Efficacy and Safety of Once-Weekly Tirzepatide in Participants With Obesity Disease: A Randomized, Double-Blind, Placebo-Controlled Trial (SURMOUNT-J)
Phase: PHASE3
Conditions: Obesity
Sponsor: Eli Lilly and Company

 
 
 
Protocol I8F-JE-GPHZ (b) 
 
 
Efficacy and Safety of Once-Weekly Tirzepatide in Participants with Obesity Disease: A 
Randomized, Double-Blind, Placebo-Controlled Trial (SURMOUNT-J) 
 
 
NCT04844918 
 
 
Approval Date: 11-Jun-2021 
 
 
 
 
 
 

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
1
Title Page
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investigation of tirzepatide (LY3298176), unless such persons are bound by a confidentiality agreement with Eli Lilly and Company 
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Protocol Title: Efficacy and Safety of Once-Weekly Tirzepatide in Participants with Obesity 
Disease: A Randomized, Double-Blind, Placebo-Controlled Trial 
(SURMOUNT-J)
Protocol Number: I8F-JE-GPHZ
Amendment Number: b
Compound: LY3298176
Study Phase: 3
Short Title: Efficacy and Safety of Tirzepatide Once Weekly Versus Placebo in Participants 
with Obesity Disease (SURMOUNT-J)
Acronym: SURMOUNT-J
Sponsor Name: Eli Lilly Japan K.K.
Legal Registered Address: LILLY PLAZA ONE BLDG, 5-1-28 Isogamidori, Chuo-ku Kobe 
City, Hyogo 651-0086 Japan
Regulatory Agency Identifier Number(s): Not applicable
Approval Date:
Amendment (b) Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 11-Jun-2021 GMT

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Protocol I8F-JE-GPHZ(b)
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Medical Monitor Name and Contact Information will be provided separately.

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Protocol I8F-JE-GPHZ(b)
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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Protocol Amendment (a) 
18-Jan-2021
Original Protocol
30-Oct-2020
Amendment [b]
Overall Rationale for the Amendment:
The correction of inclusion criteria is the primary driver for this amendment.
Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities 
Table 3
Changed from 
“IWQoL-CT”
To
“IWQoL-Lite-CT” 
Typo
5.1 Inclusion Criteria
Inclusion criteria 2a has been 
updated from 
“…and OGTT 2-hour glucose of 
≥140 mg/dL….”
to
“…, and/or OGTT 2-hour glucose 
of ≥140 mg/dL…” 
In order to improve 
enrolment feasibility 
without compromising 
scientific validity.
5.1 Inclusion Criteria
Added the following sentence to 
criteria 2a.
“In this study, IGT is defined to 
include impaired fasting glucose 
also described as “Borderline 
type” according to Japanese 
Clinical Practice Guideline for 
Diabetes 2019 (Araki et al. 
2020).”
Added for clarity.
5.2 Exclusion Criteria
Exclusion Criteria 1 has been 
updated from
“...(fasting glucose or OGTT 
0-hour ≥126 mg/dL, OGTT 
2-hour glucose ≥200 mg/dL)…”
to
Modified for clarity

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Protocol I8F-JE-GPHZ(b)
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Section # and Name
Description of Change
Brief Rationale
“…(fasting glucose or OGTT 
0-hour ≥126 mg/dL and/or OGTT 
2-hour glucose ≥200 mg/dL)…”
5.2 Exclusion Criteria
Exclusion Criteria 26 has been 
updated from 
“…or alternative remedies 
intended to promote weight loss.”
to
“…or alternative remedies 
intended to promote weight loss 
or may cause weight reduction.”
Modified for clarity
6.5 Concomitant Therapy
Description for permitted use of 
concomitant therapy has been 
updated from 
“Participants will be permitted to 
use concomitant medications on a 
stable dose for at least 3 months 
prior study entry and the dosage 
change is not allowed during the 
study other than there are 
concerns about the safety issue, 
except certain medications (for 
example; other medications for 
weight management) that may 
interfere with the assessment of 
efficacy and safety characteristics 
of the study treatments.”
to
“Participants are permitted to use 
concomitant medications that 
they require during the study,
with the exception of certain 
medications (for example; other 
medications for weight 
management) that may interfere 
with the assessment of efficacy 
and safety characteristics of the 
study treatments. 
Any concomitant medications 
taken for obesity-related health 
Rearranged wording and 
sentence structure for 
clarity. 

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Protocol I8F-JE-GPHZ(b)
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Section # and Name
Description of Change
Brief Rationale
problems on a stable dose for at 
least a period of 3 months prior to 
study entry will be permitted. 
Dosage change during the study 
will only be allowed if concerns 
for safety issue are identified.”
7.2 Participant 
Discontinuation/Withdrawal 
from the Study 
Changed from 
“At the time of discontinuing 
from the study, if possible, an 
early discontinuation visit should 
be conducted, as shown in the 
Schedule of Activities” 
to
“When discontinuing from the 
study prior to Visit 21 or Visit 99, 
an early discontinuation visit 
should be conducted if possible, 
as described in the Schedule of 
Activities”
Modified for clarity
8.1.2.2 2-Hour Oral 
Glucose Tolerance Test
Changed from
“Definition of IGT from 2-hour 
OGTT results: fasting glucose or 
0-hour OGTT = 110-125 mg/dL 
(6.1-6.9 mmol/L) and 2-hour 
OGTT = 140-199 mg/dL 
(7.8-11.0 mmol/L).”
to
“Definition of IGT from 2-hour 
OGTT results: fasting glucose or 
0-hour OGTT = 110-125 mg/dL 
(6.1-6.9 mmol/L) and/or 2-hour 
OGTT = 140-199 mg/dL 
(7.8-11.0 mmol/L).”
This change is made to 
reflect the change 
implemented in section 5.1
8.1.3 Exploratory Efficacy 
Assessments Incident 
Diabetes
Changed the laboratory evidence 
of diabetic type criteria for OGTT 
0-hr and 2-hr glucose from:
“…(fasting glucose or OGTT 
0-hour glucose ≥126 mg/dL, 
OGTT 2-hour glucose 
≥200 mg/dL)…”
Modified for clarity

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Protocol I8F-JE-GPHZ(b)
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Section # and Name
Description of Change
Brief Rationale
to
“…(fasting glucose or OGTT 
0-hour glucose ≥126 mg/dL 
and/or OGTT 2-hour glucose 
≥200 mg/dL)…”
10.12 Appendix 12: 2-Hour 
Oral Glucose Tolerance 
Test Flow Chart
Changed the 0hr and 2hr OGTT 
condition in the flowchart from 
“AND”
to 
“AND/OR” and added dashed 
line to separate the OGTT and 
HbA1c condition
This change is made to 
reflect the change 
implemented in section 5.1
and for additional clarity of 
the figure.
Protocol header
Study alias in the header has been 
changed from “Protocol I8F-JE-
GPHZ(a)” to “Protocol I8F-JE-
GPHZ(b)”
This change is made to 
reflect the amendment 
version of this protocol.

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Protocol I8F-JE-GPHZ(b)
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Table of Contents
1.
Protocol Summary ............................................................................................................11
1.1.
Synopsis.......................................................................................................................11
1.2.
Schema ........................................................................................................................18
1.3.
Schedule of Activities ..................................................................................................19
2.
Introduction ......................................................................................................................41
2.1.
Study Rationale............................................................................................................41
2.2.
Background..................................................................................................................42
2.3.
Benefit/Risk Assessment..............................................................................................44
3.
Objectives and Endpoints..................................................................................................45
4.
Study Design.....................................................................................................................51
4.1.
Overall Design .............................................................................................................51
4.2.
Scientific Rationale for Study Design...........................................................................51
4.3.
Justification for Dose ...................................................................................................52
4.4.
End of Study Definition ...............................................................................................52
5.
Study Population...............................................................................................................53
5.1.
Inclusion Criteria..........................................................................................................53
5.2.
Exclusion Criteria ........................................................................................................55
5.3.
Lifestyle Considerations...............................................................................................59
5.3.1.
Meals and Dietary Restrictions.............................................................................60
5.3.2.
Caffeine, Alcohol, and Tobacco for PK/PD Visits................................................60
5.3.3.
Physical Activity..................................................................................................60
5.4.
Screen Failures.............................................................................................................61
6.
Study Intervention.............................................................................................................62
6.1.
Study Intervention(s) Administered..............................................................................62
6.1.1.
Medical Devices...................................................................................................62
6.2.
Preparation/Handling/Storage/Accountability...............................................................63
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................63
6.4.
Study Intervention Compliance ....................................................................................64
6.5.
Concomitant Therapy...................................................................................................64
6.6.
Dose Modification........................................................................................................65
6.7.
Management of Incident Diabetes ................................................................................65
6.7.1.
Management of Participants with Gastrointestinal Symptoms...............................65
6.8.
Intervention after the End of the Study.........................................................................66
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal..............................................................................................67
7.1.
Discontinuation of Study Intervention..........................................................................67

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Protocol I8F-JE-GPHZ(b)
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7.1.1.
Temporary Study Drug Discontinuation...............................................................68
7.2.
Participant Discontinuation/Withdrawal from the Study...............................................69
7.2.1.
Discontinuation of Inadvertently Enrolled Participants.........................................70
7.3.
Lost to Follow-Up........................................................................................................70
8.
Study Assessments and Procedures ...................................................................................72
8.1.
Efficacy Assessments...................................................................................................72
8.1.1.
Primary Efficacy Assessments .............................................................................72
8.1.2.
Secondary Efficacy Assessments..........................................................................72
8.1.3.
Exploratory Efficacy Assessments .......................................................................77
8.2.
Safety Assessments ......................................................................................................79
8.2.1.
Physical Examinations .........................................................................................79
8.2.2.
Vital Signs ...........................................................................................................79
8.2.3.
Electrocardiograms ..............................................................................................79
8.2.4.
Clinical Safety Laboratory Assessments...............................................................80
8.2.5.
Depression, Suicidal Ideation and Behavior Risk Monitoring...............................83
8.2.6.
Special Safety Topics...........................................................................................84
8.3.
Adverse Events, Serious Adverse Events, and Product Complaints...............................84
8.3.1.
Timing and Mechanism for Collecting Events......................................................86
8.3.2.
Medical Device Incidents (Including Malfunctions) .............................................87
8.3.3.
Pregnancy ............................................................................................................88
8.4.
Treatment of Overdose.................................................................................................89
8.5.
Pharmacokinetics .........................................................................................................89
8.6.
Pharmacodynamics ......................................................................................................89
8.7.
Genetics .......................................................................................................................89
8.8.
Biomarkers...................................................................................................................89
8.9.
Immunogenicity Assessments.......................................................................................90
8.10. Health Economics and Medical Resource Utilization ...................................................90
9.
Statistical Considerations ..................................................................................................91
9.1.
Statistical Hypotheses ..................................................................................................91
9.2.
Sample Size Determination ..........................................................................................91
9.3.
Populations for Analyses..............................................................................................92
9.4.
Statistical Analyses ......................................................................................................92
9.4.1.
General Considerations ........................................................................................92
9.4.2.
Treatment Group Comparability...........................................................................93
9.4.3.
Efficacy Analyses ................................................................................................94
9.4.4.
Safety Analyses....................................................................................................95
9.4.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................96
9.4.6.
Evaluation of Immunogenicity .............................................................................96

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Protocol I8F-JE-GPHZ(b)
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9.4.7.
Other Analyses.....................................................................................................96
9.5.
Interim Analyses ..........................................................................................................97
10.
Supporting Documentation and Operational Considerations..............................................98
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations .............................................................................................................98
10.1.1.
Regulatory and Ethical Considerations.................................................................98
10.1.2.
Financial Disclosure.............................................................................................98
10.1.3.
Informed Consent Process....................................................................................99
10.1.4.
Data Protection ....................................................................................................99
10.1.5.
Committees Structure.........................................................................................100
10.1.6.
Dissemination of Clinical Study Data.................................................................100
10.1.7.
Data Quality Assurance......................................................................................100
10.1.8.
Source Documents .............................................................................................102
10.1.9.
Study and Site Start and Closure ........................................................................102
10.1.10. Publication Policy ..............................................................................................103
10.1.11. Long-Term Sample Retention ............................................................................103
10.2. Appendix 2: Clinical Laboratory Tests .......................................................................104
10.3. Appendix 3: Laboratory Assessments for Hypersensitivity Events..............................107
10.4. Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting .....................................................109
10.4.1.
Definition of AE ................................................................................................109
10.4.2.
Definition of SAE ..............................................................................................110
10.4.3.
Definition of Product Complaints.......................................................................111
10.4.4.
Recording and Follow-Up of AE and/or SAE and Product 
Complaints.........................................................................................................112
10.4.5.
Reporting of SAEs .............................................................................................113
10.4.6.
Regulatory Reporting Requirements...................................................................114
10.4.7.
Special Safety Topics.........................................................................................114
10.5. Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information ................................................................................................................120
10.6. Appendix 6: Genetics.................................................................................................124
10.7. Appendix 7: Liver Safety: Suggested Actions and Follow-Up 
Assessments...............................................................................................................125
10.8. Appendix 8: Management of Gastrointestinal Symptoms............................................127
10.9. Appendix 9: Medical Device Incidents:  Definition and 
Procedures for Recording, Evaluating, Follow Up, and Reporting ..............................128
10.10. Appendix 10: Medical Device Adverse Events (AEs), Adverse 
Device Effects (ADEs), Serious Adverse Events (SAEs) and 
Device Deficiencies: Definition and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .......................................................................130

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Protocol I8F-JE-GPHZ(b)
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10.11. Appendix 11: Measurement of Height, Weight, Waist 
Circumference, Vital Signs, Electrocardiogram, Oral Glucose 
Tolerance Test, Magnetic Resonance Imaging, Computed 
Tomography...............................................................................................................131
10.12. Appendix 12: 2-Hour Oral Glucose Tolerance Test Flow Chart..................................135
10.13. Appendix 13: JASSO guidelines ................................................................................136
10.14. Appendix 14: Provisions for Changes in Study Conduct During 
Exceptional Circumstances.........................................................................................137
10.15. Appendix 15: Abbreviations.......................................................................................141
10.16. Appendix 16: Protocol Amendment History...............................................................145
11.
References ......................................................................................................................146

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Protocol I8F-JE-GPHZ(b)
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1. Protocol Summary
1.1.
Synopsis
Protocol Title:
Efficacy and Safety of Once-Weekly Tirzepatide in Participants with Obesity Disease: A 
Randomized, Double-Blind, Placebo-Controlled Trial (SURMOUNT-J)
Short Title:
Efficacy and Safety of Once-Weekly Tirzepatide Versus Placebo in Participants with Obesity 
Disease (SURMOUNT-J)
Rationale:
In general, the accumulation of slight imbalances in daily energy balance causes weight gain and 
leads to obesity. Obesity is a major risk factor for many comorbid diseases, such as stroke, 
coronary artery disease, diabetes, malignant disease, and motor dysfunction, which cause a lower 
quality of life and shortened life expectancy (JASSO 2016; Haneda et al. 2018). In Japan, body 
mass index (BMI) ≥25 kg/m2 is defined as obese, and an obese person with obesity-related health 
problems and medically requiring weight loss is defined as having “obesity disease” (Matsuzawa 
2011). In particular, 3 metabolic disorders in the obesity-related health disorders (impaired 
glucose tolerance [IGT], hyperlipidemia, and non-alcoholic fatty liver disease [NAFLD]), are 
located upstream of the metabolic syndrome (Ito 2003), and promote the onset and progression 
of complications. The guidelines proposed by the Japan Society for the Study of Obesity 
(JASSO) also suggest that the objective of medical therapy for obesity disease is to accelerate 
weight loss safely, leading to improvement in complications of obesity, and to suppress the 
combined use of multiple drugs in patients who have difficulty achieving weight loss goals by 
individual efforts alone.
The gut incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and 
glucagon-like peptide-1 (GLP-1), are secreted after meal ingestion and mediate the incretin 
effect. Both hormones have effects on endocrine cells in the pancreas, increasing insulin 
biosynthesis and secretion, and modifying glucagon secretion (Skow et al. 2016). Based on these 
properties, several GLP-1 receptor (GLP-1R) agonists have been approved for pharmacological 
treatment of type 2 diabetes mellitus (T2DM) (Tomlinson et al. 2016). 
In addition to its pancreatic effects, GLP-1R activation decreases gut motility, slows gastric 
emptying, and promotes satiety (presumably through a combination of GLP-1R activation in the 
central and peripheral nervous systems), thereby regulating food intake and body weight (Baggio 
and Drucker 2007). The US Food and Drug Administration and the European Medicines Agency 
approved the GLP-1R agonist liraglutide for the treatment of individuals who are overweight or
obese (Saxenda® package insert, 2014; Saxenda® SmPc, 2015), which is not approved in Japan. 
Preclinical data indicate that GIP also exerts effects on appetite regulation and food intake, 
adipose tissue, and on peripheral energy metabolism. Although studies evaluating effects of GIP 
on body weight have yielded equivocal results, GIP receptor (GIPR) activation may play a role 

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Protocol I8F-JE-GPHZ(b)
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in body weight regulation and targeting both the GLP-1R and the GIPR simultaneously may 
result in additive or synergistic effects of the 2 incretins on body weight (Coskun et al. 2018). 
Tirzepatide is a 39-amino acid synthetic peptide dual GIP and GLP-1 receptor agonist. Its 
structure is based on the GIP sequence and includes a C20 fatty diacid moiety. It is administered 
once-weekly (QW) by subcutaneous (SC) injection (Coskun et al. 2018).
As a dual GIP/GLP-1R agonist, tirzepatide could exceed the efficacy of selective GLP-1R 
agonists by recruiting metabolically active tissues not targeted by selective GLP-1R agonists (for 
example, adipose tissue as indicated by the observation of increased energy utilization) (Müller 
et al. 2018) and has the potential to reach higher efficacy in target tissues, such as 
insulin-producing pancreatic beta cells that express both GIPR and GLP-1R, before reaching its 
therapeutic limitation. 
Study I8F-JE-GPHZ (GPHZ) is a Phase 3, multicenter, randomized, placebo-controlled, 
double-blinded study of the safety and efficacy of tirzepatide 10 mg and 15 mg QW, compared 
with placebo, when used in conjunction with a reduced-calorie diet and increased physical 
activity for weight management, in obesity disease participants with BMI ≥27 kg/m2 and at least 
2 obesity-related health problems or participants with BMI ≥35 kg/m2 and at least 
1 obesity-related health problem. The obesity-related health problems are defined as IGT, 
hyperlipidemia, and NAFLD. The co-primary endpoint will be to demonstrate that QW
tirzepatide 10 mg and/or 15 mg are superior to placebo in both mean percent changes in body 
weight and proportion of participants who achieve ≥5% body weight reduction from baseline to 
72 weeks in participants with obesity disease.

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Protocol I8F-JE-GPHZ(b)
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Objectives and Endpoints
Objectives
Endpoints
Primary
To demonstrate that once-weekly tirzepatide, at doses 
of 10 mg and/or 15 mg, is superior to placebo in
terms of body weight reduction from BL to 72 weeks 
in Japanese participants with obesity disease
o
Mean percent change in body weight at Week 72
and
o
Proportion of participants who achieve ≥5% body 
weight reduction at Week 72
Secondary
To compare the efficacy of once-weekly tirzepatide 
10 mg and/or 15 mg with placebo for
o
Improvement in obesity-related health 
problems (72 weeks)
o
Proportion of participants who met the following 
criteria at 72 weeks from BL
o
Improvement in at least 2 obesity-related 
health problems for participants with BL 
BMI >27 and <35 kg/m2, or
o
Improvement in at least 1 obesity-related 
health problem for participants with BL 
BMI >35 kg/m2
o
Improvement in laboratory tests for 
obesity-related health problems (72 weeks)
o
Mean changes in the following laboratory tests at 
72 weeks from BL
o
OGTT 2-hr glucose (only for participants 
with IGT at BL)
o
Fasting glucose (only for participants with 
IGT at BL)
o
Fasting lipids (TG) (only for participants 
with hyperlipidemia at BL)
o
HFF (only for participants diagnosed as 
NAFLD by MRI at BL)
o
Improvement of IGT (72 weeks)
o
Proportion of participants who achieved 
improvements of IGT (only for participants with 
IGT at BL)
o
Improvement of hyperlipidemia (72 weeks)
o
Proportion of participants who achieved 
improvements of hyperlipidemia (only for 
participants with hyperlipidemia at BL)
o
Improvement of NAFLD (72 weeks)a
o
Proportion of participants who achieved 
improvements of NAFLD (only for participants 
who are diagnosed as NAFLD by MRI at BL)

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Protocol I8F-JE-GPHZ(b)
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Objectives
Endpoints
o
Body mass related parameters
o
Change in body weight (24, 52, and 
72 weeks)
o
Proportion of participants who achieve the 
following criteria from BL
o
≥5% body weight reduction (only at 24 and 
52 weeks)
o
≥7% body weight reduction
o
≥10% body weight reduction
o
≥15% body weight reduction
o
≥20% body weight reduction
o
Mean change from BL in
o
Absolute body weight
o
BMI
o
Mean percent change from BL in body weight
(only at 24 and 52 weeks)
o
Mean EWL
o
Change in VAT and SAT (72 weeks)
o
Mean change from BL in
o
VAT
o
SAT
o
VAT/SAT ratio
o
Mean percent change from BL in
o
VAT
o
SAT
o
VAT/SAT ratio
o
Proportion of participants who achieve VAT 
<100 cm2 (only for participants with VAT 
≥100 cm2 at BL) from BL
o
Change in waist circumference (24, 52,
and 72 weeks)
o
Mean change from BL in waist circumference
o
IGT related parameters (only for 
participants with IGT at BL)
o
Change in IGT related parameters (24, 52, 
and 72 weeks)
o
Mean change from BL in
o
Fasting glucose
o
HbA1c
o
Fasting insulin
o
C-peptide
o
HOMA2-%B
o
HOMA2-%S
o
Hyperlipidemia related parameters (only for 
participants with hyperlipidemia at BL)
Mean change from BL in
o
TG
o
TC
o
VLDL-C
o
LDL-C (direct)
o
HDL-C
o
Non-HDL-C
o
FFA
o
Change in fasting lipids (24, 52, and 
72 weeks)

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Protocol I8F-JE-GPHZ(b)
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Objectives
Endpoints
o
NAFLD related parameters
o
Change in NAFLD/NASH biomarkers 
(24, 52, and 72 weeks)
o
Mean change from BL in
o
ALT
o
AST
o
GGT
o
AST/ALT ratio
o
K-18 (M30)
o
Pro C3
o
ELF
o
FIB-4 index
o
Other parameters
o
Change in blood pressure (24, 52, and 
72 weeks)
o
Mean changes from BL in
o
Systolic blood pressure
o
Diastolic blood pressure
o
Change in uric acid (24, 52, and 72 weeks)
o
Mean change from BL in uric acid
o
Patient-reported outcomes
o
Change in patient-reported physical 
functioning (72 weeks)
o
Mean change from BL in SF-36v2 acute form 
physical functioning domain score from BL
o
Mean change in IWQOL-Lite-CT Physical 
Function score
o
Change in patient-reported health status 
(72 weeks)
o
Mean change in EQ-5D-5L score from BL
o
Index score
o
VAS score
o
Change in dietary evaluation based on the 
meal record (24, 52, and 72 weeks)b
o
Mean change from BL in
o
Total fats
o
Total carbohydrates
o
Total proteins
o
Total caloric intake
o
Change in dietary evaluation based on 
appetite sensation (24, 52, and 72 weeks)c
o
Mean change (VAS) from BL in 
o
Satiety
o
Fullness
o
Prospective food consumption
o
Hunger
o
Overall appetite score
To characterize the population PK of tirzepatide and 
explore the relationships between the tirzepatide 
concentration and efficacy, safety, tolerability, and 
pharmacogenetics measures
o
Population PK and PD parameters
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BL = baseline; BMI = body 
mass index; ELF = enhanced liver fibrosis; EQ-5D-5L = EuroQol - 5 Dimension - 5 Level; EWL = excess weight 
loss; FIB-4 = Fibrosis-4; FFA = free fatty acid; GGT = gamma-glutamyl transferase; HbA1c = glycated 
hemoglobin; HDL-C = high density lipoprotein cholesterol; HFF = hepatic fat fraction; 
HOMA2-%B = homeostasis model assessment estimates steady state beta cell function; 
HOMA2-%S = homeostasis model assessment estimates steady state insulin sensitivity; IGT = impaired glucose 
tolerance; IWQOL-Lite-CT = Impact of Weight on Quality of Life-Lite Clinical Trials version; 
K-18 (M30) = keratin-18 M30 fragment; LDL-C = low density lipoprotein cholesterol; MRI = magnetic 

C O N FI D E N TI A L
Pr ot oc ol  I 8 F-J E-G P H Z ( b)
1 6
res o na nce i ma gi n g; N A F L D = n o n-alc o h olic fatt y li ver disease; N A S H = n o nalc o h olic steat o he patitis ;
O G T T = or al gl uc ose t olera nce test; P D = p har mac o d y na mics ; P K = p har mac o ki netics; Pr o -C 3 = a fra g me nt of t he 
N H 2 -ter mi nal pr o pe pti de of t y pe III pr oc olla ge n; S A T = s u bc uta ne o us a di p ose tiss ue; S F -3 6 v 2 = S h ort - For m 3 6 -
ite m H ealt h S ur ve y V ersi o n 2; T C = t otal c h olester ol; T G = tri gl yceri de; V A S = vis ual anal o g sca l e; 
V A T = v isceral a di p ose tiss ue; V L D L -C = ver y  l o w de nsit y li p o pr otei n c h olester ol
a
T o c o m pare t he efficac y of o nce -wee kl y tirze pati de wit h place b o, i m pr o ve me nt of N A F L D at 7 2 wee ks will be 
c o m bi ne d wit h all d oses.
b
I n di vi d ual dail y meal i nta ke i nf or mati o n ( p h ot o gra p hs a n d rec or d s heet), i ncl u di n g brea kfast, l u nc h, di n ner, a n d 
s nac ks, will be c ollecte d o n 3 c o nsec uti ve or n o n -c o nsec uti ve da y s d uri n g t he wee k bef ore t he visit. T hese 
rec or ds will be c ollecte d o nl y fr o m partici pa nt s w h o a gree t o partici pate i n ta ki n g t hese meas ure me nts.
c
A p petite se nsati o n will be meas ure d b y a 1 0 0 -m m V A S f or para meters of h u n ger, f ull ness, satiet y, a n d 
pr os pecti ve f o o d c o ns u m pti o n , i ncl u di n g s nac ks bef ore a n d after meal rec or d e d o n 3 c o nsec uti ve or 
n o n- c o nsec uti ve d a y s d uri n g t he wee k i m me diatel y bef ore t he visit. T hese rec or ds will be c ollecte d o nl y fr o m 
partici pa n ts w h o a gree t o partici pate i n ta ki n g t hese meas ure me nts.
O ver all Desi g n
St u d y  G P HZ is a P hase 3, m ul tice nter, ra n d o mize d, place b o -c o ntr olle d, d o u ble -bli n de d st u d y  t o 
e val uate t he safet y a n d efficac y of tirze pati de 1 0 m g a n d 1 5 m g a d mi nistere d s u bc uta ne o usl y 
o nce wee kl y c o m pare d wit h place b o w he n use d i n c o nj u nct i on wi t h a re d uce d-calori e diet a n d 
i ncrease d p h ysical acti vity f or w eig ht m a na ge me nt , i n parti ci pa nt s w h o ha ve
•
A B MI of 2 7 k g/ m 2 or greater a n d less t ha n 3 5 k g/ m 2 a n d at least 2 o besit y- relate d health 
pr o bl e ms; O R
•
A B MI of 3 5 k g/ m 2 or greater a n d at least 1 o besit y- relate d healt h pr o ble m.
O besit y- relate d health pr o bl e ms are defi ne d as I G T, h yperli pi de mia, or N A F L D. 
All partici pa nts will u n der g o a 4 -wee k scree ni n g peri o d a n d a 7 2 -wee k treat me nt peri o d 
i ncl u di n g a 2 0-wee k d ose escalat i on. T he safet y f oll o w-u p peri o d will be 4 wee ks . 
St u d y  p artici pa nt s will be ra n d omize d i n a 1: 1: 1 rati o t o tirze patide 1 0 m g Q W, tirze pat i de 
1 5 m g Q W, or place b o Q W, stratifie d b y

baseli ne I G T (yes or n o) 

baseli ne h y perli pi de mia ( y es or n o) 

baseli n e N A F L D ( y es or n o), a n d 

se x ( male, fe male) .

