Conditions: Obesity Overweight
Keywords: Metabolism and Nutrition Disorder Prediabetes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 783
Healthy volunteers: no

Brief summary:
This was a study of tirzepatide in participants with obesity or overweight. The main purpose was to learn more about how tirzepatide maintained body weight loss. The study had two phases: a lead-in phase in which all participants took tirzepatide and a treatment phase in which participants either continued tirzepatide or switched to placebo. The study lasted about 2 years (25 visits).

Detailed description:

Arms:
arm 1: Participants received weekly doses of tirzepatide subcutaneously (SC) for 36 weeks, starting at 2.5 milligrams (mg) and increasing by 2.5 mg every 4 weeks, as tolerated, up to the maximum tolerated dose (MTD) of either 10 mg or 15 mg. arm 2: Participants continued tirzepatide MTD (either 10 mg or 15 mg) for an additional 52 weeks. arm 3: Participants received weekly doses of placebo SC for 52 weeks.

Interventions: intervention 1: Tirzepatide intervention 2: Placebo
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol document:
Prot_000.pdf: 
 
 
 
Protocol: I8F-MC-GPHN 
 
 
Efficacy and Safety of Tirzepatide Once Weekly versus Placebo for 
Maintenance of Weight Loss in Participants without Type 2 Diabetes Who 
Have Obesity or Are Overweight with Weight-Related Comorbidities: A 
Randomized, Double-Blind, Placebo-Controlled Trial (SURMOUNT-4) 
 
 
NCT04660643 
 
 
Approval Date: 17-Nov-2020 


CONFIDENTIAL
Protocol I8F-MC-GPHN
1
Title Page
Confidential Information
   The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of tirzepatide (LY3298176), unless such persons around by a confidentiality agreement with Eli Lilly and Company or 
its subsidiaries. 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release.
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries.
Protocol Title: Efficacy and Safety of Tirzepatide Once Weekly versus Placebo for Maintenance 
of Weight Loss in Participants without Type 2 Diabetes Who Have Obesity or Are Overweight 
with Weight-Related Comorbidities: A Randomized, Double-Blind, Placebo-Controlled Trial 
(SURMOUNT-4)
Protocol Number: I8F-MC-GPHN
Amendment Number: This is the initial protocol.
Compound: LY3298176
Study Phase: 3
Short Title: Effect of Tirzepatide versus Placebo for Maintenance of Weight Loss 
(SURMOUNT-4)
Acronym: SURMOUNT-4
Sponsor Name: Eli Lilly and Company
Legal Registered Address: Indianapolis, Indiana USA  46285 
Regulatory Agency Identifier Number(s)
IND: 139721
Approval Date: Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 17-Nov-2020 GMT


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


CONFIDENTIAL
Protocol I8F-MC-GPHN
3
Table of Contents
1.
Protocol Summary......................................................................................................6
1.1.
Synopsis.......................................................................................................................6
1.2.
Schema.......................................................................................................................12
1.3.
Schedule of Activities (SoA) ......................................................................................13
2.
Introduction..............................................................................................................19
2.1.
Study Rationale ..........................................................................................................19
2.2.
Background ................................................................................................................20
2.3.
Benefit/Risk Assessment ............................................................................................21
3.
Objectives and Endpoints.........................................................................................22
4.
Study Design .............................................................................................................25
4.1.
Overall Design............................................................................................................25
4.1.1.
Overview of Study Periods .........................................................................................25
4.1.2.
Study Procedures........................................................................................................29
4.2.
Scientific Rationale for Study Design .........................................................................29
4.3.
Justification for Dose..................................................................................................31
4.4.
End of Study Definition..............................................................................................31
5.
Study Population ......................................................................................................32
5.1.
Inclusion Criteria........................................................................................................32
5.2.
Exclusion Criteria.......................................................................................................34
5.3.
Lifestyle Considerations .............................................................................................38
5.3.1.
Meals and Dietary Restrictions ...................................................................................38
5.3.2.
Physical Activity ........................................................................................................39
5.4.
Screen Failures ...........................................................................................................39
6.
Study Intervention....................................................................................................40
6.1.
Study Intervention(s) Administered ............................................................................40
6.1.1.
Medical Devices.........................................................................................................40
6.2.
Preparation/Handling/Storage/Accountability.............................................................41
6.3.
Measures to Minimize Bias: Randomization and Blinding..........................................41
6.4.
Study Intervention Compliance...................................................................................42
6.5.
Concomitant Therapy .................................................................................................42
6.6.
Dose Modification......................................................................................................43
6.6.1.
Tirzepatide .................................................................................................................43
6.6.2.
Management of Participants with Gastrointestinal Symptoms.....................................43
6.7.
Intervention after the End of the Study........................................................................43
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal....................................................................................44
7.1.
Discontinuation of Study Intervention ........................................................................44
7.1.1.
Temporary Discontinuation ........................................................................................46
7.2.
Participant Discontinuation/Withdrawal from the Study .............................................46
7.2.1.
Participant Disposition and Timing of Safety Follow-Up............................................48
7.2.2.
Discontinuation of Inadvertently Enrolled Participants ...............................................49


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Protocol I8F-MC-GPHN
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7.3.
Lost to Follow-up .......................................................................................................49
8.
Study Assessments and Procedures .........................................................................50
8.1.
Efficacy Assessments .................................................................................................50
8.1.1.
Primary Efficacy Assessments....................................................................................50
8.1.2.
Secondary Efficacy Assessments ................................................................................50
8.1.3.
Patient-Reported Outcomes Assessments....................................................................50
8.2.
Safety Assessments ....................................................................................................52
8.2.1.
Physical Examinations................................................................................................52
8.2.2.
Vital Signs..................................................................................................................52
8.2.3.
Electrocardiograms.....................................................................................................52
8.2.4.
Clinical Safety Laboratory Assessments .....................................................................53
8.2.5.
Safety Monitoring.......................................................................................................53
8.2.6.
Depression, Suicidal Ideation, and Behavior Risk Monitoring.....................................56
8.3.
Adverse Events, Serious Adverse Events, and Product 
Complaints .................................................................................................................56
8.3.1.
Timing and Mechanism for Collecting Events ............................................................57
8.3.2.
Special Safety Topics .................................................................................................59
8.4.
Treatment of Overdose ...............................................................................................64
8.5.
Pharmacokinetics........................................................................................................64
8.6.
Pharmacodynamics.....................................................................................................64
8.7.
Genetics .....................................................................................................................64
8.8.
Biomarkers.................................................................................................................64
8.9.
Immunogenicity Assessments.....................................................................................65
8.10.
Health Economics.......................................................................................................66
9.
Statistical Considerations.........................................................................................67
9.1.
Statistical Hypotheses.................................................................................................67
9.2.
Sample Size Determination.........................................................................................67
9.3.
Populations for Analyses ............................................................................................68
9.4.
Statistical Analyses.....................................................................................................68
9.4.1.
General Considerations...............................................................................................68
9.4.2.
Treatment Group Comparability .................................................................................69
9.4.3.
Efficacy Analyses.......................................................................................................69
9.4.4.
Other Safety Analyse(s)..............................................................................................71
9.4.5.
Evaluation of Immunogenicity....................................................................................72
9.4.6.
Other Analyse(s).........................................................................................................73
9.5.
Interim Analyses.........................................................................................................73
9.6.
Data Monitoring Committee (DMC)...........................................................................73
10.
Supporting Documentation and Operational Considerations ................................74
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................................74
10.1.1.
Regulatory and Ethical Considerations........................................................................74
10.1.2.
Informed Consent Process ..........................................................................................75
10.1.3.
Data Protection...........................................................................................................75
10.1.4.
Committees Structure .................................................................................................75
10.1.5.
Dissemination of Clinical Study Data .........................................................................76


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Protocol I8F-MC-GPHN
5
10.1.6.
Data Quality Assurance ..............................................................................................76
10.1.7.
Source Documents......................................................................................................77
10.1.8.
Study and Site Start and Closure.................................................................................77
10.1.9.
Publication Policy.......................................................................................................78
10.2.
Appendix 2: Clinical Laboratory Tests........................................................................79
10.3.
Appendix 3: Laboratory Assessments for Hypersensitivity 
Events ........................................................................................................................82
10.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.......................................................84
10.4.1.
Definition of AE.........................................................................................................84
10.4.2.
Definition of SAE.......................................................................................................85
10.4.3.
Definition of a Product Complaint ..............................................................................86
10.4.4.
Recording and Follow-Up of AE and/or SAE and Product 
Complaints .................................................................................................................86
10.4.5.
Reporting of SAEs......................................................................................................88
10.4.6.
Regulatory Reporting Requirements ...........................................................................89
10.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information ...............................................................................................90
10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-Up 
Assessments ...............................................................................................................94
10.7.
Appendix 7: Protocol GPHN Standardized Protocols for the 
Measurement of Height, Weight, Waist Circumference, Vital 
Signs, and Electrocardiogram .....................................................................................96
10.8.
Appendix 8: Suggested Visit Structure........................................................................98
10.9.
Appendix 9: Management of Gastrointestinal Symptoms............................................99
10.10.
Appendix 10: Provisions for Changes in Study Conduct During 
Exceptional Circumstances.......................................................................................100
10.11.
Appendix 11: Abbreviations .....................................................................................104
11.
References...............................................................................................................109


CONFIDENTIAL
Protocol I8F-MC-GPHN
6
1.
Protocol Summary
1.1.
Synopsis
Protocol Title: Efficacy and Safety of Tirzepatide Once Weekly versus Placebo for Maintenance 
of Weight Loss in Participants without Type 2 Diabetes Who Have Obesity or Are Overweight 
with Weight-Related Comorbidities: A Randomized, Double-Blind, Placebo-Controlled Trial 
(SURMOUNT-4)
Short Title: Effect of Tirzepatide versus Placebo for Maintenance of Weight Loss 
(SURMOUNT-4)
Rationale:
Obesity is a chronic disease and its increasing prevalence is a public health concern associated 
with rising incidence of Type 2 diabetes mellitus (T2DM), increased risk for premature death, 
and increased risk for some cancers (American Medical Association [AMA] 2013; Council on 
Science and Public Health 2013; Lauby-Secretan et al. 2016). Although loss of 5% to 10% body 
weight through lifestyle approaches, based on caloric restriction, physical activity, and 
behavioral therapy, has been shown to reduce obesity-related cardiovascular risk factors, and in 
some cases improve health-related quality of life (Mertens and Van Gaal 2000; Knowler et al. 
2002; Jensen et al. 2014; Kolotkin and Andersen 2017), lifestyle therapies alone fail to achieve 
sustainable weight loss in the majority of patients with obesity (Dombrowski et al. 2014). Caloric 
restriction, for example, has been shown to lead to metabolic adaptive responses, including 
increases in hunger hormones, decreases in satiety factors (including gastrointestinal [GI] 
peptides), increased appetitive drive and food intake, and lower energy expenditure (Leibel et al.
1995; Sumithran et al. 2011). These adaptations are thought to work in concert to cause regain 
and poor durability of treatment.
The gut incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-
like peptide-1 (GLP-1), are secreted after meal ingestion and mediate the incretin effect. Both 
hormones have effects on endocrine cells in the pancreas, increasing insulin biosynthesis and 
secretion, and modifying glucagon secretion (Skow et al. 2016). Based on these properties, 
several GLP-1 receptor (GLP-1R) agonists have been approved for pharmacological treatment of 
T2DM (Tomlinson et al. 2016).
In addition to its pancreatic effects, GLP-1R activation decreases gut motility, slows gastric 
emptying, and promotes satiety (presumably through a combination of GLP-1R activation in the 
central and peripheral nervous systems), thereby regulating food intake and body weight (Baggio 
and Drucker 2007). The US Food and Drug Administration and the European Medicines Agency 
approved the GLP-1R agonist liraglutide for the treatment of overweight and obesity 
(SAXENDA® package insert, 2014; SAXENDA summary of product characteristics, 2015).
Preclinical data indicate that GIP also exerts effects on appetite regulation and food intake,
adipose tissue, and peripheral energy metabolism. Although studies evaluating effects of GIP on 
body weight have yielded equivocal results, GIP receptor (GIPR) activation may play a role in 
body weight regulation, and targeting both the GLP-1R and the GIPR simultaneously could 


CONFIDENTIAL
Protocol I8F-MC-GPHN
7
potentially 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 GIPR and GLP-1R agonist. Its structure is 
based on the GIP sequence and includes a C20 fatty diacid moiety (Coskun et al. 2018). It is 
administered once weekly (QW) by subcutaneous injection.
As a dual GIP/GLP-1R agonist, tirzepatide could exceed the efficacy of selective GLP-1R 
agonists by recruiting metabolically active tissues not targeted by selective GLP-1R agonists (for 
example, adipose tissue as indicated by the observation of increased energy utilization) (Müller
et al. 2018) and has the potential to reach higher efficacy in target tissues that express both GIPR 
and GLP-1R. Therefore, tirzepatide has the potential to impact several aspects of energy 
regulation and to be a treatment for overweight and obesity. 
In a 26-week Phase 2 study in patients with T2DM, tirzepatide 10-mg and 15-mg doses produced 
statistically significant and clinically relevant weight loss compared to placebo and compared to 
the GLP-1R agonist, dulaglutide. While tirzepatide is subsequently being evaluated in Phase 3 
studies in patients with obesity for its effects on weight loss, this study aims to evaluate the effect 
of tirzepatide on weight maintenance. Because obesity is a chronic relapsing progressive disease
(Bray et al. 2017), the impact of a therapy on weight maintenance in addition to weight loss 
enables a more complete understanding of its benefit and helps to inform decisions on duration 
of therapy.
Although there is increasing recognition that adjunctive therapies to lifestyle modification, 
including pharmacotherapy, may be required to improve outcomes in patients with obesity
(AMA 2013; Apovian et al. 2015), determining the duration of therapy has not been approached 
consistently across all health systems. Obesity management guidelines recommend that 
pharmacologic interventions be continued if patients achieve at least 3% to 5% body weight loss 
during an initial period, yet there is little consensus as to the total duration of therapy or whether 
there may be a rationale for continuation of therapy to prevent weight regain, even after weight 
loss goals are achieved (Garvey et al. 2016).
Study I8F-MC-GPHN (GPHN; SURMOUNT-4) is a Phase 3, multicenter, randomized, 
parallel-arm, double-blind, placebo-controlled, 88-week study that will investigate the impact of  
maximum tolerated dose (MTD) of tirzepatide (10 mg or 15 mg QW), compared with placebo,
on the maintenance of weight loss after an initial 36-week open-label tirzepatide lead-in
treatment period, in study participants who do not have T2DM, and have obesity (body mass 
index [BMI] ≥30 kg/m2) or are overweight (BMI ≥27 kg/m2) with at least 1 weight-related 
comorbid condition.


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Protocol I8F-MC-GPHN
8
Objectives and Endpoints
Objectives
Endpoints
Primary
To demonstrate that tirzepatide MTD is 
superior to placebo for percent change in body 
weight at Week 88 

Mean percent change in body weight from 
randomization (Week 36) to 88 weeks
Key Secondary (controlled for type I error)
To demonstrate that tirzepatide MTD is 
superior to placebo in change from 
randomization (Week 36) for the following 
(measured at 88 weeks): 

Body weight 

Mean change in body weight (kg)

Waist circumference 

Mean change in waist circumference (cm)

Maintaining body weight reduction 
achieved during the 36-week
open-label period

Percentage of participants who maintain ≥80% of the 
body weight lost during the 36 weeks of open-label 
period
To demonstrate that tirzepatide MTD is 
superior to placebo in change from Visit 2 
(Week 0) for the following:

Body weight

Prevention of weight regain 
following the 36 weeks of open-label 
period
To demonstrate that tirzepatide MTD is 
superior to placebo in change from 
randomization (Week 36) for percent change 
in body weight at Week 64

Percentage of study participants who achieve 
≥5% body weight reduction at 88 weeks 

Percentage of study participants who achieve 
≥10% body weight reduction at 88 weeks

Time (in weeks), during the 52-week double-blind 
treatment period, to first occurrence of participants 
returning to >95% baseline weight for those who have 
already lost ≥5% since Week 0  

Mean percent change in body weight from 
randomization (Week 36) to 64 weeks


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Protocol I8F-MC-GPHN
9
Objectives
Endpoints
Additional Secondary
To demonstrate that tirzepatide MTD is 
superior to placebo in change from 
randomization (Week 36) for the following 
(measured at 88 weeks): 

BMI

Glycemic control

Insulin

Mean change in BMI (kg/m2)

Mean change in:
o
Fasting glucose (mg/dL)
o
HbA1c (%)

Mean change in fasting insulin (pmol/L)

Lipid parameters 

Mean change in: 
o
Total cholesterol (mg/dL)
o
LDL-cholesterol (mg/dL)
o
HDL-cholesterol (mg/dL)
o
VLDL-cholesterol (mg/dL)
o
Triglycerides (mg/dL)
o
Free Fatty acids (mg/dL)

Blood pressure 

Mean change in 
o
systolic blood pressure (mmHg)
o
diastolic blood pressure (mmHg)

Patient-Reported Outcomes 

Mean change in SF-36 v2 acute form Physical
Functioning domain score

Mean change in IWQOL-Lite-CT Physical Function 
composite score
To demonstrate that tirzepatide MTD is 
superior to placebo in change from Visit 2 
(Week 0) for the following (measured at 
88 weeks) for: 

Body weight 

Mean change in body weight (kg)

Mean percent change in body weight (%)

Mean change in BMI (kg/m2)

Percentage of study participants who achieve
≥15% body weight reduction

Waist circumference

Mean change in waist circumference (cm)


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Protocol I8F-MC-GPHN
10
Objectives
Endpoints

Glycemic control

Insulin

Lipid parameters 

Mean change in:
o
Fasting glucose (mg/dL)
o
HbA1c (%)

Mean change in fasting insulin (pmol/L)

Mean change in:
o
Total cholesterol (mg/dL)
o
LDL-cholesterol (mg/dL)
o
HDL-cholesterol (mg/dL)
o
VLDL-cholesterol (mg/dL)
o
Triglycerides (mg/dL)
o
Free fatty acids (mg/dL)

Blood pressure

Mean change in 
o
systolic blood pressure (mmHg)
o
diastolic blood pressure (mmHg)

Patient-Reported Outcomes 

Mean change in SF-36 v2 acute form Physical
Functioning domain score

Mean change in IWQOL-Lite-CT Physical Function 
composite score
Abbreviations: BMI = body mass index; HbA1c = hemoglobin A1c, HDL = high-density lipoprotein; IWQOL-Lite-
CT = Impact of Weight on Quality of Life-Lite-Clinical Trials Version; LDL = low-density lipoprotein; 
MTD = maximum tolerated dose; SF-36 v2 acute form = Short Form-36 Version 2 Health Survey acute form; 
VLDL = very low-density lipoprotein.
Overall Design
Study GPHN is a Phase 3, multicenter, randomized, parallel-arm, double-blind, 
placebo-controlled, 88-week study that will investigate the impact of MTD of tirzepatide (10 mg 
or 15 mg QW), compared with placebo, on the maintenance of weight loss after an initial 
36-week open-label tirzepatide lead-in treatment period, in study participants who do not have
T2DM, and have obesity (BMI ≥30 kg/m2) or are overweight (BMI ≥27 kg/m2) with at least 
1 weight-related comorbid condition.
Randomization at the end of the open-label lead-in treatment period will be stratified by country, 
tirzepatide MTD (10 mg versus 15 mg), percent weight loss at 36 weeks (<10% versus ≥10%), 
and sex.
Disclosure Statement: This is a study including 2 parallel treatment arms (tirzepatide MTD 
versus placebo) that is participant- and investigator-blinded.
Number of Participants:
Approximately 1000 participants will be screened and 750 participants enrolled into the 36-week 
open-label tirzepatide lead-in treatment period (including a 20-week dose-escalation period) in 
order to get approximately 600 participants to be randomized in a 1:1 ratio to tirzepatide MTD 


CONFIDENTIAL
Protocol I8F-MC-GPHN
11
(300 participants) or placebo (300 participants). An upper limit of 70% enrollment of women 
will be used to ensure a sufficiently large sample of men.
Intervention Groups and Duration:
Study participants will be randomized in a 1:1 ratio (tirzepatide MTD QW and placebo QW), 
stratified by country, tirzepatide MTD (10 mg versus 15 mg), percent weight loss at 36 weeks 
(<10% versus ≥10%), and sex.
Study GPHN will consist of 4 periods: a 2-week screening period; a 36-week open-label 
tirzepatide lead-in treatment period (including a 20-week dose-escalation period); a 52-week 
double-blind, placebo-controlled treatment period; and a 4-week safety follow-up period.
Data Monitoring Committee: No


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Protocol I8F-MC-GPHN
12
1.2.
Schema
Abbreviations: MTD = maximum tolerated dose, QW = once weekly; (T) = telephone visit.


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Protocol I8F-MC-GPHN
13
1.3.
Schedule of Activities (SoA)
The Schedule of Activities (SoA) described below should be followed for all participants enrolled in Study GPHN. However, for those 
participants whose participation in this study is affected by exceptional circumstances (such as pandemics or natural disasters), please 
refer to Section 10.10 (Appendix 10) for additional guidance.
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
99
ED
801
Week of Treatment
-2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
84
88
88
4 wks 
post end 
of TxP
Allowable Interval 
Tolerance (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±3
Fasting Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
X
X
Informed consent
X
Inclusion and exclusion 
criteria review
X
X
Preexisting conditions and 
medical history, including 
relevant surgical history
X
Medical history includes assessment of preexisting conditions (for example, history of gallbladder disease, cardiovascular disease, and medullary
thyroid carcinoma) and substance usage (such as alcohol and tobacco).
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events and product 
complaints
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Evaluation or Clinical Assessments
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight measurements should be obtained per the detailed protocol guidance in Section 10.7. Body weight must be measured in the fasting 
state. If the participant is not fasting, the participant should be called in for a new visit within the visit window to have the fasting body weight 
measured.
Waist circumference
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs (systolic and 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


CONFIDENTIAL
Protocol I8F-MC-GPHN
14
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
99
ED
801
Week of Treatment
-2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
84
88
88
4 wks 
post end 
of TxP
Allowable Interval 
Tolerance (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±3
Fasting Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
X
X
diastolic blood pressure, 
pulse rate)
Vital sign measurements should be taken before obtaining an ECG tracing and before collection of blood samples for laboratory testing, per the 
instructions in Section 10.7. 
Physical examination
X
Electrocardiogram
X
X
X
X
X
ECG measurements should be obtained per the instructions in Section 10.7. ECGs should be collected at least 30 minutes prior to collection of 
blood samples for laboratory testing, including PK samples.
Participant Education and Assessment
Lifestyle Program Instruction
X
X
X
X
X
X
X
X
X
X
X
X
Counseling on diet and exercise, to be performed by a dietician or equivalent qualified delegate, to include calculation of individualized energy 
requirement and methods to change dietary composition and amount of physical activity. The Lifestyle Program Instruction may be delivered on 
a separate day from the rest of that visit’s study procedures but must occur within the visit window. Beginning at Week 8, the Lifestyle Program 
Instruction may be delivered by phone.
Review diet and exercise 
goals
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
All training should be repeated as needed to encourage participant compliance. Study personnel to provide reinforcement and encouragement 
for lifestyle modifications.
Injection training with 
autoinjector 
demonstration device
X
Participant Diary (paper)
Dispense diary; instruct in
use
X
X
X
X
X
X
X
X
X
X
X
X
X
X
All training should be repeated as needed to encourage participant compliance.


CONFIDENTIAL
Protocol I8F-MC-GPHN
15
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
99
ED
801
Week of Treatment
-2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
84
88
88
4 wks 
post end 
of TxP
Allowable Interval 
Tolerance (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±3
Fasting Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
X
X
Diary review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient-Reported Outcomes
PGIs
X
X
X
X
X
SF-36 v2, acute form
X
X
X
X
X
IWQOL-Lite-CT
X
X
X
X
X
EQ-5D-5L
X
X
X
X
Mental Health Questionnaires
PHQ-9
X
X
X
X
X
X
X
X
X
X
X
X
PHQ-9 is self-administered and should be completed after assessment of adverse events.
C-SSRS (Baseline/Screening 
Version)
X
The C-SSRS should be administered after assessment of adverse events. For this study, the C-SSRS is adapted for the assessment of the ideation 
and behavior categories only. The Intensity of Ideation and Lethality of Behavior sections are removed.
C-SSRS (Since Last Visit 
Version)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
The C-SSRS should be administered after assessment of adverse events and capture information since most recent C-SSRS administration. For 
this study, the C-SSRS is adapted for the assessment of the ideation and behavior categories only. The Intensity of Ideation and Lethality of 
Behavior sections are removed.
Self-Harm Supplement Form
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
The Self-Harm supplement form should be administered after assessment of adverse events. 


CONFIDENTIAL
Protocol I8F-MC-GPHN
16
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
99
ED
801
Week of Treatment
-2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
84
88
88
4 wks 
post end 
of TxP
Allowable Interval 
Tolerance (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±3
Fasting Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
X
X
Self-Harm Follow-up Form
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Self-Harm Follow-up Form is only required if triggered by the Self-Harm Supplement Form, per instructions in the form.
Laboratory Tests and Sample Collections
Hematology
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
X
X
X
Chemistry panel (includes Cr 
for eGFR calculation and 
glucose)
X
X
X
X
X
X
X
X
X
X
X
The CKD-EPI equation will be used by the central lab to estimate and report eGFR.
Insulin
X
X
X
X
X
X
X
X
X
X
C-peptide
X
X
X
X
X
X
X
X
X
X
Lipid panel
X
X
X
X
X
X
X
Free fatty acids
X
X
X
X
X
X
X
Serum pregnancy 
X
For women of childbearing potential only
Urine pregnancy (local)
X
X
X
X
X
X
X
X
X
A urine pregnancy test must be performed at Visit 2 with the result available prior to first injection of study drug(s) for women of childbearing 
potential only. Additional pregnancy tests (beyond those required per the SoA) should be performed at any time during the trial if a menstrual 
period is missed, there is clinical suspicion of pregnancy, or as required by local law or regulation.
Follicle-stimulating 
Hormone (FSH)
X
Follicle-stimulating hormone test is to be performed at Visit 1 for postmenopausal women at least 40 years of age with an intact uterus, not on
hormone therapy, and who have had spontaneous amenorrhea for more than 1 year without an alternative medical cause.
Calcitonin
X
X
X
X
X
X
X
Pancreatic amylase
X
X
X
X
X
X
X


CONFIDENTIAL
Protocol I8F-MC-GPHN
17
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
99
ED
801
Week of Treatment
-2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
84
88
88
4 wks 
post end 
of TxP
Allowable Interval 
Tolerance (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±3
Fasting Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
X
X
Lipase
X
X
X
X
X
X
X
Urinary albumin/ 
creatinine ratio
X
X
X
X
X
Cystatin-c
X
X
X
X
X
Thyroid-stimulating hormone
(TSH)
X
Immunogenicity (includes PK 
sample)
X
X
X
X
X
X
X
X
X
X
In the event of systemic drug hypersensitivity reactions (immediate or nonimmediate), additional unscheduled samples should be collected as 
detailed in Section 8.3.2.7 (Hypersensitivity Reactions). Immunogenicity samples and PK samples for immunogenicity must be taken prior to drug 
administration.
Stored Samples
Pharmacogenetic sample
X
Nonpharmacogenetic 
sample
X
X
X
X
X
X
X
Randomization and Dosing
Randomization
X
Dispense study 
intervention(s)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Observe participant 
administer study 
intervention(s)
X
Patients should administer their first dose of study drug at the end of Visit 2, after other study procedures are completed.


