
right route, at the right time. 
In addition to the core 5 rights, the following may also represent medication errors: 
• dose omission associated with an AE or a product complaint 
• dispensing or use of expired medication 
• use of medication past the recommended in-use date 
• dispensing or use of an improperly stored medication 
• use of an adulterated dosage form or administration technique inconsistent with the 
medication’s labeling (for example, Summary of Product Characteristics, IB, local 
label, protocol), or 
• shared use of cartridges, prefilled pens, or both. 
MEN-2 
multiple endocrine neoplasia Type 2 
MI 
myocardial infarction 
MMRM 
mixed model for repeated measures 
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MTC 
medullary thyroid cancer 
MTD 
maximum-tolerated dose 
NAFLD 
nonalcoholic fatty liver disease 
NGSP 
National Glycohemoglobin Standardization Program 
OGTT 
oral glucose tolerance test 
participant 
Equivalent to Clinical Data Interchange Standards Consortium term “subject”: an 
individual who participates in a clinical trial, either as recipient of an investigational 
medicinal product or as a control 
PC 
product complaint 
PG 
plasma glucose 
PGIS Physical 
Activity 
Patient Global Impression of Status for Physical Activity 
PK/PD 
pharmacokinetics/pharmacodynamics 
PHQ-9 
Patient Health Questionnaire-9 
PPS 
per-protocol set: The set of data generated by the subset of participant who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the 
effects of treatment, according to the underlying scientific model 
PRO/ePRO 
patient-reported outcomes/electronic patient-reported outcomes 
PT-INR 
prothrombin time-international normalized ratio 
QTc 
corrected QT interval 
QTL 
quality tolerance limits 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
screen 
the act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study 
SD 
standard deviation 
SF-36 v2 
Short Form Health Survey Version 2 
SIB 
suicide ideation and behavior 
SoA 
Schedule of Activities 
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T1D 
Type 1 diabetes 
T2D 
Type 2 diabetes 
TBL 
total bilirubin 
TEAE 
Treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens 
relative to the pretreatment state, and does not necessarily have to have a causal 
relationship with this treatment. 
TEE 
total energy expenditure 
TSH 
thyroid-stimulating hormone 
UACR 
urine albumin creatinine ratio 
ULN 
upper limit of normal 
VLDL 
very low-density lipoprotein 
WOCBP 
women of childbearing potential 
WNOCBP 
women not of childbearing potential 
 
 
 