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
17
Disclosure Statement:
This is a parallel group-treatment study with 3 arms that is participant- and investigator-blinded. 
Number of Participants:
Approximately 348 participants will be screened to achieve 261 randomly assigned to study 
intervention for an estimated total of 87 evaluable participants per intervention group.
Intervention Groups and Duration:
All doses will be subcutaneously administered once-weekly using single-use pens. The starting 
dose of tirzepatide will be 2.5 mg QW (or matching placebo) for 4 weeks, then the dose will be 
increased by 2.5 mg (or matching placebo) every 4 weeks: 2.5 to 5 to 7.5 to 10 mg for those 
randomized to 10 mg, and continuing to 12.5 to 15 mg for those randomized to 15 mg.

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
18
1.2.
Schema
Abbreviations: QW= once weekly; T= telephone visit.
All participants will be randomized to 72 weeks of treatment.
Figure 1. Study design for Clinical Protocol I8F-JE-GPHZ.

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
19
1.3.
Schedule of Activities
Table 1.
Study Period I -Screening and Randomization
Activity
Screening
Randomization
Comments
Visit number
1
2
3
Week of treatment
-4
-2
0
Allowable deviation (days)
NA
-7/+3
-3/+7
The visit date after randomization visit is determined in relation to the date of 
the randomization visit (± the allowed visit window). 
Fasting visit
X
X
X
If the participant is not fasting, the participant should be called in for a new 
visit within the visit window.
Patients must be fasting at least 10 hours before blood sampling.
Informed consent
X
Randomization
X
Medical history
X
Obesity disease assessment
X
Eleven of obesity-related health problems defined by JASSO will be utilized
(Appendix 13, Section 10.13).
Adverse events and product complaints
X
X
X
At Visit 2, this activity can be performed on same day as OGTT test.
Concomitant medications
X
X
X
At Visit 2, this activity can be performed on same day as OGTT test.
Hand out diary, instruct in use
X
All training should be repeated as needed to ensure participant compliance. 
Lifestyle management counseling
X
Counselling on diet and exercise, to be performed by a dietician or equivalent 
qualified delegate, will include calculation of individualized energy 
requirement and methods to change dietary composition and amount of 
physical activity. The lifestyle management counseling may be delivered on a 
separate day from the rest of that visit’s study procedures but must occur within 
the visit window. 
Review diet and exercise goals
X
Injection training with auto-injector 
demonstration device
X
Dispense study drug
X

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
20
Activity
Screening
Randomization
Comments
Visit number
1
2
3
Week of treatment
-4
-2
0
Allowable deviation (days)
NA
-7/+3
-3/+7
The visit date after randomization visit is determined in relation to the date of 
the randomization visit (± the allowed visit window). 
Fasting visit
X
X
X
If the participant is not fasting, the participant should be called in for a new 
visit within the visit window.
Patients must be fasting at least 10 hours before blood sampling.
Observe participant administer study 
drug
X
Patient-reported outcomes
measurements
SF-36v2, acute form
X
IWQoL-Lite-CT
X
EQ-5D-5L
X
Patient Global Impression of Status
X
C-SSRS (baseline/screening version)
X
C-SSRS (since last visit version)
X
X
At Visit 2, C-SSRS can be performed on same day as OGTT test.
PHQ-9
X
X
Self-harm supplement form
X
X
X
At Visit 2, self-harm supplement form can be performed on same day as OGTT 
test.
Self-harm follow-up form
X
X
X
At Visit 2, self-harm follow up form can be performed on same day as OGTT 
test.
CT and MRI
Visceral and subcutaneous adipose 
tissue imaging 
X
Image analysis to be conducted centrally. Either CT or MRI can be used for the 
adipose tissue imaging. The chosen method needs to be consistent across all 
visits for each participant. 

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
21
Activity
Screening
Randomization
Comments
Visit number
1
2
3
Week of treatment
-4
-2
0
Allowable deviation (days)
NA
-7/+3
-3/+7
The visit date after randomization visit is determined in relation to the date of 
the randomization visit (± the allowed visit window). 
Fasting visit
X
X
X
If the participant is not fasting, the participant should be called in for a new 
visit within the visit window.
Patients must be fasting at least 10 hours before blood sampling.
Hepatic fat fraction by MRI-PDFF (only 
for participants who enroll as NAFLD)
X
Image analysis to be conducted centrally. For individuals where the MRI-PDFF 
image quality is in question, and re-capturing and assessment of the MRI image 
is required before 1st dose of study drug, due to the turnaround time of a central 
image analysis, a flexible screening window will be allowed. In such scenarios, 
a Visit 3 that occurs outside of the visit window will not be considered a 
protocol deviation. 
2-Hour OGTT
Glucose, insulin, and c-peptide
X
2-Hour OGTT test can occur 0 to 4 days prior to the visit.
Physical evaluation
Physical examination
X
Height
X
Weight
X
X
Body weight must be measured in fasting state. 
Waist circumference
X
Electrocardiogram
X
Triplicate ECGs should be collected centrally at Visit 3.
Vital signs (sitting BP and PR)
X
X
Vital sign measurements should be taken before collection of blood samples for 
laboratory testing, at visits where required. The participant should sit quietly 
for 5 minutes before vital sign measurements are taken. For each parameter, 
2 measurements will be taken using the same arm; the recordings should be 
taken at least 1 minute apart.
Clinical laboratory tests
Hematology
X
Clinical chemistry panel
X
X
Other chemistry

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
22
Activity
Screening
Randomization
Comments
Visit number
1
2
3
Week of treatment
-4
-2
0
Allowable deviation (days)
NA
-7/+3
-3/+7
The visit date after randomization visit is determined in relation to the date of 
the randomization visit (± the allowed visit window). 
Fasting visit
X
X
X
If the participant is not fasting, the participant should be called in for a new 
visit within the visit window.
Patients must be fasting at least 10 hours before blood sampling.
Cystatin-c
X
HbA1c
X
X
X
Collection of blood samples for HbA1c can be performed on same day as 
OGTT test. The collection must be before OGTT test. 
Urine chemistry (albumin, creatinine, 
albumin/creatinine ratio)
X
X
Urinalysis
X
X
Hormones (females)
Serum pregnancy test (β-HCG)
X
A serum pregnancy test will be performed by central laboratory at Visit 1 for 
women of childbearing potential only. 
Urine pregnancy test
X
A urine pregnancy test will be performed locally for women of childbearing 
potential
Follicle-stimulating hormone test
X
Follicle-stimulating hormone test performed at Visit 1 for postmenopausal 
women at least 40 years of age with an intact uterus, not on hormone therapy, 
and who have had spontaneous amenorrhea for more than 1 year without an 
alternative medical cause. 
Screening liver panel
X
Refer to Exclusion Criterion 3. Hepatitis B surface antigen, anti-hepatitis C 
antibodies and RNA, anti-mitochondrial antibodies should be done as clinically 
appropriate. 
Pancreas (pancreatic amylase, lipase)
X
X
Endocrine
Calcitonin
X
Thyroid stimulating hormone
X
Adiponectin (high molecular weight 
and total) and leptin
X

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
23
Activity
Screening
Randomization
Comments
Visit number
1
2
3
Week of treatment
-4
-2
0
Allowable deviation (days)
NA
-7/+3
-3/+7
The visit date after randomization visit is determined in relation to the date of 
the randomization visit (± the allowed visit window). 
Fasting visit
X
X
X
If the participant is not fasting, the participant should be called in for a new 
visit within the visit window.
Patients must be fasting at least 10 hours before blood sampling.
Insulin and C-peptide
X
Lipid panel
X
X
X
Study eligibility was determined by laboratory TG data sampled at Visits 1 and 
2, at which fasting blood samples were collected for the assessment of clinical 
laboratory findings if both TGs are ≥150 mg/dL.
Collection of blood samples for lipid panel for Visit 2 can be performed on 
same day as OGTT test. The collection must be before OGTT test.
NAFLD/NASH biomarkers (K-18, 
Pro-C3, ELF, FIB-4 index)
X
Inflammatory markers (hsCRP and 
TNFα)
X
Other tests
Immunogenicity
X
Pharmacokinetics
X
Pharmacogenetic stored sample
X
Non-pharmacogenetic stored samples
X
Dietary evaluation
Meal intake
X
Individual daily meal intake information (photographs and record sheet), 
including breakfast, lunch, dinner, and snacks, will be collected on 
3 consecutive or non-consecutive days during the week immediately before the 
visit. These records will be collected only from participants who agree to 
participate in taking these measurements.

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
24
Activity
Screening
Randomization
Comments
Visit number
1
2
3
Week of treatment
-4
-2
0
Allowable deviation (days)
NA
-7/+3
-3/+7
The visit date after randomization visit is determined in relation to the date of 
the randomization visit (± the allowed visit window). 
Fasting visit
X
X
X
If the participant is not fasting, the participant should be called in for a new 
visit within the visit window.
Patients must be fasting at least 10 hours before blood sampling.
Appetite sensation
X
Appetite sensation will be measured by a 100-mm VAS for parameters of 
hunger, fullness, satiety, and prospective food consumption including snacks 
before and after meal recorded on 3 consecutive or non-consecutive days 
during the week immediately before the visit. These records will be collected 
only from participants who agree to participate in taking these measurements.
Abbreviations: β-HCG = β-human chorionic gonadotropin; BP = blood pressure; C-SSRS = Columbia-suicide severity rating scale; CT = computed tomography; 
ECG = electrocardiogram; ELF = enhanced liver fibrosis; EQ-5D-5L = EuroQol - 5 Dimension - 5 Level; FIB-4 = Fibrosis-4; HbA1c = glycated hemoglobin; 
hsCRP = high-sensitivity C-reactive protein; IWQoL-Lite-CT = Impact of Weight on Quality of Life-Lite-Clinical trials version; JASSO = Japan Society for the Study 
of Obesity; K-18 = keratin-18 M30 fragment; MRI = magnetic resonance imaging; MRI-PDFF = magnetic resonance imaging - proton density fat fraction; NA = not 
applicable; NAFLD = non-alcoholic fatty liver disease; NASH = nonalcoholic steatohepatitis; OGTT = oral glucose tolerance test; PHQ-9 = Patient Health 
Questionnaire-9; PR = pulse rate; Pro-C3 = a fragment of the NH2-terminal propeptide of type III procollagen; RNA = ribonucleic acid; SF-36v2 = Short-Form 
36-item Health Survey Version 2; TG = triglyceride; TNFα = tumor necrosis factor-α; VAS = visual analog scale. 

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
25
Table 2. Study Period II-Treatment Period
Activity
Treatment Period
Comments
Visit number
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Week of treatment
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
Allowable deviation 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
The visit date after randomization 
visit is determined in relation to 
the date of the randomization visit 
(± the allowed visit window). 
Fasting visit
X
X
X
X
X
X
X
X
X
X
X
If the participant is not fasting, 
the participant should be called in 
for a new visit within the visit 
window.
Telephone visit
X
X
X
X
X
X
X
Telephone visits are indicated by 
shaded columns. Telephone visits 
can become office visits. Site 
documentation will serve as the 
source for telephone visits. 
Adverse events and 
product complaints
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hand out diary, instruct in 
use
X
X
X
X
X
Lifestyle management 
counseling
X
X
X
X
X
X
X
X
X
Counseling on diet and exercise, 
to be performed by a dietician or 
equivalent qualified delegate, will 
include calculation of 
individualized energy 
requirement and methods to 
change dietary composition and 
amount of physical activity. The 
lifestyle management counseling 
may be delivered on a separate 
day from the rest of that visit’s 
study procedures but must occur 
within the visit window. 

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
26
Activity
Treatment Period
Comments
Visit number
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Week of treatment
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
Allowable deviation 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
The visit date after randomization 
visit is determined in relation to 
the date of the randomization visit 
(± the allowed visit window). 
Fasting visit
X
X
X
X
X
X
X
X
X
X
X
If the participant is not fasting, 
the participant should be called in 
for a new visit within the visit 
window.
Telephone visit
X
X
X
X
X
X
X
Telephone visits are indicated by 
shaded columns. Telephone visits 
can become office visits. Site 
documentation will serve as the 
source for telephone visits. 
Review diet and exercise 
goals
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense study drug
X
X
X
X
X
X
X
X
X
X
Participant returns study 
drugs and injection 
supplies
X
X
X
X
X
X
X
X
X
X
X
Review study participant 
diary, including study drug 
compliance and 
hypoglycemic events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient-reported outcome measures
SF-36v2, acute form
X
IWQoL-Lite-CT
X
EQ-5D-5L
X

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
27
Activity
Treatment Period
Comments
Visit number
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Week of treatment
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
Allowable deviation 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
The visit date after randomization 
visit is determined in relation to 
the date of the randomization visit 
(± the allowed visit window). 
Fasting visit
X
X
X
X
X
X
X
X
X
X
X
If the participant is not fasting, 
the participant should be called in 
for a new visit within the visit 
window.
Telephone visit
X
X
X
X
X
X
X
Telephone visits are indicated by 
shaded columns. Telephone visits 
can become office visits. Site 
documentation will serve as the 
source for telephone visits. 
Patient Global Impression 
of Status
X
C-SSRS (since last visit 
version)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PHQ-9
X
X
X
X
X
X
Self-harm supplement form
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Self-harm follow-up form
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CT and MRI
Visceral and subcutaneous 
adipose tissue imaging
X
Image analysis to be conducted 
centrally. Either CT or MRI can 
be used for the adipose tissue 
imaging. The chosen method 
needs to be consistent between all 
visits for each participant. 
At Visit 21, CT or MRI can be 
done with -28/+7 days allowance, 
which means this can be 
combined with Visit 20.

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
28
Activity
Treatment Period
Comments
Visit number
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Week of treatment
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
Allowable deviation 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
The visit date after randomization 
visit is determined in relation to 
the date of the randomization visit 
(± the allowed visit window). 
Fasting visit
X
X
X
X
X
X
X
X
X
X
X
If the participant is not fasting, 
the participant should be called in 
for a new visit within the visit 
window.
Telephone visit
X
X
X
X
X
X
X
Telephone visits are indicated by 
shaded columns. Telephone visits 
can become office visits. Site 
documentation will serve as the 
source for telephone visits. 
Hepatic fat fraction by 
MRI-PDFF (only for 
participants who enroll as 
NAFLD)
X
At Visit 21, MRI can be done 
with -28/+7 days allowance, 
which means this can be 
combined with Visit 20.
2-Hour OGTT
Glucose, insulin, c-peptide 
X
X
X
2-Hour OGTT can occur 0 to 
4 days prior to the visit.
Physical evaluation
Weight
X
X
X
X
X
X
X
X
X
X
X
Body weight must be measured in 
fasting state. 
Waist circumference
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram
X
X
Single ECGs should be collected 
centrally at Visit 9 and Visit 21.

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
29
Activity
Treatment Period
Comments
Visit number
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Week of treatment
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
Allowable deviation 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
The visit date after randomization 
visit is determined in relation to 
the date of the randomization visit 
(± the allowed visit window). 
Fasting visit
X
X
X
X
X
X
X
X
X
X
X
If the participant is not fasting, 
the participant should be called in 
for a new visit within the visit 
window.
Telephone visit
X
X
X
X
X
X
X
Telephone visits are indicated by 
shaded columns. Telephone visits 
can become office visits. Site 
documentation will serve as the 
source for telephone visits. 
Vital signs
(sitting BP and PR)
X
X
X
X
X
X
X
X
X
X
X
Vital sign measurements should 
be taken before collection of 
blood samples for laboratory 
testing, at visits where required. 
The participant should sit quietly 
for 5 minutes before vital sign 
measurements are taken. For each 
parameter, 2 measurements will 
be taken using the same arm; the 
recordings should be taken at 
least 1 minute apart. 
Clinical laboratory tests
Hematology
X
X
X
X
Clinical chemistry panel
X
X
X
Other chemistry 
X
X
X
Cystatin-c
X
X
X
HbA1c
X
X
X
X
X
X
X

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
30
Activity
Treatment Period
Comments
Visit number
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Week of treatment
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
Allowable deviation 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
The visit date after randomization 
visit is determined in relation to 
the date of the randomization visit 
(± the allowed visit window). 
Fasting visit
X
X
X
X
X
X
X
X
X
X
X
If the participant is not fasting, 
the participant should be called in 
for a new visit within the visit 
window.
Telephone visit
X
X
X
X
X
X
X
Telephone visits are indicated by 
shaded columns. Telephone visits 
can become office visits. Site 
documentation will serve as the 
source for telephone visits. 
Urine chemistry
(albumin, creatinine, 
albumin/creatinine ratio)
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
Hormones (females)
Urine pregnancy test
X
X
X
X
X
X
A urine pregnancy test will be 
performed locally for women of 
childbearing potential 
Pancreas (pancreatic 
amylase, lipase)
X
X
X
X
Endocrine
Calcitonin
X
X
X
Adiponectin (high 
molecular weight and 
total) and leptin
X
X
X
Insulin and C-peptide
X
X
X
X
X
X
X
Lipid panel
X
X
X

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Protocol I8F-JE-GPHZ(b)
31
Activity
Treatment Period
Comments
Visit number
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Week of treatment
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
Allowable deviation 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
The visit date after randomization 
visit is determined in relation to 
the date of the randomization visit 
(± the allowed visit window). 
Fasting visit
X
X
X
X
X
X
X
X
X
X
X
If the participant is not fasting, 
the participant should be called in 
for a new visit within the visit 
window.
Telephone visit
X
X
X
X
X
X
X
Telephone visits are indicated by 
shaded columns. Telephone visits 
can become office visits. Site 
documentation will serve as the 
source for telephone visits. 
NAFLD/NASH 
biomarkers (K-18, 
Pro-C3, ELF, FIB-4 index)
X
X
X
Inflammatory markers
(hsCRP and TNFα)
X
X
X
Other tests
Immunogenicity 
X
X
X
X
X
Pharmacokinetics
X
X
X
X
X
Non-pharmacogenetic 
stored samples
X
X
X
X

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Protocol I8F-JE-GPHZ(b)
32
Activity
Treatment Period
Comments
Visit number
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Week of treatment
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
Allowable deviation 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
The visit date after randomization 
visit is determined in relation to 
the date of the randomization visit 
(± the allowed visit window). 
Fasting visit
X
X
X
X
X
X
X
X
X
X
X
If the participant is not fasting, 
the participant should be called in 
for a new visit within the visit 
window.
Telephone visit
X
X
X
X
X
X
X
Telephone visits are indicated by 
shaded columns. Telephone visits 
can become office visits. Site 
documentation will serve as the 
source for telephone visits. 
Dietary evaluation
Meal intake
X
X
X
Individual daily meal intake 
information (photographs and 
record sheet), including breakfast, 
lunch, dinner and snacks, will be 
collected on 3 consecutive or 
non-consecutive days during the
week immediately before the 
visit. These records will be 
collected only from participants 
who agree to participate in taking 
these measurements.

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Protocol I8F-JE-GPHZ(b)
33
Activity
Treatment Period
Comments
Visit number
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Week of treatment
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
Allowable deviation 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
The visit date after randomization 
visit is determined in relation to 
the date of the randomization visit 
(± the allowed visit window). 
Fasting visit
X
X
X
X
X
X
X
X
X
X
X
If the participant is not fasting, 
the participant should be called in 
for a new visit within the visit 
window.
Telephone visit
X
X
X
X
X
X
X
Telephone visits are indicated by 
shaded columns. Telephone visits 
can become office visits. Site 
documentation will serve as the 
source for telephone visits. 
Appetite sensation
X
X
X
Appetite sensation will be 
measured by a 100-mm VAS for 
parameters of hunger, fullness, 
satiety, and prospective food 
consumption including snacks 
before and after meal recorded on 
3 consecutive or non-consecutive
days during the week
immediately before the visit. 
These records will be collected 
only from participants who agree 
to participate in taking these 
measurements.
Abbreviations: BP = blood pressure; C-SSRS = Columbia-suicide severity rating scale; CT = computed tomography; ECG = electrocardiogram; EQ-5D-5L = EuroQol - 5 
Dimension - 5 Level; HbA1c = glycated hemoglobin; hsCRP = high-sensitivity C-reactive protein; IWQOL-Lite-CT = Impact of Weight on Quality of Life-Lite-
Clinical trials version; MRI = magnetic resonance imaging; MRI-PDFF = magnetic resonance imaging - proton density fat fraction; NAFLD = non-alcoholic fatty 
liver disease; NASH = nonalcoholic steatohepatitis; OGTT = oral glucose tolerance test; PHQ-9 = Patient Health Questionnaire-9; PR = pulse rate; SF-36v2 = Short-
Form 36-item Health Survey Version 2; TNFα = tumor necrosis factor-α; VAS = visual analog scale.

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Protocol I8F-JE-GPHZ(b)
34
Table 3.
Study Period III- Early Discontinuation and Follow-Up Period
Activity
Early Discontinuation and Follow-Up Period
Comment
Visit Number
99
ED
801
At ED visit, participants who are unable or unwilling 
to continue the study treatment for any reason will 
perform an ED visit. If the participant is 
discontinuing during an unscheduled visit or a 
scheduled visit, that visit should be performed as the 
ED visit.
At Visit 801, for participants who discontinue or 
complete the study within 72 weeks, Visit 801 
(safety follow-up visit) should be performed 4 weeks 
after the last visit during the 72-week treatment 
period.
Weeks of treatment
72
4 weeks post end 
of treatment
period
Allowable duration (days)
±7
±7
The visit date after randomization visit is determined 
in relation to the date of the randomization visit 
(± the allowed visit window). 
Fasting visit
X
X
X
If the participant is not fasting, the participant should 
be called in for a new visit within the visit window.
Adverse events and product 
complaints
X
X
X
Hypoglycemic events
X
X
X
Concomitant medications
X
X
X
Lifestyle management counseling
X
Counselling on diet and exercise, to be performed by 
a dietician or equivalent qualified delegate, will 
include calculation of individualized energy 
requirement and methods to change dietary 
composition and amount of physical activity. The 
lifestyle management counseling may be delivered 
on a separate day from the rest of that visit’s study 
procedures but must occur within the visit window. 
Review diet and exercise goals
X
Participant returns study drugs and 
injection supplies
X

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Protocol I8F-JE-GPHZ(b)
35
Activity
Early Discontinuation and Follow-Up Period
Comment
Visit Number
99
ED
801
At ED visit, participants who are unable or unwilling 
to continue the study treatment for any reason will 
perform an ED visit. If the participant is 
discontinuing during an unscheduled visit or a 
scheduled visit, that visit should be performed as the 
ED visit.
At Visit 801, for participants who discontinue or 
complete the study within 72 weeks, Visit 801 
(safety follow-up visit) should be performed 4 weeks 
after the last visit during the 72-week treatment 
period.
Weeks of treatment
72
4 weeks post end 
of treatment
period
Allowable duration (days)
±7
±7
The visit date after randomization visit is determined 
in relation to the date of the randomization visit 
(± the allowed visit window). 
Fasting visit
X
X
X
If the participant is not fasting, the participant should 
be called in for a new visit within the visit window.
Review study participant diary, 
including study drug compliance
X
Patient-reported outcome measurements
SF-36v2, acute form
X
IWQoL-Lite-CT
X
EQ-5D-5L
X
Patient Global Impression of Status
X
C-SSRS (since last visit version)
X
X
X
PHQ-9
X
X
X
Self-harm supplement form
X
X
X
Self-harm follow-up form
X
X
X

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
36
Activity
Early Discontinuation and Follow-Up Period
Comment
Visit Number
99
ED
801
At ED visit, participants who are unable or unwilling 
to continue the study treatment for any reason will 
perform an ED visit. If the participant is 
discontinuing during an unscheduled visit or a 
scheduled visit, that visit should be performed as the 
ED visit.
At Visit 801, for participants who discontinue or 
complete the study within 72 weeks, Visit 801 
(safety follow-up visit) should be performed 4 weeks 
after the last visit during the 72-week treatment 
period.
Weeks of treatment
72
4 weeks post end 
of treatment
period
Allowable duration (days)
±7
±7
The visit date after randomization visit is determined 
in relation to the date of the randomization visit 
(± the allowed visit window). 
Fasting visit
X
X
X
If the participant is not fasting, the participant should 
be called in for a new visit within the visit window.
CT and MRI
Visceral and subcutaneous adipose 
tissue imaging
X
Image analysis to be conducted centrally. Either CT 
or MRI can be used for the adipose tissue imaging. 
The chosen method needs to be consistent between all 
visits for each participant. 
At ED visit, CT or MRI should only be performed on 
participants who have had at least 9 months 
(36 weeks) study drug exposure; for those 
participants, the procedures should be done within 
2 weeks (+2 weeks) as much as possible of the last 
dose of study drug. 
Hepatic fat fraction by MRI-PDFF 
(only for participants who enroll as 
NAFLD)
X
Early discontinuation MRI-PDFF procedures should 
only be performed on participants who have had at 
least 9 months (36 weeks) study drug exposure; for 
those participants, MRI-PDFF procedures should be 
collected within 2 weeks (+2 weeks) as much as 
possible of the last dose of study drug. 

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
37
Activity
Early Discontinuation and Follow-Up Period
Comment
Visit Number
99
ED
801
At ED visit, participants who are unable or unwilling 
to continue the study treatment for any reason will 
perform an ED visit. If the participant is 
discontinuing during an unscheduled visit or a 
scheduled visit, that visit should be performed as the 
ED visit.
At Visit 801, for participants who discontinue or 
complete the study within 72 weeks, Visit 801 
(safety follow-up visit) should be performed 4 weeks 
after the last visit during the 72-week treatment 
period.
Weeks of treatment
72
4 weeks post end 
of treatment
period
Allowable duration (days)
±7
±7
The visit date after randomization visit is determined 
in relation to the date of the randomization visit 
(± the allowed visit window). 
Fasting visit
X
X
X
If the participant is not fasting, the participant should 
be called in for a new visit within the visit window.
2-Hour OGTT
Glucose, insulin, c-peptide
X
Early discontinuation 2-Hour OGTT procedures 
should only be performed on participants who have 
had at least 9 months (36 weeks) study drug 
exposure; for those participants, 2-Hour OGTT 
procedures should be collected within 2 weeks 
(+2 weeks) as much as possible of the last dose of 
study drug and participant must be fasting at least 
10 hours prior to start of the OGTT (samples taken at 
0, 30, 60, 90, and 120 minutes).
Physical evaluation
Weight
X
X
X
At Visit 99, participants wanting to discontinue the 
study before Week 72 will be asked to return for 
Visit 99 at 72 weeks ±7 days after randomization 
primarily for body weight measurement and 
assessment of adverse events. If the participant is 
unwilling to attend Visit 99, it should be documented 
in the participant medical record that the participant 
has refused to attend. 