CONFIDENTIAL
Protocol I8F-MC-GPHN
18
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
99
ED
801
Week of Treatment
-2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
80
84
88
88
4 wks 
post end 
of TxP
Allowable Interval 
Tolerance (days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±3
Fasting Visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Telephone Visit
X
X
X
X
X
X
X
X
Participant returns study 
interventions and injection 
supplies
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess study 
intervention(s) compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: CKD-EPI = Chronic Kidney Disease-Epidemiology; C-SSRS = Columbia-Suicide Severity Rating Scale; Cr = creatinine; 
ECG = electrocardiogram; ED = early discontinuation; eGFR = estimated glomerular filtration rate; HbA1c = hemoglobin A1c; IWQOL-Lite-CT = Impact of 
Weight on Quality of Life-Lite-Clinical Trials Version; PGIs = Patient Global Impression of status for physical activity; PHQ-9 = Patient Health 
Questionnaire-9; PK = pharmacokinetics; SF-36 v2 acute = Short Form-36 Version 2 Health Survey acute form; TxP = treatment period; wks = weeks. 
Note:

Visit 2 baseline assessments must be completed before processing in the interactive web-response system (IWRS).

The visit date is determined in relation to the date of Visit 2 (± the visit interval tolerance).

Visit 99 is only applicable to participants who discontinue the double-blind study treatment prematurely (after Week 36 and before Week 88) and 
decline to complete the remaining scheduled study visits. Participants wanting to discontinue the study treatment after randomization and before 
Week 88 will be asked to return for Visit 99 (88 weeks ± 7 days after Visit 2) primarily for body weight measurement and assessment of adverse events. 
If the participant is unwilling to attend Visit 99, it should be documented in the participant medical record that the participant has refused to attend. 

Participants who are unable or unwilling to continue the study 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 an ED visit.   

For all office visits, remind participants to report to the site in a fasting condition, after a period of approximately 8 hours without eating, drinking 
(except water), or any significant physical activity. Since some screening procedures need to be completed in the fasting state, Visit 1 may be conducted 
over more than 1 day to ensure necessary conditions are met.

Visit 801 (safety follow-up visit) should be performed 4 weeks after the last visit of the participant’s treatment period. 


CONFIDENTIAL
Protocol I8F-MC-GPHN
19
2.
Introduction
Obesity is a chronic disease and its increasing prevalence is a public health concern associated 
with rising incidence of Type 2 diabetes mellitus (T2DM), increased risk for premature death, 
and increased risk for some cancers (American Medical Association [AMA] 2013; Council on 
Science and Public Health 2013; Lauby-Secretan et al. 2016). Although loss of 5% to 10% body 
weight through lifestyle approaches, based on caloric restriction, physical activity, and 
behavioral therapy, has been shown to reduce obesity-related cardiovascular risk factors, and in 
some cases, improve health-related quality of life (HRQoL) (Mertens and Van Gaal 2000; 
Knowler et al. 2002; Jensen et al. 2014; Kolotkin and Andersen 2017), lifestyle therapies alone 
fail to achieve sustainable weight loss in the majority of patients with obesity (Dombrowski et al. 
2014).
Caloric restriction, for example, has been shown to lead to metabolic adaptive responses, 
including increases in hunger hormones, decreases in satiety factors (including gastrointestinal 
[GI] peptides), increased appetitive drive and food intake, and lower energy expenditure (Leibel 
et al. 1995; Sumithran et al. 2011). These adaptations are thought to work in concert to cause 
regain and poor durability of treatment. The addition of physical activity is essential and can help 
maintain weight loss, but generally, maintaining lifestyle-induced weight loss is recognized as 
being more challenging than losing weight for individuals with obesity (Swift et al. 2018).
Pharmacologic agents, in contrast to voluntary caloric restriction, can directly impact the 
physiology of energy balance, including the regulation of food intake and/or energy expenditure,
to drive towards a lower fat mass and body weight (Heymsfield et al. 2018). Some current or 
previously marketed weight-management medications have had a demonstrable effect on 
maintaining initial weight loss over time while on treatment (James et al. 2000; Smith et al. 
2010; Wadden et al. 2013). There is increasing recognition that adjunctive pharmacotherapy may 
be required to improve weight loss, weight maintenance, and health outcomes in individuals with 
obesity (AMA 2013; Apovian et al. 2015).
2.1.
Study Rationale
The gut incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-
like peptide-1 (GLP-1), are secreted after meal ingestion and mediate the incretin effect.  
Both hormones have effects on endocrine cells in the pancreas, increasing insulin biosynthesis 
and secretion, stimulating beta-cell neogenesis and proliferation, and protecting beta cells from 
apoptosis. They also exert actions on alpha cells, modifying glucagon secretion (Skow et al. 
2016). Based on these properties, several GLP-1 receptor (GLP-1R) agonists have been approved 
for pharmacological treatment of T2DM (Tomlinson et al. 2016).
In addition to its pancreatic effects, GLP-1R activation decreases gut motility, slows gastric 
emptying, and promotes satiety (presumably through a combination of GLP-1R activation in the 
central and peripheral nervous systems), thereby regulating food intake and body weight (Baggio 
and Drucker 2007). The US Food and Drug Administration (FDA) and the European Medicines 
Agency (EMA) approved the GLP-1R agonist liraglutide for the treatment of overweight and 
obesity (SAXENDA package insert, 2014; SAXENDA summary of product, 2015).


CONFIDENTIAL
Protocol I8F-MC-GPHN
20
Preclinical data indicate that GIP also exerts effects on appetite regulation and food intake as 
well as on adipose tissue and peripheral energy metabolism. Although studies evaluating effects 
of GIP on body weight have yielded equivocal results, GIP receptor (GIPR) activation may play 
a role in body weight regulation and targeting both the GLP-1R and the GIPR simultaneously 
could potentially result in additive or synergistic effects of the 2 incretins on body weight 
(Coskun et al. 2018).
Tirzepatide is a 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 diacid moiety 
(Coskun et al. 2018). It is administered once weekly (QW) by subcutaneous (SC) injection. As a 
dual GIP/GLP-1R agonist, tirzepatide could exceed the efficacy of selective GLP-1R agonists by 
recruiting metabolically active tissues not targeted by selective GLP-1R agonists (for example, 
adipose tissue as indicated by the observation of increased energy utilization) (Müller et al. 
2018) and has the potential to reach higher efficacy in target tissues that express both GIPR and 
GLP-1R. Therefore, tirzepatide has the potential to impact several aspects of energy regulation 
and be a treatment for overweight and obesity.  
Obesity management guidelines recommend that pharmacologic interventions be continued if 
patients achieve at least 5% body weight loss during an initial treatment period (Apovian et al. 
2015). Prior studies with anti-obesity medications have demonstrated durability of initial weight 
loss while on treatment and regain after withdrawal of treatment, indicating a need to continue 
therapy to maintain its benefits (James et al. 2000; Smith et al. 2010). Despite this, there is poor 
adoption of obesity management guidelines by health care providers, low adherence to most 
anti-obesity medications among patients, and little consensus as to the total duration of 
pharmacotherapy across health care systems (Garvey et al. 2016; Ganguly et al. 2018; Turner et 
al. 2018).
Study I8F-MC-GPHN (GPHN; SURMOUNT-4) is a Phase 3, multicenter, randomized, 
parallel-arm, double-blind, placebo-controlled, 88-week study that will investigate the impact of 
maximum tolerated dose (MTD) of tirzepatide (10 mg or 15 mg QW), compared with placebo, 
on the maintenance of weight loss, in study participants who do not have T2DM, and have 
obesity (body mass index [BMI] ≥30 kg/m2) or are overweight (BMI ≥27 kg/m2) with at least 
1 weight-related comorbid condition.  
2.2.
Background
There remains an unmet need in the pharmacologic treatment of obesity for drugs that are safe, 
efficacious, and well-tolerated. There are currently only a few medications FDA-approved for 
long-term use for the treatment of obesity that yield a placebo-adjusted average weight loss 
between 3% and 7% (Srivastava and Apovian 2018, FDA 2020). Although moderate weight loss 
of 5% to 10% in individuals with obesity/overweight has long been shown to yield significant 
metabolic benefits, including improvements in cholesterol, blood pressure, and glucose 
parameters (Goldstein 1992; Wing et al. 2011), greater weight loss can maximize these benefits 
and may be required to realize clinically meaningful improvements in other obesity-related 
comorbidities such as sleep apnea, nonalcoholic steatohepatitis, and cardiovascular disease 
(Ryan et al. 2017). In addition to moderate efficacy, some centrally-acting weight loss agents to
date have had adverse neurocognitive, psychiatric, or cardiovascular effects, further limiting their 
application in clinical practice (Srivastava and Apovian 2018). 


CONFIDENTIAL
Protocol I8F-MC-GPHN
21
Weight loss induced by GLP-1R agonists, while appearing to be centrally-mediated through a 
combination of hormonal inputs to satiety centers (van Bloemendaal et al. 2014), has not been 
consistently associated with changes in mental health or with potential for addiction in long-term 
studies conducted to establish cardiovascular safety in patients with diabetes (Marso et al. 2016a,
2016b; Gerstein et al. 2019). Tirzepatide, which is both a GLP-1R and GIPR agonist, has been 
associated with predominantly mild-to-moderate GI adverse effects similar to currently marketed 
GLP-1R agonists, but has also demonstrated significant weight loss at both the 10-mg and 15-mg 
doses in Phase 2 studies with nearly half of the participants in both dose arms achieving 
>10% weight loss (Frias et al. 2018).
Tirzepatide dose selection for obesity treatment has been informed by 3 clinical trials: a Phase 1 
study, Study I8F-MC-GPGA (GPGA), and 2 Phase 2 studies, Study I8F-MC-GPGB (GPGB) and 
I8F-MC-GPGF (GPGF).  
Phase 1 Study GPGA was a combination of single-ascending dose (SAD) and 
multiple-ascending dose (MAD) study in healthy subjects followed by a multiple-dose study in 
patients with T2DM. A total of 142 participants (89 healthy subjects and 53 patients with T2DM) 
received at least 1 dose of treatment. Doses of tirzepatide ranged from:

0.25 mg to 8 mg in the SAD (with MTD achieved at 5 mg) in healthy subjects,

multiple doses in the MAD from 0.5 mg to 4.5 mg QW and titrated doses up to 10 mg QW 
for 4 weeks in healthy subjects, and

multiple-doses at 0.5 mg and 5 mg QW and titrated up to 15 mg QW for 4 weeks in patients 
with T2DM.  
The safety, tolerability, and pharmacokinetic/pharmacodynamic (PK/PD) profiles of tirzepatide 
at doses and escalation regimens administered in this Phase 1 study supported further 
development of tirzepatide for QW dosing in patients with T2DM.
Phase 2 Studies GPGB and GPGF provided initial safety, tolerability, and efficacy data in the 
tirzepatide 1-mg to 15-mg dose-range when used in treatment of patients with T2DM. In the dose 
range of 5 to 15 mg, tirzepatide provided significantly greater reductions in hemoglobin A1c
(HbA1c) and body weight compared with placebo. In addition, the 10-mg and 15-mg dose arms 
demonstrated significantly greater weight loss compared to the GLP-1R agonist dulaglutide 
1.5 mg QW. The most common adverse events (AEs), which were also dose-dependent, were 
mild-to-moderate nausea, vomiting, and diarrhea. Study GPGF showed that adjustments in the 
tirzepatide dose-escalation algorithm resulted in additional reductions in the frequency of GI AEs 
and reduced the frequency of treatment discontinuations due to GI AEs. 
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of tirzepatide may be found in the Investigator’s Brochure (IB).


CONFIDENTIAL
Protocol I8F-MC-GPHN
22
3.
Objectives and Endpoints
Objectives
Endpoints
Primary
To demonstrate that tirzepatide MTD is 
superior to placebo for percent change in body 
weight at Week 88 

Mean percent change in body weight from 
randomization (Week 36) to 88 weeks
Key Secondary (controlled for type I error)
To demonstrate that tirzepatide MTD is 
superior to placebo in change from 
randomization (Week 36) for the following 
(measured at 88 weeks): 

Body weight 

Mean change in body weight (kg)

Waist circumference 

Mean change in waist circumference (cm)

Maintaining body weight reduction 
achieved during the 36-week
open-label period

Percentage of participants who maintain ≥80% of the 
body weight lost during the 36 weeks of open-label 
period
To demonstrate that tirzepatide MTD is 
superior to placebo in change from Visit 2 
(Week 0) for the following:

Body weight

Prevention of weight regain 
following the 36 weeks of open-label 
period
To demonstrate that tirzepatide MTD is 
superior to placebo in change from 
randomization (Week 36) for percent change 
in body weight at Week 64

Percentage of study participants who achieve 
≥5% body weight reduction at 88 weeks 

Percentage of study participants who achieve 
≥10% body weight reduction at 88 weeks

Time (in weeks), during the 52-week double-blind 
treatment period, to first occurrence of participants 
returning to >95% baseline weight for those who have 
already lost ≥5% since Week 0 

Mean percent change in body weight from 
randomization (Week 36) to 64 weeks


CONFIDENTIAL
Protocol I8F-MC-GPHN
23
Objectives
Endpoints
Additional Secondary
To demonstrate that tirzepatide MTD is 
superior to placebo in change from 
randomization (Week 36) for the following 
(measured at 88 weeks): 

BMI

Glycemic control

Insulin

Mean change in BMI (kg/m2)

Mean change in:
o
Fasting glucose (mg/dL)
o
HbA1c (%)

Mean change in fasting insulin (pmol/L)

Lipid parameters 

Mean change in: 
o
Total cholesterol (mg/dL)
o
LDL-cholesterol (mg/dL)
o
HDL-cholesterol (mg/dL)
o
VLDL-cholesterol (mg/dL)
o
Triglycerides (mg/dL)
o
Free Fatty acids (mg/dL)

Blood pressure 

Mean change in:
o
systolic blood pressure (mmHg)
o
diastolic blood pressure (mmHg)

Patient-Reported Outcomes 

Mean change in SF-36 v2 acute form Physical
Functioning domain score

Mean change in IWQOL-Lite-CT Physical Function 
composite score
To demonstrate that tirzepatide MTD is 
superior to placebo in change from Visit 2 
(Week 0) for the following (measured at 
88 weeks) for: 

Body weight 

Mean change in body weight (kg)

Mean percent change in body weight (%)

Mean change in BMI (kg/m2)

Percentage of study participants who achieve
≥15% body weight reduction

Waist circumference

Mean change in waist circumference (cm)

Glycemic control

Insulin

Mean change in:
o
Fasting glucose (mg/dL)
o
HbA1c (%)

Mean change in fasting insulin (pmol/L)


CONFIDENTIAL
Protocol I8F-MC-GPHN
24
Objectives
Endpoints

Lipid parameters 

Mean change in:
o
Total cholesterol (mg/dL)
o
LDL-cholesterol (mg/dL)
o
HDL-cholesterol (mg/dL)
o
VLDL-cholesterol (mg/dL)
o
Triglycerides (mg/dL)
o
Free fatty acids (mg/dL)

Blood pressure

Mean change in:
o
systolic blood pressure (mmHg)
o
diastolic blood pressure (mmHg)

Patient-Reported Outcomes 

Mean change in SF-36 v2 acute form Physical
Functioning domain score

Mean change in IWQOL-Lite-CT Physical Function 
composite score
Abbreviations: BMI = body mass index; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; IWQOL-Lite-
CT = Impact of Weight on Quality of Life-Lite-Clinical Trials Version; LDL = low-density lipoprotein; 
MTD = maximum tolerated dose; SF-36 v2 acute form = Short Form-36 Version 2 Health Survey acute form; 
VLDL = very low-density lipoprotein.


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Protocol I8F-MC-GPHN
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4.
Study Design
4.1.
Overall Design
Study GPHN is a Phase 3, multicenter, randomized, parallel-arm, double-blind, 
placebo-controlled, 88-week study that will investigate the impact of MTD of tirzepatide (10 mg 
or 15 mg QW), compared with placebo, on the maintenance of weight loss after an initial
36-week open-label tirzepatide lead-in treatment period, in study participants who do not have
T2DM, and have obesity (BMI ≥30 kg/m2) or are overweight (BMI ≥27 kg/m2) with at least 
1 weight-related comorbid condition.
Study GPHN will consist of 4 periods: a 2-week screening period; a 36-week open-label 
tirzepatide lead-in treatment period (including a 20-week dose-escalation period); a 52-week 
double-blind, placebo-controlled treatment period; and a 4-week safety follow-up period. The 
study participants will be randomized in a double-blind 1:1 ratio (tirzepatide MTD QW or 
placebo) at the end of the open-label lead-in treatment period. An upper limit of 70% enrollment 
of women will be used to ensure a sufficiently large sample of men. 
4.1.1.
Overview of Study Periods
4.1.1.1.
Visit Structure for Fasting Office Visits
On all designated fasting office visits, study participants are required to report to the site in a 
fasting condition, after a period of approximately 8 hours without eating, drinking (except 
water), or performing any significant physical activity. If a participant is adversely affected by 
the fasting condition, they are allowed to eat; however, specific study procedures need to be 
completed while fasting. See Section 10.8 for a suggested order of activities that occurs at office 
visits.  
4.1.1.2.
Main Study Period 
4.1.1.2.1. Screening Period
Visit 1
The purpose of screening procedures at Visit 1 is to establish initial eligibility and to obtain 
blood samples for laboratory assessments needed to confirm eligibility. The participant must sign 
the informed consent form (ICF) before the study procedures are performed, as outlined in the 
Schedule of Activities (SoA), Section 1.3. Since some screening procedures need to be 
completed in the fasting state (approximately 8 hours without eating, drinking [except water], or 
any significant physical activity), Visit 1 may be conducted over more than 1 day to ensure 
necessary conditions are met. Patient-reported outcomes (PROs) questionnaires should be 
administered as early as possible, as per Suggested Visit Structure (Section 10.8). Preferred 
administration order is:  
1. Patient Global Impression of status (PGIs) for physical activity 
2. Short Form-36 Version 2 Health Survey acute form (SF-36 v2 acute form)
3. Impact of Weight on Quality of Life-Lite-Clinical Trials Version (IWQOL-Lite-CT)


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Protocol I8F-MC-GPHN
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Participants who meet all applicable inclusion criteria and none of the applicable exclusion 
criteria at Visit 1 will continue to Visit 2. 
The Mental Health questionnaires (Patient Health Questionnaire-9 [PHQ-9], Columbia-Suicide 
Severity Rating Scale [C-SSRS], and C-SSRS Self-Harm Form) should be completed after the 
assessment for AEs.
4.1.1.2.2. Treatment Period
Open-Label Lead-In Treatment Period 
Visit 2
At Visit 2, eligible participants will perform all required baseline study procedures (including the 
collection of all baseline laboratory measures and questionnaires) prior to enrollment and prior to 
taking the first dose of study drug. Participants will be provided diaries and be trained to record 
key study information, as appropriate. 
Patient-reported outcomes questionnaires should be administered as early as possible, as per 
Suggested Visit Structure (Section 10.8). Preferred administration order is:  
1. PGIs for physical activity
2. SF-36 v2 acute form 
3. IWQOL-Lite-CT
4. EQ-5D-5L  
The Mental Health questionnaires (PHQ-9, C-SSRS, and C-SSRS Self-Harm Form) should be 
completed after the assessment for AEs.
Participants will receive an initial consultation with a dietician or equivalent qualified delegate, 
according to local standards, to set lifestyle goals for caloric intake and physical activity 
(Section 5.3).
End of Visit 2 to Visit 11
At the end of Visit 2, for participants that meet all the entry criteria and are enrolled in this study, 
study site personnel will demonstrate use of the autoinjector (also referred to as single-dose pen),
using the provided demonstration device and observe the study participant inject the first dose of 
tirzepatide. The date, time, and location of the first dose of study drug will be recorded on the 
electronic case report form (eCRF).  
After study enrollment, participants will undergo a 36-week open-label tirzepatide 
dose-escalation and lead-in treatment period (Visits 3 to 11 will occur as indicated in the SoA).
Patient-reported outcomes questionnaires should be administered as early as possible, as per 
Suggested Visit Structure (Section 10.8). Preferred administration order is the same as described 
for Visit 2. Mental Health questionnaires should be completed after the assessment of AEs.
Dietician consultations continue at Weeks 4, 8, 12, and then as indicated in the SoA
(Section 1.3). Study drug and injection supplies will be returned per the SoA and according to 
local requirements. New supplies will be dispensed as needed.


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Protocol I8F-MC-GPHN
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The starting dose of tirzepatide is 2.5 mg QW for 4 weeks, then the dose is increased by 2.5 mg 
every 4 weeks (2.5 to 5 to 7.5 to 10 to 12.5 to 15 mg) up to MTD (either 10 mg or 15 mg).
Interventions to optimize study drug tolerance and adherence may be employed throughout the 
study and include, but are not limited to, brief temporary interruptions and use of additional 
medications to manage GI symptoms (for example, nausea, vomiting, and diarrhea, see 
Section 6.6.2 for details). During the open-label lead-in period, participants unable to tolerate 
2.5 mg or 5 mg despite the above measures will be discontinued from the study. For participants 
unable to tolerate any dose between 7.5 mg and 15 mg inclusive, despite the above measures, the 
investigator should contact Lilly to consider a dose de-escalation step with subsequent 
re-escalation to reach either the 10-mg or 15-mg dose on or before Week 36 as described below
(only 1 cycle of dose de-escalation and re-escalation is permitted during the open-label, lead-in 
period):

7.5 mg to 5 mg, then the dose is increased by 2.5 mg every 4 weeks up to MTD (either 
10 mg or 15 mg)

10 mg to 7.5 mg, then the dose is increased by 2.5 mg every 4 weeks up to MTD (either 
10 mg or 15 mg)

12.5 mg to 10 mg, then the dose is increased by 2.5 mg every 4 weeks up to MTD (either 
10 mg or 15 mg)

15 mg to 12.5 mg, then the dose is increased by 2.5 mg every 4 weeks up to MTD (either 
10 mg or 15 mg)
Participants who tolerate 15 mg by Visit 11 will continue on 15 mg as their MTD dose.
Participants who tolerate 10 mg but do not tolerate 12.5 mg or 15 mg by Visit 11, even after 
1 de-escalation and re-escalation attempt, will continue on 10 mg as their MTD dose.
Participants who tolerate 12.5 mg but do not tolerate 15 mg by Visit 11, even after 
1 de-escalation and re-escalation attempt, will continue on 10 mg as their MTD dose.
Participants who do not tolerate up to 10 mg by Visit 11, even after 1 de-escalation and 
re-escalation attempt, will be discontinued from the study.
At Visit 11, those who successfully complete the open-label, lead-in period (reaching and 
tolerating either the 10-mg or 15-mg dose at Visit 11) will be randomized either to continue 
tirzepatide at MTD or placebo for the duration of the 52-week, double-blind treatment period.
Double-Blind Treatment Period
End of Visit 11 to Visit 24
Following randomization (end of Visit 11), office visits will occur as indicated in the SoA 
(Section 1.3). Telephone visits will occur at 4-week intervals between the office visits starting at 
Week 44.  
Office visit procedures should be conducted according to the SoA (Section 1.3), and will include:

weight, waist circumference, and vital signs measurements 

laboratory testing 


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Protocol I8F-MC-GPHN
28

administration of PROs questionnaires 

collection of AEs, product complaints, and concomitant medications

Mental Health questionnaires

review of participant diary information (to include reinforcement and compliance 
assessments for study drug administration and lifestyle goals), and 

drug dispensing.
Patient-reported outcomes questionnaires should be administered as early as possible, as per 
Suggested Visit Structure (Section 10.8). Preferred administration order is the same as Visit 2.
Mental Health questionnaires should be completed after the assessment of AEs.
Dietician consultations continue as indicated in the SoA. Study drug and injection supplies will 
be returned per the SoA and according to local requirements. New supplies will be dispensed as 
needed.
At each of the 8 scheduled telephone visits, procedures will include:

collection of AEs, product complaints, and concomitant medications

administration of Mental Health questionnaires (after the AE assessment), and  

review of participant diary information (to include reinforcement and compliance 
assessments for study drug administration and lifestyle goals)
During all treatment periods, participants should be instructed to contact the investigative site for 
assistance as soon as possible if they experience any difficulties administering their study 
medication. Participants should also be advised about the appropriate course of action in the 
event that study drug is not taken at the required time (late/missing doses).
Visit 99
Visit 99 is only applicable to participants who discontinue the double-blind study treatment 
prematurely (after Week 36 and before Week 88) and decline to complete the remaining 
scheduled study visits. These participants will be asked to return for Visit 99 at 88 weeks ±7 days 
(see Section 7.2.1.). This visit is critical to ensure complete data collection for the primary body 
weight endpoint.  
Participants should attend this visit in the fasting state. Procedures to be completed are:

measurement of weight and waist circumference

listing of concomitant medications

assessment of AEs, and 

completion of the Mental Health questionnaires (after the AE assessment).
For participants unwilling to attend this visit, their refusal to attend should be documented in the 
participant medical record. 
Early Discontinuation of Treatment Visit
Participants unable or unwilling to continue the study treatment for any reason will perform an 
early discontinuation (ED) of treatment visit (Section 7.2). If the participant is discontinuing 
during an unscheduled or a scheduled visit, that visit should be performed as an ED visit. 
Procedures should be completed according to the SoA. Patient-reported outcomes questionnaires 


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Protocol I8F-MC-GPHN
29
should be administered as early as possible, as per Suggested Visit Structure (Section 10.8). 
Administration of Mental Health questionnaires should be after the assessment for AEs. 
4.1.1.3.
Safety Follow-Up Period 
Visit 801
All participants are required to complete a safety follow-up visit (Visit 801), according to the 
SoA. Participants discontinuing the study early and performing an ED visit will also be asked to 
perform the safety follow-up visit (see Section 7.2.1). During the safety follow-up period, 
participants will not receive study drug. Participants are also required to return any remaining 
study diaries to the study site at the end of this period.
Visit 801 (safety follow-up visit) should be performed 4 weeks after the last visit in the 
double-blind treatment period (Visit 24 or Visit 99) or 4 weeks after the ED visit for those who 
discontinue during the open-label lead-in period or decline to return for Visit 99.  
4.1.2.
Study Procedures
Participants will perform study procedures listed in the SoA (Section 1.3).
Study participants will be permitted to use concomitant medications that they require during the 
study, except certain excluded medications (see Section 5.2) that may interfere with the 
assessment of efficacy and safety characteristics of the study treatments.
Study governance considerations are described in detail in Section 10.1 (Appendix 1).
4.2.
Scientific Rationale for Study Design
Tirzepatide is a 39-amino acid synthetic peptide with agonist activity at both the GIPR and 
GLP-1R. Its structure is based on the GIP sequence and includes a C20 fatty diacid moiety 
(Coskun et al. 2018). It is administered QW by SC injection. 
As a dual GIP/GLP-1R agonist, tirzepatide could exceed the efficacy of selective GLP-1R 
analogs by recruiting metabolically active tissues not targeted by selective GLP-1R analogs (for 
example, adipose tissue as indicated by the observation of increased energy utilization) (Müller
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. Results from a Phase 2 study (GPGB) demonstrated that tirzepatide use in 
participants with T2DM was associated with a substantial, dose-dependent weight loss, greater 
than the weight change observed with dulaglutide, a specific GLP-1R agonist. General safety 
characteristics of all studied doses of tirzepatide were similar to that of the GLP-1R agonist class, 
consisting mainly of nausea, vomiting, and diarrhea. In general, these events were transient and 
mild or moderate in severity, with few severe episodes. These data suggest that tirzepatide has 
the potential to be a pharmacologic treatment for chronic weight management.
Although GI AEs were more common in the 15-mg arm of tirzepatide in the Phase 2 study 
(GPGB), this dose demonstrated the highest efficacy in terms of weight loss. An optimized 
dose-escalation regimen proposed in the current Phase 3 study (GPHN) to improve tolerability
(and supported by a dose-escalation algorithm from Study GPGF and PK/PD modeling) should 
enable a use of the 15-mg dose to maximize effects on body weight.