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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 [b]: 20-Jun-2023 
Overall Rationale for the Amendment: 
The protocol is being amended from a global study to a US only study and language related to 
non-US countries is being removed. This amendment includes updates to the study intervention 
dispensing strategy that were previously included in a US only addendum. The goal of the 
addendum was reducing site inventory management burden and adding flexibility for 
participants with direct-to-participant study intervention access. A genetics sample collection has 
also been added to the protocol. The collection will be offered during informed consent and 
participants will designate if they agree to this optional sample collection in the informed consent 
document.  
Clarifications and additional changes are outlined in the table below. 
Section # and 
Name 
Description of Change 
Brief Rationale 
Throughout 
Updated “study drug” and “study treatment” 
to “study intervention” 
For consistency 
Throughout 
Updated “participant diary” to “electronic 
diary” 
Clarification 
1.3 Schedule of 
Activities 
(SoA) 
Participant Diary: 
Updated “Participant Diary” to “Participant 
Electronic Diary” and updated “Diary 
review” to “Electronic diary review” 
Clarification 
Added new section “Participant Paper 3-day 
Diet and Exercise Log”, including rows for 
“Dispense paper log” and “Paper log review” 
and removed “Diet and exercise paper log 
review” row 
Clarification 
Stored Samples: Added a row for “Genetics” 
Genetic sample will be 
collected at Visit 11 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Randomization and Dosing:  
“Register visit with IWRS” row: removed X 
from all visits after Visit 2 
Updated to align with new 
study intervention 
dispensing strategy 
Removed “via IWRS” from Dispense study 
intervention and removed X from all visits 
after Visit 2 
Updated to align with new 
study intervention 
dispensing strategy 
Updated “Dispense study drug to participant 
(for at-home dosing)” row to “Site transmits 
study intervention prescription for central 
pharmacy study intervention dispensing” 
starting at Visit 3 and updated frequency to 
every 4 weeks 
Updated to align with new 
study intervention 
dispensing strategy 
Removed language about returning ancillary 
supplies from “participant returns study 
drugs and ancillary supplies” row and moved 
information about ancillary supplies being 
resupplied from central pharmacy to 
“Dispense ancillary supplies to participant” 
row 
Updated to align with new 
study intervention 
dispensing strategy 
2.3 
Benefit/Risk 
Assessment 
Removed reference to summary of product 
characteristics 
The US package insert 
contains the information 
4.1.2.2 
Treatment 
Period 
End of Visit 2 to Visit 8 
Removed language about demonstration 
device and added a reference to instructions 
for use 
Demonstration device will 
no longer be used for 
injection training 
End of Visit 8 to Visit 20 
Added information about study intervention 
prescription transmission to central pharmacy 
To align with new study 
intervention dispensing 
strategy 
6.1 Study 
Intervention(s) 
Administered 
Removed EU authorization information 
This information is no 
longer needed 
6.2.1 
Investigator 
Site 
Responsibilities 
A new section has been added to describe 
investigator site responsibilities for study 
intervention 
For clarity 
6.2.2 
Preparation, 
Handling, 
A new section has been added with 
additional information about direct-to-
participant study intervention access. 
Updated to align with new 
study intervention  
dispensing strategy 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Storage, and 
Accountability 
6.3 Measures to 
Minimize Bias: 
Randomization 
and Blinding 
Removed country, added “(yes, no)” to 
prediabetes status, and added baseline BMI 
to the list of stratification criteria 
The study will only include 
sites in the US 
6.5 Dose 
Modification 
Added instruction that the participant will 
continue to follow the lifestyle program if 
study intervention is interrupted 
Clarification 
7.1 
Discontinuation 
of Study 
Intervention 
Added instruction that the participant will 
continue to follow the lifestyle program if 
study intervention is discontinued 
Clarification 
7.1.3 
Temporary 
Discontinuation 
Added instruction that the participant will 
continue to follow the lifestyle program if 
study intervention is interrupted 
Clarification 
Removed reference to IWRS for distributing 
study intervention at the correct dose 
Updated to align with new 
study intervention 
dispensing strategy 
Removed instruction to enter data related to 
temporary interruption of study treatment on 
the CRF 
The information will be 
documented in source 
documents 
8.2.4 Clinical 
Safety 
Laboratory 
Tests 
Additional information has been added about 
repeated testing for safety laboratory tests 
and recommendation to contact the sponsor if 
technical issues arise 
To provide clarification 
about resolving technical 
issues with safety laboratory 
tests 
8.2.7 Hepatic 
Safety 
Monitoring 
CBC has been added to the list of laboratory 
tests to be repeated to confirm abnormality 
Based upon recent guidance 
on hepatic monitoring 
8.3.3 Adverse 
Events of 
Special Interest 
Updated “depression” to “major depressive 
disorder” and updated “behavior monitoring” 
to “suicidal behaviors” 
For consistency with the 
SURMOUNT program 
8.3.3.9 
Injection Site 
Reactions 
Added a clarification that ISR information is 
collected for both tirzepatide and semaglutide 
Clarification 
8.3.3.13 Major 
Depressive 
Disorder, 
Suicidal 
Updated title of Section from “Depression, 
Suicidal Ideation, or Behavior Monitoring” 
to “Major Depressive Disorder, Suicidal 
Ideation, or Suicidal Behavior Monitoring” 
For consistency with the 
SURMOUNT program 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Ideation, or 
Suicidal 
Behavior 
Monitoring 
8.6 Genetics 
Added additional information about optional 
genetics sample collection 
To align with the genetics 
sample collection at Visit 11 
Added “obesity-related diseases” 
For consistency with the 
SURMOUNT program 
8.7 Biomarkers 
Updated information about biomarker 
research and collection 
To provide additional 
information 
9.3.1 General 
Considerations 
Removed geographic area from the analysis 
model and added baseline BMI category in 
the model. 
This study will only include 
sites in the US 
9.3.2. Primary 
Endpoint 
Analysis 
Removed geographic area from the analysis 
model and added baseline BMI category in 
the model. 
This study will only include 
sites in the US 
9.3.3 
Secondary 
Endpoints 
Analysis 
Removed geographic area from the analysis 
model and added baseline BMI category in 
the model. 
 