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
38
Activity
Early Discontinuation and Follow-Up Period
Comment
Visit Number
99
ED
801
At ED visit, participants who are unable or unwilling 
to continue the study treatment for any reason will 
perform an ED visit. If the participant is 
discontinuing during an unscheduled visit or a 
scheduled visit, that visit should be performed as the 
ED visit.
At Visit 801, for participants who discontinue or 
complete the study within 72 weeks, Visit 801 
(safety follow-up visit) should be performed 4 weeks 
after the last visit during the 72-week treatment 
period.
Weeks of treatment
72
4 weeks post end 
of treatment
period
Allowable duration (days)
±7
±7
The visit date after randomization visit is determined 
in relation to the date of the randomization visit 
(± the allowed visit window). 
Fasting visit
X
X
X
If the participant is not fasting, the participant should 
be called in for a new visit within the visit window.
Waist circumference
X
X
X
Electrocardiogram 
X
X
Single ECGs should be collected centrally at ED and 
Visit 801
Vital signs (sitting BP and PR)
X
X
Vital sign measurements should be taken before 
collection of blood samples for laboratory testing, at 
visits where required. The participant should sit 
quietly for 5 minutes before vital sign measurements 
are taken. For each parameter, 2 measurements will 
be taken using the same arm; the recordings should 
be taken at least 1 minute apart.
Clinical laboratory tests
Hematology
X
X
Clinical chemistry
X
X
Other chemistry
Cystatin-c
X
X

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
39
Activity
Early Discontinuation and Follow-Up Period
Comment
Visit Number
99
ED
801
At ED visit, participants who are unable or unwilling 
to continue the study treatment for any reason will 
perform an ED visit. If the participant is 
discontinuing during an unscheduled visit or a 
scheduled visit, that visit should be performed as the 
ED visit.
At Visit 801, for participants who discontinue or 
complete the study within 72 weeks, Visit 801 
(safety follow-up visit) should be performed 4 weeks 
after the last visit during the 72-week treatment 
period.
Weeks of treatment
72
4 weeks post end 
of treatment
period
Allowable duration (days)
±7
±7
The visit date after randomization visit is determined 
in relation to the date of the randomization visit 
(± the allowed visit window). 
Fasting visit
X
X
X
If the participant is not fasting, the participant should 
be called in for a new visit within the visit window.
HbA1c
X
X
Urine chemistry (albumin,
creatinine, albumin/creatinine 
ratio)
X
X
Urinalysis
X
X
Hormones (females)
Urine pregnancy test
X
A urine pregnancy test will be performed locally for 
women of childbearing potential
Pancreas (pancreatic amylase, 
lipase)
X
X
Endocrine
Calcitonin
X
X
Adiponectin (high molecular 
weight and total) and leptin
X
X
Insulin and C-peptide
X
X

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
40
Activity
Early Discontinuation and Follow-Up Period
Comment
Visit Number
99
ED
801
At ED visit, participants who are unable or unwilling 
to continue the study treatment for any reason will 
perform an ED visit. If the participant is 
discontinuing during an unscheduled visit or a 
scheduled visit, that visit should be performed as the 
ED visit.
At Visit 801, for participants who discontinue or 
complete the study within 72 weeks, Visit 801 
(safety follow-up visit) should be performed 4 weeks 
after the last visit during the 72-week treatment 
period.
Weeks of treatment
72
4 weeks post end 
of treatment
period
Allowable duration (days)
±7
±7
The visit date after randomization visit is determined 
in relation to the date of the randomization visit 
(± the allowed visit window). 
Fasting visit
X
X
X
If the participant is not fasting, the participant should 
be called in for a new visit within the visit window.
Lipid panel
X
X
NAFLD/NASH biomarkers
(K-18, Pro-C3, ELF, FIB-4 index)
X
X
Inflammatory markers (hsCRP 
and TNFα)
X
X
Other tests
Immunogenicity 
X
X
Pharmacokinetics
X
X
Non-pharmacogenetic stored 
samples
X
X
Abbreviations: BP = blood pressure; C-SSRS = Columbia-suicide severity rating scale; CT = computed tomography; ED = early discontinuation; EQ-5D-5L = EuroQol -
5 Dimension - 5 Level; HbA1c = glycated hemoglobin; hsCRP = high-sensitivity C-reactive protein; IWQoL-Lite-CT = Impact of Weight on Quality of Life-Lite Clinical 
trials; MRI = magnetic resonance imaging; MRI-PDFF = magnetic resonance imaging - proton density fat fraction; NAFLD = non-alcoholic fatty liver disease; 
NASH = nonalcoholic steatohepatitis; OGTT = oral glucose tolerance test; PHQ-9 = Patient Health Questionnaire-9; PR = pulse rate; SF-36v2 = Short-Form 36-item 
Health Survey Version 2; TNFα = tumor necrosis factor-α.

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Protocol I8F-JE-GPHZ(b)
41
2. Introduction
In general, the accumulation of slight imbalances in daily energy balance causes weight gain and 
leads to obesity. Obesity is a major risk factor for many comorbid diseases, such as stroke, 
coronary artery disease, diabetes, malignant disease, and motor dysfunction, which cause a lower 
quality of life and shortened life expectancy (JASSO 2016; Haneda et al. 2018). In Japan, body 
mass index (BMI) ≥25 kg/m2 is defined as obese, and an obese person with obesity-related health 
problems and medically requiring weight loss is defined as having “obesity disease” (Matsuzawa 
2011). In particular, 3 metabolic disorders in the obesity-related health disorders (impaired 
glucose tolerance [IGT], hyperlipidemia, and non-alcoholic fatty liver disease [NAFLD]), are 
located upstream of the metabolic syndrome (Ito 2003), and promote the onset and progression 
of complications. The guidelines proposed by the Japan Society for the Study of Obesity 
(JASSO) also suggest that the objective of medical therapy for obesity disease is to accelerate 
weight loss safely, leading to improvement in complications of obesity, and to suppress the 
combined use of multiple drugs in patients who have difficulty achieving weight loss goals by 
individual efforts alone.
2.1.
Study Rationale
The gut incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and 
glucagon-like peptide-1 (GLP-1), are secreted after meal ingestion and mediate the incretin 
effect. Both hormones have effects on endocrine cells in the pancreas, increasing insulin 
biosynthesis and secretion, stimulating beta-cell neogenesis and proliferation, and protecting beta 
cells from apoptosis. They also exert actions on alpha cells, modifying glucagon secretion (Skow 
et al. 2016). Based on these properties, several GLP-1 receptor (GLP-1R) agonists have been 
approved for pharmacological treatment of type 2 diabetes mellitus (T2DM) (Tomlinson et al. 
2016).
In addition to its pancreatic effects, GLP-1R activation decreases gut motility, slows gastric 
emptying, and promotes satiety (presumably through a combination of GLP-1R activation in the 
central and peripheral nervous system), thereby regulating food intake and body weight 
(Baggio and Drucker 2007). The US Food and Drug Administration and the European Medicines 
Agency approved the GLP-1R agonist liraglutide for the treatment of individuals who are 
overweight or obese (SAXENDA® package insert, 2014; SAXENDA® SmPc, 2015); this drug is 
not approved in Japan.
Preclinical data indicate that GIP exerts effects on appetite regulation and food intake, on 
adipose tissue and on peripheral energy metabolism. Although studies evaluating effects of GIP 
on body weight have yielded equivocal results, GIP receptor (GIPR) activation may play a role 
in body weight regulation and targeting both the GLP-1R and the GIPR simultaneously may 
result in additive or synergistic effects of the 2 incretins on body weight (Coskun et al. 2018).
Tirzepatide is a 39-amino acid synthetic peptide with agonist activity at both the GIPR and 
GLP-1R. Its structure is based on the GIP sequence and includes a C20 fatty di-acid moiety 
(Coskun et al. 2018). It is administered once weekly (QW) by subcutaneous (SC) injection. As a 

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Protocol I8F-JE-GPHZ(b)
42
dual GIP/GLP-1R agonist, tirzepatide could exceed the efficacy of selective GLP-1R agonists by 
recruiting metabolically active tissues not targeted by selective GLP-1R agonists (for example, 
adipose tissue as indicated by the observation of increased energy utilization) (Müller et al. 
2018) and has the potential to reach higher efficacy in target tissues that express both GIPR and 
GLP-1R. 
Study I8F-JE-GPHZ (GPHZ) is a Phase 3, multicenter, randomized, placebo-controlled, 
double-blinded study, to investigate the safety and efficacy of tirzepatide 10 mg and 15 mg QW, 
compared with placebo, when used in conjunction with a reduced-calorie diet and increased 
physical activity for body weight management in participants with BMI ≥27 kg/m2 and at least 
2 obesity-related health problems or participants with BMI ≥35 kg/m2 and at least 
1 obesity-related health problem. The obesity-related health problems are defined as IGT, 
hyperlipidemia, or NAFLD. The co-primary endpoint will be to demonstrate that QW tirzepatide 
10 mg and/or 15 mg are superior to placebo in both mean percent changes in body weight and 
proportion of participants who achieve ≥5% body weight reduction from baseline to 72 weeks in 
patients with obesity disease.
2.2.
Background
In Japan, if obesity disease is diagnosed, the patients try lifestyle intervention including diet, 
exercise, and behavioral therapy for 3 to 6 months to improve body weight and health problems. 
If improvement of the health problems is achieved by lifestyle modification therapy, the therapy 
is continued. If not, and any of following criteria are met; 1) BMI ≥25 kg/m2, visceral fat area 
≥100 cm2 and 2 or more health problems, 2) BMI ≥35 kg/m2 with 1 or more health problems, 
medical therapy is indicated. There remains an unmet need in the pharmacologic treatment of 
obesity for drugs that are safe, efficacious, and well tolerated. At present in Japan, Sanorex®
(mazindol) is covered only for severely obese subjects by national health insurance with a 
prescription limit of 3 months or less. Chinese herbal medicines are also available. Bariatric 
surgery is also approved for severely obese subjects, but only laparoscopic sleeve gastrectomy is 
covered by national health insurance and some facilities implement laparoscopic sleeve 
gastrectomy with duodenojejunal bypass as an advanced medical treatment (JSTO 2013). Weight 
loss induced by GLP-1R agonists appears to be mediated through a combination of hormonal 
inputs to satiety centers (van Bloemendaal et al. 2014) and has not been consistently associated 
with changes in mental health or with potential for addiction in long-term studies conducted to 
establish cardiovascular safety in patients with diabetes (Marso et al. 2016a; Marso et al. 2016b;
Gerstein et al. 2019). Tirzepatide, which is both a GLP-1R and GIPR agonist, has been 
associated with significant dose-dependent weight loss at 5-, 10-, and 15-mg doses in Phase 2 
studies (Frias et al. 2018).
Dose selection for obesity treatment has been informed by 4 clinical trials: 2 Phase 1 studies
(Study I8F-MC-GPGA [GPGA] and I8F-JE-GPGC [GPGC]), and 2 Phase 2 studies (Study 
I8F-MC-GPGB [GPGB] and I8F-MC-GPGF [GPGF]). 
Phase 1 Study GPGA was a combination of single ascending dose and multiple ascending dose 
studies in healthy subjects and a multiple dose study in patients with T2DM. A total of 

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Protocol I8F-JE-GPHZ(b)
43
142 participants (89 healthy subjects and 53 patients with T2DM) received at least 1 dose of 
treatment. Doses of tirzepatide ranged from: 

0.25 mg to 8 mg in the single ascending dose study (with maximum tolerated dose 
achieved at 5 mg) 

multiple doses from 0.5 mg to 4.5 mg QW and titrated doses up to 10 mg QW for 
4 weeks in healthy subjects

multiple doses at 0.5 mg and 5 mg QW and titrated up to 15 mg QW for 4 weeks in
patients with T2DM in the multiple ascending dose study
The safety and tolerability and pharmacokinetic/pharmacodynamic (PK/PD) profiles of 
tirzepatide at doses and escalation regimens administered in this Phase 1 study supported further 
development of tirzepatide for QW dosing in patients with T2DM. 
In addition, the safety, tolerability, and PK/PD of tirzepatide were evaluated in Study GPGC; a 
Phase 1, 8-week multiple ascending dose study in Japanese patients with T2DM. This study 
involved a comparison of 3 QW, SC dose levels of tirzepatide or placebo:

2.5-mg to 10-mg titration regimen for Cohort 1

5-mg to 15-mg titration regimen for Cohort 2

5-mg fixed dose for Cohort 3
The safety and tolerability data and PK/PD profiles of tirzepatide in Study GPGC supported the 
use of doses up to 15 mg of tirzepatide in Japanese patients.
Phase 2 Study GPGB provided initial safety, tolerability, and efficacy data in the tirzepatide 1- to
15-mg dose range when used in treatment of patients with T2DM. In the dose range of 5 to 
15 mg, tirzepatide provided significantly greater reductions in hemoglobin A1c (HbA1c) and 
body weight compared with dulaglutide 1.5 mg QW. The most common adverse events (AEs), 
which were also dose dependent, were mild-to-moderate nausea, vomiting, and diarrhea (Frias et 
al. 2018).
Phase 2 Study GPGF showed that adjustments in the tirzepatide dose-escalation algorithms 
resulted in additional reduction in the frequency of gastrointestinal (GI) AEs and reduced the 
frequency of treatment discontinuations due to GI AEs. Dose-escalation algorithms starting at a 
low dose of 2.5 mg accompanied by dose escalation of 2.5-mg increments every 4 weeks should 
permit time for development of tolerance to GI events and are predicted to minimize GI 
tolerability concerns. The maximum proposed dose of 15 mg maintains an exposure multiple of 
1.6 to 2.4 to the no-observed adverse-effect level doses in 6-month monkey and rat toxicology 
studies. Based on interim data in Study GPGC, there were no clinically meaningful differences in 
the PK, PD, and safety profile between Japanese patients and non-Japanese patients with T2DM. 
Hence, the doses and associated escalation schemes chosen for this Phase 3 Study GPHZ are the 
same as that chosen for global studies. 
These doses and associated escalation schemes were selected based on assessment of safety, 
efficacy (weight loss), and GI tolerability data, followed by exposure-response modeling of data 

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Protocol I8F-JE-GPHZ(b)
44
in patients in Phase 1 and 2 studies that predicted weight loss in obese and overweight patients 
without T2DM. 
2.3.
Benefit/Risk Assessment
Because tirzepatide is a long-acting, GIP and GLP-1 receptor dual agonist, the potential risks 
associated with tirzepatide may be similar to the risks associated with currently available 
long-acting GLP-1 receptor agonists. The known risks associated with increased GLP-1 receptor 
activity include but are not limited to: GI effects (particularly nausea, vomiting, and diarrhea), 
hepatobiliary effects (gall bladder disease and hepatic safety), pancreatic safety, cardiovascular 
risk (heart rate and blood pressure), hypoglycemic events, thyroid safety, developmental safety, 
and allergic/hypersensitivity reactions.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of tirzepatide may be found in the Investigator’s Brochure. 
Considering the measures taken to minimize risks to participants in this study, the identified 
potential risks in association with Study GPHZ are justified by the anticipated benefits that may 
be afforded to participants with obesity disease.

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Protocol I8F-JE-GPHZ(b)
45
3. Objectives and Endpoints
Objectives
Endpoints
Primary
To demonstrate that once-weekly tirzepatide, at doses 
of 10 mg and/or 15 mg, is superior to placebo in
terms of body weight reduction from BL to 72 weeks 
in Japanese participants with obesity disease
o
Mean percent change in body weight at Week 72
and
o
Proportion of participants who achieve ≥5% body 
weight reduction at Week 72
Secondary
To compare the efficacy of once-weekly tirzepatide 
10 mg and/or 15 mg with placebo for
o
Improvement in obesity-related health 
problems (72 weeks)
o
Proportion of participants who met the following 
criteria at 72 weeks from BL
o
Improvement in at least 2 obesity-related 
health problems for participants with BL 
BMI >27 and <35 kg/m2, or
o
Improvement in at least 1 obesity-related 
health problem for participants with BL 
BMI >35 kg/m2
o
Improvement in laboratory tests for 
obesity-related health problems (72 weeks)
o
Mean changes in the following laboratory tests at 
72 weeks from BL
o
OGTT 2-hr glucose (only for participants 
with IGT at BL)
o
Fasting glucose (only for participants with 
IGT at BL)
o
Fasting lipids (TG) (only for participants 
with hyperlipidemia at BL)
o
HFF (only for participants diagnosed as 
NAFLD by MRI at BL)
o
Improvement of IGT (72 weeks)
o
Proportion of participants who achieved 
improvements of IGT (only for participants with 
IGT at BL)
o
Improvement of hyperlipidemia (72 weeks)
o
Proportion of participants who achieved 
improvements of hyperlipidemia (only for 
participants with hyperlipidemia at BL)
o
Improvement of NAFLD (72 weeks)a
o
Proportion of participants who achieved 
improvements of NAFLD (only for participants 
who are diagnosed as NAFLD by MRI at BL)

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
46
Objectives
Endpoints
o
Body mass related parameters
o
Change in body weight (24, 52, and 
72 weeks)
o
Proportion of participants who achieve the 
following criteria from BL
o
≥5% body weight reduction (only at 24 and 
52 weeks)
o
≥7% body weight reduction
o
≥10% body weight reduction
o
≥15% body weight reduction
o
≥20% body weight reduction
o
Mean change from BL in
o
Absolute body weight
o
BMI
o
Mean percent change from BL in body weight
(only at 24 and 52 weeks)
o
Mean EWL
o
Change in VAT and SAT (72 weeks)
o
Mean change from BL in
o
VAT
o
SAT
o
VAT/SAT ratio
o
Mean percent change from BL in
o
VAT
o
SAT
o
VAT/SAT ratio
o
Proportion of participants who achieve VAT 
<100 cm2 (only for participants with VAT 
≥100 cm2 at BL) from BL
o
Change in waist circumference (24, 52,
and 72 weeks)
o
Mean change from BL in waist circumference
o
IGT related parameters (only for 
participants with IGT at BL)
o
Change in IGT related parameters (24, 52, 
and 72 weeks)
o
Mean change from BL in
o
Fasting glucose
o
HbA1c
o
Fasting insulin
o
C-peptide
o
HOMA2-%B
o
HOMA2-%S

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Protocol I8F-JE-GPHZ(b)
47
Objectives
Endpoints
o
Hyperlipidemia related parameters (only for 
participants with hyperlipidemia at BL)
o
Change in fasting lipids (24, 52, and 
72 weeks)
Mean change from BL in
o
TG
o
TC
o
VLDL-C
o
LDL-C (direct)
o
HDL-C
o
Non-HDL-C
o
FFA
o
NAFLD related parameters
o
Change in NAFLD/NASH biomarkers 
(24, 52, and 72 weeks)
o
Mean change from BL in
o
ALT
o
AST
o
GGT
o
AST/ALT ratio
o
K-18 (M30)
o
Pro C3
o
ELF
o
FIB-4 index
o
Other parameters
o
Change in blood pressure (24, 52, and 
72 weeks)
o
Mean changes from BL in
o
Systolic blood pressure
o
Diastolic blood pressure
o
Change in uric acid (24, 52, and 72 weeks)
o
Mean change from BL in uric acid
o
Patient-reported outcomes
o
Change in patient-reported physical 
functioning (72 weeks)
o
Mean change from BL in SF-36v2 acute form 
physical functioning domain score from BL
o
Mean change in IWQOL-Lite-CT Physical 
Function score
o
Change in patient-reported health status 
(72 weeks)
o
Mean change in EQ-5D-5L score from BL
o
Index score
o
VAS score
o
Change in dietary evaluation based on the 
meal record (24, 52, and 72 weeks)b
o
Mean change from BL in
o
Total fats
o
Total carbohydrates
o
Total proteins
o
Total caloric intake
o
Change in dietary evaluation based on 
appetite sensation (24, 52, and 72 weeks)c
o
Mean change (VAS) from BL in 
o
Satiety
o
Fullness
o
Prospective food consumption
o
Hunger
o
Overall appetite score

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Protocol I8F-JE-GPHZ(b)
48
Objectives
Endpoints
To characterize the population PK of tirzepatide and 
explore the relationships between the tirzepatide 
concentration and efficacy, safety, tolerability, and 
pharmacogenetics measures
o
Population PK and PD parameters
Exploratory
To compare the efficacy of once-weekly tirzepatide 
10 mg and/or 15 mg with placebo for
o
Improvement in obesity-related health problems 
at 72 weeks
o
Proportion of participants who met the following 
criteria at 72 weeks from BL
o
improvement in ≥2 obesity-related health 
problems for participants with BL BMI ≥27 
and <35 kg/m2
o
improvement in ≥1 obesity-related health 
problems for participants with BL BMI 
≥35 kg/m2
o
Proportion of participants who achieved the 
following number of improvements of obesity-
related health problems regardless of BMI at BL
o
Achieved 2 or 3 improvements (only for 
participants with 3 defined obesity-related 
health problems)
o
Achieved 2 improvements (only for 
participants with 2 defined obesity-related 
health problems)
o
Achieved 1 improvement (only for 
participants with 1 defined obesity-related 
health problems)
o
IGT related parameters (all participants)
o
Change in OGTT (24, 52, and 72 weeks)
o
Mean change from BL in
o
OGTT 2-hr glucose
o
fasting glucose
o
insulin
o
C-peptide
o
Hyperlipidemia related parameters (all 
participants)
o
Change in fasting lipids (24, 52, and 
72 weeks)
o
Mean change from BL in
o
TG
o
TC
o
VLDL-C
o
LDL-C (direct)
o
HDL-C
o
non-HDL-C
o
FFA

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
49
Objectives
Endpoints
o
Other parameters
o
Change in laboratory tests (24, 52, and 72 
weeks)
o
Mean change from BL in
o
Adiponectin
o
Leptin
o
hs-CRP
o
TNFα
o
Mean change from BL in
o
eGFR
o
Urinary albumin/creatinine ratio
o
Patient-reported outcomes
o
Change in SF-36v2 acute scores other than 
physical functioning (72 weeks)
o
Mean change from BL in
o
role-physical score
o
bodily pain score
o
general health score
o
vitality score
o
social functioning score
o
role-emotional score
o
mental health score
o
physical component summary
o
mental component summary
o
Change in IWQOL-Lite-CT scores other 
than physical functioning (72 weeks)
o
Mean change from BL in
o
physical score
o
psychosocial score
o
total score
o
Change in Patient Global Impression of 
Status (72 weeks)
o
Shift of the ordinal response category from BL
To compare once-weekly tirzepatide (all doses 
combined) with placebo for participants with IGT at 
BL
o
Delayed progression to T2DM at 72 weeks
o
Time to onset of T2DM during 72-week treatment 
period from BL
To explore once-weekly tirzepatide (all participants 
combined) 10 mg and/or 15 mg and placebo for
o
Immunogenicity assessment
o
The frequency and percentage of participants with 
preexisting ADA, with TE ADA, and with 
neutralizing TE ADA to tirzepatide 
Abbreviations: ADA = antidrug antibody; ALT = alanine aminotransferase; AST = aspartate aminotransferase;
BL = baseline; BMI = body mass index; ELF = enhanced liver fibrosis; EQ-5D-5L = EuroQol – 5 Dimension –
5 Level; EWL = excess weight loss; FIB-4 = Fibrosis-4; FFA = free fatty acid; GGT = gamma-glutamyl 
transferase; HbA1c = glycated hemoglobin; HDL-C = high density lipoprotein cholesterol; HFF = hepatic fat 
fraction; HOMA2-%B = homeostasis model assessment estimates steady state beta cell function; 
HOMA2-%S = homeostasis model assessment estimates steady state insulin sensitivity;
hs-CRP = high-sensitivity C-reactive protein; IGT = impaired glucose tolerance; IWQOL-Lite-CT = Impact of 
Weight on Quality of Life-Lite Clinical Trials version; K-18 = keratin-18 M30 fragment; LDL-C = low density 
lipoprotein cholesterol; MRI = magnetic resonance imaging; NAFLD = non-alcoholic fatty liver disease; 
NASH = nonalcoholic steatohepatitis; OGTT = oral glucose tolerance test; Pro-C3 = a fragment of the 

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
50
NH2-terminal propeptide of type III procollagen; PD = pharmacodynamics, PK = pharmacokinetics, 
SAT = subcutaneous adipose tissue; SF-36v2 = Short-Form 36-item Health Survey Version 2; T2DM = type 2 
diabetes mellitus; TC = total cholesterol; TE = treatment-emerged; TG = triglyceride; TNFα = tumor necrosis 
factor-α; VAS = visual analog scale; VAT = visceral adipose tissue; VLDL-C = very low density lipoprotein 
cholesterol.
a
To compare the efficacy of once-weekly tirzepatide with placebo, improvement of NAFLD at 72 weeks will be 
combined with all doses.
b Individual daily meal intake information (photographs and record sheet), including breakfast, lunch, dinner, and 
snacks, will be collected on 3 consecutive or non-consecutive days during the week before the visit. These 
records will be collected only from participants who agree to participate in taking these measurements.
c
Appetite sensation will be measured by a 100-mm VAS for parameters of hunger, fullness, satiety, and 
prospective food consumption including snacks before and after meal recorded on 3 consecutive or 
non-consecutive days during the week immediately before the visit. These records will be collected only from 
participants who agree to participate in taking these measurements.

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
51
4. Study Design
4.1.
Overall Design
Study GPHZ is a Phase 3, multicenter, randomized, placebo-controlled, double-blinded study to 
evaluate the safety and efficacy of subcutaneously administered tirzepatide 10 mg and/or 15 mg 
QW compared with placebo when used in conjunction with a reduced calorie diet and increased 
physical activity for weight management, in obesity disease participants with BMI ≥27 and 
<35 kg/m2 and at least 2 obesity-related health problems or BMI ≥35 kg/m2 and at least 
1 obesity-related health problem. The obesity-related health problems are IGT, hyperlipidemia, 
or NAFLD.
The study population will be enriched for participants who have NAFLD and IGT, such that 
more than 40% of the total study population will consist of participants with NAFLD, and more 
than 60% of the total study population will consist of participants with IGT.
Study GPHZ will consist of 3 periods: a 4-week screening period, followed by a 72-week 
treatment period including a 20-week dose escalation, and a 4-week safety, off-drug, follow-up 
period. Approximately, 261 participants will be randomized in a 1:1:1 ratio to tirzepatide 10 mg, 
15 mg, or placebo. 
4.2.
Scientific Rationale for Study Design
This study is designed to determine the comparative benefits and risks of tirzepatide 10 mg 
and/or 15 mg QW versus placebo in participants with obesity disease who have obesity-related 
health problems (see Table 4). 
Table 4.
Scientific Rationale for Study Design
Study Design Element
Scientific Rationale
Double blinded parallel-group 
study
It is appropriate to minimize participant and investigator bias in assessments 
for efficacy, safety, and study drug tolerability.
Placebo-controlled study
It was chosen to determine the comparative benefits and risks of tirzepatide 
10 mg and/or 15 mg QW versus placebo in participants who have obesity 
disease with obesity-related health problems defined as glucose intolerance, 
hyperlipidemia (hypertriglyceridemia), or non-alcoholic fatty liver disease.
Conjunction with a reduced 
calorie diet and increased 
physical activity for weight 
management
It follows the JASSO guideline that the obesity disease patients may initiate 
medical therapy, if despite adequate lifestyle interventions including diet, 
exercise, and behavioral therapy for 3 to 6 months body weight and associated 
health problems are not improved.
Primary and secondary 
endpoints
This study is based on the regulatory guidance (JASSO Guideline for the 
management of obesity disease [JASSO 2016]). JASSO guideline for the 
management of obesity disease emphasizes the importance of improving 
obesity-related health problems as a secondary endpoint, although reducing 
body weight loss is set as the primary endpoint.
Study duration
The planned duration of treatment for the primary endpoint at 72 weeks 
includes a dose escalation period to either 10 or 15 mg and at least 52-week 

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
52
treatment period with the assigned dose. This duration is considered 
appropriate to assess the full effects and benefit/risk of each maintenance dose 
of tirzepatide compared with placebo on body weight and improvement of 
associated obesity-related comorbidities. It is consistent with regulatory 
guidelines (FDA 2007; EMA 2016) and agreed by PMDA. 
Concomitant medications
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 treatment.
(Section 6.5).
Abbreviations: JASSO = Japan Society for the Study of Obesity; PMDA = Pharmaceuticals and Medical Devices 
Agency; QW = once weekly.
4.3.
Justification for Dose
Tirzepatide doses of 10 and 15 mg QW will be evaluated in this study.
These doses and associated escalation schemes were selected based on assessments of safety,
efficacy (glycemic and weight loss effect), and GI tolerability data, followed by data from 
exposure response modeling in participants with T2DM in Phase 1 and 2 studies.
Dosing scheme starting at a low dose of 2.5 mg accompanied by a gradual dose escalation of 
2.5-mg increments every 4 weeks should allow the development of tolerance to GI events and
intends to minimize GI AEs.
The maximum proposed dose of 15 mg maintains an exposure multiple of 1.6 to 2.4 to the no
observed adverse-effect level doses in 6-month monkey and rat toxicology studies.
The selected dose and escalation scheme would enable further evaluation of benefit/risk
considerations for 10-mg and 15-mg doses of tirzepatide.
4.4.
End of Study Definition
A participant is considered to have completed the study if he or she has completed all required
phases of the study including the last visit or the last scheduled procedure shown in Section 1.3.
The end of the study is defined as the date of the last visit of the last participant in the study or 
the last scheduled procedure shown in the Schedule of Activities (Section 1.3), for the last 
participant in the trial.