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Study GPHN is designed to determine the impact of treatment with MTD of tirzepatide 
compared with placebo on maintenance of weight loss in participants without T2DM who have 
obesity or are overweight. Because obesity is a chronic relapsing progressive disease (Bray et al. 
2017), the impact of a therapy on weight maintenance in addition to weight loss enables a more 
complete understanding of its benefit and helps to inform decisions on duration of therapy. 
There is not a clear consensus on how best to define weight maintenance, weight regain, or 
treatment failure. Recently, some studies have attempted to evaluate different measures of weight 
maintenance and correlate them with clinical outcomes. Berger et al. (2019) analyzed data from 
over 1500 participants in the Look AHEAD study who had >3% initial weight loss, and defined 
maintenance/regain according to 5 dichotomized cut-offs (0%, 25%, 50%, 75%, and 100%). 
They correlated different levels of maintenance with cardiometabolic risk factors and found that 
those who maintained >75% of the initial weight loss had the most cardiometabolic benefit. 
Conducting a similar study in a bariatric surgery cohort, which experienced much greater initial 
weight loss than the Look AHEAD cohort, King et al. (2018) found that 20% or greater regain 
correlated the same or better than other cut-offs with most cardiometabolic risk factors. Based on 
these recent data, maintaining 75% to 80% of initial weight loss regardless of therapeutic 
modality appears to be clinically relevant. That being said, it does not seem reasonable to define 
therapeutic failure at the same cut-off. Perhaps a more appropriate definition of complete 
therapeutic failure is regaining weight to the point that an individual falls below the 5% weight 
loss threshold which is used to define initial success of treatment in the first place. To have a 
more complete picture of therapeutic benefit, an evaluation of both maintenance (at an 
80% threshold of maximum weight loss) and time to complete failure (defined as returning to 
>95% of initial weight) is likely warranted. Therefore, both these measures are being evaluated
in the randomized weight-maintenance phase of Study GPHN.
A double-blind design after 36 weeks (randomization) was selected to minimize participant and 
investigator bias in assessments for efficacy, safety, and study drug tolerability. In addition, the 
objective of Study GPHN is to evaluate maintenance of initial weight loss, and therefore,
achieving a near-maximum weight loss effect and body weight plateau prior to randomization is 
important. Thirty-six weeks was chosen as the time point for randomization based on PK/PD 
modeling which shows that by 36 weeks (including 20-week dose escalation) most participants 
will reach a near-plateau of body weight. 
A placebo comparator was selected for this trial in accordance with regulatory guidance (FDA 
2007; EMA 2016). In addition, all participants, regardless of treatment assignment, will receive 
lifestyle-modification counseling consistent with current guidelines for weight management 
(Jensen et al. 2014). Specifically, participants will consult with a dietician, or equivalent 
qualified delegate, throughout the study to achieve an approximately 500 kcal/day energy deficit 
through a combination of caloric restriction and increased physical activity (see Section 5.3).
The planned duration of treatment for the primary endpoint at 88 weeks allows for a 52-week 
treatment period at the dose achieved following dose escalation to either 10 mg or 15 mg. This 
duration is considered appropriate to assess the full effects and balance of risk and benefit for 
tirzepatide MTD compared with placebo on body weight and is consistent with regulatory 
guidelines (FDA 2007; EMA 2016).
The effects of study intervention cessation will be assessed in the 4-week safety 
follow-up/observational period. To minimize the potential confounding effect of changes to 


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Protocol I8F-MC-GPHN
31
concomitant medications, participants will be permitted to use concomitant medications that do 
not interfere with the assessment of efficacy or safety characteristics of the study treatments.
4.3.
Justification for Dose
Tirzepatide MTD (10 mg or 15 mg QW) will be evaluated in this study. These doses and 
associated escalation schemes were selected based on assessment of safety, efficacy (weight 
loss), and GI tolerability data in Phase 1 and 2 studies in patients with T2DM, followed by 
exposure-response modeling of the data that predicted weight loss in patients with overweight or 
obesity. 
In a 26-week, Phase 2 study (GPGB) of participants with T2DM, tirzepatide reduced body 
weight by 4.8 kg, 8.7 kg, and 11.3 kg at dose levels of 5, 10, and 15 mg, respectively, whereas 
the weight loss observed in participants on dulaglutide, a selective GLP-1R agonist, used at the 
dose of 1.5 mg, was 2.7 kg (Frias et al. 2018).  
Similar to the GLP-1R agonist class, most of the tirzepatide AEs were dose-dependent and 
GI-related, consisting mainly of nausea, vomiting, and diarrhea. In general, these events were 
mild or moderate in severity, with few severe episodes, and transient. 
Tirzepatide doses of 10 mg and 15 mg were selected based principally on the following criteria:

each dose provides robust weight loss relative to placebo

the percent of patients achieving ≥10% is higher with 15 mg than 10 mg, and 

safety and tolerability were supported by Phase 2 results and/or PK/PD modeling.
Dosing algorithms starting at a low dose of 2.5 mg accompanied by dose escalation of 2.5-mg 
increments every 4 weeks should permit time for development of tolerance to GI events and are 
predicted to minimize GI tolerability concerns. The maximum proposed dose of 15 mg maintains 
an exposure multiple of 1.6 to 2.4 to the no-observed adverse effect level doses in 6-month 
monkey and rat toxicology studies.
4.4.
End of Study Definition
Section 7.2 describes the criteria used to determine if a participant has completed the study.
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA for the last participant in the trial globally.


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Protocol I8F-MC-GPHN
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5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Have a BMI of:

≥30 kg/m2 or

≥27 kg/m2 and previously diagnosed with at least 1 of the following 
weight-related comorbidities:
o
Hypertension: treated or with systolic blood pressure ≥130 mmHg 
or diastolic blood pressure ≥80 mmHg
o
Dyslipidemia: treated or with low-density lipoprotein (LDL) 
≥160 mg/dL (4.1 mmol/L) or triglycerides ≥150 mg/dL
(1.7 mmol/L), or high-density lipoprotein (HDL) <40 mg/dL 
(1.0 mmol/L) for men or HDL <50 mg/dL (1.3 mmol/L) for 
women 
o
Obstructive sleep apnea
o
Cardiovascular disease (for example, ischemic cardiovascular 
disease, New York Heart Association [NYHA] Functional 
Classification Class I-III heart failure) 
2. Have a history of at least 1 self-reported unsuccessful dietary effort to lose body 
weight 
3. In the investigator’s opinion, are well-motivated, capable, and willing to:

learn how to self-inject study drug, as required for this protocol (visually impaired 
persons who are not able to perform the injections must have the assistance of a 
sighted individual trained to inject the study drug; persons with physical 
limitations who are not able to perform the injections must have the assistance of 
an individual trained to inject the study drug) 

inject study drug (or receive an injection from a trained individual if visually 
impaired or with physical limitations)

follow study procedures for the duration of the study, including, but not limited 
to, following lifestyle advice (for example, dietary restrictions, exercise plan), 
maintaining a study diary, and completing required questionnaires
Participant Characteristics
4. Are at least 18 years of age and age of majority per local laws and regulations 


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a.
Male participants:

Male participants with partners of childbearing potential should be willing to 
use reliable contraceptive methods throughout the study and for 5 half-lives of 
study drug plus 90 days, corresponding to 4 months after the last injection 
b. Female participants:

Female participants not of childbearing potential may participate and include 
those who are:
o
infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation) or congenital anomaly (such as
Mullerian agenesis)
or
o
Postmenopausal – defined as either:

A woman at least 40 years of age with an intact uterus, not on 
hormone therapy, who has cessation of menses for at least 
1 year without an alternative medical cause AND a 
follicle-stimulating hormone (FSH) >40 mIU/mL; women in 
this category must test negative in pregnancy test prior to study 
entry
or

A woman 55 or older not on hormone therapy, who has had at 
least 12 months of spontaneous amenorrhea 
or

A woman at least 55 years of age with a diagnosis of 
menopause prior to starting hormone replacement therapy

Female participants of childbearing potential (not surgically sterilized and 
between menarche and 1-year postmenopausal) must
o
test negative for pregnancy at Visit 1 based on a serum pregnancy 
test
o
if sexually active, agree to use 2 forms of effective contraception, 
where at least 1 form is highly effective for the duration of the trial 
plus 30 days, corresponding to 2 months after the last injection, 
and
o
not be breastfeeding
Note: Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
Informed Consent
5. Capable of giving signed informed consent as described in Section 10.1 (Appendix 1),
which includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol


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5.2.
Exclusion Criteria 
Participants are excluded from study enrollment if they meet any of the following criteria: 
Medical Conditions
Diabetes-Related
6. Have Type 1 diabetes mellitus (T1DM) or T2DM, history of ketoacidosis, or 
hyperosmolar state/coma
7. Have at least 1 laboratory value suggestive of diabetes mellitus during screening, 
including 1 or more of: HbA1c ≥6.5% (≥48 mmol/mol), fasting glucose ≥126 mg/dL 
(≥7.0 mmol/L), and random glucose ≥200 mg/dL (≥11.1 mmol/L)
Obesity-Related
8. Have a self-reported change in body weight >5 kg within 3 months prior to screening
9. Have a prior or planned surgical treatment for obesity (excluding liposuction or 
abdominoplasty if performed >1 year prior to screening)
10. Have or plan to have endoscopic and/or device-based therapy for obesity or have had 
device removal within the last 6 months prior to screening
Examples:

mucosal ablation 

gastric artery embolization 

intragastric balloon 

duodenal-jejunal endoluminal liner 
Other Medical
11. Have renal impairment measured as estimated glomerular filtration rate (eGFR) 
<30 mL/min/1.73 m2, calculated by Chronic Kidney Disease-Epidemiology as 
determined by central laboratory during screening
12. Have a known clinically significant gastric emptying abnormality (for example, severe 
gastroparesis or gastric outlet obstruction) or chronically take drugs that directly affect GI
motility 
13. Have a history of chronic or acute pancreatitis
14. Have thyroid-stimulating hormone (TSH) outside of the range of 0.4 to 6.0 mIU/L at the
screening visit
Note: Participants receiving treatment for hypothyroidism may be included, provided 
their thyroid hormone replacement dose has been stable for at least 3 months and their 
TSH at screening falls within the range indicated above.
Note: Participants with a history of subclinical hypothyroidism but a TSH at screening 
within the range indicated above, may be included if, in the investigator’s opinion, the 


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Protocol I8F-MC-GPHN
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patient is unlikely to require initiation of thyroid hormone replacement during the course 
of the study.
15. Have obesity induced by other endocrinologic disorders (for example, Cushing 
syndrome) or diagnosed monogenetic or syndromic forms of obesity (for example, 
Melanocortin 4 Receptor deficiency or Prader Willi Syndrome)
16. Have a history of significant active or unstable major depressive disorder (MDD) or other 
severe psychiatric disorder (for example, schizophrenia, bipolar disorder, or other serious 
mood or anxiety disorder) within the last 2 years
Note: Participants with MDD or generalized anxiety disorder whose disease state is 
considered stable for the past 2 years and expected to remain stable throughout the course 
of the study, in the opinion of the investigator, may be considered for inclusion if they are 
not on excluded medications.
17. Have a lifetime history of suicide attempt
18. Have a PHQ-9 score of 15 or more on or before Visit 2
19. On the C-SSRS on or before Visit 2:

a “yes” answer to Question 4 (Active Suicidal Ideation with Some Intent to Act, 
Without Specific Plan) on the “Suicidal Ideation” portion of the C-SSRS
or

a “yes” answer to Question 5 (Active Suicidal Ideation with Specific Plan and 
Intent) on the “Suicidal Ideation” portion of the C-SSRS 
or

a “yes” answer to any of the suicide-related behaviors (actual attempt, interrupted 
attempt, aborted attempt, preparatory act or behavior) on the “Suicidal Behavior” 
portion of the C-SSRS 
and

the ideation or behavior occurred within the past month 
20. Have uncontrolled hypertension (systolic blood pressure above or equal to 160 mmHg 
and/or diastolic blood pressure above or equal to 100 mmHg)
21. Have any of the following cardiovascular conditions within 3 months prior to Visit 2 
acute myocardial infarction
cerebrovascular accident (stroke) 
unstable angina
hospitalization due to congestive heart failure (CHF)
22. Have NYHA Functional Classification Class IV CHF
23. Have acute or chronic hepatitis, signs and symptoms of any other liver disease other than 
nonalcoholic fatty liver disease (NAFLD), or any of the following, as determined by the 
central laboratory during screening:


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
alanine aminotransferase (ALT) level >3.0X upper limit of normal (ULN) for the 
reference range

alkaline phosphatase (ALP) level >1.5X ULN for the reference range, or

total bilirubin (TBL) level >1.2X ULN for the reference range (except for 
cases of known Gilbert’s Syndrome)
Note: Participants with NAFLD are eligible to participate in this trial if their ALT level is 
≤3.0X ULN for the reference range  
24. Have a serum calcitonin level (at Visit 1) of:

≥20 ng/L, if eGFR ≥60 mL/min/1.73 m2

≥35 ng/L, if eGFR <60 mL/min/1.73 m2
25. Have a family or personal history of medullary thyroid carcinoma (MTC) or multiple 
endocrine neoplasia (MEN) syndrome type 2
26. Have a history of an active or untreated malignancy or are in remission from a clinically 
significant malignancy (other than basal or squamous cell skin cancer, in situ carcinomas 
of the cervix, or in situ prostate cancer) for less than 5 years
27. Have any other condition not listed in this section (for example, hypersensitivity or 
intolerance) that is a contraindication to GLP-1R agonists
28. Have a history of any other condition (such as known drug or alcohol abuse, diagnosed 
eating disorder, or other psychiatric disorder) that, in the opinion of the investigator, may 
preclude the participant from following and completing the protocol  
29. Have history of use of marijuana or tetrahydrocannabinol (THC)-containing products 
within 3 months of enrollment or unwillingness to abstain from marijuana or 
THC-containing products use during the trial. 
Note: If a participant has used cannabidiol oil during the past 3 months but agrees to 
refrain from use for the duration of the study, the participant can be enrolled. 
30. Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or awaiting an 
organ transplant
31. Have any hematological condition that may interfere with HbA1c measurement (for 
example, hemolytic anemias, sickle cell disease)
Prior/Concomitant Therapy
32. Are receiving or have received within 3 months prior to screening chronic (>2 weeks or 
>14 days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, 
intra-articular, or inhaled preparations) or have evidence of a significant, active 
autoimmune abnormality (for example, lupus or rheumatoid arthritis) that has required 
(within the last 3 months) or is likely to require, in the opinion of the investigator, 
concurrent treatment with systemic glucocorticoids (excluding topical, intraocular, 
intranasal, intra-articular, or inhaled preparations) during the course of the study 


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


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37. Within the last 30 days, have participated in a clinical study and received treatment, 
whether active or placebo. If the study involved an IP, 5 half-lives or 30 days, whichever 
is longer, should have passed
38. Have previously completed or withdrawn from this study or any other study investigating 
tirzepatide after receiving at least 1 dose of IP
Other Exclusions
39. Are investigator site personnel directly affiliated with this study and/or their immediate 
families. Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted
40. Are Lilly employees
5.3.
Lifestyle Considerations
Per the SoA (Section 1.3), participants will consult with a dietician, or equivalent qualified 
delegate, according to local standards, to receive lifestyle management counseling at Weeks 0, 4, 
8, and 12 during dose escalation and then at Weeks 24, 36, 40, 52, 64, 76, and 88. 
Diet and exercise goals established during the lifestyle consultation and the importance of 
adherence to the lifestyle component of the trial will be reinforced at each trial contact by study 
staff.
5.3.1.
Meals and Dietary Restrictions
At Visit 2 and subsequent visits, study participants will receive dietary counseling by a dietitian,
or equivalent qualified delegate, according to local standard. Dietary counseling will consist of 
advice on healthy food choices and focus on calorie restriction using a hypocaloric diet with 
macronutrient composition of:
maximum 30% of energy from fat,
approximately 20% of energy from protein,
approximately 50% of energy from carbohydrates, and 
an energy deficit of approximately 500 kcal/day compared to the participant’s 
estimated total energy expenditure (TEE). 
To encourage adherence, it is recommended that a 3-day diet and exercise log be completed prior 
to each counseling visit. During each visit, the participant’s diet will be reviewed and advice to 
maximize adherence will be provided if needed.
The hypocaloric diet will be continued throughout the treatment period. If a BMI ≤22 kg/m2 is 
reached, the recommended energy intake should be recalculated with no kcal deficit for the 
remainder of the trial.
Total energy expenditure is calculated by multiplying the estimated basal metabolic rate (BMR) 
(see table below) with a Physical Activity Level value of 1.3 (Food and Agriculture Organization 
of the United Nations/World Health Organization [WHO]/United Nations University 2004), 
which reflects an inactive lifestyle. This calculation provides a conservative estimate of caloric 
requirements:


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TEE (kcal/day) = BMR X 1.3
Equations for Estimating BMR in kcal/Day*
Sex
Age
BMR (kcal/day)
Men
18 to 30 years
15.057 X actual weight in kg + 692.2
31 to 60 years
11.472 X actual weight in kg + 873.1
>60 years
11.711 X actual weight in kg + 587.7
Women
18 to 30 years
14.818 X actual weight in kg + 486.6
31 to 60 years
8.126 X actual weight in kg + 845.6
>60 years
9.082 X actual weight in kg + 658.5
Abbreviation: BMR = basal metabolic rate; FAO = Food and Agriculture Organization of the United Nations; 
UNU = United Nations University; WHO = World Health Organization.
*Revised WHO equations (adapted from: FAO/WHO/UNU 2004).
5.3.2.
Physical Activity
At Visit 2 and all subsequent visits, participants will be advised to increase their physical activity 
to moderate intensity (for example, brisk walking) for at least 150 minutes per week.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to study intervention. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.


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6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol.
6.1.
Study Intervention(s) Administered
ARM Name
Tirzepatide MTD
Placebo
Dose 
10 mg or 15 mg QW
N/A
Route of 
Administration
SC
Sourcing
Provided centrally by the sponsor and dispensed via IWRS
Packaging and 
Labeling
Study intervention will be provided in autoinjectors (single-dose pens) 
packaged in cartons to be dispensed. Clinical study materials will be 
labeled according to country regulatory requirements.
Abbreviations: IWRS = interactive web-response system; MTD = maximum tolerated dose; N/A = not applicable;
QW = once weekly; SC = subcutaneous.
There are no restrictions on the time of day each weekly dose of study drug is given, but it is 
advisable to administer the SC injections on the same day and same time each week. The actual 
date, time, and injection-site location of all dose administrations will be recorded in the diary by 
the participant. If a dose of study drug is missed, the participant should take it as soon as 
possible, unless it is within 72 hours of the next dose, in which case that dose should be skipped,
and the next dose should be taken at the appropriate time. The day of weekly administration can 
be changed if necessary, as long as the last dose was administered 72 or more hours before.
All participants will inject study drug SC in the abdomen or thigh using the injection supplies 
provided; a caregiver may administer the injection in the participant’s upper arm. The injection-
site location of all dose administrations will be recorded in the diary by the participant. A new
autoinjector will be used for each injection. If study drug is to always be injected in the same 
body region, participants should be advised to rotate injection sites each week.
6.1.1.
Medical Devices
The combination products provided for use in the study are tirzepatide investigational 
autoinjector (or matching placebo). Any AE resulting from device deficiencies, misuse, or 
malfunctions must be detected, documented, and reported by the investigator throughout the 
study (see Section 10.4.3).


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6.2.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.

Only participants enrolled in the study may receive study intervention. Only study 
personnel may supply, prepare, or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized study personnel.

The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (for example, receipt, 
reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study interventions 
are provided in the study training materials. 
6.3.
Measures to Minimize Bias: Randomization and Blinding
This is a double-blind, randomized study.
Participants will undergo a 36-week open-label tirzepatide lead-in treatment period. Those who 
successfully complete the lead-in period (reaching either a 10-mg or 15-mg dose) will be 
randomized (1:1) in a double-blind fashion to either continue tirzepatide at MTD or switch to 
placebo for the duration of the double-blind treatment period. Assignment to treatment groups
will be determined by a computer-generated random sequence using the interactive web-
response system (IWRS).  
The randomization will be stratified by country, sex (female, male), tirzepatide MTD dose at 
36 weeks (10 mg versus 15 mg), and percent weight loss at 36 weeks (<10% versus ≥10%). 
Investigators, site staff, clinical monitors, and participants will remain blinded to the treatment 
assignments of the double-blinded treatment period until the study is complete.
Emergency unblinding for AEs may be performed through the IWRS. This option may be used 
ONLY if the participant’s well-being requires knowledge of the participant’s treatment 
assignment. All emergency unblinding events are recorded and reported by the IWRS.
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be discontinued from the study. In cases where there are ethical reasons to have 
the participant remain in the study, the investigator must obtain specific approval from a Lilly 
clinical research physician (CRP) for the participant to continue in the study.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a participant’s treatment assignment is warranted for medical management of the event. The 
participant’s safety must always be the first consideration in making such a determination. If a 
participant’s treatment assignment is unblinded, Lilly must be notified immediately. If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.


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6.4.
Study Intervention Compliance
Participant compliance with study intervention will be assessed at each visit. 
Study drug compliance will be determined by the following: 

Study drug administration data will be recorded by the participant and reviewed 
by the investigator at each study visit.

The participants will be instructed to return any unused study drug and/or empty 
cartons at the next office visit to the study site for the purpose of performing drug 
accountability.
Treatment compliance for each visit interval is defined as taking at least 75% of the required 
doses of study drug. Similarly, a participant will be considered significantly noncompliant if he 
or she is judged by the investigator to have intentionally or repeatedly taken more than the 
prescribed amount of medication (more than 125%).  
In addition to the assessment of a participant’s compliance with the study drug administration, 
other aspects of compliance with the study treatments will be assessed at each visit based on the 
participant’s adherence to the visit schedule, completion of study diaries, and any other 
parameters the investigator considers necessary.
Participants considered to be poorly compliant with their medication and/or the study procedures 
will receive additional training and instruction, as required, and will be reminded of the 
importance of complying with the protocol.
6.5.
Concomitant Therapy
Participants will be permitted to use concomitant medications that they require during the study, 
except certain medications (for example, other medications for weight management, see 
Section 5.2) that may interfere with the assessment of efficacy and safety characteristics of the 
study treatments.
Participants who develop diabetes during the study may initiate medication for glucose control, 
with the exception of dipeptidyl-peptidase-4 (DPP-4) inhibitors or GLP-1R agonists. Initiation of 
metformin for the treatment of diabetes is permitted, but metformin should not be initiated 
during the study for the treatment of other metabolic conditions (for example, PCOS, diabetes 
prevention). Management of incident diabetes should be performed by participants’ usual care 
providers.
Investigative site staff will inform participants that they must consult with the investigator or a 
designated site staff member upon being prescribed any new medications during the study. This 
may not be possible when initiated for treatment of medical emergencies, in which case, the 
participant will inform the investigator or a designated site staff member as soon as possible.  
Nonstudy medications taken by participants who are screened but not assigned to study 
intervention will not be reported to Lilly unless an SAE or AE occurs that the investigator 
believes may have been caused by a study procedure.