This study will only include 
sites in the US 
 
 
Updated analysis method for categorical 
endpoints 
Alignment with regulatory 
guidance and considerations 
for missing data imputation 
9.3.4.2 Major 
Depressive 
Disorder, 
Suicidal 
Ideation and 
Suicidal 
Behavior 
Updated title of Section from “Depression, 
Suicidal Ideation and Behavior” to “Major 
Depressive Disorder, Suicidal Ideation and 
Suicidal Behavior” 
For consistency with the 
SURMOUNT program 
10.1.5 
Committees 
Structure 
Added deaths to the list of events that will be 
adjudicated by an independent committee 
To align with Section 8.3.3 
10.2 Appendix 
2: Clinical 
Laboratory 
Tests 
Updated the “Genetics Sample” section to 
“Stored Samples”, moved “Exploratory 
biomarker samples” to “Stored Samples” 
section, and added whole blood for genetics 
and epigenetic samples. 
To align with the genetics 
sample collection at Visit 11 
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Section # and 
Name 
Description of Change 
Brief Rationale 
10.4.2 
Contraception 
Guidance 
Added “bilateral tubal ligation” as an 
example of female sterilization 
Clarification 
10.10 
Appendix 10: 
Country-
Specific 
Requirements 
This section has been removed. 
This study will only include 
sites in the US 
11. References 
Additional references have been added 
To align with content added 
to Section 9.3.3 
Reference for Wegovy SMPC has been 
removed 
This information is no 
longer needed in Section 2.3 
Reference for Wegovy package insert has 
been updated 
To reflect the most recent 
information 
 
Amendment [a]: 29-Jul-2022 
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The purposes for this amendment are outlined in the table below. 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3. 
Schedule of 
Activities (SoA) 
Corrected format issue 
regarding ECG schedule 
Error correction 
Added language to 
distinguish paper log from 
electronic diary 
For clarity 
Added separate line for 
paper log review 
Added line for weight 
history questionnaire  
To specify when questionnaire should be 
administered 
Added line for study 
intervention injection 
training 
To specify when training should occur 
Section 4.1. 
Overall Design 
Corrected statement as 
follows: 
Error correction 
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Section # and 
Name 
Description of Change 
Brief Rationale 
“Study GPHJ is a Phase 3b, 
multicenter, randomized, 
parallel-arm, open-label, 
comparator-controlled, 72-
week trial that will 
investigate the efficacy and 
safety of 15 mg or MTD 
tirzepatide…” 
Section 5.3.1. 
Meals and Dietary 
Restrictions 
Modified statement as 
follows: 
“Additionally, if a BMI 
≤22 kg/m
2 is reached in 
participants receiving 
tirzepatide, the site 
physician should contact 
Lilly for consideration of a 
single dose reduction for 
remainder of trial (for 
example, 15 mg to 10 mg or 
10 mg to 5 mg).” 
Modification to improve participant 
experience and limit IP discontinuation 
and to reduce potential safety risk of 
reaching below the normal BMI range 
Section 8.2.6. 
Suicidal Ideation 
and Behavior Risk 
Monitoring 
Corrected statement to read 
as follows: 
“The C-SSRS and PHQ-9 
will be performed for 
baseline assessment of 
suicidal ideation and 
behavior and monitoring for 
intervention emergent 
suicidal ideation and 
behavior.” 
For clarity 
Section 8.3.3.10. 
Antidrug 
Antibodies 
Removed original section 
To clarify that antidrug antibodies are 
only being collected for hypersensitivity 
or injection site reactions 
Section 8.6. 
Genetics 
Corrected sample retention 
period from 15 years to 7 
years 
Error correction 
Section 8.8. 
Immunogenicity 
Assessments 
Replaced wording in section 
with the following: 
“Exploratory biomarker 
samples collected during the 
To clarify that immunogenicity 
assessments may occur 
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Section # and 
Name 
Description of Change 
Brief Rationale 
study may be used to 
perform any 
immunogenicity-related 
assessments as deemed 
appropriate.” 
Section 10.1.7. 
Data Quality 
Assurance 
Added reference to weight 
history questionnaire in 
Data Capture System 
subsection 
To note that data from questionnaire will 
be collected by authorized study 
personnel 
Section 10.1.12. 
Sample Retention 
Revised “Hypersensitivity 
(ADA) samples” to 
“Tirzepatide antidrug 
antibodies (ADA)b” and 
defined footnote b 
To clarify that antidrug antibodies are 
only being collected for hypersensitivity 
or injection site reactions 
Section 10.2. 
Appendix 2. 
Clinical 
Laboratory Tests 
Removed first bullet: 
“Local laboratory 
results…must be recorded” 
and added bullet: 
“In the event…if possible.” 
To modify laboratory language in 
response to site feedback 
Section 10.2.1. 
Appendix 10.2.1. 
Laboratory 
Samples to be 
Obtained at the 
Time of a 
Systemic 
Hypersensitivity 
Event 
Separated complements C3 
and C3a/C5a into their 
correct sample types 
Error correction 
Section 10.5. 
Appendix 5. 
Genetics  
Replaced incorrect sample 
retention period (15 years) 
with reference to section 
10.1.12 
Section 10.7. 
Appendix 7. 
Suggested Visit 
Structure 
Corrected diagram by 
switching first and second 
boxes 
Throughout 
“Telehealth” corrected to 
“telephone” 
To align with current study language 
Throughout 
Minor editorial changes 
For clarity 
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