C O N FI D E N TI A L
Pr ot oc ol  I 8 F-J E-G P H Z( b)
5 3
5. St u d y  P o p ul ati o n
Pr os pecti ve a p pr o val o f pr ot oc ol  de viatio ns t o recr ui t me nt a n d e nr o ll me nt criteria, als o k n o w n as 
pr ot oc ol  wai vers or e xe m pti ons, is n ot per mitte d.
5. 1.
I n cl u si o n Crit eri a
P arti cipa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all o f t he fol l owi n g criteria a p pl y:
A ge
1.
P arti cip a nt m ust be 2 0 years or ol der at t he ti me of si g ni n g t he i nf or me d c o nse nt.
T y pe of P artici p a nt a n d Dise ase C h ar acteristics
2.
Ha ve B MI of  
•
≥2 7 k g/ m 2 a n d < 3 5 k g/ m 2 wi t h at least 2 o besit y -relate d health pr o bl e ms or
•
≥3 5 k g/ m 2 wi t h at le ast 1 o besit y- r elate d healt h pr o bl e ms
•
Heal t h pr o bl e ms are I G T, h yperli pi de mia, or N A F L D at scree ni n g ( Visit 1 a n d 
Vi sit 2). 
a.
I G T: ha ve oral gl uc ose t olera nce test ( O G T T) 0 - h o ur gluc ose of ≥1 1 0 m g/ d L 
a n d/ or O G T T 2- h o u r gluc ose of ≥1 4 0 m g/ d L at V isit 2 a n d d o n ot m eet dia g n ost ic 
criteria f or dia betes mellit us (D M ) at Visit 1 a n d Visit 2. I n t his st u d y, I G T is 
defi ne d t o i ncl u de i m paire d fast i n g gl uc ose als o descri be d as “B or derli ne t y p e ”
acc or di n g t o Ja pa nese Cli nical Pract ice G ui deli ne f or Dia betes 2 0 1 9 ( Ara ki et al. 
2 0 2 0) .
b.
h y perli pi de mia: ha ve fast i n g tri gl yceri de ≥1 5 0 m g/ d L at scree ni n g at Visit 1 a n d 2
c.
N A F L D ( parti cipa nt s wit h N A F L D ca n be e nr olle d O N L Y at cli nical sites w hic h 
ha ve ma g net ic res o na nce i ma gi n g [M RI ] – pr ot o n de nsit y fat fracti on [P D F F ]
a vaila bilit y a n d/ or ca n o btai n s u p p ort fr o m i ma gi n g sites f or M RI-P D F F)
i. ha ve he pat ic fat fracti o n ( H F F) ≥5 % as m eas ure d b y M RI-P D F F i ma gi n g 
(ce ntral e valu ati o n) at Visit 2
3.
Ha ve a hist or y  of at least 1 self-re p orte d u ns uccessf ul dietar y eff ort t o lose b o d y  wei g ht
a.
I n t he i n vesti gat or’s o pi ni on, are well -m o tivate d, ca pa ble, a n d willi n g t o learn
h o w t o self -i nject st u d y i nter ve nt i on , as re q uire d f or t his pr ot oc ol ( vis uall y 
i m paire d pers o ns w h o are n ot a ble t o perf or m t he i njecti ons m ust ha ve t he 
assista nce of a si g hte d i n di vi d ual trai ne d t o i nject st u d y  i nter ve nt i on ; pers o ns wit h 
p h ysical li mitat i ons w h o are n ot a ble t o perf or m t he i nject i ons m u st ha ve t he 
assista nce of a n i n di vid ual  trai ne d t o i nject st u d y i nter ve nt i on ) 
an d
b.
i nject st u d y i nter ve nt i on ( or recei ve a n i njecti on fr o m a trai ne d i n di vi d ual if 
vis uall y i m paire d or wit h p h ysical li mitat i ons)
an d
c.
f oll ow st u d y  pr oce d ures f or t he d urati o n of t he st u d y, i ncl u di n g, b ut n ot li mite d 
t o: f oll ow lifest yle a d vice (f or e xa m ple, dietar y restricti o ns a n d e xercise pla n), 
mai ntai n a st u d y  di ar y, a n d c o mplete re q ui re d q uestio n nai r es

C O N FI D E N TI A L
Pr ot oc ol  I 8 F-J E-G P H Z( b)
5 4
Se x
4.
Mal e a n d/ or fe male
C o ntrace pti ve use b y me n or w o me n s h o ul d be c o nsiste nt wit h l ocal re g ulat i ons r e gar di n g 
t he met h o ds of c o ntrace pti o n f or t h ose partici pat i n g i n cli nical st u dies.
a.
Male parti ci pa nts:
•
Male parti ci pa nts wit h part ners of c hil d beari n g p ote ntial s h o uld be willi n g t o 
use relia ble c o ntrace pti ve met h o ds t hr o u g h o ut t he st u d y  a n d for 5 half -li ves 
of  st u d y i nter ve nt i on pl us 9 0 da ys, c orres p o n di n g t o 4 m o nt hs after t he last 
i njecti on.
b.
Fe male partici pa nts :
i.
Fe male partici pa nts of c hil d beari n g p ote ntial ( n ot s ur gicall y  sterilize d a n d 
bet wee n m e narc he a n d 1-ye ar p ost me n o pa usal) m ust:
A.
test ne gati ve f or pre g na nc y at Visit 1 base d o n a ser u m pre g na nc y 
test,
B.
if se x uall y acti ve, a gree t o use 2 f or ms of effecti ve c o ntrace pti o n, 
w here at least 1 f or m is hi g hl y effecti ve, f or t he d urati o n of t he 
trial a n d for 3 0 da ys t hereafter , a n d
C.
n ot be breastfee di n g
ii.
W o me n n ot of c hil d beari n g p ote ntial ma y partici pate a n d i ncl u de t h ose 
w h o are:
A.
i nfertile d ue t o s ur gical sterilizati on ( h ysterect o m y, bilateral 
o o p h orect o m y , or t u bal li gati on), c o n ge nital a n o mal y s uc h as 
M ulleria n
a ge nesis; or
B.
p ost -me n o pa usal – defi ne d as eit her

A w o ma n at l east 4 0 years of a ge wit h a n i ntact uter us, n ot o n 
h or m o ne t hera p y , w h o has cessati on of me nses f or at least 
1 year wit h o ut a n alter nat i ve me d ical ca use, A N D a 
f ollicle-sti m ulati n g h or m o ne > 4 0 mI U/ m L; w o me n i n t his 
cate g or y must test ne gati ve i n pre g na nc y tes t prior t o t he 
st u d y e ntr y
or

A w o ma n 5 5 or ol der n ot o n h or m o ne t hera p y , w h o has ha d at 
least 1 2 m o nt hs of s p o nta ne o us a me n orr hea 
or

A w o ma n at l east 5 5 years of a ge wit h a dia g n osis of 
me n o pa use pri or t o starti n g h or m o ne re place me nt t hera p y

CONFIDENTIAL
Protocol I8F-JE-GPHZ(b)
55
Informed Consent
5. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1),
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Have DM according to Japanese Clinical Practice Guideline for Diabetes 2019 (Araki et 
al. 2020), history of ketoacidosis or hyperosmolar state/coma, or laboratory evidence of 
diagnostic of DM during screening including either HbA1c >6.5%, or glucose levels 
(fasting glucose or OGTT 0-hour ≥126 mg/dL and/or OGTT 2-hour glucose 
≥200 mg/dL);
a.
Diagnosis of DM
i. Both glucose level and HbA1c meets diabetic type criteria
ii. Only glucose level meets diabetic type criteria at Visit 1

With typical symptoms of DM or definite diabetic retinopathy

Without typical symptoms of DM or definite diabetic 
retinopathy, re-exam at Visit 2 and
o
Both glucose level and HbA1c meet diabetic type criteria
o
Only glucose level meets diabetic type criteria
o
Only HbA1c meets diabetic type criteria
iii. Only HbA1c meets diabetic type criteria, re-exam at Visit 2 and

Both glucose level and HbA1c meet diabetic type criteria

Only glucose level meets diabetic type criteria

Only HbA1c meets diabetic type criteria
b. Prior treatment (within 3 months prior to Visit 1) with DPP-4 inhibitors, oral 
GLP-1 RA, or any injectable therapy for T2DM 
2. Alcohol consumption >7 units (140 g of pure alcohol)/week for women and >10.5 units
(210 g of pure alcohol)/week for men (JSG 2014)
3. Evidence of acute or chronic liver disease other than NAFLD
a.
Alcoholic liver disease
b. Hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg)
c.
Hepatitis C as defined by presence of hepatitis C virus (HCV) ribonucleic acid 
(RNA) or positive hepatitis C antibody (anti-HCV). Participants treated for 
hepatitis C (and diagnosed as cured) must be RNA negative for at least 3 years 
prior screening in order to be eligible for the study
d. Primary biliary cirrhosis as defined by the presence of at least 2 of the 
following:
i. Biochemical evidence of cholestasis based mainly on alkaline 
phosphatase (ALP) elevation

C O N FI D E N TI A L
Pr ot oc ol  I 8 F-J E-G P H Z( b)
5 6
ii. Prese nce of a nt i-mit oc h o n drial a nt i b o d y
iii. Hi st orical e vi de nce of n o ns u p p urat i ve destr ucti ve c h olan git is a n d 
destr ucti o n of i nterl o b ular bile d ucts
e.
E vi de nce of a ut oi m m u ne li ver disease as defi ne d b y  c o mpat i ble li ver hist ol o g y
f.
Pri mar y scler osi n g c h o lan git is
g.
C urre nt  dr u g-i n d uce d li ver disease as defi ne d o n t he basis of t ypical e x p os ure 
a n d hist or y
h.
S us pecte d or pr o ve n li ver ca ncer
i.
Ha ve ac ute or c hr o nic he pat itis, si g ns a n d s y m pt o ms of a n y ot her li ver disease 
ot her t ha n N A F L D , or a n y of t h e foll o wi n g, as deter mi ne d b y t he ce ntral
la b orat or y d uri n g scree ni n g:
•
ala ni ne a mi n otra nsferase ( A L T) le vel > 3. 0 × t he u p per li mit of n or mal
( U L N) f or t he refere nce ra n ge
or
•
A L P l e vel > 1. 5 × t he U L N f or t he refere nce ra n ge
or
•
t otal bilir u bi n ( T B L) le vel > 1. 2× t he U L N f or t he refere nce ra n ge
(e xce pt f or cases of k n o w n Gil bert’s S y n dr ome)
N ote: Parti ci pa nts wit h N A F L D are eli gi ble t o partici pate i n t his trial if t heir 
A L T level is ≤3. 0 × t he U L N f or t he refere nce ra n ge.
4.
H a ve a self-re p orte d c ha n ge i n b o d y wei g ht > 5 k g wit hi n 3 m o nt hs pri or t o scree ni n g
5.
Ha ve or pl a n t o ha ve e n d osc o pic a n d/ or de vice-base d t hera p y  for o besi t y or ha ve ha d 
de vice re m o val wit hi n t he l ast 6 m o nt hs 
E xa m ple s:
•
m uc osal a blat i on
•
gastri c arter y e m b olizati on
•
i ntra gastric ball o o n
•
d u o de nal -jej u nal b y pass slee ve e n d olu mi nal li ner
6.
Ha ve re nal i m pair me nt meas ure d as est i mate d gl o mer ular filtrati on rate (e G F R) 
< 3 0 m L/ mi n/ 1. 7 3 m 2, calc ulate d b y Ja pa nese S ociet y of  Ne p hr olo g y  c oefficie nt-m o difie d 
C hr o nic Ki d ne y  Disease-E pi de mi ol o g y e q uat i on as deter mi ne d b y ce ntral la b orat or y 
d uri n g scree ni n g
7.
Ha ve a k n o w n cli nicall y si g nifica nt gastric e m pt yi n g a b n or malit y (f or e xa m ple, se vere 
gastr o paresi s or gastric o utlet o bstr ucti o n) or c hr o nicall y ta ke dr u gs t hat direct l y affect GI 
m o tility
8.
Ha ve ha d a hist or y  of c hr o nic or ac ute pa ncreatitis
9.
Ha ve t h yr oid- sti m ulati n g h or m o ne o utsi de of t he ra n ge of 0. 4 t o 6. 0 μ I U/ mL at scree ni n g 
visit 
N ote: Parti ci pa nt s recei vi n g treat me nt f or h y p ot h yr oi dis m ma y be i ncl u de d, pr o vi de d 
t heir t h yr oid h or m o ne re pl ace me nt d ose has bee n sta ble f or at least 3 m o nt hs.

C O N FI D E N TI A L
Pr ot oc ol  I 8 F-J E-G P H Z( b)
5 7
N ote: T h yr oi d -sti m ulati n g h or m o ne val ues a b o ve t he n or mal ra n ge ca n, i n s o me 
parti ci pa nts, s u g gest s u bcli nical h y p ot h yr oidis m. If, i n t he i n vesti gat or’s o pi ni on, t he 
parti ci pa nt has s u bcli nical h y p ot h yr oidis m a n d m a y re q uire i nitiat i on of t h y r oid 
h or m o ne re pl ace me nt d uri n g t he c o urse of t he st u d y, t he parti ci pa nt s h o uld be e xcl u de d 
fr om t he st u d y. 
1 0. Ha ve o besit y i n d uce d b y ot her e n d ocri n olo gi c dis or ders (f or e xa m ple, C us hi n g ’s
S y n dr o me) or dia g n ose d m o n o ge net ic or s y n dr omic f or ms of o besit y (for e xa m ple, 
Mela n oc orti n 4 Rece pt or deficie nc y or Pra der Willi S y n dr o me)
1 1. Ha ve a hist or y  of si g nifica nt acti ve or u nsta ble m aj or d e pressi ve d is or der or ot her se vere 
ps yc hiatric dis or der (f or e xa m ple, sc hiz o p hre nia, bi p o lar dis or der, or ot her seri o us m o o d 
or a n xiet y dis or der) wi t hi n t he last 2 years
N ote: P artici pa nt s wit h m ajor d e pressi ve d is or der or ge neralize d a n xiet y dis or der 
w h ose disease state is c o nsi dere d sta ble f or t he past 2 years a n d e x pecte d t o re mai n 
sta ble t hr o u g h o ut t he c o urse of t he st u d y, i n t he o pi ni on of t he i n vesti gat or, ma y be 
c o nsi dere d f or i ncl usi o n if t he y are n ot o n e xcl u de d me dicat i ons
1 2. Ha ve a n y lifeti me hist or y  of a s uici de att e mpt
1 3. Ha ve a Patie nt Healt h Q uesti o n naire -9 ( P H Q -9) sc ore of 1 5 or m ore at Visit 1 or 3, pri or 
t o ra n d o mizati on
1 4. O n t he C ol u m bia -S uici de Se veri t y Rati n g Scale (C -S S R S ) at Visits 1 or 3, pri or t o 
ra n d omizat i on:
a.
a “ yes” a ns wer t o eit her Q uesti o n 4 ( Act i ve S uici dal I deati o n with S o m e I nte nt t o 
Act, Wit h o ut S pecific Pla n)
or
b.
a “ yes” a ns wer t o Q uesti o n 5 ( Act i ve S uici dal I deati o n wit h S pecific Pla n a n d 
I nte nt) o n t he “S uici dal  I deati on” p orti o n of  t he C- S S R S
or
c.
a “ yes” a ns wer t o a n y of t he s uicid e -r elate d be ha vi ors ( Act ual Atte m pt, 
I nterr u pte d Atte m pt, A b orte d Atte m pt, Pre parat or y Act or Be ha vi or) o n t he 
“ S uici dal Be ha vi or” p orti o n of  t he C-S S R S
a n d
d.
t he id e ati o n or be ha vi or occ urre d wit hi n t he past m o nt h
1 5. Ha ve a n y of t he f o ll owi n g car di o vasc ular c o n di tio ns wi t hi n 3 m o nt hs pri or t o 
ra n d omizat i on: 
•
ac ute m yocar dial  infarct i on
•
cere br o vasc ular acci de nt (str o ke)
•
u nsta ble a n gi na
•
h os pi talizatio n d ue t o c o n gesti ve heart fail ure
•
u nc o ntr olle d h y perte nsi o n ( s ystolic bl o o d press ure a b o ve or e q ual t o 1 6 0 m m H g 
a n d/ or diast olic bl o o d press ure a b o ve or e q ual t o 1 0 0 m m H g)
1 6. Ha ve N e w Y or k H eart A ss ociat i on F u nct i onal Classificati o n I V c o n gest i ve heart fail ure
1 7. Ha ve a ser u m calcit o ni n le vel (at Visit 1) of 3 5 n g/ L or m or e, as deter mi ne d b y ce ntral 
la b orat or y at Visit 1

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Protocol I8F-JE-GPHZ(b)
58
18. Have a family or personal history of medullary thyroid carcinoma or Multiple Endocrine 
Neoplasia Syndrome type 2
19. 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
20. Have any other condition not listed in this section (for example, hypersensitivity or 
intolerance) that is a contraindication to GLP-1R agonists
21. 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
22. Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or awaiting an 
organ transplant
23. Have any hematological condition that may interfere with HbA1c measurement (for 
example, hemolytic anemias, sickle cell disease)
Prior/Concomitant Therapy
24. Have current or potential needs of glucocorticoid therapy:
a.
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) 
b. Have evidence of a significant, active autoimmune abnormality (for example, 
lupus or rheumatoid arthritis) that has required (within the last 3 months) or is 
likely to require, in the opinion of the investigator, concurrent treatment with 
systemic glucocorticoids (excluding topical, intraocular, intranasal, intra-articular,
or inhaled preparations) during the study
25. 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 for example:

imipramine

amitriptyline

mirtazapine

paroxetine

phenelzine

chlorpromazine

thioridazine

clozapine

olanzapine

valproic acid and its derivatives

lithium
Note: Selective serotonin reuptake inhibitors other than paroxetine are permitted.

C O N FI D E N TI A L
Pr ot oc ol  I 8 F-J E-G P H Z( b)
5 9
2 6. Ha ve ta ke n wit hi n 3 m o nt hs pri or t o ra n d o mizati on, m e dicat i ons ( prescri be d , i m p orte d or 
o ver t he c o u nter) or alter nat i ve re me dies i nte n de d t o pr o m ote wei g ht l oss or ma y ca use 
w ei g ht re d ucti o n . E xa m ples i ncl u de, b ut are n ot li mite d t o:

Sa n ore x ® ( mazi n d o l)

B of u -ts us h o-sa n® ( Chi nese her bal me dici ne)

Sa xe n da ® (lira gl ut i de 3. 0 m g)

Xe nical ® ( orlistat)

Meri dia ® (si b utra mi ne)

Ac utri m ® ( p he n yl pr o pa n olami ne)

A d i pe x® ( p he nter mi ne)

B E L VI Q ® (lorcaseri n)

Qs y mia ® ( p he nter mi ne/t o pira mate c o m bi nati on)

C o ntra ve ® ( naltre x o ne/ b u pr o pi o n)
N ote : 
•
Use of met f or mi n or a n y ot her gluc ose -l oweri n g me dicat i on, w het her 
prescri be d f or p ol yc yst ic o var y s y n dr ome or dia betes pre ve nt i on is n ot 
per mitte d.
•
Use of s e ma gl ut i de t hat ma y ca use si g nifica nt wei g ht re d ucti o n is n ot all o we d
wi t hi n 1 2 m o nt hs pri or t o ra n d o miz atio n .
2 7. Ha ve starte d i m pla nta ble or i njecta ble c o ntrace pti ves (s uc h as De p o -Pr o vera ® ) wit hi n 
1 8 m o nt hs pri or t o scree ni n g
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce
2 8. Are c urre nt l y e nr olle d i n a n y ot her cli nical st u d y in v o l vi n g a n i n vesti gati onal pr o d uct 
(I P) or a n y  ot her t ype of me dical researc h j u d ge d n ot t o be scie nt ificall y or me dicall y 
c o mpat i ble wit h t his st u d y
2 9. Wit hi n t he last 3 0 d a y s pri or t o scree ni n g , ha ve parti ci pate d i n a cli nical st u d y a n d 
recei ve d treat me nt, w het her acti ve or place b o. If t he st u d y i n v ol ve d a n I P, 5 half -li ves or 
3 0 d a y s, w hic he ver is lo n ger, s h o uld ha ve passe d
3 0. Ha ve pre vi o usl y c o m p lete d or wit h dra w n fr om t his st u d y or a n y ot her st u d y in vest i gati n g 
tirze pati de
Ot her E xcl usi o ns
3 1. Are i n vest i gat or site pers o n nel directl y affiliate d with t his st u d y a n d/ or t heir i m me diate 
fa mil y. I m me diate fa mil y is defi ne d as a s p o use, le gal part ner, pare nt, c hil d, or si bli n g, 
w het her bi o l ogi c al or le gall y a d o pte d
3 2. Are Eli Lill y a n d C o m pa n y ( Lill y) e m pl o yees
5. 3.
Lif e st yl e C o n si d er ati o n s
Per t he Sc he d ule of Ac tivit ies (Secti o n 1. 3 ), partici pa nts will c o ns ult wit h a diet icia n, or 
e q ui vale nt q ualifie d dele gate, acc or di n g t o l ocal sta n dar ds, t o recei ve lifest yle ma na ge me nt 

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Protocol I8F-JE-GPHZ(b)
60
counseling at Weeks 0, 4, 8, and 12 during dose escalation and then at Week 24, 36, 48, 52, and 
60 through 72 weeks as defined in the Schedule of Activities (Section 1.3).
Diet and exercise goals (based on JASSO guidelines) established during the lifestyle 
management counseling 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
Per the Schedule of Activities (Section 1.3), study participants will receive diet counselling by a 
dietician/nutritionist, or equivalent qualified delegate, according to JASSO guidelines. Dietary 
counseling will consist of advice on healthy food choices and focus on calorie restriction using a 
hypocaloric diet with macronutrient composition of 

Approximately 50% to 60% of energy from carbohydrate

Approximately 15% to 20% of energy from protein

Approximately 20% to 25% of energy from fat, and

Daily energy intake up to 25 kCal/kg × standard body weight (as determined by 
BMI = 22 kg/m2) for the participant whose BMI is ≥27 kg/m2 and 20 to 25 kcal/kg 
× standard body weight for the participant whose BMI is ≥35 kg/m2.
To encourage adherence, it is recommended that a 3-day diet and exercise diary be completed 
prior to each counseling visit. During each visit, the participant’s diet is reviewed and advice to 
maximize adherence is provided if needed.
The recommended diet is continued after randomization and throughout the treatment period. 
Dietary evaluation and appetite sensation are described in Sections 8.1.2.9.5.1 and 8.1.2.9.5.2, 
respectively. 
5.3.2. Caffeine, Alcohol, and Tobacco for PK/PD Visits
1. During each dosing session at the site visit, participants will abstain from ingesting 
caffeine- or xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 
at least 10 hours before the start of dosing until after collection of the final PK and/or PD
sample.
2. During each dosing session at the site visit, participants will abstain from alcohol for 
24 hours before the start of dosing until after collection of the final PK and/or PD sample.
3. Participants who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the clinical 
unit. Use of tobacco products will be abstained for 8 hours before the start of dosing until 
after collection of the final laboratory sampling.
5.3.3. Physical Activity
Participants will abstain from strenuous exercise for 24 hours before each blood collection for 
clinical laboratory tests. Participants may participate in light recreational activities during onsite 
study procedures (e.g., watching television, reading).

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Protocol I8F-JE-GPHZ(b)
61
At Visit 3 and all subsequent visits, participants will be advised to increase their physical activity 
to at least 150 minutes per week. Please see Appendix 13 (Section 10.13) for detail guidance of 
physical activity.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to the study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure), will have 
an opportunity to have 1 additional screening visit with repeat screening laboratory tests at the 
discretion of the investigator. Before rescreening is performed, the patient must sign a new ICF 
and receive a new identification number. If, in the opinion of the investigator, an ineligible 
laboratory test result is the result of an error or extenuating circumstance, then that parameter can 
be retested once without the patient having to be rescreened.

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6. Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol.
6.1.
Study Intervention(s) Administered
ARM Name
Tirzepatide 10 mg
Tirzepatide 15 mg
Placebo
Dosage Level(s)
10 mg QW
15 mg QW
Placebo QW
Route of Administration
SC
SC
SC
Sourcing
Provided centrally by the sponsor and dispensed via IWRS  
Packaging and Labeling
Study Intervention will be provided in autoinjectors (single-dose pens), packaged in 
cartons to be dispensed. Clinical study materials will be labeled according to 
country regulatory requirements. 
Abbreviations: IWRS = interactive web response service; QW = once-weekly; SC = subcutaneous.
There are no restrictions on the time of day each weekly dose of study intervention is given, but 
it is advisable to administer the SC injections on the same day and same time each week. The 
actual date, time and injection site location of all dose administrations will be recorded in the 
diary by the participant. If a dose of study intervention is missed, the participant should take it as 
soon as possible unless it is within 72 hours of the next dose, in which case that dose should be 
skipped, and the next dose should be taken at the appropriate time. The day of weekly 
administration can be changed if necessary, as long as the last dose was administered 72 or more 
hours before.
All participants will inject study intervention subcutaneously in the abdomen or thigh using the 
injection supplies provided; a caregiver may administer the injection in the participant’s upper 
arm. The injection site location of all dose administrations will be recorded by the participant. A 
new autoinjector will be used for each injection. If study intervention is to always be injected in 
the same body region, participants should be advised to rotate injection sites each week.
6.1.1. Medical Devices
The product provided for use in the study is tirzepatide investigational autoinjector (or matching 
placebo). Any medical-device incidents, including those resulting from malfunctions of the 
device, must be detected, documented, and reported by the investigator throughout the study (see 
Section 10.9).
All product complaints (including malfunction, use error and inadequate labelling) shall be 
documented and reported by the investigator throughout the clinical investigation (see 
Section 8.3) and appropriately managed by the sponsor.

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Protocol I8F-JE-GPHZ(b)
63
6.2.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 

Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply 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 site staff.

Study site staff must regularly assess whether the participant is correctly administering the 
assigned study intervention and storing study drug according to the provided instructions

The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study interventions are 
provided in the study training documents. 
6.3.
Measures to Minimize Bias: Randomization and Blinding
Interactive web-response system
All participants will be randomly assigned to study intervention using a central interactive-web 
response system (IWRS) at the end of Visit 3 after participant’s eligibility is confirmed. Before 
the study is initiated, the log in information and directions for the IWRS will be provided to each 
site. Study intervention will be dispensed at the study visits summarized in the Schedule of 
Activities (Section 1.3). 
The randomization will be stratified by 

baseline IGT (yes or no) 

baseline hyperlipidemia (yes or no) 

baseline NAFLD (yes or no), and 

sex
Blind break
Investigators, site staff, clinical monitors and participants will remain blinded to the treatment 
assignments until the study is complete. 
The IWRS will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding a participant’s intervention 
assignment is warranted. Participant safety must always be the first consideration in making such 
a determination. If a participant’s intervention assignment is unblinded, the sponsor must be 
notified immediately after breaking the blind. The date and reason that the blind was broken 
must be recorded in the source documentation.