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6.6.
Dose Modification
6.6.1.
Tirzepatide
Tirzepatide is given QW by SC injection. There are no restrictions on the time of day each 
weekly dose of tirzepatide is given, but it is advisable to administer the SC injections on the 
same day of the week and similar time each week. If a dose of tirzepatide is missed, the 
participant should take it as soon as possible unless it is within 72 hours of the next dose, in 
which case, that dose should be skipped and the next dose should be taken at the appropriate time 
(see Section 6.1).
Study drug dose modification is not permitted, except for management of intolerable GI 
symptoms during the 36-week lead-in period (see Section 6.6.2).  
6.6.2.
Management of Participants with Gastrointestinal Symptoms
Participants who experience intolerable GI symptoms (for example, nausea, vomiting, or 
diarrhea) at any time during the study, should first be counseled on dietary behaviors that may 
help mitigate nausea and vomiting (for example, eating smaller meals, splitting 3 daily meals 
into 4 or more smaller ones, and stopping eating when they feel full). If symptoms persist, the 
participant should be prescribed, at the investigator’s discretion, symptomatic medication (for 
example, antiemetic or antidiarrheal medication). A temporary interruption of study drug for 
1 dose is permitted, provided the participant has taken the last 3 weekly doses. Study treatment 
should be resumed immediately, either alone or in combination with symptomatic medication, 
which can also be utilized to manage symptoms. Management of study drug after interruptions 
>1 dose is discussed in Section 7.1.1.
During the 36-week open-label tirzepatide lead-in treatment period, if intolerable GI symptoms 
(for example, nausea, vomiting, or diarrhea) persist despite the above measures, the investigator 
should contact Lilly to consider a dose de-escalation step with subsequent re-escalation 
(Section 4.1.1.2.2). During the 52-week, post-randomization treatment period, dose de-escalation 
with subsequent re-escalation or dose de-escalation to a lower maintenance dose is not permitted. 
Those with intolerable GI symptoms that develop after randomization and persist despite the 
above measures (for example, dietary counseling, symptomatic medication, and interruption of 
study drug for 1 dose) should discontinue study drug but remain in the study for continued 
follow-up. 
6.7.
Intervention after the End of the Study
Tirzepatide will not be made available to participants after conclusion of the study.


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued during the 
open-label lead-in period, the participant will not be randomized and will be permanently 
discontinued from study. If study intervention is definitively discontinued after randomization,
the participant will remain in the study to be evaluated for any trial endpoint at the end of the 
study. See the SoA for data to be collected at the time of discontinuation of study intervention 
and follow-up and for any further evaluations that need to be completed. 
Possible reasons leading to permanent discontinuation of study intervention:

Participant decision
o
The participant requests to discontinue study intervention

Clinical considerations
o
Initiation of open-label GLP-1R agonist or DPP-4 inhibitor, if participant will not or 
cannot discontinue them
o
Intolerable GI symptoms despite management as described in Section 6.6.2
o
BMI ≤18.5 kg/m2 is reached at any time during the treatment period 
Note: The investigator should contact the sponsor CRP to discuss whether it is medically 
appropriate for the participant to continue study treatment. 
o
Diagnosis of T1DM
o
Diagnosis of MTC or MEN syndrome type 2
o
Significant elevation of calcitonin (Section 8.3.2.4) 
o
Diagnosis of acute or chronic pancreatitis 
o
Diagnosis of an active or untreated malignancy (other than basal or squamous cell 
skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer)
o
If the investigator, after consultation with the sponsor-designated medical monitor, 
determines that a systemic hypersensitivity reaction has occurred related to study 
drug administration, the participant should be permanently discontinued from the 
investigational drug  
o
Onset of pregnancy in a female participant 
o
Occurrence of any other treatment-emergent AE (TEAE), SAE, or clinically 
significant finding for which the investigator believes that permanent study drug 
discontinuation is the appropriate measure to be taken
o
Inadvertent enrollment if continued treatment with study drug would not be medically 
appropriate
o
PHQ-9 score ≥15  

Participants should be referred to a mental health professional (MHP) to assist 
in deciding whether the participant should be discontinued from study drug. If 


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a participant’s psychiatric disorder can be adequately treated with 
psycho- and/or pharmacotherapy, then the participant, at the discretion of the 
investigator (in agreement with the MHP), may be continued in the trial on 
randomized therapy.  
o
In addition, study drug may be discontinued if participants: 

answered “yes” to 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 study intervention due to a hepatic event or 
liver test abnormality should have additional hepatic safety data collected via eCRF
o
Discontinuation of the study intervention for abnormal liver tests should be
considered by the investigator when a participant meets one of the following 
conditions after consultation with the Lilly-designated medical monitor:

ALT or aspartate aminotransferase (AST) >8X ULN

ALT >2X baseline value or ≥300 U/L, whichever occurs first, if baseline 
ALT ≥2X ULN

ALT or AST >5X ULN for more than 2 weeks

ALT or AST >3X ULN and TBL >2X ULN or international normalized 
ratio (INR) >1.5 

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)

ALP >3X ULN

ALP >2.5X ULN and TBL >2X ULN

ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Participants who stop the study drug permanently postrandomization and prior to 88 weeks 
should continue to attend all scheduled study visits to collect all planned efficacy and safety 


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measurements. Participants who stop the study treatment postrandomization and prior to 88 
weeks, but are unwilling to attend remaining scheduled visits, should return for Visit 99 for a 
final weight measurement. If these participants are unwilling to attend Visit 99, their refusal to 
attend should be documented in the patient medical record.
See the SoA for data to be collected at the time of intervention discontinuation and follow-up and 
for any further evaluations that need to be completed.
7.1.1.
Temporary Discontinuation 
In certain situations, the investigator may need to temporarily interrupt study drug. Every effort 
should be made by the investigator to maintain participants on study drug and to restart study 
drug after any temporary interruption, as soon as it is safe to do so. Distribution of study 
medication at the correct dose will be per IWRS instructions.  
If study drug 
interruption is….
and…
then participant…
2 consecutive doses 
or less 
occurs between Weeks 0 
and 36
restarts study drug at last administered 
dose, as per escalation schedule.
2 consecutive doses 
or less 
occurs between Weeks 36 
and 88
restarts study drug at chosen MTD at 
randomization.
3 consecutive doses 
or more 
occurs between Weeks 0 
and 36
is not randomized and will be discontinued 
from study.
3 consecutive doses 
or more
occurs between Weeks 36 
and 88
restarts study drug at 5 mg and repeats
dose-escalation scheme to achieve the same 
MTD assigned at randomization.
Abbreviation: MTD = maximum tolerated dose.
If study drug interruption is due to an AE, then the event is to be documented and followed 
according to the procedures in Section 10.4 of this protocol.
If study drug interruption is due to intolerable persistent GI AE, participants should be treated as 
suggested in Section 6.6.2.
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 randomized participants in the study 
irrespective of the following:

adherence to or discontinuation from study drug


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
adherence to visit schedule

missing assessments

study drug discontinuation due to AE 

development of comorbidities

development of clinical outcomes
The circumstances listed above are not valid reasons for discontinuation from the study. 
A participant may withdraw from the study:

at any time at his/her own request 

at the request of his/her designee (for example, parents or legal guardian)

at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons

if enrolled in any other clinical study involving an IP or enrolled in any other 
type of medical research judged not to be scientifically or medically 
compatible with this study

if the participant, for any reason, requires treatment (for example, 
pharmacological, device-based, or surgical) that has been demonstrated to be 
effective for treatment of the study indication, discontinuation from the study 
occurs prior to introduction of the new treatment.
A participant will withdraw from the study:

if a female participant becomes pregnant

if study intervention is definitively discontinued during the open-label lead-in period, 
the participant will not be randomized and will be permanently discontinued from 
study.
Participation in the study can be stopped for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and Good Clinical Practice (GCP). Participants who 
agree to provide information relevant to any trial endpoint at the end of the study are not 
considered to have discontinued from the study.
At the time of discontinuing from the study, if possible, an ED visit should be conducted, as 
shown in the SoA. See SoA for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. The participant will be 
permanently discontinued 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.


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7.2.1.
Participant Disposition and Timing of Safety Follow-Up
Abbreviations: ED = early discontinuation; Wk = Week; wks = weeks.


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7.2.2.
Discontinuation of Inadvertently Enrolled Participants
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, the investigator and the sponsor CRP must agree whether continuing 
the study treatment is medically appropriate. Continuation of inadvertently enrolled participants 
in the study, with or without study drug treatment, requires documented approval from the 
sponsor CRP. Safety follow-up should be performed as outlined in Section 1.3 (SoA), 
Section 8.3 (Adverse Events, Serious Adverse Events, and Product Complaints), and Section 8.2
(Safety Assessments) of the protocol.
7.3.
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designees are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed-up by the site.
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those 
who did not get IP. Public sources may be searched for vital status information. If vital status is 
determined 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


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8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA (Section 1.3).

Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue 
or discontinue study intervention.

Adherence to the study design requirements, including those specified in the 
SoA, is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that
potential participants meet all eligibility criteria. The investigator will 
maintain a screening log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable.
8.1.
Efficacy Assessments
8.1.1.
Primary Efficacy Assessments
The primary efficacy measurement in this study is body weight. Body weight measurements will 
be collected at specific clinic visits as summarized in the SoA. Methods for measuring body 
weight are described in Section 10.7.
8.1.2.
Secondary Efficacy Assessments
The following secondary efficacy measures will be collected at the times shown in the SoA
(Section 1.3):

BMI (derived using body weight in kilograms divided by the square of height in 
meters)

Waist circumference (measuring method is described in Section 10.7)

Fasting insulin (measured through central lab)

HbA1c (measured through central lab)

Fasting glucose (measured through central lab)

Blood pressure (measuring method is described in Section 10.7)

Lipids (measured through central lab)
8.1.3.
Patient-Reported Outcomes Assessments
The self-administered questionnaires will be translated into the native language of the region, 
linguistically validated and administered according to the SoA (Section 1.3). At these visits, the 
questionnaires should be completed before the participant has discussed their medical condition 
or progress in the study with the investigator and/or site staff, if the participant is not adversely 
affected by their fasting condition.


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8.1.3.1.
Short Form-36 Version 2 Health Survey Acute Form, 1-Week Recall Version
The SF-36 v2 acute form, 1-week recall version is a 36-item, generic, participant-administered
measure designed to assess the following 8 domains:

Physical Functioning 

Role-Physical 

Bodily Pain

General Health

Vitality

Social Functioning 

Role-Emotional

Mental Health 
The Physical Functioning domain assesses limitations due to health “now” while the remaining 
domains assess functioning “in the past week.” Each domain is scored individually and 
information from these 8 domains are further aggregated into 2 health-component summary 
scores: Physical-Component Summary and Mental-Component Summary. Items are answered on 
Likert scales of varying lengths (3-, 5-, or 6-point scales). Scoring of each domain and both 
summary scores are norm-based and presented in the form of T-scores, with a mean of 50 and 
standard deviation (SD) of 10; higher scores indicate better levels of function and/or better health 
(Maruish 2011).  
8.1.3.2.
Impact of Weight on Quality of Life-Lite Clinical Trials Version
The IWQOL-Lite-CT is a 20-item, obesity-specific PRO instrument developed for use in obesity 
clinical trials. It assesses 2 primary domains of obesity-related and HRQoL: physical (7 items) 
and psychosocial (13 items). A 5-item subset of the physical domain, the physical-function 
composite is also supported. Items in the physical-function composite describe physical impacts 
related to general and specific physical activities. All items are rated on either a 5-point 
frequency (“never” to “always”) scale or a 5-point truth (“not at all true” to “completely true”) 
scale (Kolotkin et al. 2017, 2019). 
8.1.3.3.
EQ-5D-5L
Generic HRQoL will be assessed using the EQ-5D-5L (EuroQoL Research Foundation 2019). 
The EQ-5D-5L is a standardized 5-item instrument for use as a measure of health outcome. It 
provides a simple descriptive profile and a single index value for health status that can be used in 
the clinical and economic evaluation of health care as well as population health surveys. The 
EQ-5D-5L comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression). The 5L version, introduced in 2005, scores each 
dimension at 5 levels (no problems, slight problems, moderate problems, severe problems, or 
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 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.  


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The EQ-5D-5L is used worldwide and is available in more than 170 different languages. Details 
on the instrument, and scoring, organizing, and presenting the data collected can be found in the 
EQ-5D-5L User Guide (EuroQoL Research Foundation 2019).
8.1.3.4.
Patient Global Impression of Status for Physical Activity
Study participants will be asked to complete a PGIs item specifically developed for this study. 
This is a participant-rated assessment of current limitation on physical activity due to health and 
is rated on a 5-point scale ranging from “1- not at all limited” to “5- extremely limited.”
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of 
the cardiovascular, respiratory, GI, and neurological systems, as well as 
thyroid exam. Height, weight, and waist circumference will also be measured 
and recorded, per Section 10.7.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.2.2.
Vital Signs
For each participant, vital signs should be measured according to the SoA (see Section 1.3) and
Section 10.7.
Any clinically significant findings from vital sign measurements that result in a diagnosis should 
be reported to Lilly or its designee as an AE via the eCRF.
8.2.3.
Electrocardiograms
For each participant, single-tracing 12-lead electrocardiograms (ECGs) should be collected 
according to the SoA and Section 10.7.
Electrocardiograms will initially be interpreted by a qualified physician (the investigator or 
qualified designee) at the site as soon after the time of ECG collection as possible, and ideally 
while the participant is still present, for immediate participant management, should any clinically 
relevant findings be identified. Any clinically significant findings from ECGs that result in a 
diagnosis should be reported to Lilly or its designee as an AE via the eCRF.
All digital ECGs will be obtained using centrally provided ECG machines and will be 
electronically transmitted to a designated central ECG laboratory. The central ECG laboratory 
will perform a basic quality control check (for example, demographics and study details) and 
then store the ECGs in a database. At a future time, the stored ECG data may be overread by a 
cardiologist at the central ECG laboratory for further evaluation of machine-read measurements 
or to meet regulatory requirements. The machine-read ECG intervals and heart rate may be used 
for data analysis and report-writing purposes, unless a cardiology overreading of the ECGs is 
conducted prior to completion of the final study report (in which case, the overread data would 
be used).


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8.2.4.
Clinical Safety Laboratory Assessments

See Section 10.2, Appendix 2: “Clinical Laboratory Tests” for the list of 
clinical laboratory tests to be performed, and to the SoA for the timing and 
frequency.
Note: See Section 10.2, Appendix 2: “Clinical Laboratory Tests” for clinical 
laboratory tests reported or not reported to the investigator.

The investigator must review the laboratory results, document this review, and 
report any clinically relevant changes occurring during the study as an AE.
The laboratory results must be retained with source documents unless a 
Source Document Agreement or comparable document cites an electronic 
location that accommodates the expected retention duration. Clinically 
significant abnormal laboratory findings are those which are not associated 
with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant’s condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 4 weeks after the last dose of study 
intervention should be repeated until the values return to normal or 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 Section 10.2,
must be conducted in accordance with the SoA, standard collection 
requirements, and laboratory manual.

If laboratory values from nonprotocol-specified laboratory assessments 
performed at an investigator-designated local laboratory require a change in 
participant management or are considered clinically significant by the 
investigator (for example, SAE, AE, or dose modification), then report the 
information as an AE.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. Unless otherwise stated in the subsections below, all samples collected for specified 
laboratory tests will be destroyed within 60 days of receipt of confirmed test results. Certain 
samples may be retained for a longer period, if necessary, to comply with applicable laws, 
regulations, or laboratory certification standards.
8.2.5.
Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods. The study team will review safety reports in a blinded fashion (for applicable blinded 
study period) according to the schedule provided in the Trial-Level Safety Review plan. Lilly 
will also review SAEs within time frames mandated by company procedures. The Lilly CRP 


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will, as appropriate, consult with the functionally independent Global Patient Safety therapeutic 
area physician or clinical scientist.
8.2.5.1.
Hepatic Safety Monitoring
Close Hepatic Monitoring 
Laboratory tests (Section 10.6), including ALT, AST, ALP, TBL, direct bilirubin, gamma-
glutamyltransferase, and creatine kinase, should be repeated within 48 to 72 hours to confirm the 
abnormality and to determine if it is increasing or decreasing, if 1 or more of these conditions 
occur: 
If a participant with baseline results of…
develops the following elevations:
ALT or AST <1.5X ULN 
ALT or AST ≥3X ULN
ALP <1.5X ULN 
ALP ≥2X ULN 
TBL <1.5X ULN 
TBL ≥2X ULN (except for patients with Gilbert’s 
syndrome)
ALT or AST ≥1.5X ULN
ALT or AST ≥2X baseline 
ALP ≥1.5X ULN 
ALP ≥2X baseline 
TBL ≥1.5X ULN 
TBL ≥1.5X baseline (except for patients with 
Gilbert’s syndrome)
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal.
If the abnormality persists or worsens, clinical and laboratory monitoring and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, and history of alcohol 
drinking and other substance abuse.
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and lab results stabilize. Monitoring of ALT, AST, ALP, and 
TBL should continue until levels normalize or return to approximate baseline levels.


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Comprehensive Hepatic Evaluation  
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of these conditions occur: 
If a participant with baseline results of…
develops the following elevations:
ALT or AST <1.5X ULN 
ALT or AST ≥3X ULN with hepatic 
signs/symptoms*, or ALT or AST ≥5X ULN 
ALP <1.5X ULN 
ALP ≥3X ULN 
TBL <1.5X ULN 
TBL ≥2X ULN (except for patients with 
Gilbert’s syndrome) 
ALT or AST ≥1.5X ULN
ALT or AST ≥2X baseline with hepatic 
signs/symptoms*, or ALT or AST ≥3X baseline 
ALP ≥1.5X ULN 
ALP ≥2X baseline 
TBL ≥1.5X ULN 
TBL ≥2X baseline (except for patients with 
Gilbert’s syndrome)
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal
* Hepatic signs/symptoms are severe fatigue, nausea, vomiting, jaundice, right upper-quadrant abdominal pain, 
fever, rash, and/or eosinophilia >5%. 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for prothrombin-time-INR; tests for viral hepatitis A, 
B, C, or E; tests for autoimmune hepatitis; and an abdominal imaging study (for example, 
ultrasound or computed tomography [CT] scan).
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus, 
cytomegalovirus, Epstein-Barr virus, acetaminophen levels, acetaminophen protein adducts, 
urine toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl glucuronide, and 
blood phosphatidylethanol. Based on the circumstances and the investigator’s assessment of the 
participant’s clinical condition, the investigator should consider referring the participant for a 
hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy.  
Additional Hepatic Data Collection (Hepatic Safety CRF) in Study Participants Who Have 
Abnormal Liver Tests During the Study
Additional hepatic safety data collection in hepatic safety case report forms (CRFs) should be 
performed in study participants who meet 1 or more of the following 5 conditions: 
1. Elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5X ULN) 

In participants with baseline ALT ≥1.5X ULN, the threshold is ALT ≥3X baseline on 
2 or more consecutive tests 


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2. Elevated TBL to ≥2X ULN (if baseline TBL <1.5X ULN) (except for cases of known 
Gilbert’s syndrome) 

In participants with baseline TBL ≥1.5X ULN, the threshold should be 
TBL ≥2X baseline 
3. Elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5X ULN) 

In participants with baseline ALP ≥1.5X ULN, the threshold is ALP ≥2X baseline on 
2 or more consecutive blood tests 
4. Hepatic event considered to be an SAE 
5. Discontinuation of study drug due to a hepatic event
Note: The interval between the 2 consecutive blood tests should be at least 2 days. 
8.2.6.
Depression, Suicidal Ideation, and Behavior Risk Monitoring
Patients who have obesity or are overweight are at increased risk for depression (Luppino et al. 
2010). Depression can increase the risk for suicidal ideation and behavior. Therefore, study 
participants will be screened at trial entry and monitored during the study for depression, suicidal 
ideation, and behavior.  
Participants should be monitored appropriately and observed closely for suicidal ideation and 
behavior or any other unusual changes in behavior, especially at the beginning and end of the 
course of treatment, or at the time of dose changes, either increases or decreases. Consideration 
should be given to discontinuing the study intervention in participants who experience signs of 
suicidal ideation or behavior, following a risk assessment.
Baseline and treatment-emergent assessment of depression, suicidal ideation, and behavior will 
be monitored during the study using the C-SSRS and PHQ-9 (Section 8.3.2.13). 
8.3.
Adverse Events, Serious Adverse Events, and Product Complaints
The definitions of the following events can be found in Section 10.4 (Appendix 4):

Adverse events (AEs)

Serious adverse events (SAEs)

Product complaints (PCs)
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention, study device or device constituent, or 
study procedures, or that caused the participant to discontinue the study intervention (see 
Section 7).
Care will be taken not to introduce bias when detecting events. Open-ended and nonleading 
verbal questioning of the participant is the preferred method to inquire about event occurrences.


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After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs, will be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). For 
product complaints, the investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality. Further 
information on follow-up procedures is provided in Section 10.4.
8.3.1.
Timing and Mechanism for Collecting Events
This table describes the timing, deadlines, and mechanism for collecting events.
Event
Collection 
Start
Collection Stop
Timing for 
Reporting 
to Sponsor 
or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
Adverse Event
AE
Signing of 
the informed 
consent form 
(ICF)
The safety follow-
up visit OR 
participation in 
study has ended
As soon as 
possible 
upon site 
awareness
AE eCRF
N/A
Serious Adverse Event
SAE and SAE 
updates – prior to 
start of study 
intervention and
deemed reasonably 
possibly related with 
study procedures
Signing of 
the ICF
Start of intervention
Within 
24 hours of 
awareness
SAE eCRF 
SAE paper 
form
SAE and SAE 
updates – after start 
of study intervention
Start of 
intervention
The safety follow-
up visit OR 
participation in 
study has ended
Within 
24 hours of 
awareness
SAE eCRF 
SAE paper 
form
SAE – after 
participant’s study 
participation has 
ended and the 
investigator 
becomes aware
After 
participant’s 
study 
participation 
has ended
N/A
Promptly
SAE paper form
N/A


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Event
Collection 
Start
Collection Stop
Timing for 
Reporting 
to Sponsor 
or 
Designee
Mechanism for 
Reporting
Back-up 
Method of 
Reporting
Pregnancy
Pregnancy in female 
participants and 
female partners of 
male participants
After the 
start of study 
intervention
Four months after 
the last injection for 
female partners of
male participants 
and 2 months after 
the last injection for 
female participants
Within 
24 hours 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
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 (after 
participant’s study 
participation has 
ended and the 
investigator 
becomes aware)
After 
participant’s 
study 
participation 
has ended
N/A
Promptly
Product 
Complaint form
N/A
Abbreviations: AE = adverse event; eCRF = electronic case report form; N/A = not applicable; PC = product 
complaint; SAE = serious adverse event. 


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8.3.2. Special Safety Topics
8.3.2.1.
Hypoglycemia 
Upon ICF signing, all participants will be educated about signs and symptoms of hypoglycemia,
how to treat hypoglycemia, and how to collect appropriate information for each episode of
hypoglycemia. Hypoglycemia may be identified by spontaneous reporting of symptoms from 
participants (whether confirmed or unconfirmed by simultaneous glucose values) or by blood 
glucose (BG) samples collected during study visits.
All participants who develop diabetes during the study will be provided with glucometers. 
Participants without diabetes may be given glucometers to assist in the evaluation of reported 
symptoms consistent with hypoglycemia at the investigator’s discretion. Participants receiving 
glucometers will be provided a diary to record relevant information (for example, glucose values, 
symptoms).
All hypoglycemic episodes will be recorded on a specific eCRF (Hypoglycemic Events eCRF) 
and should not be recorded on the AE eCRF, unless the event meets serious criteria. If a 
hypoglycemic event meets severe criteria (see definition below), it should be recorded as serious 
on the AE and SAE eCRFs, and reported to Lilly as an SAE. All posttreatment hypoglycemic 
events collected on the hypoglycemic eCRF will be considered as treatment-emergent and 
included in the analysis of incidence and rate of hypoglycemic events.
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the BG values in this section refer to values 
determined by a laboratory or International Federation of Clinical Chemistry and Laboratory 
Medicine blood-equivalent glucose meters and strips) in accordance with the 2020 American 
Diabetes Association position statement on glycemic targets (American Diabetes Association 
2020):
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 
BG level of <70 mg/dL (<3.9 mmol/L).

Documented asymptomatic hypoglycemia is defined as any event not accompanied by 
typical symptoms of hypoglycemia, but with a measured BG <70 mg/dL (<3.9 mmol/L).

Documented unspecified hypoglycemia is defined as any event with no information 
about symptoms of hypoglycemia available, but with a measured BG <70 mg/dL 
(<3.9 mmol/L).
Clinically Significant Hypoglycemia (Level 2):

Documented symptomatic hypoglycemia is defined as any time a participant feels that 
he or she is experiencing symptoms and/or signs associated with hypoglycemia and has a 
BG level of <54 mg/dL (<3.0 mmol/L).

Documented asymptomatic hypoglycemia is defined as any event not accompanied by 
typical symptoms of hypoglycemia but with a measured BG <54 mg/dL (<3.0 mmol/L).