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Protocol I8F-JE-GPHZ(b)
64
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be discontinued from the study. In cases where there are ethical reasons to have 
the participant remain in the study, the investigator must obtain specific approval from a Lilly 
clinical research physician (CRP) and/or clinical research scientist (CRS) for the participant to 
continue in the study. 
6.4.
Study Intervention Compliance
Participant compliance with study intervention will be assessed at each visit. Compliance will be 
assessed by direct questioning, reviewing the study diary, and counting of unused study drug 
and/or empty cartons returned.
Treatment compliance for each visit interval is defined as taking at least 75% of the required 
doses of study drug. Similarly, a participant will be considered significantly noncompliant if he 
or she is judged by the investigator to have intentionally or repeatedly taken more than the 
prescribed amount of medication (more than 125%). 
Participants considered to be poorly compliant with their medication and/or the study procedures 
will receive additional training and instruction, as required, and will be reminded of the 
importance of complying with the protocol.
6.5.
Concomitant Therapy
Participants are permitted to use concomitant medications that they require during the study, with 
the exception of certain medications (for example; other medications for weight management) 
that may interfere with the assessment of efficacy and safety characteristics of the study 
treatments.
Any concomitant medications taken for obesity-related health problems on a stable dose for at 
least a period of 3 months prior to study entry will be permitted. Dosage change during the study 
will only be allowed if concerns for safety issue are identified.
Participants who develop DM during the study may initiate medication for glucose control, with 
the exception of dipeptidylpeptidase-4 (DPP-4) inhibitors or GLP-1 receptor agonists. Initiation 
of metformin for the treatment of DM is permitted, but metformin should not be initiated during 
the study for the treatment of other metabolic conditions (for example, polycystic ovarian 
syndrome, diabetes prevention).
Investigative site staff will inform participants that they must consult with the investigator or a 
designated site staff member upon being prescribed any new medications during the study. This 
may not be possible when initiated for treatment of medical emergencies, in which case, the 
participant will inform the investigator or a designated site staff member as soon as possible. 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with:

Reason for use

C O N FI D E N TI A L
Pr ot oc ol  I 8 F-J E-G P H Z( b)
6 5

Dates of a d mi nistrati o n i ncl u di n g start a n d e n d dates

D osa ge i nf or mati o n i ncl u di n g d ose a n d fre q ue nc y
T he m e dical mo ni t or s h o uld be c o ntacte d if t here are a n y  q uestio ns re gar di n g c o nc o mita nt or 
pri or t hera p y .
N o n -st u d y me dicat i ons ta ke n b y partici pa nts w h o are scree ne d b ut n ot ra n d o mize d will n ot be 
re p orte d t o Lill y u nless an S A E or A E occ urs t hat t he i n vest i gat or belie ves ma y ha ve bee n 
ca use d b y a st u d y pr oce d ure.
6. 6.
D o s e M o difi c ati o n
St u d y  dr u g d ose m o dificati on is n ot per mitte d, e xce pt f or ma na ge me nt of i nt olera ble GI 
s y m pt o ms (see Secti o n 6. 7. 1 ).
6. 7.
M a n a g e m e nt of In ci d e nt D i a b et e s
P arti cipa nts w h o de vel o p di a betes d uri n g t he st u d y will be
•
pr o vi de d a n d trai ne d t o use a gl uc o meter
•
e d ucate d o n t he si g ns a n d s y m pt o ms of h y p o gl yce mia a n d it s treat me nt, a n d
•
pr o vi de d a di ar y t o rec or d h yp o gl yce mic e pis o des per Secti o n 1 0. 4. 7. 1 .
P arti cipa nts will be referre d t o t heir us ual care pr o vi der a n d pr o vi d e d wi t h a letter s h o wi n g t he 
st u d y res ults i n dicati ve of dia betes. T he decisi on t o f urt her e val uate, t o i nitiate 
a nt i h y per gl yce mic t hera p y, a n d t he c h oice of a nti h y per gl yce mic me dicati on will be at t he 
di scretio n of  t he partici pa nt’s us ual care pr o vi der, wit h t he e xce pti o n of use of D P P -4 i n hi bit ors 
a n d G L P -1 R a g o nists, w hic h are pr o hi bite d i n t he st u d y . M o nit ori n g f or h yp o gl yce mia i ncl u des 
ca pt ure of e ve nts as defi ne d i n Sect i on 1 0. 4. 7. 1 . Date of dia g n osis of dia betes will be ca pt ure d i n 
t he electr o nic case re p ort f or m ( e C R F).
6. 7. 1.
M a n a g e m e nt of P arti ci p a nt s wit h G a str oi nt e sti n al S y m pt o m s
P arti cipa nts w h o e x peri e nce i nt olera ble GI s y m pt o ms (f or e xa m ple; na usea, v o mit i n g, or 
di arr hea) at a n y time d uri n g t he st u d y , s h o uld fi rst be c o u nselle d o n dietar y be ha viors t hat m a y 
hel p mit i gate na usea a n d v omit i n g, (f or e xa m ple, eati n g s maller meals, s plitti n g 3 dail y  meals 
i nto 4 or m ore s mall er o nes, a n d st o p pi n g eat i n g w he n t he y feel f ull). If s y m pt o ms persist, t he 
parti ci pa nt s h o uld be prescri be d, at t he i n vesti gat or’s discret i on, s y m pt o mat ic me dicat i on (f or 
e xa m ple, a ntie met ic or a nti diarr heal me dicati o n). 
Te m p or ar y i nterr u pti o n
A te m p orar y i nterr u ptio n of  st u d y i nter ve nt i on f or 1 d ose i s per mitte d, pr o vi de d t he partici pa nt 
has ta ke n t he last 3 wee kl y d oses. St u d y  treat me nt s h o uld be res u me d i m me diatel y, eit her al o ne 
or i n c o m bi nati o n wit h s y m pt o m atic me dicat i on, w hic h ca n als o be utilize d t o ma na ge 
s y m pt o ms.
Ma na ge me nt of  st ud y i nter ve nt i on after i nterr u ptio ns > 1 d ose i s disc usse d i n 
Secti o n 7 .

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66
Dose modification
If intolerable GI symptoms (for example, nausea, vomiting, or diarrhea) persist despite the above 
measures, the investigator should contact Lilly to consider reinitiating study intervention at the 
next lowest maintenance dose in a blinded fashion (for example, 15 mg and 12.5 mg reduced to 
10 mg, 10 mg or lower reduced to placebo). Only 1 dose reduction per participant will be 
permitted during the course of the study. The dose modification is not allowed without prior 
discussion with Lilly’s CRP and/or CRS. 
6.8.
Intervention after the End of the Study
Tirzepatide will not be made available to participants after conclusion of the study.

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7. Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for all planned efficacy and safety 
measurements. See the Schedule of Activities for data to be collected at the time of 
discontinuation of study intervention and follow-up and for any further evaluations that need to 
be completed.
Possible reasons leading to permanent discontinuation of IP:

participant decision
o
the participant requests to discontinue IP

clinical considerations
o
initiation of GLP-1R agonist or DPP-4 inhibitor, if participants will not or cannot 
discontinue them
o
intolerable GI symptoms despite management as described in Section 10.8
Note: If intolerable GI symptoms persist despite symptomatic treatment, temporary 
drug interruption, and resumption at a lower dose of study intervention, the participant 
should be discontinued from the study intervention. 
o
BMI ≤18.5 kg/m2 with clinically significant health condition is reached at any time 
during the treatment period 
Note: The investigator should contact the sponsor CRP and/or CRS to discuss whether 
it is medically appropriate for the participant to continue study treatment. 
o
diagnosis of type 1 diabetes mellitus
o
diagnosis of medullary thyroid cancer after randomization
o
significant elevation of calcitonin (Section 10.4.7.3) 
o
diagnosis of acute or chronic pancreatitis 
o
diagnosis of an active or untreated malignancy (other than basal or squamous cell 
skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) after 
randomization
o
development of any significant study intervention-related hypersensitivity reaction
o
onset of pregnancy in a female participant 
o
occurrence of any other treatment-emergent adverse event (TEAE), SAE, or clinically 
significant finding for which the investigator believes that permanent study
intervention discontinuation is the appropriate measure to be taken
o
inadvertent enrollment if continued treatment with study intervention would not be 
medically appropriate (Section 7.2.1)
o
PHQ-9 score ≥15 

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
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
in addition, study intervention may be discontinued if participants:

answered “yes” to either Question 4 (Active Suicidal Ideation with Some Intent 
to Act, Without Specific Plan) on the “Suicidal Ideation” portion of the C-SSRS
or

answered “yes” to Question 5 (Active Suicidal Ideation with Specific Plan and 
Intent) on the “Suicidal Ideation” portion of the C-SSRS 
or 

answered “yes” to any of the suicide-related behaviors (Actual attempt, 
Interrupted attempt, Aborted attempt, Preparatory act or behavior) on the 
“Suicidal Behavior” portion of the C-SSRS.
Note: A psychiatrist or appropriately trained professional may assist in the decision to 
discontinue the participant.

discontinuation due to a hepatic event or liver test abnormality
o
Participants who are discontinued from IP due to a hepatic event or liver test 
abnormality should have additional hepatic safety data collected via eCRF.
o
Discontinuation of the IP for abnormal liver tests should be considered by the 
investigator when a participant meets 1 of the following conditions after consultation 
with the Lilly designated medical monitor:

ALT or aspartate aminotransferase (AST) >8× ULN

ALT>2× baseline value OR ≥300 U/L, whichever occurs first, if baseline 
ALT≥2× ULN

ALT or AST >5× ULN for more than 2 weeks

ALT or AST >3× ULN and TBL >2× ULN or international normalized ratio 
(INR) >1.5 

ALT or AST >3× ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

ALP >3× ULN

ALP >2.5× ULN and TBL >2× ULN

ALP >2.5× ULN with the appearance of fatigue, nausea, vomiting, 
right-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
7.1.1. Temporary Study Drug Discontinuation
In certain situations, after randomization, the investigator may need to temporarily interrupt 
study drug. Every effort should be made by the investigator to maintain participants on study 
drug and to restart study drug after any temporary interruption, as soon as it is safe to do so. 
Distribution of study medication at the correct dose will be per IWRS instructions.

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If study drug interruption is…
then…
2 consecutive doses or less 
participant restarts study drug at last administered dose, as per escalation 
schedule.
3 consecutive doses or more 
participant restarts study drug (at 5 mg, managed by IWRS) and repeats 
dose escalation scheme.
due to an AE
the event is to be documented and followed according to the procedures in 
Section 8.3 of this protocol.
due to intolerable persistent GI AE
participants should be treated as suggested in Section 10.8.
Abbreviations: AE = adverse event; GI = gastrointestinal; IWRS = interactive web response service.
Investigators should inform Lilly that study drug has been temporarily interrupted. The data 
related to temporary interruption of study treatment will be documented in source documents and 
entered on the eCRF.
7.2.
Participant Discontinuation/Withdrawal from the Study
To minimize the amount of missing data and to enable assessment of study objectives as planned 
in the study protocol, every attempt will be made to keep participants in the study irrespective of 
the following:

adherence to or discontinuation from study drug

adherence to visit schedule

missing assessments

study drug discontinuation due to AE 

development of comorbidities

development of clinical outcomes
The circumstances listed above are not valid reasons for discontinuation from the study. 
Participants will be withdrawn from the study in the following circumstances: 

enrollment in any other clinical study involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study

participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and Good Clinical Practice (GCP)

participant requests to be withdrawn from the study and clearly indicates that there will 
be no further contact of any kind with the site
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.
A participant may withdraw from the study:
●
at any time at his/her own request 
●
at the request of his/her designee (for example, parents or legal guardian)

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●
at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons
●
if the participant becomes pregnant during the study
●
if enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study
●
if the participant, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent. 
Discontinuation is expected to be uncommon.
When discontinuing from the study prior to Visit 21 or Visit 99, an early discontinuation visit 
should be conducted if possible, as described in the Schedule of Activities. See Schedule of 
Activities for data to be collected at the time of study discontinuation and follow-up and for any 
further evaluations that need to be completed. The participant will be permanently discontinued 
both from the study intervention and from the study at that time.
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant
withdraws from the study, he/she may request destruction of any samples taken and not tested,
and the investigator must document this in the site study records.
Participants discontinuing from the study prematurely for any reason should complete AE and 
other safety follow-up per Section 1.3 (Schedule of Activities), Section 8.3 (Adverse Events and 
Serious Adverse Events), and Section 8.2 (Safety Assessments) of this protocol.
7.2.1. Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, then the participant should be discontinued from study treatment 
unless there are extenuating circumstances that make it medically necessary for the participant to 
continue on study treatment. If the investigator and the sponsor CRP and/or CRS agree it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
sponsor CRP and/or CRS to allow the inadvertently enrolled participant to continue in the study 
with or without treatment with investigational product. Safety follow-up should be performed as 
outlined in Section 1.3 (Schedule of Activities), Section 8.2 (Safety Assessments), and 
Section 8.3 (Adverse Events and Serious Adverse Events) of the protocol.
7.3.
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site.

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Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those 
who did not receive investigational product. Public sources may be searched for vital status 
information. If vital status is determined to be deceased, this will be documented and the 
participant will not be considered lost to follow-up.
Lilly personnel will not be involved in any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.9.

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8. Study Assessments and Procedures
●
Study procedures and their timing are summarized in the Schedule of Activities.
●
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 
Schedule of Activities, is essential and required for study conduct.
●
All screening evaluations must be completed and reviewed to confirm that
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.
8.1.
Efficacy Assessments
8.1.1. Primary Efficacy Assessments
The primary efficacy assessment in this study is body weight. Body weight measurements will 
be collected at specific clinic visits as summarized in the Schedule of Activities (Section 1.3). 
Participants will be weighed on an electronic scale in light clothing at approximately the same 
time after an overnight fast (or fast of at least 10 hours) and evacuation of any bowel and bladder 
contents (Appendix 11, Section 10.11). The scale’s performance will be monitored at least 
monthly using standard weights, and records of these assessments will be kept in the study 
binder. 
8.1.2. Secondary Efficacy Assessments
The following secondary efficacy assessments will be collected according to the Schedule of 
Activities (Section 1.3).
8.1.2.1.
Defined Obesity-Related Health Problems
The definition of improvements of defined obesity-related health problems are:

IGT (only for participants with IGT at baseline)
o
Return to normal blood glucose range

OGTT 0-hour glucose <110 mg/dL AND

OGTT 2-hour glucose <140 mg/dL

Hyperlipidemia (only for participants with hyper-triglyceridemia [triglyceride (TG)
≥150 mg/dL] at baseline)
o
Return to normal range (TG <150 mg/dL) OR
o
Reduced by 30% from baseline 

NAFLD (only for participants with diagnosis of NAFLD [HFF ≥5%] by MRI at 
baseline)
o
Return to normal range (HFF <5%) OR

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o
Reduced by 30% from baseline 
The assessments will include:

Proportion of participants who met the following criteria
o
improvement in at least 2 obesity-related health problems for participants with 
baseline BMI >27 and <35 kg/m2, or 
o
improvement in at least 1 obesity-related health problem for participants with 
baseline BMI >35 kg/m2

Proportion of participants who had improvement in IGT (only for participants with IGT 
at baseline)

Proportion of participants who had improvement in hyperlipidemia (only for participants
with hyper-triglyceridemia [TG ≥150 mg/dL] at baseline)

Proportion of participants who had improvement in NAFLD (only for participants with a 
diagnosis of NAFLD [HFF ≥5%] by MRI-PDFF at baseline and all tirzepatide dose 
combined)
8.1.2.2.
2-Hour Oral Glucose Tolerance Test
All participants attending Screening Visit 2 will undergo a 2-hour OGTT test as outlined in the 
Schedule of Activities (Section 1.3). These results, in combination with those obtained from 
Screening Visit 1 and 2, will be used to determine study eligibility and randomization glycemic 
status.
Definition of IGT from 2-hour OGTT results: fasting glucose or 0-hour OGTT = 110-125 mg/dL 
(6.1-6.9 mmol/L) and/or 2-hour OGTT = 140-199 mg/dL (7.8-11.0 mmol/L). 
8.1.2.3.
Hepatic Fat Fraction Determined from Magnetic Resonance Imaging
Hepatic fat fraction will be determined using MRI-PDFF. The fat fraction is the proportion of 
mobile protons in liver tissue attributable to fat and is a noninvasive MRI-based biomarker of 
liver triglyceride concentration. The participants who are diagnosed NAFLD by MRI can be 
enrolled ONLY at clinical sites which have MRI-PDFF availability and/or can obtain support 
from imaging sites for MRI-PDFF as outlined in the Schedule of Activities (Section 1.3). See 
Appendix 11 (Section 10.11). Even if someone has been previously diagnosed NAFLD, they 
cannot be considered as a NAFLD patient unless their NAFLD was defined by MRI
measurement. MRI images will be transmitted to a central reader for evaluation of the 
MRI-based efficacy endpoints.
8.1.2.4.
Body mass related parameters
8.1.2.4.1. Body Weight
Absolute body weight will be measured as described above (see Section 8.1.1). 
Body mass index (kg/m2) will be derived using body weight in kilograms divided by the square 
height in meters. 
Excess weight loss (%) will be derived using [(initial weight) – (current weight)]/[(initial weight) 
– (ideal weight)] x 100), with ideal weight considered as the weight corresponding to a 
BMI = 22 kg/m2.

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8.1.2.4.2. Measurement of Visceral Adipose Tissue (VAT), Subcutaneous Adipose 
Tissue (SAT), and VAT/SAT Ratio
Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) will be collected 
according to the Schedule of Activities (Section 1.3).
Single slice imaging will be performed at the umbilicus level in a supine position using 
computerized tomography (CT) or MRI scanner at each site. The assessments will include VAT, 
SAT, and VAT/SAT ratio and will be calculated using software. Measurements of the adipose 
area will be performed centrally. 
For patients participating in HFF analysis, MRI for visceral and subcutaneous assessments may 
be used by multiple slices acquisition during MRI, which will be captured in central vendor site 
acquisition manual and described in the imaging charter. For further comments, see Appendix 11
(Section 10.11).
8.1.2.4.3. Waist Circumference
Waist circumference will be collected according to the Schedule of Activities (Section 1.3). 
Waist circumference should be measured in the horizontal plane and at the umbilicus level 
according to JASSO guideline. For further comments, see Appendix 11 (Section 10.11).
8.1.2.5.
IGT related parameters
The following IGT related parameters will be collected according to the Schedule of Activities 
(Section 1.3).

Fasting glucose (mg/dL) (measured at central laboratory)

HbA1c (%) (measured at central laboratory)

Insulin (pmol/L) (measured at central laboratory)

C-peptide (ng/mL) (measured at central laboratory)

Homeostatic Model Assessment for Beta Cell and Insulin Sensitivity (HOMA2-%B and 
HOMA2-%S): Fasting glucose and insulin values will be used to calculate beta-cell 
function and insulin sensitivity using the updated Homeostasis Model Assessment 
(HOMA2) (Wallace et al. 2004). 
Fasting glucose samples must be obtained after 10 hours or more without eating, drinking 
(other than water) or performing any significant physical activity.
8.1.2.6.
Hyperlipidemia related parameters
The following hyperlipidemia related parameters will be collected according to the Schedule of 
Activities (Section 1.3).

Fasting lipids (measured at central laboratory)
o
TG, TC, VLDL-C, LDL-C (direct), HDL-C, non-HDL-C (mg/dL)
o
FFA (μEq/L)
8.1.2.7.
NAFLD related parameters
The following NAFLD related parameters will be collected during the study according to the 
Schedule of Activities (Section 1.3) and change from baseline will be analyzed. 

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75

NAFLD/nonalcoholic steatohepatitis (NASH) biomarkers 
o
ALT, AST, gamma-glutamyl transferase (GGT) (U/L) (measured and calculated 
by central laboratory)
o
AST/ALT ratio (measured and calculated by central laboratory)
o
K-18 (M30) (U/L) (measured at central laboratory)
o
Pro C3 (ng/mL) (measured at central laboratory)
o
Enhanced Liver Fibrosis score (ELF score = 2.278+0.851ln(CHA
[ng/mL])+0.751ln(CPIIINP [ng/mL])+ln(CTIMP-1 [ng/mL])). (Hyaluronic Acid, 
PIIINP and TIMP-1 measured and calculated by central laboratory) (Guha et al. 
2008)
o
Fibrosis-4 (FIB-4 index) (AST, ALT, and platelet), (measured and calculated by 
central laboratory)
8.1.2.8.
Other parameters
The following parameters will be collected according to the Schedule of Activities (Section 1.3).

Blood pressure (SBP/DBP) (mmHg)

Uric acid (mg/dL) (measured at central laboratory)
8.1.2.9.
Patient-Reported Outcomes Assessments
The self-reported questionnaires will be translated into Japanese, linguistically validated, and 
administered according to the Schedule of Activities (Section 1.3). At these visits, the 
questionnaires should be completed before the participant has discussed their medical condition 
or progress in the study with the investigator and/or site staff, if the participant is not adversely 
affected by their fasting condition.
8.1.2.9.1. Short-Form 36 Version 2, Acute, 1-Week Recall Version
The Short-Form Health Survey Version 2 (SF-36v2) acute, 1-week recall version is a 36-item, 
generic, patient-administered measure designed to assess the following 8 domains:

Physical functioning

Role-physical

Bodily pain

General health

Vitality

Social functioning

Role-emotional

Mental health
The Physical-Functioning domain assesses limitations due to health “now” while the remaining 
domains assess functioning “in the past week.” Each domain is scored individually and 
information from these 8 domains are further aggregated into 2 health-component summary 
scores: Physical-Component Summary and Mental-Component Summary. Items are answered on 
Likert scales of varying lengths (3-, 5-, or 6-point scales). Scoring of each domain and both 
summary scores are norm-based and presented in the form of T-scores, with a mean of 50 and 

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standard deviation (SD) of 10; higher scores indicate better levels of function and/or better health 
(Maruish 2011).
8.1.2.9.2. Impact of Weight on Quality of Life-Lite Clinical Trials Version
The Impact of Weight on Quality of Life-Lite Clinical Trials version (IWQOL-Lite-CT) is a 
20-item, obesity-specific patient-reported outcome instrument developed for use in obesity 
clinical trials. It assesses 2 primary domains of obesity-related health-related quality of life:
physical (7 items), and psychosocial (13 items). A 5-item subset of the physical domain, the 
physical-function composite, is also supported. Items in the physical-function composite describe 
physical impacts related to general and specific physical activities. All items are rated on either a 
5-point frequency (“never” to “always”) scale or a 5-point truth (“not at all true” to “completely 
true”) scale (Kolotkin et al. 2017, 2018).
8.1.2.9.3. EQ-5D-5L
Generic health-related quality of life will be assessed using the EuroQol – 5 Dimension – 5 Level
(EQ-5D-5L) (EuroQoL Group 2015). The EQ-5D-5L is a standardized 5-item instrument for use 
as a measure of health outcome. It provides a simple descriptive profile and a single index value 
for health status that can be used in the clinical and economic evaluation of health care as well as 
population health surveys. The EQ-5D-5L comprises 5 dimensions of health (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression). The 5L version, introduced in 2005, 
scores each dimension at 5 levels (no problems, slight problems, moderate problems, severe 
problems, unable to perform/extreme problems), for a total of 3125 possible health states. In 
addition to the health profile, a single health state index value can be derived based on a formula 
that attaches weights to each of the levels in each dimension. This index value ranges between 
˂0 (where 0 is a health state equivalent to death; negative values are valued as worse than dead) 
to 1 (perfect health) (Dolan 1997). In addition, the EQ visual analog scale (VAS) records the 
respondent’s self-rated health status on a vertical graduated (0 to 100) scale. In conjunction with 
the health state data, it provides a composite picture of the respondent’s health status. The 
EQ-5D-5L is used worldwide and is available in more than 170 different languages. Details on 
the instrument, and scoring, organizing, and presenting the data collected will follow C2H 
guidelines (Ikeda et al. 2015; C2H 2019).
8.1.2.9.4. Patient Global Impression of Status for Physical Activity
Study participants will be asked to complete a PGIS item specifically developed for this study. 
This is a patient-rated assessment of current health limitation and is rated on a 5-point scale 
ranging from “1- not at all limited” to “5- extremely limited.”
8.1.2.9.5. Dietary Evaluation
All participants fulfilling inclusion criteria will be asked to collect their meal record and appetite 
sensation. These records will be collected only from patients who additionally agree to 
participate in taking these measurements.
8.1.2.9.5.1.
Meal Intake
Meal record will be collected before each meal (including breakfast, lunch, dinner, and snacks)
for a day. In case if patients cannot finish them all, meal records after the meal will be collected. 

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Meal records will be collected on 3 consecutive or non-consecutive days during the week (at 
least 1 day should be working day and at least 1 day should be resting day) immediately before 
the visits: Visit 3 (Week 0), Visit 9 (Week 24), Visit 16 (Week 52), and Visit 21 (Week 72). The
Lilly-designated vendor will calculate the volume of total fats, total carbohydrates, total protein, 
and total caloric intake based on the meal record.
8.1.2.9.5.2.
Appetite Sensation
The subjective rating of appetite sensations is measured by a 100-mm VAS for parameters of 
hunger, fullness, satiety, and prospective food consumption including snacks. The meal record
will be collected on 3 consecutive or non-consecutive days during the week (at least 1 day should 
be working day and at least 1 day should be resting day) immediately before the visits: Visit 3 
(Week 0), Visit 9 (Week 24), Visit 16 (Week 52), and Visit 21 (Week 72). For each meal, 
including breakfast, lunch, dinner and snacks, participant should complete the VAS 10 minutes 
before the meal and immediately after the meal. The timing of the record should be on the same 
date as the meal intake record. In case of frequent snacking on each recording day, if a 
participant consumes several snacks a day, they will be asked to complete the meal intake record 
for all snacks, but will only be required to complete VAS measurement for the first afternoon
snack. The VAS is a validated tool to assess appetite sensation parameters (Flint et al. 2000). The 
VAS is presented as a 10-cm (100-mm) line, anchored by verbal descriptors, usually “extremely” 
and “not at all.” Participants are required to rate their subjective sensations on four 100-mm 
scales combined with the questions:

“How hungry do you feel right now?”

“How satisfied do you feel right now?”

“How full do you feel right now?”

“How much food do you think you could eat right now?”
A staff member will use a caliper to measure the distance from 0 to the mark that the participant
placed on the VAS and record the measurement in the source document.
Overall appetite score is calculated as the average of the 4 individual scores (van Can et al. 2014) 
below:
[Satiety] + [Fullness] + {(100 – [Prospective food consumption]) + (100 – [Hunger])} / 4.
The higher overall appetite score indicates less appetite, and the lower score indicates more 
appetite.
8.1.3. Exploratory Efficacy Assessments
The following exploratory assessment will be collected at the times shown in the Schedule of 
Activities (Section 1.3). 

C O N FI D E N TI A L
Pr ot oc ol  I 8 F-J E-G P H Z( b)
7 8
O besit y -rel ate d he alt h pr o ble ms

Pr o p orti o n of  p artici pa nts w h o ac hie ve d t he f o ll owi n g i m pr o ve me nts of o besit y- relate d 
healt h pr o bl e ms at 7 2 wee ks re gar dless of B MI at baseli ne;
o
A c hie ve d i mpr o ve me nt i n ≥2 o besit y- relate d health pr o bl e ms f or partici pa nts wit h 
baseli ne B MI ≥2 7 a n d < 3 5 k g/ m 2
o
Ac hie ve d i m pr o ve me nt i n ≥1 o besit y- relate d health pr o bl e ms f or partici pa nts wit h 
baseli ne B MI ≥3 5 k g/ m 2
o
Ac hie ve d 2 or 3 i m pr o ve me nts ( o nl y f or partici pa nts wit h 3 defi ne d o besit y- relate d 
healt h pr o bl e ms) re gar dless of B MI at baseli ne
o
Ac hie ve d 2 i m pr o ve me nts ( o nl y f or partici pa nts with 2 defi ne d o besit y- relate d health 
pr o bl e ms re gar dless of B MI at baseli ne)
o
Ac hie ve d 1 i m pr o ve me nt ( o nl y f or partici pa nts wit h 1 defi ne d o besit y- relate d health 
pr o bl e m re gar dless of B MI at baseli ne)
Ot her p ar a meters

A d i p o necti n ( μ g/ m L) ( b ot h hi g h m olec ular wei g ht a n d t otal adi p o nect i n, meas ure d at 
ce ntral la b orat or y)

Le pt i n ( p g/ m L) ( meas ure d at ce ntral la borat or y )

hi g h -se nsitivit y C- reacti ve pr otei n (hs C R P ) ( n g/ d L) ( meas ure d at ce ntral la borat or y )

T N F -α ( p g/ m L) ( meas ure d at ce ntral la borat or y )

e G F R ( m L/ mi n/ 1. 7 3 c m 2) (creati ni ne meas ure d at ce ntral la b orat or y) calc ulate d usi n g t he 
Ja pa nese S ociety of  N e p hr olo g y  for m ula: 1 9 4 × Cr 1. 0 9 4 × A ge 0. 2 8 7 [if fe male; × 
0. 7 3 9]

Uri nar y  al b u mi n/creati ni ne rati o ( m g/ g Cre) ( meas ure d at ce ntral la b orat or y)
I nci de nt Di a betes

Ti me t o o nset of T 2 D M d uri n g t he 7 2- wee k treat me nt peri o d
o
Defi nit i on a n d Ma na ge me nt of I nci de nt Dia betes 
Defi nit i on o f i nci de nt dia betes
I nci de nt dia betes is f oll owe d b y  Ja pa nese Cli nical Practice G ui deli ne f or Dia betes 
2 0 1 9 ( Ara ki et al. 2 0 2 0 ) a n d defi ne d w he n a n y 1 of t he f oll owi n g occ ur after 
ra n d omizat i on:
•
u ne q ui v ocal h y per gl yce mia (ra n d o m gl uc ose ≥2 0 0 m g/ d L) wit h si g ns or 
s y m pt o ms of h y per gl yce mia (e. g., dr y mo ut h, p ol y p osia, p ol y uria, b o d y  
w ei g ht l oss, or dia bet ic reti n o pat h y).
•
wi t hi n a 4-wee k peri o d, t he f o ll owi n g la b orat or y  e vi de nce of dia bet ic ty pe 
criteria i ncl u di n g eit her H b A 1c ≥6. 5 %, or gl uc ose le vels (fast i n g gl uc ose or 
O G T T 0- h o ur gl uc ose ≥1 2 6 m g/ d L a n d/ or O G T T 2- h o ur gl uc ose 
≥2 0 0 m g/ d L) are o bser ve d:
i.
B ot h gl uc ose l e vel a n d H b A 1c meets di a b etic t ype criteria

C O N FI D E N TI A L
Pr ot oc ol  I 8 F-J E-G P H Z( b)
7 9
ii.
O nl y gl uc ose le vel meets dia betic t y pe crit eria
-
Wit h t y pi c al  s y m pt o ms of D M or defi nite dia betic reti n o pat h y
-
Wit h o ut t y pical s y m pt o m s of D M or defi nite dia betic reti n o pat h y, 
r e-e xa m wit hi n 1 m o nt h a n d: 

B ot h gl uc ose l e vel a n d H b A 1c meets di a b etic t ype criteria

O nl y gl uc ose le vel meets dia betic t y pe crit eria

O nl y H b A 1c me ets dia bet ic t y pe crit eria
iii.
O nl y H b A 1c me ets dia bet ic t y pe crit eria, r e-e xa m wit hi n 1 m o nt h a n d
-
B ot h gl uc ose l e vel a n d H b A 1c meet di a bet ic t y pe criteria
-
O nl y gl uc ose le vel meets dia betic t y pe crit eria
•
i nitiati on of a n y me dicat i on f or t he treat me nt of dia betes
8. 2.
S af et y A s s e s s m e nt s
Pl a n ne d ti me p o i nts f or all safety assess me nts are pr o vi de d i n t he Sc he d ule o f Act i vities 
( Sectio n 1. 3 ).
8. 2. 1.
P h y si c al E x a mi n ati o n s
●
A c o m p lete p h ysical e xa mi nat i on will i ncl u de, at a mi ni m u m, assess me nts of t he 
car dio vasc ular, res pirat or y, GI , a n d n e ur olo gi cal s yste ms, as well as a t h yr oid 
e xa m. H eig ht , wei g ht , a n d waist circ u mfere nce will als o be meas ure d a n d 
rec or de d, per A p pe n di x 1 1 ( Secti o n 1 0. 1 1 ).
●
I n vesti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us 
serio us ill nesses.
8. 2. 2.
Vit al Si g n s
F or eac h parti ci pa nt, vit al si gns m eas ure me nts s h o uld be c o n d ucte d acc or di n g t o t he 
Sc he d ule of Act i vities ( Secti o n 1. 3 ) a n d A p pe n di x 1 1 ( Secti o n 1 0. 1 1 ).
Vi t al si g n meas ure me nts s h o uld be ta ke n bef ore o btai ni n g a n electr ocar dio gr a m  (E C G )
traci n g a n d bef ore c ollecti on of bl o o d sa m ples f or la b orat or y  testi n g, at visits w here 
re q uire d (see Secti o n 1. 3 ). T he partici pa nt s h o ul d be re q uire d t o sit q uiet l y f or 5 mi n utes 
bef ore vital si g n meas ure me nts are ta ke n. A n a p pr o priatel y size d c uff (c uff bla d der
e ncircli n g at least 8 0 % of t he ar m) s h o ul d be use d t o e ns ure t he acc urac y o f bl o o d 
press ure meas ure me nts (syst olic a n d diast olic bl o o d press ures [m m H g ]).
8. 2. 3.
El e ctr o c ar di o gr a m s
F or eac h partici pa nt, 1 2 -Lea d E C Gs s h o ul d be c ollecte d acc or di n g t o t he Sc he d ule of Acti vit ies 
( Sectio n 1. 3 ) a n d A p pe n di x 1 1 ( Secti o n 1 0. 1 1 ). 
Electr ocar di o gra ms will i nit iall y be i nter prete d b y a q ualifie d p h ysicia n (t he i n vesti gat or or 
q ualifie d desi g nee) at t he site as s o o n after t he ti me of E C G c ollecti o n as p ossi ble, a n d i dea ll y 
w hile t he partici pa nt is still prese nt, f or i m me diate parti ci pa nt ma na ge me nt, s h o ul d a n y  cli nicall y 
r ele va nt fi n di n gs be i de ntifie d. A n y cli nicall y  si g nifica nt fi n di n gs fr o m E C Gs t hat res ult i n a 

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diagnosis and that occur after signing of the ICF should be reported to Lilly or its designee as an 
AE via the eCRF. 
All digital ECGs will be obtained using centrally provided ECG machines and will be 
electronically transmitted to a designated central ECG laboratory. The central ECG laboratory 
will perform a basic quality control check (for example, demographics and study details) and 
then store the ECGs in a database. At a future time, the stored ECG data may be overread by a 
cardiologist at the central ECG laboratory for further evaluation of machine-read measurements 
or to meet regulatory requirements. The machine-read ECG intervals and heart rate may be used 
for data analysis and report-writing purposes, unless a cardiologist overreading of the ECGs is 
conducted prior to completion of the final study report (in which case, the overread data would 
be used).
8.2.4. Clinical Safety Laboratory Assessments
●
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be 
performed and the Schedule of Activities (Section 1.3) 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 Source 
Document Agreement or comparable document cites an electronic location that 
accommodates the expected retention duration. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, 
unless judged by the investigator to be more severe than expected for the 
participant’s condition.
●
All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or 4 weeks after the last dose of study 
intervention 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/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
(Section 10.2), must be conducted in accordance with the standard collection 
requirements, and laboratory manual and the Schedule of Activities
(Section 1.3).

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 
(e.g., SAE or AE or dose modification), then the results must be recorded in the 
CRF.

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Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. Unless otherwise stated in the subsections below, all samples collected for specified 
laboratory tests will be destroyed within 60 days of receipt of confirmed test results. Certain 
samples may be retained for a longer period, if necessary, to comply with applicable laws, 
regulations, or laboratory certification standards.
8.2.4.1.
Hepatic Safety Monitoring
8.2.4.1.1. Close Hepatic Monitoring
Laboratory tests (Appendix 3 [Section 10.3]), including ALT, AST, ALP, TBL, direct bilirubin, 
GGT, and creatine kinase, should be repeated within 48 to 72 hours to confirm the abnormality 
and to determine if it is increasing or decreasing, if 1 or more of these conditions occur: 
If a participant with baseline results of …
develops the following elevations:
ALT or AST <1.5× ULN
ALT or AST ≥3× ULN
ALP <1.5× ULN
ALP ≥2× ULN
TBL <1.5× ULN
TBL ≥2× ULN (except for participants with Gilbert’s syndrome)
ALT or AST ≥1.5× ULN
ALT or AST ≥2× baseline
ALP ≥1.5× ULN
ALP ≥2× baseline
TBL ≥1.5× ULN
TBL ≥2× baseline (except for participants with Gilbert’s syndrome)
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal.
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include 

physical examination and a thorough medical history, including 
o
symptoms, and
o
recent illnesses, for example, heart failure, systemic infection, hypotension, or 
seizures 

recent travel 

history of concomitant medications including 
o
over-the-counter, and
o
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. 

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8.2.4.1.2. Comprehensive Hepatic Evaluation
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions occur:
If a participant with baseline results of…
develops the following elevations:
ALT or AST <1.5× ULN
ALT or AST ≥3× ULN with hepatic signs/symptoms*, or 
ALT or AST ≥5× ULN
ALP <1.5× ULN
ALP ≥3× ULN
TBL <1.5× ULN
TBL ≥2× ULN (except for participants with Gilbert’s syndrome)
ALT or AST ≥1.5× ULN
ALT or AST ≥2× baseline with hepatic signs/symptoms*, or
ALT or AST ≥3× baseline
ALP ≥1.5× ULN
ALP ≥2× baseline
TBL ≥1.5× ULN
TBL ≥1.5× baseline (except for participants with Gilbert’s syndrome) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal.
* Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%.
At a minimum, this evaluation should include 

physical examination 

a thorough medical history, as outlined above 

tests for prothrombin time, INR (PT-INR)

tests for viral hepatitis A, B, C, or E

tests for autoimmune hepatitis, and 

an abdominal imaging study, for example, ultrasound or CT scan.
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for 

hepatitis D virus 

cytomegalovirus 

Epstein-Barr virus 

acetaminophen levels 

acetaminophen protein adducts 

urine toxicology screen 

Wilson’s disease 

blood alcohol levels 

urinary ethyl glucuronide, and 

serum phosphatidylethanol. 
Based on the circumstances and the investigator’s assessment of the participant’s clinical 
condition, the investigator should consider referring the participant for 

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
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 ≥5× ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5× ULN)
In participants with baseline ALT ≥1.5× ULN, the threshold is ALT ≥3× baseline 
on 2 or more consecutive tests
2. Elevated TBL to ≥2× ULN (if baseline TBL <1.5× ULN) (except for cases of known 
Gilbert’s syndrome)
In participants with baseline TBL ≥1.5× ULN, the threshold should be 
TBL ≥2× baseline
3. Elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5× ULN)
In participants with baseline ALP ≥1.5× ULN, the threshold is ALP ≥2× 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. 
8.2.5. Depression, Suicidal Ideation and Behavior Risk Monitoring
Overweight and obese patients are at increased risk for depression (Luppino et al. 2010). 
Depression can increase the risk for suicidal ideation and behavior. Therefore, study participants 
will be screened at trial entry and monitored during the study for depression, and suicidal 
ideation and behavior. 
Participants should be monitored appropriately and observed closely for suicidal ideation and 
behavior or any other unusual changes in behavior, especially at the beginning and end of the 
course of treatment, or at the time of dose changes, either increases or decreases. Consideration 
should be given to discontinuing study medication in subjects who experience signs of suicidal 
ideation or behavior, following a risk assessment (Section 10.4.7.12). 
Baseline and treatment-emergent assessment of depression, suicidal ideation and behavior will 
be monitored during the study using the C-SSRS and PHQ-9 (Section 10.4.7.12).

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8.2.6. Special Safety Topics
Adverse events of special interest (AESIs) are AEs which the sponsor specifies as being of 
special interest based on standard drug registration topics, safety findings from previous studies 
in development program, potential risks associated with GLP-1 receptor agonists as noted in 
product labels and published literature, and comorbidities and risk factors prevalent in the 
studied populations.
AESIs for this program include:
a)
severe hypoglycemia
b)
pancreatitis (adjudicated)
c)
thyroid malignancies and C-cell hyperplasias
d)
major adverse cardiovascular events (adjudicated); includes, but not limited to 
cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization 
for heart failure
e)
supraventricular arrhythmias and cardiac conduction disorders
f)
hypersensitivity events
g)
injection site reactions
h)
allergic/hypersensitivity reactions; includes injection site reactions and antidrug 
antibody (ADA) formation
i)
hepatobiliary disorders
j)
severe GI AEs
k)
acute renal events
l)
depression, suicidal ideation, or behavior
If “a” to “l” above are reported, sites will be prompted to collect additional details/data.
Please see Appendix 4 (Section 10.4), for detailed information.
8.3.
Adverse Events, Serious Adverse Events, and Product 
Complaints
The definitions of the following events can be found in Appendix 4 (Section 10.4). 

AEs

SAEs

product complaints (PCs)
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention, study device or device constituent, or 
study procedures, or that caused the participant to discontinue the study intervention (see 
Section 7).

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The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the study 
intervention or the study, or that caused the participant to discontinue the study intervention
before completing the study. The participant should be followed until the event resolves, 
stabilizes with appropriate diagnostic evaluation, or is reasonably explained. The frequency of 
follow-up evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed, study site personnel will record via eCRF the occurrence and nature of 
each participant’s preexisting conditions, including clinically significant signs and symptoms of 
the disease under treatment in the study. In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs. Investigators should record their assessment of the 
potential relatedness of each AE to protocol procedure and study intervention via eCRF. 
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the IP, 
study device, and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a participant’s study intervention is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF, clarifying if possible, the circumstances 
leading to any dosage modifications or discontinuations of treatment.
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences.
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs, and AEs of special interest (as defined in Section 9.4.4.3), 
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 (Section 10.10).

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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
the follow-up 
visit
As soon as possible 
upon site awareness
AE eCRF
N/A
Serious Adverse Event
SAE and SAE 
updates – prior 
to start of study 
intervention and
deemed 
reasonably 
possibly related 
with study 
procedures
signing of 
the ICF
start of 
intervention
Within 24 hours of 
awareness
eCRF
SAE paper 
form
SAE* and SAE 
updates
start of 
intervention
participation 
in study has 
ended
Within 24 hours of 
awareness
eCRF
SAE paper 
form
SAE* – after 
participant’s 
study 
participation has 
ended and the 
investigator 
becomes aware
After 
participant’s 
study 
participation 
has ended
N/A
Promptly
SAE paper form
N/A
Pregnancy
Pregnancy in 
female 
participants and 
female partners 
of male 
participants
After the 
start of study 
intervention
3 months 
after the last 
dose of study 
drug
Within 24 hours of 
learning of the 
pregnancy
eCRF
SAE paper 
form
Product Complaints
PC associated 
with an SAE or 
might have led 
to an SAE
Start of study 
intervention
End of study 
intervention
Within 24 hours of 
awareness
Product Complaint 
Form
N/A

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Event
Collection 
Start
Collection 
Stop
Timing for Reporting 
to Sponsor or 
Designee
Mechanism for 
Reporting
Back-Up 
Method of 
Reporting
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
N/A
Abbreviations: AE = adverse event; eCRF = electronic case report form; ICF = informed consent form; N/A = not 
applicable; PC = product complaint; SAE = serious adverse event.
8.3.2. Medical Device Incidents (Including Malfunctions)
Medical devices are being used in this study for the purposes of administering tirzepatide. In 
order to fulfill regulatory reporting obligations worldwide, the investigator is responsible for the 
detection and documentation of events meeting the definitions of incident or malfunction that 
occur during the study with such devices.
The definition of a medical device incident can be found in Section 10.9 (Appendix 9).
Note: Incidents fulfilling the definition of an AE/SAE will also follow the processes outlined in 
Section 8.3.1.
8.3.2.1.
Time Period for Detecting Medical Device Incidents

Medical device incidents, or malfunctions of the device that result in an incident, will 
be detected, documented, and reported to the sponsor during all periods of the study 
in which the medical device is used.

If the investigator learns of any incident at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to a 
medical device used during the study, the investigator will promptly notify the 
sponsor through the complaints process.
The method of documenting medical device incidents is provided in Section 10.9 (Appendix 9).

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8.3.2.2.
Follow-Up of Medical Device Incidents

All medical device incidents involving an AE will be followed and reported in the 
same manner as other AEs (see Section 8.3.1). This applies to all participants, 
including those who discontinue study intervention.

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident.

New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator.
8.3.2.3.
Prompt Reporting of Medical Device Incidents and Malfunctions to 
Sponsor

Medical device incidents or malfunctions will be reported to the sponsor within a 
business day or as determined for the study, after the investigator determines that the 
event or issue meets the protocol definition of a medical device incident or 
malfunction.

Medical device incidents or malfunctions that result in an SAE will be reported to the 
sponsor within 24 hours, in the same manner as other SAEs. 

Malfunctions will be reported via the Product Complaint Form and sent to the 
sponsor per training and per instructions provided on the Product Complaint Form.

The same individual at the site will be the contact for the receipt of medical device 
reports and SAEs.
8.3.2.4.
Regulatory Reporting Requirements for Medical Device Incidents

The investigator will promptly report to the sponsor all incidents occurring with any 
medical device provided for use in the study in order for the sponsor to fulfill the 
legal responsibility to notify appropriate regulatory authorities and other entities 
about certain safety information relating to medical devices being used in clinical 
studies.

The investigator, or responsible person according to local requirements (for example; 
the head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC).
8.3.3. Pregnancy
Pregnancy (maternal or paternal exposure to study intervention) does not meet the definition of 
an AE. However, to fulfill regulatory requirements, any pregnancy should be reported following 
the SAE reporting process to collect data on the outcome for both mother and fetus.
●
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
●
Report Timing is provided in Section 8.3.1.

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8.4.
Treatment of Overdose
Study drug overdose (more than the specified number of injections) will be reported as an AE. In 
the event of overdose, refer to the Investigator’s Brochure for tirzepatide.
8.5.
Pharmacokinetics
Pharmacokinetic samples should be collected prior to the dose administration and at the same 
time as the immunogenicity sample. Population PK and PD parameters may be derived. 
Relationship between tirzepatide exposure and safety, tolerability and efficacy measures may be 
explored.
8.6.
Pharmacodynamics
The area under the curve from 0 to 2 hours (AUC[0-2h]) for glucose and insulin during an 
OGTT will be calculated using the trapezoidal rule. The AUC(0-2h) as well as other derived 
parameters or observed concentration at specific time points for each participant on the study day 
will also be baseline-adjusted. The concentrations on Day -1 will be used as baseline.
8.7.
Genetics
A whole blood sample will be collected for pharmacogenetic analysis as specified in the 
Schedule of Activities (Section 1.3) where local regulations allow. 
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future. Samples will be used to investigate variable response to tirzepatide and to 
investigate genetic variants thought to play a role in obesity. Assessment of variable response 
may include evaluation of AEs or differences in efficacy.
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the investigator site personnel. 
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and/or 
ethical review boards (ERBs)/IRBs impose shorter time limits. This retention period enables use 
of new technologies, response to regulatory questions, and investigation of variable response that 
may not be observed until later in the development of tirzepatide or after tirzepatide becomes 
commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named. However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, and candidate gene studies. Regardless of 
technology utilized, genotyping data generated will be used only for the specific research scope 
described in this section.
8.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of participant response (including safety), and 

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clinical outcome. Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including deoxyribonucleic acid (DNA), 
proteins, lipids, and other cellular elements. 
Serum, whole blood, and plasma samples for biomarker research will be collected at the times 
specified in the Schedule of Activities (Section 1.3) where local regulations allow. 
Samples will be used for research on the drug target, disease process, variable response to 
tirzepatide, pathways associated with obesity, mechanism of action of tirzepatide, and/or 
research method or in validating diagnostic tools or assay(s) related to obesity. 
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the investigator site personnel. 
Samples will be retained at a facility selected by Lilly or its designee for a maximum 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and 
ERBs/IRBs impose shorter time limits. This retention period enables use of new technologies, 
response to regulatory questions, and investigation of variable response that may not be observed 
until later in the development of tirzepatide or after tirzepatide become(s) commercially 
available. 
8.9.
Immunogenicity Assessments
At the visits and times specified in the Schedule of Activities (Section 1.3), venous 
blood samples will be collected to determine antibody production against tirzepatide. 
To interpret immunogenicity results, a venous blood sample will be collected at the same time 
points to determine the blood concentration of tirzepatide. All samples for immunogenicity 
should be taken predose when applicable and possible. The actual date and time (24-hour clock 
time) of each sampling will be recorded. Immunogenicity will be assessed by a validated assay 
designed to detect ADAs in the presence of tirzepatide at a laboratory approved by the sponsor. 
Antibodies may be further characterized for cross-reactive binding to endogenous counterparts,
and their ability to neutralize the activity of tirzepatide or endogenous counterparts. Sample 
collected at Visit 801 will assess immunogenicity at washout of tirzepatide (5 half-lives post end 
of treatment).
Treatment-emergent ADAs are defined in Section 9.4.5. 
Long-term sample retention is defined in Section 10.1.11.
8.10. Health Economics and Medical Resource Utilization
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study.

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9. Statistical Considerations
9.1.
Statistical Hypotheses
The alternative hypotheses for the primary objective are the following: 

H10: QW tirzepatide 10 mg is superior to placebo for percent change in body weight 
from randomization AND percentage of participants who achieve ≥5% body weight
reduction at 72 weeks.

H15: QW tirzepatide 15 mg is superior to placebo for percent change in body weight 
from randomization AND percentage of participants who achieve ≥5% body weight 
reduction at 72 weeks. 
The above 2 hypotheses will be tested in parallel, each at a 2-sided significance level of 0.025.
9.2.
Sample Size Determination
Approximately, 348 participants will be screened to achieve 261 randomly assigned to study 
intervention (approximately 87 participants per intervention group). 
The sample size determination assumes that evaluation of superiority of tirzepatide 10 mg and 
tirzepatide 15 mg to placebo will be conducted in parallel, each at a 2-sided significance level of 
0.025 using a 2-sample t-test. Additionally, a difference of at least 11% mean body weight 
percentage reduction from randomization at 72 weeks for tirzepatide 10 mg and/or tirzepatide 
15 mg compared with placebo, a common SD of 10%, and a dropout rate of 25% are assumed for 
statistical power calculations. Under the assumptions above, randomizing 261 participants in a 
1:1:1 ratio to tirzepatide 10 mg, tirzepatide 15 mg, and placebo provides more than 90% power 
to demonstrate superiority of each tirzepatide dose to placebo. 
The chosen sample size and randomization ratio also provides >90% power to establish 
superiority of tirzepatide 10-mg and/or tirzepatide 15-mg doses to placebo in terms of proportion 
of participants achieving at least 5% body weight reduction at 72 weeks, conducted in parallel 
using a Fisher’s exact test, each at a 2-sided significance level of 0.025, assuming 25% of 
placebo-treated participants and 90% of tirzepatide-treated participants achieve the goal and a 
dropout rate of 25%. 

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

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Kaplan-Meier method will be used for estimation of cumulative event-free survival rates over 
time, and Cox proportional hazards regression analysis will be used to compare hazard rates 
among treatments.
Summary statistics for categorical measures (including categorized continuous measures) will 
include sample size, frequency, and percentages. Logistic regression will be used to examine the 
treatment difference in binary efficacy outcomes if there is a need to adjust for covariates. 
Otherwise, Fisher’s exact test will be used to examine the treatment difference in categorical 
outcomes. 
Summary statistics for discrete count measures will include sample size, mean, SD, median, 
minimum, and maximum. The negative binomial regression model will be used for the treatment 
comparison of discrete count measures. 
Other statistical methods may be used, as appropriate, and details will be described in the SAP.
9.4.2. Treatment Group Comparability
9.4.2.1.
Participant Disposition
A detailed description of participant disposition will be provided at the end of the study. 
Frequency counts and percentages of all participants screened, randomized, and receiving at least 
1 dose of study drug will be presented by treatment groups. Of the participants in the mITT set,
frequency counts and percentages of participants who completed the study, prematurely 
discontinued the study (and/or study drug), including reason for premature discontinuation, will 
be presented by treatment groups. 
A Kaplan-Meier analysis of the following time periods by treatment group will be provided
•
time from randomization to premature discontinuation from study, and
•
time from randomization to premature discontinuation from study treatment.
9.4.2.2.
Participant Characteristics
Demographics and other baseline characteristics related to obesity disease including 
comorbidities of 11 obesity-related health problems defined by JASSO guidelines in 
Appendix 13 (Section 10.13), socioeconomic status (such as employment status and length of 
education), and day life environment (such as marital and living status) will be summarized by 
treatment group for all randomized participants.
9.4.2.3.
Concomitant Therapy
Concomitant medications, including previous therapy, will be summarized by treatment arm for 
SS. 
9.4.2.4.
Treatment Compliance
Frequency counts and percentages of participants compliant to study drug will be summarized by 
treatment groups and visits for FAS.

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9.4.3. Efficacy Analyses
9.4.3.1.
Primary Analyses
The primary efficacy analysis will be guided by the “efficacy” estimand, which represents 
efficacy prior to discontinuation of study drug under missing at random assumption. The efficacy 
analyses will be conducted using the EAS. The primary analysis model will be a MMRM for 
body weight percentage change over time and longitudinal logistic regression for proportion of 
participants achieving at least 5% body weight reduction over time. The response variable of 
MMRM will be the percent change in body weight from baseline values obtained at each 
scheduled postbaseline visit. The response variable of longitudinal logistic regression will be the 
achievement of at least 5% body weight reduction at each scheduled postbaseline visit. The 
independent variables of both analysis models are treatment group (tirzepatide 10 mg, tirzepatide 
15 mg, and placebo), visit, and treatment by visit interaction, stratification factors: baseline IGT 
(yes or no); baseline hyperlipidemia (based on TG; yes or no); baseline NAFLD (yes or no) and 
sex (female, male), and baseline body weight as a covariate. An unstructured covariance 
structure will model relationship of within-patient errors. The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom. Since the mean percent change in body 
weight and the percentage of participants with ≥5% body weight reduction needs to be achieved 
at the same time, no multiplicity adjustment is planned for these 2 tests.
For the supplemental purpose, sensitivity analysis of the primary efficacy analysis will be 
performed that will be guided by the “treatment-regimen” estimand and conducted using the 
FAS, which represents efficacy regardless of adherence to study drug. This assessment will 
analyze percent change in body weight obtained at the 72-week visit using an analysis of 
covariance (ANCOVA) and the percentage of participants achieving at least 5% body weight 
reduction obtained at the 72-week visit using a logistic regression model. Both models will 
include terms of treatment, stratification factors, and baseline body weight as a covariate. 
Missing value of change in body weight at the 72-week visit will be imputed based on observed 
body weight change from baseline values at the visit from participants in the same treatment 
group who had their efficacy assessed after early discontinuation of study drug. In cases where 
there are not enough retrieved dropouts to provide a reliable imputation model (for example, the 
model implemented by the SAS program does not converge), an alternative multiple imputation 
method with reference to the placebo group (placebo multiple imputation) will be used. Analysis 
will be conducted with multiple imputations. 
9.4.3.2.
Secondary Analyses
Proportion of participants who achieved improvement of obesity-related health problems (IGT, 
hyperlipidemia, or NAFLD) for each treatment group will be compared based on “efficacy” 
estimand using EAS. For improvement of each obesity-related health problem, composite 
endpoints (improvement of >1 obesity-related health problem), logistic regression analysis with 
treatment and sex as factor will be used. For improvement of hyperlipidemia and other 
categorical efficacy endpoints, longitudinal logistic regression will be used.
Other continuous efficacy endpoints will be analyzed using a MMRM model.