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
Documented unspecified hypoglycemia is defined as any event with no information 
about symptoms of hypoglycemia available but with a measured BG <54 mg/dL 
(<3.0 mmol/L).
Severe hypoglycemia (Level 3):

Severe hypoglycemia is defined as an episode with severe cognitive impairment,
requiring the assistance of another person to actively administer carbohydrate, glucagon, 
or other resuscitative actions. These episodes may be associated with sufficient 
neuroglycopenia to induce seizure or coma. Blood glucose measurements may not be 
available during such an event, but neurological recovery attributable to the restoration of 
BG to normal is considered sufficient evidence that the event was induced by a low BG 
concentration.
To avoid duplicate reporting, all consecutive BG values <70 mg/dL (<3.9 mmol/L) occurring 
within a 1-hour period may be considered to be a single hypoglycemic event 
(Weinberg et al. 2010; Danne et al. 2013).  
8.3.2.2.
Pancreatitis 
Diagnosis of Acute Pancreatitis
Acute pancreatitis is an AE of interest in all studies with tirzepatide, including this study. The 
diagnosis of acute pancreatitis requires 2 of the following 3 features (Banks and Freeman 2006;
Koizumi et al. 2006): 

abdominal pain, characteristic of acute pancreatitis (that is, epigastric pain radiating to the 
back, often associated with nausea and vomiting)

serum amylase (total, pancreatic, or both) and/or lipase ≥3X ULN

characteristic findings of acute pancreatitis on CT scan or magnetic resonance imaging 
(MRI)
If acute pancreatitis is suspected, the investigator should:

obtain appropriate laboratory tests, including pancreatic amylase (p-amylase) and lipase

perform imaging studies, such as abdominal CT scan with or without contrast, abdominal 
MRI, or gallbladder ultrasound
Note: Abdominal ultrasound may be used as an alternative method only if CT and MRI 
cannot be performed.

evaluate for possible causes of acute pancreatitis, including alcohol use, gallstone/gall 
bladder disease, hypertriglyceridemia, and concomitant medications
Discontinuation for Acute Pancreatitis
If acute pancreatitis is diagnosed, the participant must discontinue use of the study intervention. 
Case Adjudication and Data Entry
An independent clinical endpoint committee (CEC) will adjudicate all suspected cases of acute 
pancreatitis. In addition, AEs of severe or serious abdominal pain of unknown etiology will also 


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be submitted to the adjudication committee to assess for possible pancreatitis or other pancreatic
disease. 
Asymptomatic Elevation of P-Amylase and/or Lipase
Serial measures of pancreatic enzymes have limited clinical value for predicting episodes of 
acute pancreatitis in asymptomatic patients (Nauck et al. 2017; Steinberg et al. 2017a, 2017b). 
Therefore, further diagnostic follow-up of cases of asymptomatic elevation of pancreatic 
enzymes (lipase and/or p-amylase ≥3X ULN) is not mandated but may be performed based on 
the investigator’s clinical judgment and assessment of the participant’s overall clinical condition.
8.3.2.3.
Thyroid Malignancies and C-Cell Hyperplasia 
Individuals with personal or family history of MTC and/or MEN-2 will be excluded from the 
study. Participants who are diagnosed with MTC and/or MEN-2 during the study will have study 
drug stopped and should continue follow-up with an endocrinologist.
The assessment of thyroid safety during the trial will include reporting of any case of thyroid 
malignancy (including MTC, papillary carcinoma, and others) and measurements of calcitonin. 
These data will be captured in specific eCRFs. The purpose of calcitonin measurements is to 
assess the potential of tirzepatide to affect thyroid C-cell function, which may indicate 
development of C-cell hyperplasia and neoplasms. 
8.3.2.4.
Calcitonin Measurements 
If an increased calcitonin value (see definitions below) is observed in a participant who has been 
administered a medication that is known to increase serum calcitonin, then this medication 
should be stopped, and calcitonin levels should be measured after an appropriate washout period.
For participants who require additional endocrine assessment because of increased calcitonin 
concentration as defined in this section, data from the follow-up assessment will be collected in 
the specific section of the eCRF.
Calcitonin Measurements in Participants with eGFR ≥60 mL/min/1.73 m2
A significant increase in calcitonin for participants with eGFR ≥60 mL/min/1.73 m2 is defined 
below. If a participant’s laboratory results meet these criteria, these clinically significant 
laboratory results should be recorded as an AE.  

Serum calcitonin value ≥20 ng/L and <35 ng/L AND ≥50% increase from the screening 
value. These participants will be asked to repeat the measurement within 1 month. If this 
repeat value is increasing (≥10% increase), the study drug should be stopped, and the 
participant encouraged to undergo additional endocrine assessment and longer-term 
follow-up by an endocrinologist to exclude any serious adverse effect on the thyroid.

Serum calcitonin value ≥35 ng/L AND ≥50% over the screening value. In these 
participants, study drug should be stopped, and the participant recommended to 
immediately undergo additional endocrine assessments and longer-term follow-up by an 
endocrinologist.  


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Calcitonin Measurement in Participants with eGFR <60 mL/min/1.73 m2  
A significant increase in calcitonin for participants with eGFR <60 mL/min/1.73 m2 is defined as 
a serum calcitonin value ≥35 ng/L AND ≥50% over the screening value. If a participant’s labs 
meet these criteria, these clinically significant labs should be recorded as an AE.  
In these participants, study drug should be discontinued (after first confirming the value) and the 
participant recommended to immediately undergo additional endocrine assessments and 
longer-term follow-up by an endocrinologist to exclude any serious adverse effect on the thyroid.  
8.3.2.5.
Major Adverse Cardiovascular Events 
Deaths and nonfatal cardiovascular AEs will be adjudicated by a committee of physicians 
external to Lilly with cardiology expertise. This committee will be blinded to treatment 
assignment. The nonfatal cardiovascular AEs to be adjudicated include

myocardial infarction

hospitalization for unstable angina

hospitalization for heart failure

coronary interventions (such as coronary artery bypass graft or percutaneous coronary 
intervention), and 

cerebrovascular events, including cerebrovascular accident (stroke) and transient 
ischemic attack.
8.3.2.6.
Supraventricular Arrhythmias and Cardiac Conduction Disorders
Treatment-emergent cardiac conduction disorders will be further evaluated. Participants who 
develop any event from these groups of disorders should undergo an ECG, which should be 
submitted to the central reading center. Additional diagnostic tests to determine exact diagnosis 
should be performed, as needed. The specific diagnosis will be recorded as an AE. Events that 
meet criteria for serious conditions as described in Section 10.4 must be reported as SAEs. 
8.3.2.7.
Hypersensitivity Reactions
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data describing each symptom should be provided
to the sponsor in the eCRF. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study drug. It is recommended that participants
who experience a systemic hypersensitivity reaction be treated per national and international 
guidelines.
In the case of generalized urticaria or anaphylaxis, additional blood and urine samples should be 
collected as described in Section 10.3, Appendix 3: “Laboratory Assessments for 
Hypersensitivity Events.” Laboratory results are provided to the sponsor via the central 
laboratory.


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8.3.2.8.
Injection-Site Reactions
Symptoms of a local injection site reaction may include erythema, induration, pain, pruritus, and 
edema. If an injection site event is reported, the AE will be recorded, and additional data will be 
provided to the sponsor in the Injection Site Reaction eCRF.  
At the time of AE occurrence, samples will be collected for measurement of tirzepatide antidrug 
antibodies (ADAs) and tirzepatide concentration.
8.3.2.9.
Antidrug Antibodies
The occurrence of ADA formation will be assessed as outlined in Section 8.9.
8.3.2.10.
Hepatobiliary Disorders
All events of treatment-emergent biliary colic, cholecystitis, or other suspected events related to 
gallbladder disease should be evaluated and additional diagnostic tests performed, as needed. In 
cases of elevated liver markers, hepatic monitoring should be initiated as outlined in 
Section 8.2.5.1.
8.3.2.11.
Severe Gastrointestinal Adverse Events 
Tirzepatide may cause severe GI AEs, such as nausea, vomiting, and diarrhea. Information about 
severe GI AEs as well as antiemetic/antidiarrheal use will be collected in the eCRF/AE form. For 
detailed information concerning the management of GI AEs, please refer to Section 6.6.2.
8.3.2.12.
Acute Renal Events
Renal safety will be assessed based on repeated renal function assessment, as well as assessment 
of AEs suggestive of acute or worsening of chronic renal failure. Gastrointestinal AEs have been 
reported with tirzepatide, including nausea, diarrhea, and vomiting. This is consistent with other 
GLP-1R agonists (Aroda and Ratner 2011). The events may lead to dehydration, which could 
cause a deterioration in renal function, including acute renal failure. Participants should be 
advised to notify investigators in case of severe nausea, frequent vomiting, or symptoms of 
dehydration.
8.3.2.13.
Depression, Suicidal Ideation, or Behavior Monitoring
Participants will be monitored for depression and suicidal ideation or behavior through AE 
collection and by using the C-SSRS and the PHQ-9. Participants will be referred to an MHP if in 
the opinion of the investigator it is necessary for the safety of the participant or if the participant 
had any of the following:

a PHQ-9 score ≥15

C-SSRS responses of
o
A “yes” answer to Question 4 (Active Suicidal Ideation with Some Intent to Act, 
Without Specific Plan) on the “Suicidal Ideation” portion of the C-SSRS
or
o
A “yes” answer to Question 5 (Active Suicidal Ideation with Specific Plan and 
Intent) on the “Suicidal Ideation” portion of the C-SSRS 
or


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o
A “yes” answer to any of the suicide-related behaviors (actual attempt, interrupted 
attempt, aborted attempt, preparatory act, or behavior) on the “Suicidal Behavior”
portion of the C-SSRS
8.4.
Treatment of Overdose
Study drug overdose (more than the specified number of injections) will be reported as an AE. In 
the event of an overdose, refer to the IB for tirzepatide.
8.5.
Pharmacokinetics
Not applicable.
8.6.
Pharmacodynamics
Samples to assess the PD properties of tirzepatide are included in the efficacy measures and not 
applicable in this section.
8.7.
Genetics
A whole blood sample will be collected for pharmacogenetic analysis as specified in the SoA
(Section 1.3) where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future. Samples will be used to investigate variable response to tirzepatide and to 
investigate genetic variants thought to play a role in obesity. Assessment of variable response 
may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the investigator site personnel.  
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and/or 
Ethical Review Boards (ERBs)/Institutional Review Boards (IRBs) impose shorter time limits. 
This retention period enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development of 
tirzepatide or after tirzepatide 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 
clinical outcome. Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including DNA, proteins, lipids, and other 
cellular elements.


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Serum and plasma samples for biomarker research (nonpharmacogenetic stored samples) will be 
collected at the times specified in the SoA (Section 1.3) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
tirzepatide, pathways associated with obesity, mechanism of action of tirzepatide, and/or 
research method or in validating diagnostic tools or assay(s) related to obesity.  
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the investigator site personnel.  
Samples will be retained at a facility selected by Lilly or its designee for a maximum 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and ERBs 
impose shorter time limits. This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in the development of tirzepatide or after tirzepatide becomes commercially available.
8.9.
Immunogenicity Assessments
Where local regulations and ERBs allow, blood samples for immunogenicity testing will be 
collected to determine antibody production against tirzepatide as specified in the SoA
(Section 1.3).
For immunogenicity testing, venous blood samples will be collected from each participant
according to the SoA (Section 1.3) to determine antibody production against tirzepatide. To 
interpret the results of immunogenicity, a venous blood sample will be collected at the same time 
points to determine the plasma concentrations of tirzepatide. All samples for immunogenicity 
should be taken predose when applicable and possible.  
In the event of systemic drug hypersensitivity reactions (immediate or nonimmediate), additional 
unscheduled samples should be collected as detailed in Section 8.3.2.7 (Hypersensitivity 
Reactions). Instructions for the collection and handling of blood samples will be provided by the 
sponsor. The actual date and time (24-hour clock time) of each sampling will be recorded. 
Samples collected at Visit 801 will assess immunogenicity at washout of tirzepatide (5 half-lives 
post end of treatment).
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of tirzepatide at a laboratory approved by the sponsor. Antibodies may be further characterized 
for their ability to neutralize the activity of tirzepatide on GIPR and GLP-1R. Positive tirzepatide
ADA samples will be tested for cross-reactivity with native GIP and GLP-1, and, if positive, may 
then be tested for neutralizing antibodies against native GIP and/or GLP-1. In vivo laboratory 
indicators for effect on weight loss and PK will be utilized to detect potential neutralizing effect 
of ADAs against tirzepatide.
Treatment-emergent ADAs are defined in Section 9.4.5.  
Samples will be retained for a maximum of 15 years after the last participant visit, or for a 
shorter period if local regulations and ERBs allow, at a facility selected by the sponsor. The 
duration allows the sponsor to respond to future regulatory requests related to tirzepatide. Any 
samples remaining after 15 years will be destroyed. 


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Concentrations of tirzepatide will be assayed using a validated liquid chromatography mass
spectrometry method. Bioanalytical samples collected to measure tirzepatide concentrations will 
be retained for a maximum of 1 year following last subject visit for the study. During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses such as 
metabolism work, protein binding, and/or bioanalytical method cross-validation.
8.10.
Health Economics
Health Economics parameters are not evaluated in this study.


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9.
Statistical Considerations
9.1.
Statistical Hypotheses
The alternative hypothesis for the primary objective is the following: 
H1: QW tirzepatide MTD is superior to placebo for percent change from randomization
(Week 36) in body weight at 88 weeks.
The alternative hypotheses for the key secondary objectives controlling for Type 1 error rate are 
the following: 
H2: QW tirzepatide MTD is superior to placebo for change from randomization (Week 36) in 
body weight (kg) at 88 weeks.
H3: QW tirzepatide MTD is superior to placebo for change from randomization (Week 36) in 
waist circumference (cm) at 88 weeks.
H4: QW tirzepatide MTD is superior to placebo for percentage of participants who maintain 
≥80% of the body weight lost during the open-label lead-in period at 88 weeks.
H5: QW tirzepatide MTD is superior to placebo for delaying the onset of returning to 
>95% body weight at baseline (Week 0) during the double-blind treatment period.
H6: QW tirzepatide MTD is superior to placebo for percentage of participants who achieve 
≥5% body weight reduction from Visit 2 (Week 0) at 88 weeks.
H7: QW tirzepatide MTD is superior to placebo for percentage of participants who achieve 
≥10% body weight reduction from Visit 2 (Week 0) at 88 weeks.
H8: QW tirzepatide MTD is superior to placebo for percent change from randomization (Week 
36) in body weight at 64 weeks.
9.2.
Sample Size Determination
Approximately 1000 participants will be screened and 750 participants enrolled into the 36-week 
open-label tirzepatide lead-in treatment period in order to get approximately 600 participants to 
be randomized in a 1:1 ratio to tirzepatide MTD (300 participants) or placebo (300 participants).
The sample size determination assumes that evaluation of superiority of tirzepatide MTD to 
placebo will be conducted at a 2-sided significance level of 0.05 using a 2-sample t-test. 
Additionally, a difference of at least 6% mean body weight percentage change from 
randomization (36 weeks) to 88 weeks between tirzepatide MTD and placebo, a common SD of 
8%, and a dropout rate of 25% are assumed for statistical power calculations. Under the 
assumptions above, randomizing 600 participants in a 1:1 ratio to tirzepatide MTD (300
participants) and placebo (300 participants) provides more than 90% power to demonstrate 
superiority of tirzepatide MTD to placebo. 


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9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Entered
All participants who sign informed consent
Enrolled
All participants who are assigned to open-label tirzepatide treatment
Randomized
All participants who are randomly assigned a study treatment (double-blind)
Modified Intent-to-Treat (mITT) 
All enrolled participants who are exposed to at least 1 dose of study drug.  
Efficacy Analysis Set (EAS)
Data obtained during the double-blind treatment period from the mITT
population, excluding data after discontinuation of study drug (last dose date + 
7 days). 
Full Analysis Set (FAS)
Data obtained during the double-blind treatment period from the mITT
population, regardless of adherence to study drug. 
Safety Analysis Set (SS)
Data obtained during the double-blind period and safety follow-up period from 
the mITT population, regardless of adherence to study drug. 
9.4.
Statistical Analyses
9.4.1. General Considerations
Statistical analysis of this study will be the responsibility of the sponsor 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) and the clinical study report (CSR). Additional exploratory 
analyses of the data will 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 all confidence intervals will be given at a 2-sided 95% level. In statistical summaries 
and analyses, data will be analyzed as randomized.
Unless specified otherwise, efficacy analyses will be conducted using the efficacy analysis set
(EAS), and safety analyses will be conducted using the safety analysis set (SS). 
Unless specified otherwise, for analyses in the double-blind treatment period, baseline is defined 
as the last nonmissing data collected prior to or at randomization (Week 36); for analyses in the 
lead-in period, baseline is defined as the last nonmissing data collected prior to or at study entry
(Week 0).
Summary statistics for continuous measures will include sample size, mean, SD, median, 
minimum, and maximum. The analysis model to make comparisons among treatment arms 
relative to continuous measurements assessed over time will be a mixed-model for repeated 
measures (MMRM) with terms of treatment, visit, treatment-by-visit interaction, stratification 
factors, and baseline measurement as a covariate. An unstructured covariance structure will 
model the relationship of within-patient errors.
The Kaplan-Meier method will be used for estimation of cumulative event-free survival rates 
over time, and Cox proportional hazards regression analysis will be used to compare hazard rates 
among treatments.


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Summary statistics for categorical measures (including categorized continuous measures) will 
include sample size, frequency, and percentages. Logistic regression will be used to examine the 
treatment difference in binary efficacy outcomes if there is a need to adjust for covariates. 
Otherwise, Fisher’s exact test will be used to examine the treatment difference in categorical 
outcomes.   
Summary statistics for discrete count measures will include sample size, mean, SD, median, 
minimum, and maximum. The negative binomial regression model will be used for the treatment 
comparison of discrete count measures. 
Other statistical methods may be used, as appropriate, and details will be described in the SAP.
9.4.2.
Treatment Group Comparability
9.4.2.1.
Participant Disposition
A detailed description of participant disposition will be provided at the end of the study. 
Frequency counts and percentages of all participants screened, enrolled, and randomized will be 
summarized. 
Frequency counts and percentages of participants who completed the study and those who 
prematurely discontinued the study (and/or study drug), including reason for premature 
discontinuation, will be summarized for both the open-label lead-in period and the double-blind 
period. 
A Kaplan-Meier analysis of time from randomization to premature discontinuation from study 
and/or study treatment during the double-blind period by treatment group will be provided.
9.4.2.2.
Participant Characteristics
Demographics will be summarized for all enrolled participants.
Demographics will also be summarized by treatment group for all randomized participants.
9.4.2.3.
Concomitant Therapy 
Concomitant medications during the double-blind treatment period will be summarized by 
treatment group for all randomized participants.  
Concomitant medications during the open-label lead-in treatment period may also be 
summarized for all enrolled participants.
9.4.2.4.
Treatment Compliance 
Frequency counts and percentages of participants compliant to study drug will be summarized 
for both the open-label lead-in period and double-blind period.
9.4.3.
Efficacy Analyses
9.4.3.1.
Primary Analyses
There will be 2 estimands of interest in comparing efficacy of tirzepatide MTD with placebo. 


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For the FDA, the primary efficacy analysis will be guided by the “hybrid” estimand and will be 
conducted using the full analysis set (FAS). This assessment will analyze percent change in body 
weight from randomization (Week 36) to the 88-week visit using an analysis of covariance 
(ANCOVA). The model will include terms of treatment, stratification factors, and baseline body 
weight as a covariate. Missing data solely due to a pandemic or natural disaster (after other 
reasons for missing data are ruled out) will be considered missing at random, and missing data 
will be imputed using all nonmissing data of the primary outcome from the same treatment arm.
Missing data of the primary outcome measurement due to all other Intercurrent Events will be 
imputed based on retrieved dropouts in the same treatment arm, defined as observed primary 
outcome measurements from participants in the same treatment group who had their efficacy 
assessed after early discontinuation of study drug. In cases where there are not enough retrieved 
dropouts to provide a reliable imputation model (for example, the model implemented by the 
SAS program does not converge), an alternative multiple imputation method with reference to 
the placebo group (that is, placebo multiple imputation) will be used. Analysis will be conducted 
with multiple imputations.  
For all other purposes, the primary efficacy analysis will be guided by the “efficacy” estimand, 
which reflects efficacy prior to discontinuation of study drug and is conducted using the EAS. 
The primary analysis model will be an MMRM for body weight percent change over time. The 
response variable of MMRM will be the percent change in body weight from randomization
obtained at each scheduled postbaseline visit. The independent variables are treatment group 
(tirzepatide MTD and placebo), visit, treatment-by-visit interaction, stratification factors, and 
baseline body weight as a covariate. An unstructured covariance structure will model the
relationship of within-patient errors. The Kenward-Roger approximation will be used to estimate 
the denominator degrees of freedom.
9.4.3.2.
Key Secondary Efficacy Analyses

superiority of tirzepatide MTD to placebo for change from randomization (Week 36) in 
body weight (kg) to the 88-week visit

superiority of tirzepatide MTD to placebo for change from randomization (Week 36) in 
waist circumference (cm) to the 88-week visit

superiority of tirzepatide MTD to placebo for the percentage of participants who maintain 
≥80% of the body weight lost during the open-label lead-in period to 88 weeks

superiority of tirzepatide MTD to placebo for delaying the onset of returning to 
>95% body weight at baseline (Week 0) during the double-blind treatment period

superiority of tirzepatide MTD to placebo for percentage of participants who achieve
≥5% body weight reduction from Visit 2 (Week 0) to 88 weeks

superiority of tirzepatide MTD to placebo for percentage of participants who achieve 
≥10% body weight reduction from Visit 2 (Week 0) to 88 weeks

superiority of tirzepatide MTD to placebo for percent change from randomization (Week 
36) in body weight to 64 weeks
Additional details, including analysis methods for key secondary endpoints and the strategy for 
controlling the overall Type 1 error rate at a 2-sided alpha of 0.05 of primary and key secondary 
endpoint evaluation, will be provided in the SAP.


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9.4.3.3.
Other Secondary Efficacy Analyses 
All other efficacy analyses will be guided by the “efficacy” estimand and will be conducted 
using the EAS.  
Efficacy outcomes during the open-label lead-in treatment period may also be summarized for all 
enrolled participants.
Details will be provided in the SAP.
9.4.4.
Other Safety Analyse(s)
Unless specified otherwise, safety assessments will be guided by an estimand comparing the 
safety of tirzepatide MTD with placebo irrespective of adherence to study drug.
Safety outcomes during the open-label lead-in treatment period may also be summarized for all 
enrolled participants.
9.4.4.1.
Study Drug Exposure
Exposure to each study treatment will be calculated for each participant and summarized. The 
details will be provided in the SAP.
9.4.4.2.
Adverse Events
Adverse events will be coded from the actual term using the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be reported with Preferred Terms and System Organ Classes. 
Counts and proportions of participants experiencing events will be reported for each randomized
treatment group, and Fisher’s exact test will be used to compare the treatment groups.
The percentage of participants experiencing TEAEs, SAEs, and discontinuation due to AEs will 
be summarized by treatment group.
9.4.4.3.
Special Safety Topics
This section includes areas of interest whether due to observed safety findings, potential findings 
based on drug class, or agreed upon consultation with regulatory agencies for the reasons 
previously mentioned.
The following AEs are adverse events of special interest (AESIs) for this study:

severe hypoglycemia

major adverse cardiovascular events (adjudicated); includes, but not limited to,
cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and 
hospitalization for heart failure

treatment-emergent supraventricular arrhythmias and cardiac conduction 
disorders

hepatobiliary disorders; includes biliary colic, cholecystitis, and other gallbladder 
disease

severe GI events

acute renal events

MDD/suicidal behavior and ideation  


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
pancreatitis (adjudicated)

C-cell hyperplasia and thyroid malignancies, and

allergic/hypersensitivity reactions; includes injection site reactions and ADA
formation.
Summaries and analyses for the incidence of AESIs will be provided. The details of analysis of 
AESIs will be provided in the SAP.
9.4.4.4.
Other Adverse Events Assessments 
9.4.4.4.1. Gastrointestinal Events
Summaries and analyses for incidence and severity of nausea, vomiting, and diarrhea will be 
provided by each treatment.  
9.4.4.4.2. Events related to Potential Abuse Liability
Summaries and analyses for incidence of potential abuse liability TEAEs will be provided. 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 the 
C-SSRS, and depression-related symptoms will be assessed using the PHQ-9. 
The analysis details will be provided in the SAP.
9.4.4.4.4. Central Laboratory Measures, Vital signs, and Electrocardiograms
Actual values and change from randomization of central laboratory measures, vital signs, and 
selected ECG parameters will be summarized by treatment group at each scheduled visit.
The percentages of participants with treatment-emergent abnormal, high, or low measures 
(including lab, vital, and ECG parameters) at any time will be summarized and compared 
between treatment groups using Fisher’s exact test.
The analysis details will be provided in the SAP.
9.4.5.
Evaluation of Immunogenicity 
The frequency and percentage of participants with preexisting ADA and with treatment-
emergent ADA positive (TE ADA+) to tirzepatide will be tabulated. Treatment-emergent ADAs 
are defined as those with a titer 2-fold (1 dilution) greater than the minimum required dilution 
(1:10) of the ADA assay if no ADAs were detected at baseline (treatment-induced ADA), or 
those with a 4-fold (2 dilutions) increase in titer compared to baseline if ADAs were detected at 
baseline (treatment-boosted ADA). For the TE ADA+ participants, the distribution of maximum 
titers will be described. The frequency of neutralizing antibodies, if assessed, and crossreactivity 
to native GIP and GLP-1 may also be tabulated in TE ADA+ participants.
The relationship between the presence of antibodies and the PK parameters and PD response,
including safety and efficacy to tirzepatide, may be assessed.


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9.4.6.
Other Analyse(s)
9.4.6.1.
Health Outcomes
Analyses of actual and change from randomization in the domains and/or summary scores of 
PROs questionnaires will be conducted using the EAS. The details on questionnaire-specific 
analyses will be provided in the SAP.
Health outcomes during the open-label lead-in treatment period may also be summarized for all 
enrolled participants.
9.4.6.2.
Subgroup Analyses for Primary Outcome
Details of the subgroup analyses will be provided in the SAP.  
The following subgroup variables will be considered (but not limited to):

age (<65 years and ≥65 years)

sex (female and male)

race 

ethnicity 

BMI at study entry (<30, ≥30 and <35, ≥35, and <40, ≥40 kg/m2), and

Percent body weight loss at 36 weeks (<10% and ≥10%).
The outcome measures for the subgroup analyses will include percent change in body weight 
from randomization at 88 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.
A database lock may occur after all enrolled participants complete or discontinue the 36-week 
open-label lead-in treatment period. This is not considered an interim lock since the enrolled 
participants who complete the 36-week open-label lead-in treatment period will be randomized 
to a double-blind, placebo-controlled treatment period, and there is no plan to modify the study 
based on the results from this open-label lead-in database lock.
9.6.
Data Monitoring Committee (DMC)
Not applicable. 


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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the 
following:
○
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 Harmonization (ICH) GCP 
Guidelines
○
Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents 
(for example, advertisements) must be submitted to an IRB/Independent 
Ethics Committee (IEC) by the investigator and reviewed and approved by the 
IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.

Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants.