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Additional details will be provided in the SAP.
9.4.4. Safety Analyses
Unless specified otherwise, safety assessments will be guided by an estimand comparing safety 
of tirzepatide doses with placebo irrespective of adherence to study drug. Thus, safety analysis 
will be conducted using SS. 
9.4.4.1.
Study Drug Exposure
Exposure to each study treatment will be calculated for each participant and summarized by 
treatment group.
9.4.4.2.
Adverse Events
Adverse events will be coded from the actual term using the Medical Dictionary for Regulatory 
Activities (MedDRA) and reported with preferred terms and system organ class. Counts and 
percentages of participants experiencing events will be reported for each treatment group, and 
Fisher’s exact test will be used to compare the treatment groups.
The percentage of participants experiencing TEAEs, SAEs, discontinuations due to AEs, will be 
summarized by treatment group.
9.4.4.3.
Adverse Event of Special Interest
Analysis of AESIs 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.
Adverse events of special interest for this study are listed in Section 8.2.6. Summaries and 
analyses for incidence of AESIs will be provided by treatment. The details of analysis of AESIs
will be provided in the SAP.
9.4.4.4.
Other Adverse Event Assessments 
9.4.4.4.1. Gastrointestinal Events
Summaries and analyses for incidence and severity of nausea, vomiting, and diarrhea will be 
provided by each treatment. 
9.4.4.4.2. Events Related to Potential Abuse Liability
Summaries and analyses for incidence of potential abuse liability terms will be provided by
treatment. The details will be provided in the SAP.
9.4.4.4.3. Depression, Suicidal Ideation, and Behavior
In addition to the summary of TEAEs, suicidal ideation and behavior will be assessed by 
C-SSRS, and depression-related symptoms will be assessed using PHQ-9. 
The analysis details will be provided in the SAP.
9.4.4.4.4. Central Laboratory Measures, Vital Signs, and Electrocardiograms
Actual values and change from randomization to postrandomization values of central laboratory 
measures, vital signs, and selected ECG parameters will be summarized at each scheduled visit. 

C O N FI D E N TI A L
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9 6
C ha n ge fr o m ra n d o mizati on t o p ostra n d omizat i on val ue will  be s u m marize d f or partici pa nts w h o 
ha ve b ot h a ra n d o mizati on a n d at least 1 p ost ra n d o mizati on res ult.
T he perce nta ges of partici p a nts wit h treat m e nt -e mer ge nt ( TE) ab n or mal, hi g h, or l o w meas ures 
(incl u di n g la b orat or y, vital, a n d E C G para meters) will be s u m marize d a n d c o m pa re d bet wee n 
treat me nt gr o u ps usi n g Fis her’ s e xact test. 
T he a nal ysis d etails will  be pr o vide d i n t he S A P.
9. 4. 5.
P h ar m a c o ki n eti c/ P h ar m a c o d y n a mi c A n al y s e s
Ti rze patide c o nce ntrati o n data will be a nal yze d usi n g a p o p ulat i on P K a p pr oac h via n o nli near
mi xe d -effects mo deli n g wi t h t he N O N M E M® s oft ware. T he relati ons hi p bet wee n t irze pat i de
d ose a n d/ or c o nce ntrati o n a n d efficac y , t olera bilit y, a n d safety e n d p o i nts ma y be c haracterize d.
A d dit i onall y , t he i m pact of i ntri nsic a n d e xtri nsic partici pa nt fact ors s uc h as a ge, wei g ht, se x,
a n d re nal f u nct i on o n P K a n d/ or P D para meters ma y be e xa mi ne d as nee de d. If A D A titers are
detecte d fr o m i m m u n o ge nicit y testi n g, t he n t he i m pact of i m m u n o ge nicity titers o n tirze pati de
P K or a n y  r ele va nt P D para met ers ma y als o be e xa mi ne d.
9. 4. 6.
E v al u ati o n of I m m u n o g e ni cit y
T he fre q ue nc y a n d perce nta ge of  parti ci pa nts wi t h pree xisti n g A D A a n d wit h T E A D A + t o 
tirze pati de will be ta b ulate d. Treat me nt -e mer ge nt A D As are defi ne d as t h ose wit h a titer 2 -f ol d 
( 1 dil ut i on) greater t ha n t he mi ni m u m re q uire d dil uti o n of t he A D A assa y if n o A D As were 
detecte d at baseli ne (treat me nt -i n d uce d A D A) or t h ose wit h a 4-f ol d ( 2 dil ut i ons) i ncrease i n t iter 
c o mpare d wi t h baseli ne if A D As were detecte d at baseli ne (treat me nt -b o oste d A D A). F or t he T E 
A D A + parti ci pa nts, t he distri b utio n of  ma xi m u m titers will be descri be d. T he fre q ue nc y of 
ne utralizi n g a nt i b o dies, if assesse d, a n d cr oss reacti vity t o nati ve GI P a n d G L P-1 ma y  als o be 
ta b ulate d i n T E A D A + partici pa nts. T he rel at i ons hi p bet wee n t he prese nce of a nti b o dies a n d t he 
P K para meters a n d P D re s p o nse i ncl u di n g safet y a n d efficac y t o tirze pat i de ma y be assesse d.
9. 4. 7.
Ot h er A n al y s e s
9. 4. 7. 1.
S u b gr o u p A n al y s e s f or Pri m ar y O ut c o m e
Details o f t he s u b gr o u p a nal yses will be s h o w n i n t he S A P. 
T he f oll owi n g s u b gr o u p varia bles will be c o nsi dere d ( b ut n ot li mite d t o) :

a ge ( < 6 5 ye ars a n d ≥6 5 years )

se x (fe male a n d male)

baseli ne B MI ( ≥2 7 a n d < 3 0, ≥3 0 a n d < 3 5 , ≥3 5 k g/ m 2)

gl yce mic stat us at scree ni n g ( n or m o gl yce mia v ers us I G T) 

h y perli pi de mia stat us at scree ni n g ( TG; ≥1 5 0 a n d < 1 5 0 m g/ d L )

N A F L D stat us at scree ni n g ( H F F; ≥5 % a n d < 5 % ) 

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The outcome measures for the subgroup analyses will include

percent change in body weight from randomization at 72 weeks, and

percentage of participants achieving at least 5% body weight reduction at 72 weeks.
9.5.
Interim Analyses
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended.

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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 (CIOMS) International Ethical Guidelines
○
Applicable International Council for Harmonisation (ICH) GCP Guidelines
○
Applicable laws and regulations
●
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is 
initiated.
●
Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. ●The 
investigator will be responsible for the following:
○
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 the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), 
and all other applicable local regulations
●
Investigator sites are compensated for participation in the study as detailed in the 
clinical trial agreement.
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 

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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 his/her representative will explain the nature of the study, 
including the risks and benefits, to the participant or his/her legally authorized 
representative and answer all questions regarding the study.
●
Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.
●
The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.
●
Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.
●
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative and is kept on file.
10.1.4. 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 his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for his/her data to be used as described in the informed consent.
●
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
●
The sponsor has processes in place to ensure data protection, information security 
and data integrity. These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach.

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10.1.5. Committees Structure
Prospective adjudication of major adverse cardiovascular events and pancreatic AEs will be 
performed for this study. Appendix 4 (Section 10.4) outlines additional information on 
pancreatic and cardiovascular adjudication committees. 
10.1.6. Dissemination of Clinical Study Data
Registration
Required clinical trial registries (e.g., ClinicalTrials.gov) will be updated with the results from 
registered clinical trials regardless of the research outcome in accordance with local laws and 
regulations. 
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.  
Data
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of PK or genetic data.  Data are available to request 6 months 
after the indication studied has been approved in the United States and European Union 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, SAP, 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.  
10.1.7. Data Quality Assurance
●
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 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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●
Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues 
that can impact participant safety and/or reliability of study results. These pre-
defined 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 (e.g., 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 
(e.g., contract research organizations).
●
Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.
●
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the time period outlined in the 
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.

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Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An electronic data capture system 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 electronic data capture 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.
Data collected via the sponsor-provided data capture systems will be stored at third parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture systems. Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and electronic transfers will be provided to the investigator 
for review and retention. Data will subsequently be transferred from the central vendor to the 
sponsor data warehouse.
Data from complaint forms submitted to 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 the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available.
●
Definition of what constitutes source data can be found in Section 10.1.6.
10.1.9. Study and Site Start and Closure
The sponsor 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.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
●
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines

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●
Inadequate recruitment of participants by the investigator
●
Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and assures
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.
Long-Term 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
tirzepatide or after tirzepatide become(s) commercially available.
Sample Type
Custodian
Retention Period After 
Last Patient Visit*
Non-pharmacogenetic stored
samples
Sponsor or designee
15 years
Pharmacokinetics
Sponsor or designee
2 years
Pharmacogenetic stored sample
Sponsor or designee
15 years
Immunogenicity
Sponsor or designee
15 years
*Retention periods may differ locally.

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10.2. Appendix 2: Clinical Laboratory Tests
●
The tests detailed below will be performed by the central laboratory unless 
otherwise stated.
●
Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study intervention administration and/or 
response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time. Additionally, if the local 
laboratory results are used to make either a study intervention decision or 
response evaluation, the results must be entered into the CRF.
●
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.
●
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
●
Refer to Section 5.1 (Inclusion Criteria) for screening pregnancy criteria. 
Investigators must document their review of each laboratory safety report.
Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel.

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Clinical Laboratory Tests
Hematologya
Clinical Chemistrya
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Calcium
Mean cell volume
Chloride
Mean cell hemoglobin concentration
Phosphate
Leukocytes (WBC)
Bicarbonate
Neutrophils, segmented
Total bilirubin
Lymphocytes
Direct bilirubin
Monocytes
Alkaline phosphatase (ALP)
Eosinophils
Alanine aminotransferase (ALT)
Basophils
Aspartate aminotransferase (AST)
Platelets
Gamma-glutamyl transpeptidase (GGT)
Blood urea nitrogen (BUN)
Urine Chemistrya
Creatinine
Albumin
Uric acid
Creatinine
Glucose
Albumin/Creatinine Ratio
Total protein
Albumin
Urinalysisa
Creatine kinase (CK)j
pH
Protein
Other chemistrya
Glucose
HbA1c
Blood
Cystatin-C
Leukocyte esterase
Endocrinea
Hormones (females)a
Calcitonin
Serum pregnancy test (β-HCG)b
Thyroid-stimulating hormone (TSH)
Urine pregnancy testc,d
Adiponectin (total and high molecular weight)
Follicle stimulating hormone (FSH)e
Leptin
Insulin
Screening Liver Panela
C-peptide
Hepatitis B surface antigen (HBsAg)
Anti-hepatitis C antibodies
Lipid Panela
HCV RNA
Total cholesterol
Anti-mitochondrial antibodies
Direct LDL-C
HDL-C
Pancreas (exocrine)a
VLDL-C
Pancreatic amylase
Triglycerides
Lipase
Free fatty acids
Non-HDL-C
NAFLD/NASH Biomarkersa,f
K-18 (M30)
Inflammatory Markersa
Pro-C3
hsCRP
ELF score (calculated from Hyaluronic Acid, TIMP-1 
and PIIINP)
TNFαf
FIB-4 index

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Pharmacokinetics Samplesf,h,i
Calculationsg
eGFR (calculated by Japanese Society of Nephrology 
coefficient-modified CKD-EPI equation)
Pharmacogenetics Samplea
Urine albumin/creatinine ratio (UACR)
Whole blood (EDTA)
AST/ALT ratio
Nonpharmacogenetic Stored Samplesa
Immunogenicityf,h,i
Serum
Anti-tirzepatide antibodies
EDTA plasma
Anti-tirzepatide neutralizing antibodies
P800 plasma
Abbreviations: ADA = antidrug antibody; ALT = alanine aminotransferase; ALP = alkaline phosphatase; 
AST = aspartate aminotransferase; BUN = blood urea nitrogen; CK = creatinine kinase, eGFR = estimated 
glomerular filtration rate; EDTA = ethylenediaminetetraacetic acid; ELF = enhanced liver fibrosis, FIB-4
index = fibrosis-4 index, FSH = follicle-stimulating hormone; HbA1c = hemoglobin A1c; HDL = high-density 
lipoprotein; IWRS = interactive web-response system; LDL = low-density lipoprotein; PIIINP = N-terminal 
procollagen III propeptide, PK = pharmacokinetics; RBC = red blood cells; TIMP-1 = tissue inhibitor of 
metalloproteinase-1, TSH = thyroid-stimulating hormone; UACR = urine albumin/creatinine ratio; VLDL = very 
low-density lipoprotein; WBC = white blood cells.
a
Tests will be performed by or samples stored at a Lilly-designated central laboratory, unless otherwise noted.
b
A serum pregnancy test will be performed at Visit 1 for women of childbearing potential only. If required per 
local regulations and/or institutional guidelines, pregnancy testing can also be performed at other times during 
the study treatment period.
c
Evaluated locally. 
d
Urine pregnancy test will be performed and result confirmed at Visit 3 prior to randomization and first injection 
of study drug(s) for women of childbearing potential only. Additional pregnancy tests (beyond those required per 
the Schedule of Activities [Section 1.3]) should be performed at any time during the trial if a menstrual period is 
missed, there is clinical suspicion of pregnancy, or as required by local law or regulation.
e
Follicle-stimulating hormone test performed at Visit 1 for postmenopausal women at least 40 years of age with 
an intact uterus, not on hormone therapy, and who have had spontaneous amenorrhea for more than 1 year 
without an alternative medical cause. 
f
Results will not be provided to the investigative sites.
g
Calculated by the central laboratory and result provided to investigative sites.
h
In the event of systemic drug hypersensitivity reactions (immediate or nonimmediate), additional blood samples 
will be collected including ADA, PK, and exploratory biomarker samples. PK samples for immunogenicity must 
be taken prior to drug administration. 
i
Assayed by a Lilly-designated laboratory.
j
Creatine kinase MB (CK-MB) is to be assayed if creatine kinase result >1000 U/L.

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10.3. Appendix 3: Laboratory Assessments for Hypersensitivity 
Events

Laboratory assessments should be performed if the participant experiences 
generalized urticaria or if anaphylaxis is suspected.

Collect sample after the participant has been stabilized, and within 1 to 2 hours of 
the event; however, samples may be obtained as late as 12 hours after the event as 
analytes can remain altered for an extended period of time. Record the time at 
which the sample was collected.

Obtain a follow-up sample at the next regularly scheduled visit or after 4 weeks, 
whichever is later.
The table below summarizes the laboratory parameters that will be evaluated. These laboratory 
tests are bundled in the hypersensitivity laboratory testing kit.

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Clinical Laboratory Tests for Hypersensitivity Events
Hypersensitivity Tests
Notes
Selected test may be obtained in the event of anaphylaxis or systemic 
allergic/hypersensitivity reactions.
Tirzepatide ADAs 
(immunogenicity/ADA)
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigative sites.
Tirzepatide concentrations 
(PK)
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigative sites.
Tryptase
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigative sites.
Note: If a tryptase sample is obtained more than 2 hours after the event (that is, 
within 2 to 12 hours), or is not obtained because more than 12 hours have 
lapsed since the event, obtain urine sample for N-methylhistamine testing. Note 
that for tryptase serum samples obtained within 2 to 12 hours of the event, 
urine N-methylhistamine testing is performed in addition to tryptase testing. 
Collect the first void urine following the event. Obtain a follow-up urine for 
N-methylhistamine testing at the next regularly scheduled visit or after 
4 weeks, whichever is later.
N-methylhistamine
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigative sites.
Drug-specific IgE
Will be performed if a validated assay is available.
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigative sites.
Basophil activation test
Will be performed if a validated assay is available.
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigative sites.
Note: The basophil activation test is an in vitro cell based assay that only 
requires a serum sample. It is a surrogate assay for drug specific IgE, but is not 
specific for IgE.
Complement (C3, C3a, and 
C5a)
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigative sites.
Cytokine panel (IL‐6, IL‐
1β, IL‐10)
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigative sites.
Abbreviations: ADA = antidrug antibody; IgE = immunoglobulin E; IL = interleukin; PK = pharmacokinetics.

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10.4. Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting

The definitions and procedures detailed in this appendix are in accordance with 
International Organization for Standardization (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).
10.4.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory finding) in study participants, users, or 
other persons, whether or not related to the investigational medical device. This 
definition includes events related to the investigational medical device or comparator 
and events related to the procedures involved except for events in users or other 
persons, which only include events related to investigational devices. 
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (that is, not related to progression 
of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though they may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 

“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as 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 which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (e.g., endoscopy, 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.
10.4.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been admitted to hospital 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during hospitalization 
are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 

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and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.
g.
Resulted in medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
10.4.3. Definition of Product 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 in 
order to ensure the safety of participants, monitor quality, and to facilitate process and 
product improvements.

Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed.

An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE.

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10.4.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints
AE, SAE, and Product Complaint Recording

When an AE/SAE/product complaint occurs, it is the responsibility of the investigator 
to review all documentation (e.g., 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 (e)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 AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living.

Moderate: A type of AE is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.

Severe: A type of AE that interrupts usual activities of daily living, 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.

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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to 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 his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-Up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible.
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide sponsor or designee with a copy of any 
post-mortem findings including histopathology. 
10.4.5. Reporting of SAEs
SAE Reporting via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE will be the electronic data collection 
tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

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
The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the sponsor by telephone.

Contacts for SAE reporting can be found in the site training documents.
SAE Reporting via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the sponsor.

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 site training documents.
10.4.6. Regulatory Reporting Requirements
SAE Regulatory Reporting
●
Prompt notification by the investigator to the sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation 
are met. 
●
The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/IEC, and investigators. 
●
An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
10.4.7. Special Safety Topics
10.4.7.1. Hypoglycemia
Upon ICF signing, all participants will be educated about signs and symptoms of hypoglycemia, 
how to treat hypoglycemia, and how to collect appropriate information for each episode of 
hypoglycemia. 

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Hypoglycemia may be identified by spontaneous reporting of symptoms from participants 
(whether confirmed or unconfirmed by simultaneous glucose values) or by blood glucose 
samples collected during study visits. 
All participants who develop diabetes during the study will be provided with glucometers. 
Participants without diabetes may, at the investigator’s discretion, be given glucometers to assist 
in the evaluation of reported symptoms consistent with hypoglycemia. Participants receiving 
glucometers will be provided a diary to record relevant information (e.g., glucose values, 
symptoms).
All hypoglycemic episodes will be recorded on a specific eCRF (hypoglycemia eCRF) and 
should not be recorded on the AEs eCRF, unless the event meets serious criteria. If a 
hypoglycemic event meets severe criteria (see definition below), it should be recorded as serious 
on the AE and SAE eCRFs, and reported to Lilly as an SAE.
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the plasma glucose values in this section 
refer to values determined by a laboratory or International Federation of Clinical Chemistry and 
Laboratory Medicine blood-equivalent glucose meters and strips) in accordance with the 2019 
American Diabetes Association position statement on glycemic targets (American Diabetes 
Association 2019):
Glucose Alert Value (Level 1):

Documented symptomatic hypoglycemia is defined as any time a participant feels 
that he or she is experiencing symptoms and/or signs associated with hypoglycemia 
and has a plasma glucose level of <70 mg/dL (<3.9 mmol/L).

Documented asymptomatic hypoglycemia is defined as any event not accompanied 
by typical symptoms of hypoglycemia, but with a measured plasma glucose 
<70 mg/dL (<3.9 mmol/L).

Documented unspecified hypoglycemia is defined as any event with no information 
about symptoms of hypoglycemia available, but with a measured plasma glucose
<70 mg/dL (<3.9 mmol/L).
Clinically Significant Hypoglycemia (Level 2):

Documented symptomatic hypoglycemia is defined as any time a participant feels 
that he or she is experiencing symptoms and/or signs associated with hypoglycemia 
and has a blood glucose level of <54 mg/dL (<3.0 mmol/L).

Documented asymptomatic hypoglycemia is defined as any event not accompanied 
by typical symptoms of hypoglycemia but with a measured blood glucose <54 mg/dL 
(<3.0 mmol/L).

Documented unspecified hypoglycemia is defined as any event with no information 
about symptoms of hypoglycemia available but with a measured blood glucose
<54 mg/dL (<3.0 mmol/L).

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Severe Hypoglycemia (Level 3):

Severe hypoglycemia is defined as an episode with severe cognitive impairment 
requiring the assistance of another person to actively administer carbohydrate, 
glucagon, or other resuscitative actions. These episodes may be associated with 
sufficient neuroglycopenia to induce seizure or coma. Blood glucose measurements 
may not be available during such an event, but neurological recovery attributable to 
the restoration of blood glucose to normal is considered sufficient evidence that the 
event was induced by a low blood glucose concentration.
To avoid duplicate reporting, all consecutive blood glucose values <70 mg/dL (3.9 mmol/L) 
occurring within a 1-hour period may be considered to be a single hypoglycemic event 
(Weinberg et al. 2010; Danne et al. 2013). 
10.4.7.2. Pancreatitis
Acute pancreatitis is defined as an AE of interest in all trials with tirzepatide, including this trial. 
Acute pancreatitis is an acute inflammatory process of the pancreas that may also involve 
peripancreatic tissues and/or remote organ systems (Banks and Freeman 2006). The diagnosis of 
acute pancreatitis requires 2 of the following 3 features:

abdominal pain, characteristic of acute pancreatitis (generally located in the 
epigastrium and radiates to the back in approximately half the cases) (Banks and 
Freeman 2006; Koizumi et al. 2006); the pain is often associated with nausea and 
vomiting

serum amylase (total and/or pancreatic) and/or lipase ≥3× ULN

characteristic findings of acute pancreatitis on CT scan or MRI.
If acute pancreatitis is suspected, appropriate laboratory tests (including levels of pancreatic 
amylase and lipase) should be obtained via the central laboratory (and locally, if needed). 
Imaging studies, such as abdominal CT scan with or without contrast, MRI, or gall bladder 
ultrasound, should be performed. Abdominal ultrasound may be used as an alternative method 
only if CT and MRI cannot be performed. If laboratory values and/or abdominal imaging support 
the diagnosis of acute pancreatitis, the participant must discontinue therapy with tirzepatide, but 
will continue in the study. A review of the participant’s concomitant medications should be 
conducted to assess any potential causal relationship with pancreatitis.
Each AE of pancreatitis must be reported. If typical signs and/or symptoms of pancreatitis are 
present and confirmed by laboratory values (lipase or amylase [total and/or pancreatic]) and 
imaging studies, the event must be reported as an SAE. For a potential case that does not meet all 
of these criteria, it is up to the investigator to determine the seriousness of the case (AE or SAE) 
and the relatedness of the event to study drug(s).
Each participant will have measurements of p-amylase and lipase (assessed at the central 
laboratory) as shown on the Schedule of Activities (Section 1.3) to assess the effects of the 
investigational doses of tirzepatide on pancreatic enzyme levels. Serial measurements of 
pancreatic enzymes have limited clinical value for predicting episodes of acute pancreatitis in 

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asymptomatic participants (Nauck et al. 2017; Steinberg et al. 2017a, 2017b). Thus, further 
diagnostic follow-up of cases of asymptomatic pancreatic hyperenzymemia (lipase and/or 
pancreatic amylase ≥3× ULN) is not mandated but may be performed based on the investigator’s 
clinical judgment and assessment of the participant’s overall clinical condition. Only cases of 
pancreatic hyperenzymemia that undergo additional diagnostic follow-up and/or are 
accompanied by symptoms suggestive of pancreatitis will be submitted for adjudication.
All suspected cases of acute or chronic pancreatitis will be adjudicated by an independent 
clinical endpoint committee. In addition, AEs of severe or serious abdominal pain of unknown 
etiology will also be submitted to the adjudication committee to assess for possible pancreatitis 
or other pancreatic disease. Relevant data from participants with acute or chronic pancreatitis
including suspected cases and those with severe or serious abdominal pain will be entered into a 
specifically designed eCRF page. The adjudication committee representative will enter the 
results of adjudication in a corresponding eCRF page.
10.4.7.3. Thyroid Malignancies and C-Cell Hyperplasia (Assessed by Calcitonin 
Measurements)
Individuals with personal or family history of medullary thyroid carcinoma and/or multiple
endocrine neoplasia type 2 will be excluded from the study. The assessment of thyroid safety 
during the trial will include reporting of any case of thyroid malignancy including medullary 
thyroid carcinoma and papillary carcinoma and measurements of calcitonin. This data will be 
captured in specific eCRFs. The purpose of calcitonin measurements is to assess the potential of 
tirzepatide to affect thyroid C-cell function, which may indicate development of C-cell 
hyperplasia and neoplasms. Tirzepatide should be discontinued, after first confirming the value, 
if post-randomization calcitonin value is 35 ng/L or more and has increased at least 50% over 
baseline. A consultation with a thyroid specialist, if not available, an endocrinologist, should be
obtained.
If an increased calcitonin value (≥35 ng/L and increases by ≥50% compared with baseline) 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. If the confirmed calcitonin value is <35 ng/L, 
tirzepatide should be restarted when it is safe to do so.
10.4.7.4. 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. Relevant data from participants who experienced death or nonfatal cardiovascular
AEs will be entered into a specifically designed eCRF page by study site.
The nonfatal cardiovascular AEs to be adjudicated include

myocardial infarction

hospitalization for unstable angina

hospitalization for heart failure

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
coronary interventions (such as coronary artery bypass graft or percutaneous coronary 
intervention), and 

cerebrovascular events, including cerebrovascular accident (stroke) and transient 
ischemic attack.
10.4.7.5. Supraventricular Arrhythmias and Cardiac Conduction Disorders
Treatment-emergent cardiac conduction disorders will be further evaluated. Participants who 
develop any event from these groups of disorders should undergo an ECG, which should be 
submitted to the central reading center. The specific diagnosis will be recorded as an AE. Events 
that meet criteria for serious conditions as described in Section 10.4.2 must be reported as SAEs. 
10.4.7.6. Hypersensitivity Events
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data describing each symptom should be provided
to the sponsor in the eCRF.  
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study drug. It is recommended that participants
who experience a systemic hypersensitivity reaction be treated per national and international 
guidelines.
In the case of generalized urticaria or anaphylaxis, additional blood and urine samples should be 
collected as described in Appendix 3 (Section 10.3). Laboratory results are provided to the 
sponsor via the central laboratory.
10.4.7.7. Injection Site Reactions
Symptoms of a local injection site reaction may include erythema, induration, pain, pruritus, and 
edema. If an injection site event is reported, the AE will be recorded, and additional data will be 
provided to the sponsor in the Injection Site Reaction eCRF.
At the time of AE occurrence, samples will be collected for measurement of tirzepatide ADA 
and tirzepatide concentrations.
10.4.7.8. Antidrug Antibodies
The occurrence of ADA formation will be assessed as outlined in Section 8.9.
10.4.7.9. Hepatobiliary Disorders
All events of TE biliary colic, cholecystitis, or other suspected events related to gallbladder 
disease should be evaluated and additional diagnostic tests performed, as needed. In cases of 
elevated liver markers, hepatic monitoring should be initiated as outlined in Section 8.2.4.1.
10.4.7.10.
Severe Gastrointestinal Adverse Events
Tirzepatide may cause severe GI AEs, such as nausea, vomiting, and diarrhea. Information about 
severe GI AEs as well as antiemetic/antidiarrheal use will be collected in the eCRF/AE form. For 
detailed information concerning the management of GI AEs, please refer to Section 6.7.1.

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10.4.7.11.
Acute Renal Events
Renal safety will be assessed based on repeated renal functional assessment as well as 
assessment of AEs suggestive of acute or worsening of chronic renal failure. Gastrointestinal 
AEs have been reported with tirzepatide, including nausea, diarrhea, and vomiting. This is 
consistent with other GLP-1R agonists (Aroda and Ratner 2011). The events may lead to 
dehydration, which could cause a deterioration in renal function, including acute renal failure. 
Participants should be advised to notify investigators in case of severe nausea, frequent vomiting, 
or symptoms of dehydration.
10.4.7.12.
Depression, Suicidal Ideation, or Behavior Monitoring
Participants will be monitored for depression and suicidal ideation or behavior through AE 
collection and by using the C-SSRS and the PHQ-9. Participants will be referred to 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
A “yes” answer to either Question 4 (Active Suicidal Ideation with Some 
Intent to Act, Without Specific Plan) 
or
o
A “yes” answer to Question 5 (Active Suicidal Ideation with Specific Plan 
and Intent) on the “Suicidal Ideation” portion of the C-SSRS 
or 
o
A “yes” answer to any of the suicide-related behaviors (actual attempt, 
interrupted attempt, aborted attempt, preparatory act, or behavior) on the 
“Suicidal Behavior” portion of the C-SSRS. 

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10.5. Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the
above, (e.g., Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Determination can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
3. Postmenopausal female is defined as, women with:

12 months of amenorrhea for women >55 years of age, with no need for 
follicle-stimulating hormone

12 months of amenorrhea for women >40 years of age with follicle-stimulating 
hormone ≥40 mIU/mL and no other medical condition such as anorexia nervosa and 
not taking medications during the amenorrhea (e.g., oral contraceptives, hormones, 
gonadotropin releasing hormone, anti-estrogens, selective estrogen receptor 
modulators, or chemotherapy that induced amenorrhea)
Contraception Guidance:
Contraceptive use by men and women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Two forms of effective contraception, where at least 1 form is highly effective, will be used. 
Effective contraception may be used as the second therapy. Barrier protection methods without 
concomitant use of a spermicide are not a reliable or acceptable method. The use of male and 
female condoms as a double barrier method is not considered acceptable due to the high failure 
rate when these methods are combined. 

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

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Men who are abstinent (if this is complete abstinence, as their preferred and usual lifestyle) or in 
a same-sex relationship (as part of their preferred and usual lifestyle) must agree to either remain 
abstinent or stay in a same-sex relationship without sexual relationships with females (usual 
lifestyle). In these situations, men are not required to use contraception. 
Men should refrain from sperm donation for the duration of the study and for 5 half-lives of 
study drug plus 90 days after the last dose of study drug, corresponding to 4 months after the last 
injection. 
Collection of Pregnancy Information
Male participants with partners who become pregnant
●
The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is 
in this study. This applies only to male participants who receive study 
intervention.
●
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
partner’s pregnancy. The female partner will also be followed to determine the 
outcome of the pregnancy. Information on the status of the mother and child will 
be forwarded to the sponsor. Generally, the follow-up will be no longer than 6 to 
8 weeks following the estimated delivery date. Any termination of the pregnancy 
will be reported regardless of fetal status (presence or absence of anomalies) or
indication for the procedure. 
Female participants who become pregnant
●
The investigator will collect pregnancy information on any female participant 
who becomes pregnant while participating in this study. 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 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 post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
protocol Section 8.3.3. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
●
Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention or be withdrawn from the study.

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10.6. Appendix 6: 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 whole blood sample will 
be collected for DNA analysis from consenting participants.
●
DNA samples will be used for research related to study intervention or indication
and related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to study intervention and indication. Genetic research may 
consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome or analysis of the entire genome (as appropriate).
●
DNA samples will be analyzed for whole genome or exome sequencing, genome 
wide association studies, and candidate gene studies. Additional analyses may be 
conducted if it is hypothesized that this may help further understand the clinical 
data.
●
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 clinical study report 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 15 years or 
other period as per local requirements.

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10.7. Appendix 7: Liver Safety: Suggested Actions and Follow-Up 
Assessments
Hepatic Evaluation Testing
See protocol Section 8.2.4.1 for guidance on appropriate test selection.
The Lilly-designated central laboratory must complete the analysis of all selected testing except 
for microbiology testing.
Local testing may be performed in addition to central testing when necessary for immediate 
participant management.
Results will be reported if a validated test or calculation is available.
Hematology
Clinical Chemistry
Hemoglobin
Total bilirubin
Hematocrit
Direct bilirubin
Erythrocytes (RBCs - red blood cells)
Alkaline phosphatase (ALP)
Leukocytes (WBCs - white blood cells)
Alanine aminotransferase (ALT)
Differential:
Aspartate aminotransferase (AST)
    Neutrophils, segmented
Gamma-glutamyl transferase (GGT)
    Lymphocytes
Creatine kinase (CK)
    Monocytes
Other Chemistry
    Basophils
Acetaminophen
    Eosinophils
Acetaminophen protein adducts
Platelets
Alkaline phosphatase isoenzymes
Cell morphology (RBC and WBC)
Ceruloplasmin
Coagulation
Copper
Ethyl alcohol (EtOH)e
Prothrombin time, INR (PT-INR)
Haptoglobin
Serology
Immunoglobulin IgA (quantitative)
Hepatitis A virus (HAV) testing:
Immunoglobulin IgG (quantitative)
    HAV total antibody
Immunoglobulin IgM (quantitative)
    HAV IgM antibody
Phosphatidylethanol (Peth)
Hepatis B virus (HBV) testing:
Urine Chemistry
    Hepatitis B surface antigen (HBsAg)
Drug screen
    Hepatitis B surface antibody (anti-HBs)
Ethyl glucuronide (EtG)
    Hepatitis B core total antibody (anti-HBc)
Other Serology
    Hepatitis B core IgM antibody
Anti-nuclear antibody (ANA)
    Hepatitis B core IgG antibody
Anti-smooth muscle antibody (ASMA)a
    HBV DNAd
Anti-actin antibodyb
Hepatis C virus (HCV) testing:
Epstein-Barr virus (EBV) testing:
    HCV antibody
    EBV antibody
    HCV RNAd
    EBV DNAd
Hepatitis D virus (HDV) testing:
Cytomegalovirus (CMV) testing:

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    HDV antibody
    CMV antibody
Hepatitis E virus (HEV) testing:
    CMV DNAd
    HEV IgG antibody
Herpes simplex virus (HSV) testing:
    HEV IgM antibody
    HSV (Type 1 and 2) antibody 
    HEV RNAd
    HSV (Type 1 and 2) DNAd
Microbiologyc
Liver kidney microsomal type 1 (LKM-1) antibody
Culture:
    Blood
    Urine
Abbreviations: DNA = deoxyribonucleic acid; Ig = immunoglobulin; INR = international normalized ratio; 
RNA = ribonucleic acid.
a
Not required if anti-actin antibody is tested.
b
Not required if anti-smooth muscle antibody is tested.
c
Assayed ONLY by investigator-designated local laboratory; no central testing available.
d
Reflex/confirmation dependent on regulatory requirements, testing availability, or both.
e
This test should be performed locally if not available at the central laboratory. 

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10.8. Appendix 8: Management of Gastrointestinal Symptoms
Abbreviations: GI = gastrointestinal; IWRS = interactive web-response system.

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10.9. Appendix 9: Medical Device Incidents:  Definition and 
Procedures for Recording, Evaluating, Follow Up, and Reporting
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study.
Medical Device Incident Definition

A medical device incident is any malfunction or deterioration in the characteristics 
and/or performance of a device as well as any inadequacy in the labeling or the 
instructions for use which, directly or indirectly, might lead to or might have led to a 
serious injury, death of a participant/user/other person, or to a serious deterioration 
in his/her state of health.

Not all incidents lead to death or serious deterioration in health. The nonoccurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:

An incident associated with a device happened.

AND

The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:

Life-threatening illness

Permanent impairment of body function or permanent damage to body structure

Condition necessitating medical or surgical intervention to prevent one of the above

Fetal distress, fetal death, or any congenital abnormality or birth defects
Examples of Incidents

A participant, user, caregiver, or health care professional is injured as a result of a 
medical device failure or its misuse.

A participant’s study intervention is interrupted or compromised by a medical 
device failure.

A misdiagnosis due to a medical device failure leads to inappropriate treatment.

A participant’s health deteriorates due to a medical device failure.

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

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10.10.
Appendix 10: Medical Device Adverse Events (AEs), 
Adverse Device Effects (ADEs), Serious Adverse Events (SAEs) 
and Device Deficiencies: Definition and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting
Refer to Appendix 4 (Section 10.4) for definitions and procedures for recording, evaluating, 
follow-up, and reporting of all events. 

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10.11.
Appendix 11: Measurement of Height, Weight, Waist 
Circumference, Vital Signs, Electrocardiogram, Oral Glucose 
Tolerance Test, Magnetic Resonance Imaging, Computed 
Tomography
The following information has been adapted from standardized physical measurement protocols 
for the World Health Organization’s STEPwise approach to Surveillance (STEPS) (WHO 2008). 
(Available at: 
https://www.who.int/ncds/surveillance/steps/Section%204%20Step%202%20Physical%20Measu
rements.pdf)
Measuring Height
Step 1. Ask the participant to remove their footwear and any headgear (light headgear worn for 
religious reasons can remain, but this should be worn by the participant at every clinic visit when 
their height is measured).
Step 2. Ask the participant to stand on the calibrated height measuring board (stadiometer) or 
against a wall with their feet together and their knees straight with their heels against the 
backboard, the stadiometer, or the wall.
Step 3. Ask the participant to look straight ahead without tilting their head up.
Step 4. Ask the participant to breathe in and stand tall. Measure and record the participant’s 
height in centimeters (cm) to 1 decimal place.
Measuring Weight

Body weight measurements should be done in a consistent manner using a calibrated 
electronic scale capable of measuring weight in kilograms (kg) to 1 decimal place.

All weights for a given participant should be measured using the same scale, whenever 
possible, at approximately the same time in the morning after evacuation of bladder 
contents.

Body weight must be measured in fasting state. If the participant is not fasting, the 
participant should be called in for a new visit within the visit window to have the fasting 
body weight measured.
Step 1. Ask the participant to empty their pockets, remove their footwear, outerwear (coat, 
jacket, etc.), and any headgear (light headgear worn for religious reasons can remain, but this 
should be worn by the participant at every clinic visit when weight is measured).
Step 2. Make sure the scale is placed on a firm, flat, even surface (not on carpet, on a sloping 
surface, or a rough, uneven surface).
Step 3. Ask the participant to step onto the scale with 1 foot on each side of the scale.
Step 4. Ask the participant to stand still with arms by sides and then record weight in kilograms 
(kg) to the nearest one-tenth kg.

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Measuring Waist Circumference

Waist circumference should be measured in the horizontal plane and at the umbilicus 
level according to JASSO guideline.

Measurements should be taken at the end of a normal expiration using a nonstretchable 
measuring tape. The tape should lie flat against the skin without compressing the soft 
tissue.

The waist circumference should be measured twice, rounded to the nearest 0.5 cm. The 
measuring tape should be removed between the 2 measurements. Both measurements 
will be recorded in the eCRF. If the difference between the 2 measurements exceeds 
1 cm, this set of measurements should be discarded and the 2 measurements repeated.
Step 1. Ask the participant to wear light clothing (if available, patient gowns could also be used).
Step 2. Ask the participant to stand with their feet close together, arms at their side, body weight 
evenly distributed.
Step 3. Ask the participant to relax and measure the participant’s waist circumference.
Vital Sign Measurements (blood pressure and heart rate)

Vital sign measurements (blood pressure and heart rate, measured by pulse) should be 
taken before obtaining an ECG tracing and before collection of blood samples for 
laboratory testing

The participant should sit quietly for 5 minutes before vital signs measurements are 
taken

For each parameter, two 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 blood pressure needs to be recorded in the eCRF

Blood pressure must be taken with a same type of sphygmomanometer 
(e.g., sphygmomanometer, mercury manometer) throughout the study. 

If blood pressure and pulse measurements are taken separately, pulse should be taken
prior to blood pressure.
Note: In the event pulse measurement cannot be taken via an automated blood pressure 
instrument, the preferred location for measurement of pulse is the radial artery.
Electrocardiogram

All digital ECGs will be obtained using centrally provided ECG machines and will be 
electronically transmitted to a designated central ECG laboratory.

12-lead ECGs should be obtained after the subject has rested in a supine position for at 
least 10 minutes.

Electrocardiograms should be collected at least 30 minutes prior to collection of blood 
samples for laboratory testing, including PK samples.

Triplicate ECGs (obtained at Visit 3) should be obtained approximately 1 minute apart, 
with all 3 tracings to be obtained within approximately 5 minutes. Measurements that 
deviate substantially from previous readings should be repeated immediately.

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2-Hour Oral Glucose Tolerance Test

Participants should maintain adequate carbohydrate intake for 3 days prior to the 
scheduled 2-hour OGTT.

In the 24 hours preceding the test, participants should refrain from drinking any alcohol 
or performing any extreme physical activity.

Participants should fast for at least 10 hours before the administration of the test and 
should not eat until the test is complete.

Placement of a venous cannula, preferably in an antecubital vein, is recommended to 
simplify collection of multiple blood samples for glucose, insulin, and C-peptide at time 
0, 30, 60, 90, and 120 minutes.

Immediately after collection of the time 0 sample, a 75-gram glucose dose will be given 
orally, using a commercial product approved for this use (and in a total volume of not 
more than 350 mL).

The participant should consume the glucose load within 5 minutes.

The participant should remain minimally active for the duration of the test.
Magnetic Resonance Imaging

Participants will undergo 2 liver and abdominal visceral/subcutaneous adipose 
tissue-directed MRI evaluations. For participant safety, images should also be over-read 
locally to assure there are no underlying liver pathologies other than NAFLD/NASH. 

In the event of early termination from the study drug or the study, 
o
the second MRI exam may be performed when 
-
the participant has been on treatment for at least 36 weeks, and
-
within 2 weeks of treatment discontinuation

MRIs will be performed after a fast of at least 8 hours. Participants are allowed to take 
necessary medications and small quantities of water during the fast. Additional 
exclusion criteria apply for MRI examination eligibility, which do not count toward 
eligibility for study participation. These exclusions are: 
o
a contraindication to MRI examinations
o
extreme claustrophobia
o
weight or girth exceeds the scanner capabilities
o
any condition or circumstance that, in the opinion of the investigator, would 
interfere with completion of MRI examinations

For participants with claustrophobia in MRI machines, investigators may offer, at their 
discretion, a light sedative. However, if the participant is not willing to attempt MRI 
with light sedation, the participant should be excluded from the MRI evaluation but 
should not be excluded from the study.

To obtain consistent and quality data for central review, investigators participating in 
the study will be provided with detailed instructions on the MRI acquisition protocol to 
be used.

The MRI acquisition protocol will include sequences for measurement of the following:
o
Hepatic fat fraction (HFF)
o
Visceral adipose tissue (VAT) area
o
Abdominal subcutaneous adipose tissue (SAT) area
o
VAT/SAT ratio

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
For patients participating in HFF analysis, they may use MRI for visceral and 
subcutaneous assessments by multiple slices acquisition during MRI, which will be
captured in central vendor site acquisition manual and described in the imaging charter.

Scans will be performed at 1.5 Tesla (T) or 3 T. The same scanner and imaging 
acquisition should be used for all subject time points. Any exceptions must be approved 
in advance of scanning by the imaging core laboratory. A standardized imaging 
acquisition will be utilized at all MRI centers and details will be provided in an MRI 
Site Manual.
Computed Tomography

Single slice imaging will be performed at the umbilicus level in a supine position using 
CT scanner at each site.

The CT imaging conditions will be adjusted appropriately on the basis of predefined 
Hounsfield unit thresholds (-190 to -30) and a slice thickness of 5 mm. To obtain 
consistent and quality data for central review, investigators participating in the study
will be provided with detailed instructions on the CT acquisition protocol to be used.

The CT acquisition protocol will include sequences for measurement of the following:
o
Visceral adipose tissue area (VAT)
o
Subcutaneous adipose tissue area (SAT)
o
VAT/SAT

The system will also be divided and analyzed CT-scanned images into 2 areas (VAT
and SAT) and others.

Measurements of the adipose tissue area will be performed by a software technologist 
and a radiologists blinded to the clinical and pathological data.

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10.12.
Appendix 12: 2-Hour Oral Glucose Tolerance Test Flow 
Chart
Abbreviations: DM = diabetes mellitus; FG = fasting glucose; HbA1c = hemoglobin A1c; IGT = impaired glucose 
tolerance; OGTT = oral glucose tolerance test.

C O N FI D E N TI A L
Pr ot oc ol  I 8 F-J E-G P H Z( b)
1 3 6
1 0. 1 3.
A p p e n di x 1 3 : J A S S O g ui d eli n e s
Ele ve n o besit y- rel ate d he alt h pr o ble ms
T he J A S S O g ui deli ne defi nes 1 1 healt h dis or ders f or dia g n osis of “ O besit y Disease” t o s u bjects 
w h o nee d wei g ht re d ucti o n fr o m me dical reas o n.
1 ）Gl uc ose i nt ol era nce dis or der (T 2 D M , I G T, a n d s o o n)
2 ）D ysli pi de mia
3 ）H y perte nsi o n 
4 ）H y per urice mia a n d G o ut
5 ）Car di o vasc ular di sease, m yo c ar dial i nfarct i on a n d A n gi na
6 ）Cere bral i nfarct i on a n d TI A (tra nsie nt isc he mic attac k)
7 ）N o n -alc o h o lic fatt y li ver d isease ( N A F L D)
8 ）Me nstr uati o n di s or der a n d i nfertility
9 ）O bstr ucti ve slee p a p nea s y n dr ome ( O S A S) a n d o besit y -h y p o ve nt ilati o n s y n dr ome
l 0 ）M ot or d y sf u ncti on: art hri tis/ oste oart hritis ( k nee, hi p j oi nt, s u pi ne a n d s o o n)
1 1 ）O besit y -relate d re nal disease
P h ysic al acti vit y 
T he J A S S O g ui deli ne i n dicate d t he a m o u nt of p h ysical act i vity acc or di n g t o t he p ur p ose of 
w ei g ht l oss;

f or pre ve nti on of wei g ht gai n; 1 5 0 t o 2 5 0 mi n utes ( 1, 2 0 0-2, 0 0 0 kcal) per wee k 

f or w eig ht l oss;
o
m o derate -i nte nsit y p h ysical  a cti vit y less t ha n 1 5 0 mi n utes per wee k t o pr o vi de o nl y  
m o dest wei g ht l oss
o
m o derate -i nte nsit y p h ysical  a cti vit y bet wee n 2 2 5 a n d 4 2 0 mi n utes per wee k t o 
pr o vi de 5 t o 7. 5 k g wei g ht l oss
o
greater a m o u nts of p h ysical act i vity t o pr o vid e m or e w ei g ht l oss
F or e xa m ple, m o derate -i nte nsit y p h ysical act i vities ( 3- 6 M E Ts) are sli g ht l y fast walki n g 
( 4 k m/ h o ur) a n d bic yc le c o m m uti n g ( < 1 6 k m / ho ur), etc.
Bef ore starti n g e xercise t hera p y , p artici pa nts will be c o nfir me d t he de gree of o besit y- relate d 
healt h pr o bl e ms s uc h as lifest yle-relate d diseases, ort h o pe dic diseases, t he prese nce or a bse nce of 
treat me nt, me dical hist or y , a n d e xercise ha bits, a n d disc usse d c o nte nts of p h ysical act i vities t hat 
ca n be safel y i m ple me nte d acc or di n g t o t he partici pa nt’s sit u atio n ( J A S S O 2 0 1 6).

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10.14.
Appendix 14: 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 onsite visits or to conduct planned study procedures.
Implementing changes under exceptional circumstances
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations.
After approval by local ERBs, regulatory bodies and any other relevant authorities, 
implementation of these exceptional circumstance changes will not typically require additional 
notification to these groups, unless they have specific conditions in which notification is 
required. To protect the safety of study participants, urgent changes may be implemented before 
approval but need to be reported as soon as possible. All approvals must be retained in the study 
records.
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed.
Considerations for making a change
The prevailing consideration for making a change is ensuring the safety of study participants.
Additional important considerations for making a change are compliance with GCP, enabling 
participants to continue safely in the study and maintaining the integrity of the study.
Informed Consent
Additional consent from the participant will be obtained, as applicable, for

participation in remote visits, as defined under “Remote Visits” below.

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

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Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed.
The following changes in study conduct will not be considered protocol deviations.
1.  Remote visits
In source documents and the CRF, the study site should capture the visit location and method,
with a specific explanation for the reason of conducting a remote visit instead of an onsite visit.
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, AEs and product complaints, concomitant medications, review of 
study participant diary (including study drug compliance), review diet and exercise goals, 
C-SSRS (Since Last Visit Version), Self-Harm Supplement Form, Self-Harm Follow-up 
Form (if applicable), and PHQ-9.
Mobile healthcare: Healthcare visits may be performed by a mobile healthcare provider
at locations other than the study site when participants cannot travel to the site due to an 
exceptional circumstance if written approval is provided by the sponsor. Procedures 
performed at such visits include, but are not limited to, weight and waist measurements, 
physical assessments, vital signs, ECG, patient reported outcome questionnaires 
administration, collection of blood samples and health information. 
Other alternative locations: Laboratory draws may be done at an alternate location in 
exceptional circumstances.
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and product complaints remain unchanged. Furthermore, every effort 
should be made to enable participants to return to on-site visits as soon as reasonably possible, 
while ensuring the safety of both the participants and the site staff.
2.  Local laboratory testing option
Local laboratory testing may be conducted in lieu of central laboratory testing. The local 
laboratory must be qualified in accordance with applicable local regulations.
3.  Study intervention and ancillary supplies (including participant diaries)
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the sponsor to determine appropriate actions. These actions may
include

asking the participant to go to the site and receive study supplies from site staff 
without completion of a full study visit

asking the participant’s designee to go to the site and receive study supplies on a
participant’s behalf, and

arranging delivery of study supplies.

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These requirements must be met before action is taken:

Alternate delivery of study intervention should be performed in a manner that 
does not compromise treatment blinding and ensures product integrity. The 
existing protocol requirements for product accountability remain unchanged, 
including verification of participant’s receipt of study supplies.

When delivering supplies to a location other than the study site (for example,
participant’s home), the investigator, sponsor, or both should ensure oversight of 
the shipping process to ensure accountability and product quality (that is, storage 
conditions maintained and intact packaging upon receipt).

Instructions may be provided to the participant or designee on the final disposition 
of any unused or completed study supplies.
4.  Screening period guidance
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
prior to Visit 3 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 paused for less than 90 days from Visit 1 to Visit 3: the participant will proceed 
to the next study visit per the usual Schedule of Activities, provided that Visit 3
must be conducted within 90 days from Visit 1.
o
The site should conduct the next visit if the participant’s eligibility criteria
are confirmed, and the site should document the reason for delay in the
CRF.
o
Due to the pause in screening, sites should also reconfirm the impacted
participant’s consent and document this confirmation in the source 
documentation.

If paused for more than 90 days from Visit 1 to Visit 3: The participant must be 
discontinued because of screening interruption due to an exceptional 
circumstance.  This is documented as a screen fail in the CRF with a reason of
exceptional circumstance.  This screen fail is allowed in addition to the main 
protocol screen fail. The participant can reconsent and be rescreened as a new 
participant. The screening procedures per the usual Schedule of Activities should 
be followed, starting at Visit 1 to ensure participant eligibility by Visit 3.
5.  Adjustments to Visit Windows
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual Schedule of Activities. To maximize the possibility that these visits 
can be conducted as on-site visits, 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.

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Protocol I8F-JE-GPHZ(b)
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Visit Number
Tolerance
Visit 4 through Visit 21 and 
Visit 801
Primary endpoint visit (Visit 21 or 99) and 4 weeks post end of 
treatment visit (Visit 801) should be completed as per original 
schedule whenever possible and safe to do so. However, the visit 
windows may be brought forward no sooner than 14 days or 
extended up to 28 days upon specific guidance from the sponsor. 
For 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/shipment records of study intervention and relevant communications, 
including delegation, should be filed with site study records.

Source documents generated at a location other than the study site should be part 
of the investigator’s source documentation and should be transferred to the site in 
a secure and timely manner.

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10.15.
Appendix 15: Abbreviations
Term
Definition
ADA
anti-drug antibodies
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the participant is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the participant are not.
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the subjects 
are aware of the treatment received.
BMI
body mass index
C-SSRS
Columbia-Suicide Severity Rating Scale
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.
CRP
clinical research physician: Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician and global safety 
physician or other medical officer.
CRS
clinical research scientist: Individual responsible for the medical conduct of the study as 
same as CRP
CT
computerized tomography
device deficiencies
Equivalent to product complaint
DM
diabetes mellitus
DNA
deoxyribonucleic acid
EAS
Efficacy Analysis Set
ECG
electrocardiogram

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eCRF
electronic case report form
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.
EQ-5D-5L
EuroQol – 5 Dimension – 5 Level
ERB
ethical review board
FAS
Full Analysis Set
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GI
gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide
GIPR
glucose-dependent insulinotropic polypeptide receptor
GLP-1
glucagon-like peptide-1
GLP-1R
glucagon-like peptide-1 receptor
HbA1c
hemoglobin A1c
HFF
hepatic fat fraction
hsCRP
high-sensitivity C-reactive protein
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IGT
impaired glucose tolerance
informed consent
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate. Informed consent is 
documented by means of a written, signed and dated informed consent form.
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.

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investigational 
product (IP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IRB
Institutional Review Board
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.
IWQOL-Lite-CT
Impact of Weight on Quality of Life-Lite Clinical Trials Version
IWRS
interactive web-response system
JASSO
Japan Society for the Study of Obesity
mITT
modified intention-to-treat
MMRM
mixed model for repeated measures
MRI
magnetic resonance imaging
NAFLD
non-alcoholic fatty liver disease
NASH
nonalcoholic steatohepatitis
OGTT
oral glucose tolerance test
participant
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control
PDFF
proton density fat fraction
PGIS
Patient Global Impression of Status for Physical Activity
PHQ-9
Patient Health Questionnaire-9
PK/PD
pharmacokinetics/pharmacodynamics
QTc
corrected QT interval
QTL
quality tolerance limit
QW
once weekly
SAE
serious adverse event
SAP
statistical analysis plan

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SAT
subcutaneous adipose tissue
SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SD
standard deviation
SF-36v2
Short-Form 36-item Health Survey Version 2
SS
Safety Analysis Set
T2DM
type 2 diabetes mellitus
TBL
total bilirubin
TE
treatment-emergent
TEAE
Treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
TG
triglyceride
ULN
upper limit of normal
VAS
visual analog scale
VAT
visceral adipose tissue

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Protocol I8F-JE-GPHZ(b)
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10.16.
Appendix 16: Protocol Amendment History
Amendment [a]
Overall Rationale for the Amendment:
The correction of inclusion criteria is the primary driver for this amendment.
Section # and Name
Description of Change
Brief Rationale
5.1
Inclusion Criteria
Inclusion criteria 2a has been 
updated from 
“…, and/or OGTT 2-hour glucose of 
≥140 mg/dL…” 
to 
“…and OGTT 2-hour glucose of 
≥140 mg/dL….”
This corrects an error in the 
original protocol.
8.1.2.9.5.1
Meal Intake
The object of vendor calculation has 
been changed from “percentage” to 
“volume.”
This addition is made to 
clarify protocol procedure.
10.1.7
Data Quality 
Assurance
Languages about quality tolerance 
limits has been added.
This addition is made to 
clarify protocol procedure.
10.5
Contraceptive 
Guidance and 
Collection of 
Pregnancy Information
The definition of still birth has been 
changed from “at >20 weeks 
gestational age” to “at ≥20 weeks 
gestational age.”
This corrects an error in the 
original protocol.
10.15
Abbreviations
Definition of QTL is added.
This addition is made to keep 
alignment with the change.
Protocol header
Study alias in the header has been 
changed from “I8F-MC-GPHZ” to 
“Protocol I8F-JE-GPHZ.”
This corrects an error in the 
original protocol.

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11.
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asurements.pdf. 

Leo Document ID = 31b4518a-697d-4f5b-8fb8-f552f96cfc73
Approver: 
Approval Date & Time: 11-Jun-2021 01:08:18 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 11-Jun-2021 04:28:51 GMT
Signature meaning: Approved
PPD
PPD