The investigator will be responsible for the following:
○
Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC
○
Notifying the IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures
○
Providing oversight of study conduct for participants under their 
responsibility and adherence to requirements of 21 Code of Federal 
Regulations (CFR), ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations

Investigator sites are compensated for participation in the study as detailed in the 
clinical trial agreement (CTA).


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10.1.2.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study, 
including the risks and benefits, to the participant or his/her legally authorized 
representative and answer all questions regarding the study.

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 reconsented to the most current version of the ICF(s) 
during their participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative and is kept on file.
10.1.3.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any 
participant records, datasets, or tissue samples that are transferred to the 
sponsor will contain the identifier only; participant names or any information 
which would make the participant identifiable will not be transferred.

The participant must be informed that his/her personal study-related data will 
be used by the sponsor in accordance with local data protection law. The level 
of disclosure must also be explained to the participant who will be required to 
give consent for his/her data to be used as described in the informed consent.

The participant must be informed that his/her medical records may be 
examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the sponsor, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.

The sponsor has processes in place to ensure data protection, information 
security, and data integrity. These processes include appropriate contingency 
plan(s) for appropriate and timely response in the event of a data security 
breach.
10.1.4.
Committees Structure
Prospective adjudication of major adverse cardiovascular events and pancreatic AEs will be 
performed for this study. Sections 8.3.2.5 and 8.3.2.2 outline additional information on 
cardiovascular and pancreatic adjudication committees. 


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10.1.5.
Dissemination of Clinical Study Data
Required clinical trial registries (for example, ClinicalTrials.gov) will be updated with the results 
from registered clinical trials, regardless of the research outcome in accordance with local laws 
and regulations. 
All CSRs, amendments, and addenda will be submitted to external regulatory authorities, 
external partners (as applicable), and sites. 
The publication policy for Study GPHN is outlined in Section 10.1.9 and further described in the 
CTA.
10.1.6.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or eCRF 
unless transmitted to the sponsor or designee electronically (for example, 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/IEC 
review, and regulatory agency inspections and provide direct access to source 
data documents.

Monitoring details describing strategy (for example, risk-based initiatives in 
operations and quality such as risk management, mitigation strategies, and 
analytical risk-based monitoring), methods, responsibilities, and requirements, 
including handling of noncompliance issues and monitoring techniques are 
provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals 
(for example, contract research organizations).

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of 
participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of 
this study must be retained by the investigator for the time period outlined in 
the CTA unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period 
without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor.


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
In addition, sponsor or its representatives will periodically check a sample of 
the participant data recorded against source documents at the study site. The 
study may be audited by sponsor or its representatives, and/or regulatory 
agencies at any time. Investigators will be given notice before an audit occurs.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An electronic data capture (EDC) system will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Additionally, clinical outcome assessment (COA) data (participant-focused outcome instrument) 
and other data (for example, diary) will be collected by the participant, caregiver, or authorized 
study personnel, via a paper source document and will be transcribed by the authorized study 
personnel into the EDC system.
Data collected via the sponsor-provided data capture system(s) will be stored at third parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system(s). Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system. Data will subsequently be transferred from the central 
vendor to the sponsor data warehouse.
Data from complaint forms submitted to sponsor will be encoded and stored in the global 
product complaint management system.
10.1.7.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at 
the investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request 
previous medical records or transfer records, depending on the study. Also, 
current medical records must be available.

Definition of what constitutes source data can be found in study training 
material.
10.1.8.
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.


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The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include, but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP 
guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IRBs/IECs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and assure 
appropriate participant therapy and/or follow-up.
10.1.9.
Publication Policy
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal.

The sponsor will comply with the requirements for publication of study results. 

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

The publication policy for Study GPHN is described in the CTA.


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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed below will be performed by a central lab, unless designated 
as local in the SoA and in the table below. In circumstances where the sponsor 
approves local laboratory testing in lieu of central laboratory testing (in the 
table below), the local laboratory must be qualified in accordance with 
applicable local regulations.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy testing (Refer to Section 5.1 Inclusion Criteria for screening 
pregnancy criteria).

Investigators must document their review of each laboratory safety report.

Laboratory results that could unblind the study will not be reported to 
investigative sites or other blinded personnel and are denoted in the table 
below.


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Clinical Laboratory Tests
Hematologya
Clinical Chemistrya
Hemoglobin
Bicarbonate
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils, segmented
ALT
Lymphocytes
AST
Monocytes
BUN
Eosinophils
Creatinine
Basophils
Uric acid
Platelets
Calcium
Glucose
Urine Chemistriesa
Albumin
Albumin
Creatine kinase
Creatinine
Cystatin-Ca
Hormones (females)
Pregnancy Test serum a and/or urine (local)
Follicle-stimulating hormone (FSH)a
HbA1ca
Endocrinea
Calcitonin
Pancreas (exocrine)a
Thyroid-stimulating hormone (TSH)
Pancreatic amylase
Lipase
Nonpharmacogenetic Stored Samplesa,b
Serum
EDTA plasma
P800 plasma
Immunogenicitya,b
Anti-tirzepatide antibodies
Anti-tirzepatide antibody neutralization
Pharmacokinetic Sample for Immunogenicity
Lipid Panela
Pharmacogenetics Samplea,b
Whole blood (EDTA)
Cholesterol
Triglycerides
VLDL-C   
HDL-C   
LDL-Cc   
Free Fatty Acidsa
Insulina
C-Peptidea
Calculationsa
eGFR (calculated by CKD-EPI equation)
UACR


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Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
CKD-EPI = Chronic Kidney Disease-Epidemiology; eGFR = estimated glomerular filtration rate; 
EDTA = ethylenediaminetetraacetic acid; HbA1c = hemoglobin A1c; HDL-C = high-density lipoprotein
cholesterol; LDL-C = low-density lipoprotein cholesterol; RBC = red blood cells; UACR = urine albumin to 
creatinine ratio; VLDL-C = very low-density lipoprotein cholesterol; WBC = white blood cells.
a
All tests will be performed by a Lilly-designated central laboratory, unless otherwise noted.
b Results will not be provided to the investigative sites.
c
This value will be calculated. If triglycerides are >400 mg/dL, the direct LDL will be assayed.


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


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


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10.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.4.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product and which does not necessarily have a causal relationship with the study 
intervention. An AE can therefore be any unfavourable and unintended sign (including an
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not 
related to progression of underlying disease).

Exacerbation of a chronic or intermittent preexisting 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 an AE or SAE if they fulfill the definition of an 
AE or SAE.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 


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that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of 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 (for example, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been admitted to hospital for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.

Hospitalization for elective treatment of a 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, and 
accidental trauma (for example, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect

Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs


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


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


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


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


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10.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
If fertility is unclear (for example, amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered women of childbearing potential:
Article I.
Premenarchal
Article II. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (for example, Mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Determination can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Article III. Postmenopausal female

A postmenopausal state is defined as either
o
A woman at least 40 years of age with an intact uterus, not on hormone 
therapy, who has cessation of menses for at least 1 year without an alternative 
medical cause, AND an FSH ≥40 mIU/mL; or 
o
A woman 55 or older not on hormone therapy, who has had at least 12 months 
of spontaneous amenorrhea; or 
o
A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormonal replacement therapy (HRT). 

Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the nonestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Guidance:
Contraceptive use by men and women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.


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Two forms of effective contraception, where at least 1 form is highly effective, will be used. 
Effective contraception may be used as the second therapy. Barrier protection methods without 
concomitant use of a spermicide are not a reliable or acceptable method. The use of male and 
female condoms as a double-barrier method is not considered acceptable due to the high failure 
rate when these methods are combined. 
Highly Effective Methods of Contraception:

Combined oral contraceptive pill and mini pill

NuvaRing

Implantable contraceptives

Injectable contraceptives (such as Depo Provera)

Intrauterine device (such as Mirena® and ParaGard®)

Contraceptive patch – ONLY women <198 pounds or 90 kg

Total abstinence (if this is their preferred and usual lifestyle) or in a same-sex 
relationship with no sexual relationship with males (as part of their preferred and 
usual lifestyle), and agrees to maintain this status throughout trial follow-up 
Note: Periodic abstinence (for example, calendar, ovulation, symptothermal, and 
postovulation methods), declaration of abstinence just for the duration of a trial, and 
withdrawal are not acceptable methods of contraception.

Vasectomy – for men in clinical studies
Note: Implantable contraceptives and injectable contraceptives (such as Depo Provera) 
are only permitted if started more than 18 months prior to screening. Participants should 
not start these methods of contraception after being enrolled in the study.
Effective Methods of Contraception (Must Use Combination of 2 Methods):

Male condom with spermicide

Female condom with spermicide

Diaphragm with spermicide

Cervical sponge

Cervical cap with spermicide
Men, regardless of their fertility status, with nonpregnant women of childbearing potential 
partners must agree to either remain abstinent (if this is their preferred and usual lifestyle) or use 
condoms plus 1 additional highly effective (less than 1% failure rate) method of contraception 
(such as combination oral contraceptives, implanted contraceptives, or intrauterine device) or
effective method of contraception (such as diaphragms with spermicide or cervical sponge) for 
the duration of the study and for 5 half-lives of study drug plus 90 days, which is approximately 
4 months after the last injection. Periodic abstinence (for example, calendar, ovulation, 
symptothermal, and postovulation methods), declaration of abstinence just for the duration of a 
trial, and withdrawal are not acceptable methods of contraception.


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Men with pregnant partners should use condoms during intercourse for the duration of the study 
and until the end of estimated relevant potential exposure in women of childbearing potential. 
Men who are abstinent (if this is complete abstinence, as their preferred and usual lifestyle) or in 
a same-sex relationship (as part of their preferred and usual lifestyle) must agree to either remain 
abstinent or stay in a same-sex relationship without sexual relationships with females. In these 
situations, men are not required to use contraception. 
Men should refrain from sperm donation for the duration of the study and for 5 half-lives of 
study drug plus 90 days after the last dose of study drug, corresponding to 4 months after the last 
injection. 
Collection of Pregnancy Information
Male participants with partners who become pregnant

The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant 
is in this study. 

After obtaining the necessary signed informed consent from the pregnant 
female partner directly, the investigator will record pregnancy information on 
the appropriate form and submit it to the sponsor within 24 hours of learning 
of the partner’s pregnancy. The female partner will also be followed to 
determine the outcome of the pregnancy. Information on the status of the 
mother and child will be forwarded to the sponsor. Generally, the follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date. Any 
termination of the pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) and 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. 


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
A spontaneous abortion (occurring at <20 weeks gestational age) or still birth 
(occurring at >20 weeks gestational age) is always considered to be an SAE 
and will be reported as such. 

Any poststudy pregnancy-related SAE considered reasonably related to the 
study intervention by the investigator will be reported to the sponsor as 
described in protocol. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting.

Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention and be withdrawn from the study. 


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10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-Up 
Assessments 

For testing selected, analysis is required to be completed by the Lilly-designated 
central laboratory, except for microbiology.

Local testing may be performed in addition to central testing when required for 
immediate participant management.

Results will be reported if a validated test or calculation is available.
Hepatic Evaluation Labs
Hematology
Clinical Chemistry
Hemoglobin
Total bilirubin
Hematocrit
Direct bilirubin
Erythrocytes (RBCs – red blood cells)
Alkaline phosphatase (ALP)
Leukocytes (WBCs – white blood cells)
Alanine aminotransferase (ALT)
Differential:
Aspartate aminotransferase (AST)
Neutrophils, segmented
Gamma-glutamyl transferase (GGT)
Lymphocytes
Creatine kinase (CK)
Monocytes
Other Chemistry
Basophils
Acetaminophen
Eosinophils
Acetaminophen protein adducts
Platelets
Alkaline phosphatase isoenzymes
Cell morphology (RBC and WBC)
Ceruloplasmin
Coagulation
Copper
Prothrombin Time, INR (PT-INR)
Ethyl Alcohol
Serology
Haptoglobin
Hepatitis A Virus (HAV) testing:
IgA (Quantitative)
HAV total antibody
IgG (Quantitative)
HAV IgM antibody
IgM (Quantitative)
Hepatis B Virus (HBV) Testing:
Phosphatidylethanol (Peth)
Hepatitis B surface antigen (HbsAg)
Urine Chemistry
Hepatitis B surface antibody (Anti-HBs)
Drug Screen
   Hepatitis B core total antibody (Anti-HBc)
Ethyl glucuronide (EtG)
Hepatitis B core IgM antibody
Other Serology
   Hepatitis B core IgG antibody
Anti-nuclear antibody (ANA)


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


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10.7.
Appendix 7: Protocol GPHN Standardized Protocols for the 
Measurement of Height, Weight, Waist Circumference, Vital Signs, 
and Electrocardiogram
The following information has been adapted from standardized physical measurement protocols 
for the World Health Organization’s STEPwise approach to Surveillance (STEPS) (WHO 2017).
Measuring Height
Step 1. Ask the participant to remove their footwear and any headgear (light headgear worn for 
religious reasons can remain, but this should be worn by the participant at every clinic 
visit when their height is measured).
Step 2. Ask the participant to stand on the calibrated height measuring board (stadiometer) or 
against a wall with their feet together and their knees straight with their heels against the 
backboard, the stadiometer, or the wall.
Step 3. Ask the participant to look straight ahead without tilting their head up.
Step 4. Ask the participant to breathe in and stand tall. Measure and record the participant’s 
height in centimeters to 1 decimal place. 
Measuring Weight
Body weight measurements should be done in a consistent manner using a calibrated 
electronic scale capable of measuring weight in kilograms to 1 decimal place.
All weights for a given participant should be measured using the same scale, whenever 
possible, at approximately the same time in the morning after evacuation of bladder 
contents.  
Body weight 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 
to the nearest one-tenth kilogram.
Measuring Waist Circumference

Waist circumference should be measured in the horizontal plane and at the midpoint 
between the lower margin of the last palpable rib and the top of the iliac crest.

Measurements should be taken at the end of a normal expiration using a nonstretchable 
measuring tape. The tape should lie flat against the skin without compressing the soft 
tissue.


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
The waist circumference should be measured twice, rounded to the nearest 0.5 cm. The 
measuring tape should be removed between the 2 measurements. Both measurements will 
be recorded in the eCRF. If the difference between the 2 measurements exceeds 1 cm, 
this set of measurements should be discarded and the 2 measurements repeated.
Step 1. Ask the participant to wear little clothing (if available, patient gowns could also be 
used).
Step 2. Ask the participant to stand with their feet close together, arms at their side, body weight 
evenly distributed.
Step 3. Ask the participant to relax and measure the participant’s waist circumference.
Vital Sign Measurements

Vital sign measurements (blood pressure and heart rate, measured by pulse) 
should be taken before obtaining an ECG tracing and before collection of blood 
samples for laboratory testing.

The participant should sit quietly for 5 minutes before vital signs measurements 
are taken.

For each parameter, 2 measurements will be taken using the same arm, preferably 
the nondominant arm.

The recordings should be taken at least 1 minute apart. Each measurement of 
sitting pulse and blood pressure needs to be recorded in the eCRF.

Blood pressure must be taken with an automated blood pressure instrument.

If blood pressure and pulse measurements are taken separately, pulse should be 
taken prior to blood pressure. 
Note: In the event pulse measurement cannot be taken via an automated blood pressure 
instrument, the preferred location for measurement of pulse is the radial artery. 
Electrocardiogram

All digital ECGs will be obtained using centrally provided ECG machines and will be 
electronically transmitted to a designated central ECG laboratory.

12-lead ECGs should be obtained after the subject has rested in a supine position for at 
least 10 minutes.

Electrocardiograms should be collected at least 30 minutes prior to collection of blood 
samples for laboratory testing, including immunogenicity/PK samples.


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


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10.9.
Appendix 9: Management of Gastrointestinal Symptoms
Abbreviations: GI = gastrointestinal; MTD = maximum tolerated dose.


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10.10.
Appendix 10: Provisions for Changes in Study Conduct During 
Exceptional Circumstances
Implementation of this appendix
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator.
Exceptional circumstances
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study.
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures.
Implementing changes under exceptional circumstances
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations. 
After approval by local ERBs, regulatory bodies, and any other relevant local authorities, 
implementation of these exceptional circumstance changes will not typically require additional 
notification to these groups, unless they have specific conditions in which notification is 
required. To protect the safety of study participants, urgent changes may be implemented before 
approval but need to be reported as soon as possible. All approvals must be retained in the study 
records.
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed.
Considerations for making a change
The prevailing consideration for making a change is ensuring the safety of study participants.
Additional important considerations for making a change are compliance with GCP, enabling 
participants to continue safely in the study and maintaining the integrity of the study. 
Informed consent
Additional consent from the participant will be obtained, if required, for:

participation in remote visits, as defined in Section “Remote visits,”

dispensation of additional study intervention during an extended treatment period, 

alternate delivery of study intervention and ancillary supplies, and

provision of their personal or medical information required prior to implementation of 
these activities. 
Changes in study conduct during exceptional circumstances
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed.
The following changes in study conduct will not be considered protocol deviations.


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


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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 2 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 2: The participant will proceed to 
the next study visit per the usual SoA, provided that Visit 2 must be conducted within 
90 days from Visit 1.
o
The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay in the CRF.
o
Due to the pause in screening, sites should also reconfirm the impacted
participant’s consent and document this confirmation in the source 
documentation.

If paused for more than 90 days from Visit 1 to Visit 2: The participant must be 
discontinued because of screening interruption due to an exceptional 
circumstance. This is documented as a screen failure in the CRF. The participant can 
reconsent and be rescreened as a new participant. The screening procedures per the 
usual SoA should be followed, starting at Visit 1 to ensure participant eligibility by 
Visit 2.
5. Adjustments to visit windows 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA. To maximize the possibility that these visits can be conducted as 
on-site visits, the windows for visits may be adjusted, upon further guidance from the sponsor. 
This minimizes missing data and preserves the intended conduct of the study.
Primary endpoint visit (Visits 24 or 99) 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 relative to the target visit date.
For Visit 18 (key secondary endpoint visit), the visit windows may be brought forward no sooner 
than 7 days or extended up to 7 days relative to the target visit date, upon specific guidance from 
the sponsor.
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study.


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


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10.11.
Appendix 11: Abbreviations
Term
Definition
ADA
antidrug antibody
AE
adverse event: Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AMA
American Medical Association
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BG
blood glucose
BMI
body mass index
BMR
basal metabolic rate
CEC
Clinical endpoint committee
CFR
Code of Federal Regulations
CHF
congestive heart failure
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease-Epidemiology
CSR
clinical study report
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, GCP, and applicable regulatory requirements.
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form


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CRP
clinical research physician: Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer.
C-SSRS
Columbia-Suicide Severity Rating Scale
CT
computed tomography
CTA
clinical trial agreement
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DPP-4
dipeptidyl-peptidase-4
EAS
efficacy analysis set
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
enroll
The act of assigning a patient to a treatment. Participants who are enrolled in the study 
are those who have been assigned to a treatment. In this study enroll refers to all 
participants who are assigned to the open-label treatment period.
enter
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives.
ERB
Ethical Review Board
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide
GIPR
glucose-dependent insulinotropic polypeptide receptor
GLP-1
glucagon-like peptide-1
GLP-1R
glucagon-like peptide-1 receptor


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HbA1c
hemoglobin A1c
HDL
high-density lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
HRQoL
health-related quality of life
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonization 
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the patient’s decision to participate. Informed consent is documented by 
means of a written, signed and dated informed consent form.
INR
international normalized ratio
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
IP
Investigational product; a pharmaceutical form of an active ingredient or placebo being 
tested or used as a reference in a clinical trial, including products already on the market 
when used or assembled (formulated or packaged) in a way different from the 
authorized form, or marketed products used for an unauthorized indication, or marketed 
products used to gain further information about the authorized form.
IRB/IEC
Institutional Review Board/Independent Ethics Committee
IWQOL-Lite-CT
Impact of Weight on Quality of Life-Lite-Clinical Trials Version
IWRS
interactive web-response system
LDL
low-density lipoprotein
MAD
multiple-ascending dose
MDD
major depressive disorder
MedDRA
Medical Dictionary for Regulatory Activities
MEN
multiple endocrine neoplasia
MHP
mental health professional
MMRM
mixed-model for repeated measures
MRI
magnetic resonance imaging
MTC
medullary thyroid carcinoma


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MTD
maximum tolerated dose
NAFLD
nonalcoholic fatty liver disease
NYHA
New York Heart Association
p-amylase
pancreatic amylase
PCOS
polycystic ovarian syndrome
PGIs
Patient Global Impression of status
PHQ-9
Patient Health Questionnaire-9
PK/PD
pharmacokinetic(s)/pharmacodynamic(s)
PRO
patient-reported outcome
QW
once weekly
randomized
All participants who are indiscriminately assigned a study drug.
SAD
single-ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous(ly)
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SD
standard deviation
SF-36 v2
Short Form-36 Version 2 Health Survey
SoA
Schedule of Activities
SS
safety analysis set
T1DM
Type 1 diabetes mellitus
T2DM
Type 2 diabetes mellitus
TBL
total bilirubin level
TEAE
treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
TEE
total energy expenditure


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THC
tetrahydrocannabinol
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
WHO
World Health Organization


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11.
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Kolotkin RL, Ervin CM, Meincke HH, et al. Development of a clinical trials version of the 
Impact of Weight on Quality of Life-Lite Questionnaire (IWQOL-Lite clinical trials version): 
results from two qualitative studies. Clin Obes. 2017;7(5):290-299. 
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Kolotkin RL, Williams VSL, Ervin CM, et al. Validation of a new measure of quality of life in 
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review and meta-analysis of longitudinal studies. Arch Gen Psychiatry. 2010;67(3):220-229. 
https://doi.org/10.1001/archgenpsychiatry.2010.2


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type 2 diabetes. N Engl J Med. 2016a;375(19):1834-1844.
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polyagonists. Pharmacol Rev. 2018;70(4):712‐746. https://doi.org/10.1124/pr.117.014803 
Nauck MA, Meier JJ, Schmidt WE. Incretin-based glucose-lowering medications and the risk of 
acute pancreatitis and/or pancreatic cancer: reassuring data from cardio-vascular outcome 
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Leo Document ID = 83395c48-ef8d-4811-a7e9-298881bcbe1c
Approver: 
Approval Date & Time: 16-Nov-2020 21:10:03 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 17-Nov-2020 00:17:36 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
 
 
 
 
 Statistical Analysis Plan: I8F-MC-GPHN (Version 3) 
 
 
Efficacy and Safety of Tirzepatide Once Weekly versus Placebo for 
Maintenance of Weight Loss in Participants without Type 2 Diabetes Who 
Have Obesity or Are Overweight with Weight-Related Comorbidities: A 
Randomized, Double-Blind, Placebo-Controlled Trial (SURMOUNT-4) 
 
 
NCT04660643 
 
 
Approval Date: 03-Feb-2023 


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I8F-MC-GPHN Statistical Analysis Plan Version 3 
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Title Page  
Protocol Title: Efficacy and Safety of Tirzepatide Once Weekly versus Placebo for Maintenance 
of Weight Loss in Participants without Type 2 Diabetes Who Have Obesity or Are Overweight 
with Weight-Related Comorbidities: A Randomized, Double-Blind, Placebo-Controlled Trial 
Protocol Number: I8F-MC-GPHN 
Compound Number: LY3298176 
 
Short Title: Effect of Tirzepatide versus Placebo for Maintenance of Weight Loss 
(SURMOUNT-4) 
Acronym: SURMOUNT-4 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana USA 46285 
Regulatory Agency Identifier Number(s): IND 139721 
 
 
Confidential Information 
The information contained in this document is confidential and the information contained within it may not be reproduced 
or otherwise disseminated without the approval of Eli Lilly and Company or its subsidiaries 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential 
information exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior 
to any public release. In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 
and may not be reproduced or otherwise disseminated without the written approval of Eli Lilly and Company or its 
subsidiaries. 
 
Document ID: VV-CLIN-076401 
 
 
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List of Abbreviations  
Term 
Definition 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event(s) of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
BG 
blood glucose 
BMI 
body mass index 
Bpm 
beats per minute 
CI 
confidence interval 
CN 
conventional 
CRF 
case report form 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTR 
Clinical Trial Registry 
DBP 
diastolic blood pressure 
EAS 
Efficacy Analysis Set 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED 
early discontinuation 
FAS 
Full Analysis Set 
GI 
gastrointestinal 
GIP 
glucose-dependent insulinotropic polypeptide 
GIPR 
glucose-dependent insulinotropic polypeptide receptor 
GLP-1 
glucagon-like peptide-1 
GLP-1R 
glucagon-like peptide-1 receptor 
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Term 
Definition 
HDL 
High-density lipoprotein 
HLT 
High Level Term 
ICE 
intercurrent event 
ICH 
International Council for Harmonisation 
ISR 
injection site reaction 
IWQOL-Lite-CT 
Impact of Weight on Quality of Life-Lite-Clinical Trials Version 
IWRS 
interactive web-response system 
Lilly 
Eli Lilly and Company 
LLT 
Lowest Level Term 
LOCF 
last observation carried forward 
LSM 
least squares mean 
MACE 
major adverse cardiovascular event(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMRM 
mixed model for repeated measures 
MRD 
minimum required dilution 
MTD 
maximum tolerated dose 
NAb(+/-) 
neutralizing antibody (positive/negative) 
PG 
plasma glucose 
PGIS 
Patient Global Impression of Status for Physical Activity 
PHQ-9 
Patient Health Questionnaire 
PK 
pharmacokinetic(s) 
PT 
Preferred Term 
QTcF 
Fridericia’s corrected QT interval 
QW 
once weekly 
REML 
restricted maximum likelihood 
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Term 
Definition 
SAP 
statistical analysis plan 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
SI 
Système International 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
SS 
Safety Analysis Set 
TE ADA (+/-) 
treatment-emergent anti-drug antibody (positive/negative) 
TEAE 
treatment-emergent adverse event 
T2DM 
type 2 diabetes mellitus 
UACR 
urine albumin-to-creatinine ratio 
ULN 
upper limit of normal 
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Table of Contents  
Title Page ........................................................................................................................................1 
List of Abbreviations .....................................................................................................................2 
Table of Contents ...........................................................................................................................5 
Version history ...............................................................................................................................9 
1. 
Introduction ...................................................................................................................10 
1.1. 
Objectives and Endpoints ...............................................................................................10 
1.2. 
Estimands ........................................................................................................................12 
1.2.1. 
Primary Estimand............................................................................................................12 
1.2.2. 
Estimands for Secondary Endpoints ...............................................................................14 
1.3. 
Study Design ...................................................................................................................15 
2. 
Statistical Hypotheses ...................................................................................................17 
2.1. 
Multiplicity Adjustment ..................................................................................................17 
3. 
Analysis Sets ..................................................................................................................19 
4. 
Statistical Analyses .......................................................................................................20 
4.1. 
General Considerations ...................................................................................................20 
4.2. 
Participant Dispositions ..................................................................................................21 
4.3. 
Primary Endpoint Analysis .............................................................................................22 
4.3.1. 
Definition of Endpoint ....................................................................................................22 
4.3.2. 
Main Analytical Approach ..............................................................................................22 
4.4. 
Secondary Endpoint(s) Analysis .....................................................................................24 
4.4.1. 
Main Analytical Approach for Categorical Outcome Related to 
Weight Measurement ......................................................................................................24 
4.4.2. 
Key Secondary Efficacy Analyses Subject to Type 1 Error Rate 
Control ............................................................................................................................25 
4.4.3. 
Additional Secondary Endpoint(s) ..................................................................................26 
4.5. 
Exploratory Endpoint(s) Analysis ..................................................................................28 
4.6. 
(Other) Safety Analyses ..................................................................................................29 
4.6.1. 
Extent of Exposure ..........................................................................................................30 
4.6.2. 
Adverse Events ...............................................................................................................31 
4.6.3. 
Additional Safety Assessments .......................................................................................31 
4.6.4. 
Patient Narratives ............................................................................................................35 
4.6.5. 
Special Safety Topics ......................................................................................................35 
4.7. 
Other Analyses ................................................................................................................50 
4.7.1. 
Health Outcomes .............................................................................................................50 
4.7.2. 
Subgroup Analyses .........................................................................................................52 
4.8. 
Interim Analyses .............................................................................................................53 
4.8.1. 
Data Monitoring Committee ...........................................................................................53 
4.9. 
Changes to Protocol-Planned Analyses ..........................................................................53 
5. 
Sample Size Determination ..........................................................................................54 
6. 
Supporting Documentation ..........................................................................................55 
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6.1. 
Appendix 1: Demographic and Other Characteristics of Study 
Population .......................................................................................................................55 
6.1.1. 
Patient Characteristics .....................................................................................................55 
6.1.2. 
Historical Illnesses and Preexisting Conditions ..............................................................55 
6.1.3. 
Concomitant Medications ...............................................................................................55 
6.2. 
Appendix 2: Treatment Compliance ...............................................................................56 
6.3. 
Appendix 3: Important Protocol Deviations ...................................................................56 
6.4. 
Appendix 4: Analyses for the Open-Label Lead-in Period ............................................56 
6.4.1. 
General consideration .....................................................................................................56 
6.4.2. 
Patient Characteristics .....................................................................................................57 
6.4.3. 
Disposition ......................................................................................................................57 
6.4.4. 
Efficacy Analysis ............................................................................................................57 
6.4.5. 
Treatment Compliance ....................................................................................................58 
6.4.6. 
Medical History, Preexisting condition, and Concomitant 
Medicines ........................................................................................................................58 
6.4.7. 
Extent of Exposure ..........................................................................................................58 
6.4.8. 
Adverse Events ...............................................................................................................59 
6.4.9. 
Additional Safety Assessments .......................................................................................59 
6.4.10. Special Safety topics .......................................................................................................59 
6.4.11. Important Protocol Deviations ........................................................................................60 
6.5. 
Appendix 5: Clinical Trial Registry Analyses ................................................................60 
6.6. 
Appendix 6: Exceptional Circumstances Impact ............................................................60 
6.6.1. 
General Consideration ....................................................................................................60 
6.6.2. 
Exposure .........................................................................................................................61 
6.6.3. 
Protocol Deviation ..........................................................................................................61 
6.6.4. 
Patient Disposition ..........................................................................................................61 
6.6.5. 
Adverse Events ...............................................................................................................61 
6.6.6. 
Major Depressive Disorder/Suicidal Ideation .................................................................61 
6.6.7. 
Local Lab ........................................................................................................................62 
6.6.8. 
Missing Data Due to Exceptional Circumstances ...........................................................62 
6.7. 
Appendix 7: Searching Criteria for Special Safety Topics .............................................62 
7. 
References ......................................................................................................................64 
 
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Table of Contents 
Table 
Page 
Table GPHN.1.1. 
Objectives and Endpoints ..........................................................................10 
Table GPHN.1.2. 
Attribute Description of Secondary Estimands..........................................14 
Table GPHN.3.1. 
Description of Analysis Population and Analysis Datasets .......................19 
Table GPHN.4.1. 
Baseline and Postbaseline Definitions for Safety Outcomes 
in Double-Blind treatment Period ..............................................................21 
Table GPHN.4.2. 
Secondary Measures Controlled for Type 1 Error .....................................25 
Table GPHN.4.3. 
Secondary Efficacy Measures Not Controlled for Type 1 
Error ...........................................................................................................26 
Table GPHN.4.4. 
Exploratory Efficacy Analysis ...................................................................28 
Table GPHN.4.5. 
Categorical Criteria for Treatment-Emergent Abnormal 
Blood Pressure and Pulse Measurement for Adults ...................................32 
Table GPHN.4.6. 
Selected Categorical Limits for ECG Data ................................................34 
Table GPHN.4.7. 
Sample ADA Assay Results ......................................................................40 
Table GPHN.4.8. 
Sample Clinical ADA Interpretation Results .............................................40 
Table GPHN.4.9. 
In Silico Classification for Cross-Reactive NAb .......................................41 
Table GPHN.4.10. 
Adverse Events for Analysis with Immunogenicity Results .....................44 
Table GPHN.6.1. 
Baseline and Postbaseline Definitions in Open-Label 
Period .........................................................................................................56 
Table GPHN.6.2. 
Efficacy Analysis for the Open-Label Period ............................................58 
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Table of Contents 
Figure 
Page 
Figure GPHN.1.1. 
Illustration of study design for Clinical Protocol 
I8F-MC-GPHN. .........................................................................................15 
Figure GPHN.2.1. 
GPHN type 1 error control strategy for primary and key 
secondary efficacy endpoints. ....................................................................18 
Figure GPHN.4.1. 
Flowchart of immunogenicity multitiered testing approach. .....................39 
 
 
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Version history  
This SAP for Study I8F-MC-GPHN (GPHN) is based on the protocol dated 17 November 2020. 
SAP Version History Summary 
SAP 
Version 
Approval Date 
Change 
Rationale 
1 
26-Mar-2021 
Not Applicable 
Original version 
2 
12-Oct-2022 
Details can be 
found in SAP 
Version History  
Details can be found in SAP 
Version History  
3 
See date on Page 1 
See below 
See below  
The key changes for GPHN SAP Version 3 and rationale are summarized below: 
1. Clarified that the population-level summary for the “difference in response percentage 
between treatment conditions” is assessed by odds ratio per the US FDA feedback (see 
Table GPHN.1.2).   
2. Clarified that placebo multiple imputation will be used for missing data imputation in 
Category 1 for treatment-regimen estimand if there are not enough retrieved dropouts to 
impute missing data in Category 2 (see Section 4.3.2.3). 
3. Added sensitivity analyses to evaluate the robustness of the primary results with respect 
to different missing data imputation methods per the US FDA feedback (see Section 
4.3.2.4). 
4. Clarified the covariate in the analysis model (see Section 4.4):  
o For the analyses of endpoints that were compared to the time of “randomization 
(Week 36)” 
▪ Weight-related endpoints (ie, weight, BMI): stratification factors (except 
percentage weight loss at randomization [Week 36]) and corresponding 
value at randomization (Week 36) were included as covariates. 
▪ Other endpoints: all stratification factors and corresponding values at 
randomization (Week 36) were included as covariates. 
o For the analyses of endpoints that were compared to the time of “baseline 
(Week 0)” 
▪ Weight related endpoints (ie, weight, BMI): stratification factors (except 
percentage weight loss at randomization [Week 36]) and corresponding 
values at randomization (Week 36) and at baseline (Week 0) were 
included as covariates. 
▪ Other endpoints: all stratification factors and corresponding values at 
baseline (Week 0) were included as covariates. 
 
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1. 
Introduction  
The main SAP focuses on describing the analysis plan for the double-blinded treatment period. 
Details of the analysis plan for the open-label lead-in period can be found in Appendix 4. 
Changes to the protocol-planned analyses are described in Section 4.9. 
1.1. 
Objectives and Endpoints  
Table GPHN.1.1. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To demonstrate that tirzepatide MTD is 
superior to placebo for percent change in body 
weight at Week 88  
 
Mean percent change in body weight from 
randomization (Week 36) to 88 weeks  
Key Secondary (controlled for type I error) 
 
To demonstrate that tirzepatide MTD is 
superior to placebo in change from 
randomization (Week 36) for the following 
(measured at 88 weeks):  
 
 
 
Body weight  
 
Mean change in body weight (kg) 
 
Waist circumference  
 
 
Mean change in waist circumference (cm) 
 
Maintaining body weight reduction 
achieved during the 36-week 
open-label period 
 
Percentage of participants who maintain ≥80% of the 
body weight lost during the 36 weeks of open-label 
period 
 
To demonstrate that tirzepatide MTD is 
superior to placebo in change from Visit 2 
(Week 0) for the following: 
 
 
Body weight 
 
 
 
 
 
 
 
 
 
 
Prevention of weight regain 
following the 36 weeks of open-label 
period 
 
 
 
 
 
 
Percentage of study participants who achieve 
≥5% body weight reduction at 88 weeks  
 
Percentage of study participants who achieve 
≥10% body weight reduction at 88 weeks 
 
Percentage of study participants who achieve 
≥15% body weight reduction at 88 weeks 
 
Percentage of study participants who achieve 
≥20% body weight reduction at 88 weeks 
 
 
 
Time (in weeks), during the 52-week double-blind 
treatment period, to first occurrence of participants 
returning to >95% baseline weight for those who have 
already lost ≥5% since Week 0   
 
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Objectives 
Endpoints 
To demonstrate that tirzepatide MTD is 
superior to placebo in change from 
randomization (Week 36) for percent change 
in body weight at Week 64 
 
Mean percent change in body weight from 
randomization (Week 36) to 64 weeks 
Additional Secondary 
 
To demonstrate that tirzepatide MTD is 
superior to placebo in change from 
randomization (Week 36) for the following 
(measured at 88 weeks):  
 
 
BMI  
 
 
Glycemic control 
 
 
 
Insulin 
 
Mean change in BMI (kg/m2) 
 
 
Mean change in: 
o 
Fasting glucose (mg/dL) 
o 
HbA1c (%)  
 
 
Mean change in fasting insulin (pmol/L) 
 
Lipid parameters  
 
Mean change in:  
o 
Total cholesterol (mg/dL) 
o 
LDL-cholesterol (mg/dL) 
o 
Non-HDL-cholesterol (mg/dL) 
o 
HDL-cholesterol (mg/dL) 
o 
VLDL-cholesterol (mg/dL) 
o 
Triglycerides (mg/dL) 
o 
Free Fatty acids (mg/dL) 
 
Blood pressure  
 
Mean change in:  
o 
systolic blood pressure (mmHg) 
o 
diastolic blood pressure (mmHg) 
 
Patient-Reported Outcomes  
 
Mean change in SF-36 v2 acute form in: 
o 
Physical Functioning domain (PF)  
o 
Role-Physical domain (RP) 
o 
Role-Emotional domain (RE) 
o 
Mental Health domain(MH) 
 
Mean change in IWQOL-Lite-CT Physical Function 
composite score 
To demonstrate that tirzepatide MTD is 
superior to placebo in change from Visit 2 
(Week 0) for the following (measured at 
88 weeks) for:  
 
 
 
Body weight  
 
 
 
Mean change in body weight (kg) 
 
Mean percent change in body weight (%) 
 
Mean change in BMI (kg/m2) 
 
 
Waist circumference 
 
Mean change in waist circumference (cm) 
 
Glycemic control 
 
 
Mean change in: 
o 
Fasting glucose (mg/dL) 
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Objectives 
Endpoints 
 
 
 
Insulin 
 
 
Lipid parameters  
o 
HbA1c (%) 
 
 
Mean change in fasting insulin (pmol/L) 
 
 
Mean change in:  
o 
Total cholesterol (mg/dL) 
o 
LDL-cholesterol (mg/dL) 
o 
Non-HDL-Cholesterol (mg/dL) 
o 
HDL-cholesterol (mg/dL) 
o 
VLDL-cholesterol (mg/dL) 
o 
Triglycerides (mg/dL) 
o 
Free fatty acids (mg/dL) 
 
Blood pressure 
 
Mean change in:  
o 
systolic blood pressure (mmHg) 
o 
diastolic blood pressure (mmHg) 
 
Patient-Reported Outcomes  
 
Mean change in SF-36 v2 acute form in Physical 
Functioning domain (PF). 
 
 
Mean change in IWQOL-Lite-CT Physical Function 
composite score 
Abbreviations: BMI = body mass index; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; IWQOL-Lite-
CT = Impact of Weight on Quality of Life-Lite-Clinical Trials Version; LDL = low-density lipoprotein; 
MTD = maximum tolerated dose; SF-36 v2 acute form = Short Form-36 Version 2 Health Survey acute form; 
VLDL = very low-density lipoprotein. 
1.2. 
Estimands  
1.2.1. 
Primary Estimand  
The primary clinical question of interest is: What is the impact of MTD of tirzepatide (10 mg or 
15 mg) QW, compared with placebo, on the maintenance of weight loss after an initial 36-week 
open-label tirzepatide lead-in treatment period, in study participants who do not have T2DM, and 
have obesity (BMI ≥30 kg/m2) or are overweight (BMI ≥27 kg/m2) with at least 1 weight-related 
comorbid condition?  
For primary disclosure of Study GPHN including submission to the US FDA 
The estimand is described by the following attributes: 
 Population: patients qualifying for study entry per protocol inclusion/exclusion criteria 
who reach and tolerate either tirzepatide 10-mg or 15-mg dose at Visit 11(Week 36).  
 Endpoint: percent change in body weight from randomization (Week 36) to 88 weeks.  
 Treatment condition of interest: tirzepatide MTD versus placebo, regardless of study drug 
adherence.  
 Handling of intercurrent events (ICEs): The ICEs leading to treatment discontinuation for 
any reason are addressed by the treatment condition of interest attribute and handled by 
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treatment policy strategy as described in the International Council for Harmonisation 
(ICH) E9 (R1) Addendum (ICH 2019). Further details can be found in Section 4.3.2.3. 
 Population-level summary: difference in mean between treatment conditions. 
Rationale for estimand: the primary estimand was requested by US FDA; it aims at reflecting 
how participants are treated in clinical practice, irrespective to the compliance to planned course 
of treatment. 
This de facto estimand is referred as the “treatment regimen” estimand in the latter sections of 
this document, which is equivalent to the “hybrid” estimand in the protocol. 
For all other purposes 
The estimand is described by the following attributes: 
 Population: patients qualifying for study entry per protocol inclusion/exclusion criteria 
who reach and tolerate either tirzepatide 10-mg or 15-mg dose at Visit 11(Week 36).  
 Endpoint: percent change in body weight from randomization (Week 36) to 88 weeks.  
 Treatment condition of interest: tirzepatide MTD versus placebo, excluding data after 
discontinuation of study drug. 
 Handling of ICEs: The ICEs leading to treatment discontinuation for any reason are 
addressed by the treatment condition of interest attribute and handled by the hypothetical 
strategy as described in the ICH E9 (R1) Addendum (ICH 2019). 
 Population-level summary: difference in mean between treatment conditions. 
Rationale for estimand: this estimand aims at reflecting treatment efficacy in an envisaged 
scenario in which the intercurrent events leading to treatment discontinuation would not occur.   
We will refer to this estimand as “efficacy” estimand in the latter sections. 
 
 
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1.2.2. 
Estimands for Secondary Endpoints  
Table GPHN.1.2. 
Attribute Description of Secondary Estimands 
Secondary Estimand 
Population 
Endpoint 
Treatment condition of 
interest 
Handling of intercurrent 
events 
Population-level summary 
Key secondary related to 
mean change 
Same as 
primary 
estimand 
As described in 
Table GPHN.1.1 
For primary disclosure of 
Study GPHN including 
submission to the US FDA, 
follow the same manner of the 
treatment regimen estimand in 
Section 1.2.1; for all other 
purposes, the same manner of 
the efficacy estimand in 
Section 1.2.1 
For primary disclosure of 
Study GPHN including 
submission to the US FDA, 
follow the same manner of 
the treatment regimen 
estimand in Section 1.2.1; 
for all other purposes, 
follow the same manner of 
the efficacy estimand in 
Section 1.2.1 
Difference in mean changes 
between treatment conditions 
Key secondary related to 
percentage of participants 
meeting certain criteria 
Difference in percentage of 
participants between treatment 
conditions as assessed by odds 
ratio 
Key secondary related to 
time to meet certain criteria 
Difference in time to response 
between treatment conditions 
Additional secondary 
related to mean change 
Same as 
primary 
estimand 
As described in 
Table GPHN.1.1 
Follow the same manner of the 
efficacy estimand in 
Section 1.2.1 
Follow the same manner of 
the efficacy estimand in 
Section 1.2.1 
Difference in mean changes 
between treatment conditions 
Additional secondary 
related to percentage of 
participants meeting certain 
criteria 
Difference in percentage of 
participants between treatment 
conditions as assessed by odds 
ratio 
Abbreviation: FDA = Food and Drug Administration. 
 
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Unless otherwise specified, the attributes of estimands supporting exploratory objectives will 
follow the same manner of the efficacy estimand in Section 1.2.1, with the exception of 
endpoints and population-level summary, which will be objective specific.  
1.3. 
Study Design  
Study GPHN is a Phase 3, multicenter, randomized, parallel-arm, double-blind, 
placebo-controlled, 88-week study that will investigate the impact of MTD of tirzepatide (10 mg 
or 15 mg QW), compared with placebo, on the maintenance of weight loss after an initial 
36-week open-label tirzepatide lead-in treatment period, in study participants who do not have 
T2DM, and have obesity (BMI ≥30 kg/m2) or are overweight (BMI ≥27 kg/m2) with at least 
1 weight-related comorbid condition, excluding diabetes mellitus.  
Study GPHN will consist of 4 periods: a 2-week screening period; a 36-week open-label 
tirzepatide lead-in treatment period (including a 20-week dose-escalation period); a 52-week 
double-blind, placebo-controlled treatment period; and a 4-week safety follow-up period. The 
study participants will be randomized in a double-blind 1:1 ratio (tirzepatide MTD QW or 
placebo) at the end of the open-label lead-in treatment period. Assignment to treatment groups 
will be determined by a computer-generated random sequence using the IWRS. An upper limit 
of 70% enrollment of women will be used to ensure a sufficiently large sample of men.  
The randomization will be stratified by country, sex (female, male), tirzepatide MTD dose at 
36 weeks (10 mg versus 15 mg), and percent weight loss at 36 weeks (<10% versus ≥10%). 
Where necessary to be included as a stratification factor, countries with fewer than 
10 randomized participants will be pooled into 1 category (pooled country).   
 
 
Abbreviations: MTD = maximum tolerated dose; QW = once weekly; (T) = telephone visit. 
Figure GPHN.1.1. 
Illustration of study design for Clinical Protocol I8F-MC-GPHN. 
 
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The details about the overview of study periods and study visits can be found in Study GPHN 
protocol Section 4. Details of the unique visits not displayed in Figure GPHN.1.1 are provided 
below.   
Visit 99 
Visit 99 is only applicable to participants who discontinue the double-blind study treatment 
prematurely (after Week 36 and before Week 88) and decline to complete the remaining 
scheduled study visits. These participants will be asked to return for Visit 99 at 
88 weeks ±7 days. This visit is critical to ensure complete data collection for the primary body 
weight endpoint.   
Early Discontinuation of Treatment Visit 
Participants unable or unwilling to continue the study treatment for any reason will perform an 
ED visit at the visit when the participant informs the site about the study treatment 
discontinuation. If the participant is discontinuing during an unscheduled visit or a scheduled 
visit, that visit should be performed as an ED visit.  
 
 
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2. 
Statistical Hypotheses  
The primary objective is to demonstrate that tirzepatide MTD is superior to placebo for percent 
change from randomization in body weight at Week 88. Thus, the alternative hypothesis to be 
tested in relation to the primary estimand is as follows: 
H1(wgt_pchg_wk36): QW tirzepatide MTD is superior to placebo for percent change from 
randomization (Week 36) in body weight at 88 weeks. 
The alternative hypotheses for the key secondary objectives controlling for type 1 error rate are 
the following:  
H2(wgt_chg_wk36): QW tirzepatide MTD is superior to placebo for change from randomization 
(Week 36) in body weight (kg) at 88 weeks.  
H3(wc_chg_wk36): QW tirzepatide MTD is superior to placebo for change from randomization 
(Week 36) in waist circumference (cm) at 88 weeks. 
H4(maintain80): QW tirzepatide MTD is superior to placebo for percentage of participants who 
maintain ≥80% of the body weight lost during the open-label lead-in period at 88 weeks. 
H5(return95): QW tirzepatide MTD is superior to placebo for delaying time (in weeks), during 
the 52-week double-blind treatment period, to first occurrence of participants returning to >95% 
Visit 2 (Week 0) body weight among participants who lost ≥5% body weight during the open-
label lead-in period.  
H6(wgt5_wk0): QW tirzepatide MTD is superior to placebo for percentage of participants who 
achieve ≥5% body weight reduction from Visit 2 (Week 0) at 88 weeks. 
H7(wgt10_wk0): QW tirzepatide MTD is superior to placebo for percentage of participants who 
achieve ≥10% body weight reduction from Visit 2 (Week 0) at 88 weeks. 
H8(wgt_pchg_wk64): QW tirzepatide MTD is superior to placebo for percent change from 
randomization (Week 36) in body weight at 64 weeks. 
H9(wgt15_wk0): QW tirzepatide MTD is superior to placebo for percentage of participants who 
achieve ≥15% body weight reduction from Visit 2 (Week 0) at 88 weeks. 
H10(wgt20_wk0): QW tirzepatide MTD is superior to placebo for percentage of participants 
who achieve ≥20% body weight reduction from Visit 2 (Week 0) at 88 weeks. 
2.1. 
Multiplicity Adjustment  
The type 1 error rate control strategy for primary and key secondary efficacy objectives is 
documented in Figure GPHN.2.1. Both efficacy estimand and treatment regimen estimand will 
be used to assess those objectives. As they are intended for different purposes, no multiplicity 
adjustments will be made for conducting separate analyses relative to the efficacy and treatment 
regimen estimands. In addition, no multiplicity adjustments will be made for evaluating 
additional secondary and exploratory objectives and safety assessments. 
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Figure GPHN.2.1. 
GPHN type 1 error control strategy for primary and key secondary 
efficacy endpoints. 
 
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3. 
Analysis Sets  
For purposes of analyses, Table GPHN.3.1 defines the analysis population and analysis sets.  
Table GPHN.3.1. 
Description of Analysis Population and Analysis Datasets 
Population/Analysis Set 
Description 
Entered  
All participants who sign informed consent. 
Enrolled 
All participants who are assigned to open-label tirzepatide treatment. 
Randomized 
All participants who are randomly assigned a study treatment (double-blind). 
Modified Intent-to-Treat (mITT)   
All enrolled participants who are exposed to at least 1 dose of study drug.   
Efficacy Analysis Set (EAS) 
Data obtained during double-blind treatment period from mITT, excluding 
data after discontinuation of study drug (last dose date + 7 days).   
Full Analysis Set (FAS) 
Data obtained during double-blind treatment period from mITT, regardless 
of adherence to study drug.  
Safety Analysis Set (SS) 
Data obtained during double-blind treatment period and safety follow-up 
period from mITT, regardless of adherence to study drug.  
 
Unless otherwise specified, for analyses guided by the treatment regimen estimand, FAS will be 
used. For analyses guided by the efficacy estimand, EAS will be used, and for safety analysis, SS 
will be used.  
For open-label period analysis, the analysis set is defined in Section 6.4.1.  
For immunogenicity analysis, the analysis set is defined in Section 4.6.5.5.  
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4. 
Statistical Analyses  
4.1. 
General Considerations  
Statistical analysis of this study will be the responsibility of Lilly or its designee. Some analyses 
and summaries described in this analysis plan may not be conducted if not warranted by data (eg, 
few events to justify conducting an analysis). Additional analyses of the data may be conducted 
as deemed appropriate. 
Unless otherwise noted, tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and the CI will be calculated at 95% 2-sided.  
Unless specified otherwise, efficacy and safety will be assessed using the mITT population, and 
data will be analyzed based on the assigned treatment (ie, not the actual treatment received by 
the participant). For submission to the US FDA to support the registration of tirzepatide for 
chronic weight management, the primary efficacy analysis will be conducted using FAS. For 
other purposes, the efficacy analysis of double-blind treatment period will be conducted using 
EAS. Safety analysis of double-blind treatment period will be conducted using SS.   
Unless otherwise specified, for efficacy-related analyses at 88 weeks, country/pooled country, 
sex, tirzepatide MTD dose at randomization, percent weight loss at randomization and 
corresponding baseline value will be used as a covariate.  
Summary descriptive 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 either ANCOVA or a 
MMRM.  
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 hazards 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 covariate. 
Otherwise, Fisher’s exact test will be used to examine the treatment difference.  
Summary statistics for discrete count measures will include sample size, mean, SD, median, 
minimum, and maximum.  
Unless specified otherwise, for analyses in the double-blind treatment period, baseline is defined 
as the last nonmissing data collected prior to or at randomization (Week 36); for analyses 
including data collected in open-label lead-in period, baseline is defined as the last nonmissing 
data collected prior to or at study enrollment (Week 0). 
For some specific safety related parameters, the definition of baseline and postbaseline for 
double-blind treatment period are specified in Table GPHN.4.1.  
The definition of baseline and postbaseline during the open-label lead-in treatment period can be 
found in Appendix 4. 
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Table GPHN.4.1. 
Baseline and Postbaseline Definitions for Safety Outcomes in 
Double-Blind treatment Period 
Analysis 
Set 
Analysis Type 
Baseline  
Postbaseline  
SS 
1.1) Treatment-Emergent 
Adverse Events 
Ongoing at the time of the 
randomization to the double-
blind treatment period.  
Starts after randomization visit and 
ends after the whole study period 
(including off-drug follow-up visit).  
SS 
1.2) Treatment-Emergent 
Abnormal Labsa, Vital 
Signs, and ECGs. 
Refer to Table GPHN.6.1 
for baseline definition. 
Postbaseline will be defined as above 
(1.1). All scheduled and unscheduled 
measurements will be included. 
SS 
1.4) Change from Last 
Baseline to Week xx and 
to Last Postbaseline for 
Labsa, Vital Signs, and 
ECGs. 
The last scheduled and 
unscheduled non-missing 
assessment recorded during 
the open-label lead-in 
period. 
Postbaseline will be defined as above 
(1.1). Only scheduled visits will be 
included. The ED visits are 
considered scheduled visits. 
Abbreviations: ECGs = electrocardiogram; ED = early discontinuation; SS = Safety Analysis Set. 
a Immunogenicity-related analysis is specified in Section 4.6.5.5. 
 
For the primary and key secondary efficacy endpoint analyses subject to type 1 error rate control, 
data for participants with missing values at the 88-week visit (or weight-related measurements at 
64-week visit) will be imputed based on the method described in Section 4.3.2.3. Otherwise, 
missing values will not be explicitly imputed except for the parameters with only 1 postbaseline 
measure during the analysis period per schedule of activity, where LOCF approach will be 
applied to impute the endpoint when ED measure is available.  
End of study participation for a participant will be the earliest of date of death, date of 
withdrawal from further participation in the study, or date of safety follow-up visit (Visit 801). 
For participants considered to be lost-to-follow-up, end of study participation will be the date of 
lost-to-follow-up reported by the investigator. Participant data included in the database after the 
last date of study participation will be excluded from statistical analysis.   
Statistical summaries and results of statistical analyses will be displayed in the following order: 
placebo, tirzepatide MTD. 
Not all analyses described in this SAP will necessarily be included in the CSR. Any analysis 
described in this SAP and not provided in the CSR would be available upon request. Not all 
displays will necessarily be created as a “static” display. Some may be incorporated into 
interactive display tools instead of or in addition to a static display. 
4.2. 
Participant Dispositions  
A detailed description of participant disposition will be provided at the end of the study.  
Frequency counts and percentages of all participants screened, enrolled, randomized, and 
receiving at least 1 dose of study drug will be summarized by treatment group, if applicable. Of 
the randomized population, frequency counts and percentages of participants who completed the 
study, prematurely discontinued the study (and/or study drug), including reason for premature 
discontinuation, will be summarized by treatment group. 
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The study completion status for the randomized population is defined as follows: participants 
with status reported via eCRF as “Completed” at follow-up visit (Visit 801) will be considered as 
completers; otherwise, they will be considered as non-completers. A Kaplan-Meier analysis of 
time from randomization to premature discontinuation from study and/or study treatment by 
treatment group will be provided.  
A listing of study disposition for all randomized participants will be provided at the final 
database lock. 
4.3. 
Primary Endpoint Analysis  
For primary disclosure including submission to the US FDA to support the registration of 
tirzepatide for chronic weight management, the primary efficacy assessment will be guided by 
the treatment regimen estimand conducted using the FAS. Assessment of the primary objective 
will be conducted with hybrid imputation of missing data (see Section 4.3.2.3).   
For other purposes, the assessment of primary efficacy objective will be guided by the efficacy 
estimand using the EAS. 
4.3.1. 
Definition of Endpoint  
The primary efficacy measure will be percent change in body weight from randomization. The 
percent change in body weight at each nominal visit is defined as: 
(postbaseline body weight [kg] – baseline body weight [kg]) / baseline body weight [kg] * 100%.  
Percent change in body weight will be summarized by treatment and nominal visit (week) from 
randomization (Week 36) to 88 weeks.  
4.3.2. 
Main Analytical Approach  
4.3.2.1. 
Analysis Related to the Treatment Regimen Estimand  
The analysis related to the treatment regimen estimand will be conducted using the FAS.  
The analysis for the mean percent change in body weight will be conducted utilizing ANCOVA. 
The response variable for the ANCOVA model will be percent change in body weight from 
randomization to Week 88. This model will include terms of treatment group, country/pooled 
country, sex, tirzepatide MTD dose at randomization, and body weight at randomization 
(Week 36) as covariates. The ANCOVA analysis will be conducted with multiple imputation of 
missing data guided by hybrid method at Week 88 (see Section 4.1 and Section 4.3.2.3 for 
details) and statistical inference over multiple imputation of missing data guided by Rubin 
(1987).  
With the aid of the ANCOVA model, 2-sided 95% CI for mean percent change in body weight 
from baseline to the 88-week visit between tirzepatide MTD and placebo will be derived.    
4.3.2.2. 
Analysis Related to the Efficacy Estimand  
The analysis related to the efficacy estimand will be conducted utilizing data in the EAS.  
For the mean percent body weight change from randomization, a MMRM will be conducted. 
Restricted maximum likelihood (REML) will be used to obtain model parameter estimates and 
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the Kenward-Roger option will be used to estimate the denominator degrees of freedom. The 
response variable of MMRM will be the percent change in body weight from baseline values 
obtained at each scheduled postbaseline visit.  
For the MMRM model, the independent variables of analysis model are treatment group, visit, 
treatment-by-visit interaction, and stratification factors (country/pooled country, sex, and 
tirzepatide MTD dose at randomization) as fixed effects, and body weight at randomization 
(Week 36) as a covariate. An unstructured covariance structure will model relationship of within-
patient errors. If this model fails to converge, the following variance covariance structures will 
be tested in order until convergence is achieved:  
 heterogeneous Toeplitz 
 heterogeneous first order autoregressive 
 heterogeneous compound symmetry 
 Toeplitz 
 first order autoregressive, and 
 compound symmetry. 
The first covariance structure that converges will be used.   
With the aid of the MMRM analysis, 2-sided 95% CIs for mean percent change in body weight 
from randomization to the 88-week visit for tirzepatide MTD compared to placebo will be 
derived and summarized. The resulting LSM estimates of mean percent change in body weight 
from baseline will be plotted by visit and by study treatment.  
4.3.2.3. 
Hybrid Methods of Imputation  
For efficacy analyses relative to the treatment regimen estimand, the intercurrent events and the 
resulting missing values will be handled as follows: 
 Category 1: for missing data solely due to an exceptional circumstance, such as a 
pandemic or natural disaster (after other reasons for missing data are ruled out), considers 
the missing data as missing at random. The missing data will be imputed using all 
nonmissing data of the primary outcome measurement from the same treatment arm. 
 Category 2: for missing data due to all other intercurrent events, it will be imputed based 
on retrieved dropouts in the same treatment arm, defined as observed primary outcome 
measurements, from participants in the same treatment group who had their efficacy 
assessed after early discontinuation of study drug. In cases where there are not enough 
retrieved dropouts to provide a reliable imputation model (for example, the model 
implemented by the SAS program does not converge), an alternative multiple imputation 
method with reference to the placebo group (ie, placebo multiple imputation) will be 
used. 
In cases where placebo multiple imputation method is used for missing data imputation in 
Category 2 because of not enough retrieved dropouts, the missing data in Category 1 will be 
imputed using all nonmissing data of the primary outcome measurement from the placebo group. 
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4.3.2.4. 
Sensitivity Analysis  
For submission of Study GPHN to the US FDA tirzepatide application for chronic weight 
management, additional sensitivity analyses of the primary efficacy outcomes will be conducted 
using the FAS and guided by the “treatment-regimen” estimand, which represents the efficacy 
irrespective of adherence to study drug. This assessment will analyze percent change in body 
weight obtained at the 88-week visit using an ANCOVA model. The terms of the model will be 
the same as specified in Section 4.3.2.1. These analyses are intended to assess the robustness of 
primary efficacy results using different missing data imputation methods: 
 Retrieved dropout multiple imputation: Missing values of change in body weight at the 
88-week visit will be imputed based on observed body weight change from 
randomization (Week 36) values at the visit from participants in the same treatment 
group who had their efficacy assessed after early discontinuation of study drug. In cases 
where there are not enough retrieved dropouts to provide a reliable imputation model (for 
example, the model implemented by the SAS program does not converge), the placebo 
multiple imputation method (described below) will be used. 
 Placebo multiple imputation: Missing values of change in body weight at the 88-week 
visit will be imputed based on observed body weight change from randomization 
(Week 36) at the visit from participants in the placebo treatment group. 
 2-way tipping point analysis: The analysis will begin with the primary analysis aligned to 
treatment regimen estimand and adding positive and negative penalties simultaneously to 
both the tirzepatide MTD arm and the placebo arm, considering when results tip from 
superiority to inconclusive, and then considering the clinical plausibility of such 
scenarios. 
4.4. 
Secondary Endpoint(s) Analysis  
4.4.1. 
Main Analytical Approach for Categorical Outcome Related to Weight 
Measurement  
For both treatment regimen and efficacy estimand, a logistic regression model will be used. For 
the proportion of patients achieving weight loss target since 
 Baseline (Week 0), the following covariates will be included: treatment group, 
country/pooled country, sex, and tirzepatide MTD dose at randomization, and body 
weight at randomization (Week 36) and at baseline (Week 0).  
 Randomization (Week 36), the following covariates will be included: treatment group, 
country/pooled country, sex, and tirzepatide MTD dose at randomization (Week 36), and 
body weight at randomization (Week 36).  
For missing data imputation: 
 For treatment regimen estimand: missing data will be handled by hybrid imputation of 
missing body weight at Week 88 (see Section 4.1 and Section 4.3.2.3 for details). 
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 For efficacy estimand: missing data will be handled by predicted value from MMRM 
analysis followed by dichotomization. When MMRM is used, variance-covariance 
structure for within-patient errors will be same as Section 4.3.2.2. 
4.4.2. 
Key Secondary Efficacy Analyses Subject to Type 1 Error Rate Control  
Table GPHN.4.2. 
Secondary Measures Controlled for Type 1 Error  
Objectives  
Relative to the efficacy 
measure: 
Analysis conducted in a manner 
similar to 
Additional Information 
Tirzepatide MTD 
QW is superior 
to placebo:  
Mean change in body weight 
(kg) from randomization 
(Week 36) to Week 88 
For treatment regimen estimand: 
ANCOVA model described in 
Section 4.3.2.1. 
For efficacy estimand: MMRM 
model described in Section 4.3.2.2. 
LSM estimates will be 
plotted by treatment 
through 88 weeks. 
Mean change in waist 
circumference (cm) from 
randomization (Week 36) to 
Week 88 
For treatment regimen estimand: 
ANCOVA model with terms of 
treatment group, stratification 
factors, and corresponding value at 
randomization (Week 36) as 
covariates. 
For efficacy estimand: MMRM 
model with treatment group, visit, 
treatment-by-visit interaction, all 
stratification factors as fixed 
effects, and corresponding value at 
randomization (Week 36) as 
covariates. 
LSM estimates will be 
plotted by treatment 
through 88 weeks. 
Refer to Sections 4.3.2.1 
and 4.3.2.2 for analysis 
approach detail. 
Percentage of participants 
who maintain ≥80% of the 
body weight lost during the 
36 weeks of open-label 
period  
For both treatment regimen and 
efficacy estimand: Logistic 
regression model will be 
conducted. 
Refer to Section 4.4.1 for 
analysis approach detail. 
Tirzepatide MTD 
QW is superior 
to placebo:  
Percentage of study 
participants who achieve 
≥5/10/15/20% body weight 
reduction from Visit 2 (Week 
0) to Week 88 
For both treatment regimen and 
efficacy estimand: Logistic 
regression model will be used. 
Refer to Section 4.4.1 for 
analysis approach detail. 
Time (in weeks), during the 
52-week double-blind 
treatment period, to first 
occurrence of participants 
returning to >95% baseline 
weight for those who have 
already lost ≥5% since 
Week 0   
For both treatment regimen and 
efficacy estimand: Cox-
proportional hazards model will be 
used with the terms of treatment 
group (tirzepatide MTD and 
placebo), country/pooled country, 
sex, tirzepatide MTD dose at 
randomization, and weight at 
randomization (Week 36) and at 
baseline (Week 0) as covariates.   
Only for participants 
with at least 5% body 
weight loss during the 
open-label lead-in 
period. 
For treatment regimen 
estimand: the participant 
without event will be 
censored at Week 88. 
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Objectives  
Relative to the efficacy 
measure: 
Analysis conducted in a manner 
similar to 
Additional Information 
For efficacy estimand: 
the participant without 
event will be censored at 
treatment 
discontinuation time.  
Tirzepatide MTD 
QW is superior 
to placebo:  
Mean percent change in body 
weight from randomization 
(Week 36) to Week 64 
For treatment regimen estimand: 
ANCOVA model will be 
conducted.  
For efficacy estimand: MMRM 
model will be conducted. 
LSM estimates will be 
plotted by treatment 
through 64 weeks. 
Refer to Section 4.4.1 for 
analysis approach detail. 
Abbreviations: ANCOVA = analysis of covariance; LSM = least squares mean; MTD = maximum tolerated dose; 
MMRM = mixed model for repeated measures; QW = once-weekly. 
 
Decision will be guided by the 2-sided p-values in each objective subject to type 1 error rate 
control with details outlined in Section 2.1.   
For submission of Study GPHN to the US FDA to support the registration of tirzepatide for 
chronic weight management, the key secondary efficacy assessment will be guided by the 
treatment regimen estimand conducted using the same population as for primary analysis. 
Assessment of key secondary objectives will be conducted with hybrid imputation of missing 
data (see Section 4.3.2.3).   
For other purposes, the assessment of key secondary efficacy objectives will be guided by the 
efficacy estimand using the same population as for primary analysis. 
4.4.3. 
Additional Secondary Endpoint(s)  
Unless otherwise specified, other secondary efficacy analyses will be guided by the efficacy 
estimand using the same population as for primary analysis.  
Analyses for labs including fasting glucose, hemoglobin A1c, fasting insulin, and lipid 
parameters will be performed for both SI units and CN units. 
4.4.3.1. 
Additional Secondary Efficacy Analyses  
Table GPHN.4.3. 
Secondary Efficacy Measures Not Controlled for Type 1 Error  
Analysis variable 
Analysis set 
Analysis method 
Additional Information 
Mean change in measurements 
of lab tests and vital sign  
Data from 
randomization 
(Week 36) to 
Week 88 
MMRM model with 
treatment group, visit, 
treatment-by-visit 
interaction, all stratification 
factors as fixed effects, and 
the corresponding value at 
randomization (Week 36) as 
a covariate 
Variance-covariance 
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Analysis variable 
Analysis set 
Analysis method 
Additional Information 
structure for within-patient 
errors will be same as 
Section 4.3.2.2. LSM 
estimates may be plotted by 
treatment through 
88 weeks. Log 
transformation will be 
adopted for fasting insulin 
and lipid parameters. 
Mean change in SF-36 v2 acute 
form domain score in 
 
Physical Functioning 
domain (PF)  
 
Role-Physical domain 
(RP) 
 
Role-Emotional 
domain (RE) 
 
Mental Health domain 
(MH) 
Mean change in 
IWQOL‑Lite‑CT Physical 
Function composite score 
ANCOVA model with terms 
of treatment group, all 
stratification factors, and the 
corresponding value at 
randomization (Week 36) as 
a covariate. 
Missing data will be 
imputed using LOCF. 
Mean change in measurements 
of lab tests and vital signs 
Data from 
Week 0 to 
Week 88 
MMRM model with 
treatment group, visit, 
treatment-by-visit 
interaction, all stratification 
factors, and the 
corresponding value at 
baseline (Week 0) as 
covariates. 
Variance-covariance 
structure for within-patient 
errors will be same as 
Section 4.3.2.2. LSM 
estimates may be plotted by 
treatment through 
88 weeks. Log 
transformation will be 
adopted for fasting insulin 
and lipid parameters. 
Mean change in body weight, 
BMI, and percent change in 
body weight  
MMRM model with 
treatment group, visit, 
treatment-by-visit 
interaction, country/pooled 
country and sex as fixed 
effects, and the 
corresponding value at 
baseline (Week 0) and at 
randomization (Week 36) as 
covariates. 
Variance-covariance 
structure for within-patient 
errors will be same as 
Section 4.3.2.2. LSM 
estimates may be plotted by 
treatment through 
88 weeks. 
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Analysis variable 
Analysis set 
Analysis method 
Additional Information 
Mean change in waist 
circumference 
MMRM model with 
treatment group, visit, 
treatment-by-visit 
interaction, all stratification 
factors as fixed effects, and 
the corresponding value at 
baseline (Week 0) as 
covariates. 
Variance-covariance 
structure for within-patient 
errors will be same as 
Section 4.3.2.2. LSM 
estimates may be plotted by 
treatment through 
88 weeks. 
Mean change in SF-36 v2 acute 
form in 
 
Physical Functioning 
domain (PF)  
and  
IWQOL-Lite-CT in 
 
Physical Function 
composite score 
ANCOVA model with terms 
of treatment group, all 
stratification factors, and the 
corresponding value at 
baseline (Week 0) as 
covariates. 
Missing data will be 
imputed using LOCF. 
Abbreviations: ANCOVA = analysis of covariance; BMI = body mass index; IWQOL-Lite-CT = Impact of Weight 
on Quality of Life-Lite-Clinical Trials Version; LOCF = last observation carried forward; LSM = least squares 
mean; MMRM = mixed model for repeated measures; SF-36 v2 acute form = Short Form-36 Version 2 Health 
Survey acute form. 
4.5. 
Exploratory Endpoint(s) Analysis  
Unless otherwise specified, exploratory efficacy analyses will be guided by the efficacy estimand 
using the same population as for primary analysis.  
Table GPHN.4.4. 
Exploratory Efficacy Analysis 
Objective 
Relative to the efficacy measure: 
Analysis Conducted 
Compare tirzepatide MTD 
QW with placebo from 
Visit 2 (Week 0) to 
Week 88 
Percentage of participants achieving 25% 
body weight reduction from Week 0 to Week 
88 
Refer to Section 4.4.1 for detail. 
Compare tirzepatide MTD 
QW with placebo from 
randomization to Week 88 
Percentage of participants whose BMI shifts 
between clinically relevant categories, i.e., 
from randomization to Week 88 (<25, 25 to 
<30, 30 to < 35, 35 to < 40, ≥40) 
Shift analysis will be conducted 
based on data from randomization 
to Week 88.  
Compare tirzepatide MTD 
QW with placebo from 
randomization to Week 88 
Percentage of participants whose lipid 
parameters shift between clinically relevant 
categories: 
 
LDL-cholesterol (<70, 70 to <160,  
160 to <190, ≥190mg/dL) 
 
HDL-cholesterol (male: <40, 
≥40mg/dL, female: <50, ≥50mg/dL) 
 
Triglycerides (<150, 150 to <170,  
170 to <500, ≥500mg/dL) 
Shift analysis will be conducted 
based on data from randomization 
to Week 88.  
Compare tirzepatide MTD 
QW with placebo from 
randomization to Week 88 
Percentage of participants achieving ≥5% 
and ≥10% body weight reduction from 
randomization to Week 88 
Refer to Section 4.4.1 for detail. 
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Objective 
Relative to the efficacy measure: 
Analysis Conducted 
Visualize tirzepatide MTD 
QW and placebo’s percent 
weight loss change from 
Week 0 up to safety 
follow-up after 88 weeks 
Percent body weight loss measured from 
Week 0 to 88 weeks plus 4 weeks safety 
follow-up   
Time-course plot will be generated. 
Only the participants who complete 
the 88 weeks treatment period and 
have the safety follow-up 
(Visit 801) will be included.  
Compare tirzepatide MTD 
QW with placebo from 
randomization to Week 88 
 
SF-36v2 acute form Bodily Pain domain 
(BP) 
 
SF-36v2 acute form General Health 
domain (GH) 
 
SF-36v2 acute form Vitality domain  
 
SF-36v2 acute form Social Functioning 
domain (SF) 
 
SF-36v2 acute form Physical-
Component Summary score 
 
SF-36v2 acute form Mental-Component 
Summary score 
 
IWQOL-Lite-CT total score  
 
IWQOL-Lite-CT Physical composite 
score  
 
IWQOL-Lite-CT Psychosocial 
composite score  
 
EQ-5D-5L utility score 
 
EQ-5D-5L VAS score 
Data from randomization to 
Week 88 will be included. 
ANCOVA model with terms of 
treatment (tirzepatide MTD, 
placebo), all stratification factors, 
and corresponding score at 
randomization at Week 36 as a 
covariate. Missing data will be 
imputed using LOCF. 
Abbreviations: ANCOVA = analysis of covariance; BMI = body mass index; HDL = high-density lipoprotein; 
IWQOL-Lite-CT = Impact of Weight on Quality of Life-Lite-Clinical Trials Version; LDL = low-density 
lipoprotein; MTD = maximum tolerated dose; QW = once weekly; SF-36 v2 acute form = Short Form-36 
Version 2 Health Survey acute form; VAS = visual analog scale; VLDL = very low-density lipoprotein.  
4.6. 
(Other) Safety Analyses  
Unless specified otherwise, safety assessments for the double-blind treatment period will be 
based on the SS (Table GPHN.3.1). All data collected between randomization and the end date 
of study participation will be included, regardless of the adherence to study intervention.  
Safety outcomes during the open-label lead-in treatment period will also be summarized for all 
enrolled participants. Detailed analyses can be found in Appendix 3. 
The statistical assessment of homogeneity of the distribution of categorical safety responses 
between tirzepatide MTD and placebo will be conducted using Fisher’s exact test, unless 
specified otherwise. 
The mean change from baseline differences among treatments at all scheduled visits will be 
assessed via an MMRM using REML. Unless specified otherwise, if the safety parameter is 
assessed at 88 weeks, then the model will include country/pooled country, sex, tirzepatide MTD 
dose at randomization, percent weight loss at randomization (<10% and ≥10%), treatment group, 
visit and treatment-by-visit interaction as fixed effects, and baseline value of the safety parameter 
as a covariate. To model the covariance structure within participants, the unstructured covariance 
matrix will be used. If this model fails to converge, the covariance structures specified in 
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Section 4.3.2.2 will be tested in order until convergence is met. If the data does not warrant the 
MMRM model, then ANCOVA model will be conducted.  
For selected parameters, time-to-first-event analysis via the Cox-proportional hazards model may 
be conducted. Participants without the event will be censored at the end of study participation. 
For participants experiencing the event, the “time-to-first-event” will be the time (in weeks) from 
first dose or randomization (depends on the event of interest and analysis feature, eg, for time to 
study discontinuation, time from first dose might be used; for time to AE during double-blind 
treatment period, time from randomization might be used) to first occurrence of the event. 
Where necessary, the rate of events will be analyzed using a generalized linear mixed-effects 
model assuming the number of events follows a negative binomial distribution and with 
treatment as a fixed effect. The logarithm of days during the double-blind treatment period will 
be adjusted as an offset to account for possible unequal treatment duration of follow-up between 
participants.  
4.6.1. 
Extent of Exposure  
Summary of duration of follow-up (defined as time in days from date of randomization to the 
date of the last study visit) and/or duration on study treatment in double-blind treatment period 
(defined as time in days from date of randomization to date of last dose of study treatment plus 
7 days) will be provided for all randomized participants by treatment group using data from 
randomization to 88 weeks plus safety follow-up (Visit 801).  
For the summary of duration on study and study treatment in double-blind treatment period, the 
frequency and percentage of participants in the following ranges will be summarized by planned 
treatment group as well:  
 >0 weeks 
 ≥12 weeks 
 ≥24 weeks 
 ≥36 weeks 
 ≥52 weeks. 
In addition, the frequency and percentages of participants in the following study and study 
treatment exposure ranges may be summarized by planned treatment group:  
 0 week 
 ≥0 to <12 weeks  
 ≥12 to <24 weeks  
 ≥24 to <36 weeks  
 ≥36 to <52 weeks  
 ≥52 weeks. 
No p-values will be reported in these summaries as they are intended to describe the study 
populations rather than test hypotheses about them. 
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4.6.2. 
Adverse Events  
4.6.2.1. 
Treatment Emergent Adverse Events  
A TEAE for the double-blind treatment period is defined as an event that first occurred or 
worsened in severity after the randomization to the double-blind treatment period. The definition 
of baseline and postbaseline for double-blind treatment period are specified in Table GPHN.4.1. 
The MedDRA LLT will be used in the treatment-emergent derivation. The maximum severity for 
each LLT during the baseline period including ongoing medical history will be used as baseline 
severity. For events with a missing severity during the baseline period, it will be treated as 
“mild” in severity for determining treatment-emergence. Events with a missing severity during 
the postbaseline period will be treated as “severe” and treatment-emergence will be determined 
by comparing to baseline severity.  
The counts and percentages of randomized participants with TEAEs will be summarized by 
treatment using MedDRA PT nested within SOC. Statistical comparisons will be applied at both 
the SOC and PT levels. Events will be ordered by decreasing frequency within SOC. The SOC 
will be in alphabetical order. For events that are sex-specific, the denominator and computation 
of the percentage will include only participants from the given sex. 
An overview of the number and percentage of participants who experienced a TEAE, SAE, 
death, discontinued from study treatment or study due to an AE, relationship to study drug will 
be summarized for all randomized participants by treatment. 
The counts and percentages of randomized participants with TEAEs by maximum severity will 
be summarized by treatment using MedDRA PT. For each participant and TEAE, the maximum 
severity for the MedDRA PT is the maximum postbaseline severity observed from all associated 
LLTs mapping to the MedDRA PT. The maximum severity will be determined based on the 
nonmissing severities. If all severities are missing for the defined postbaseline period of interest, 
it will show as missing in the table.   
4.6.2.2. 
Common Adverse Events  
The counts and percentages of randomized participants with TEAEs, overall and common 
(common TEAEs occurred in ≥5% of participants in any treatment group before rounding), will 
be summarized by treatment using MedDRA PT. Events will be ordered by decreasing 
frequency.  
4.6.3. 
Additional Safety Assessments  
4.6.3.1. 
Deaths  
Listing of all deaths will be provided by study period. The listing will include participant 
identification including the treatment, site number, date of death, age at the time of enrollment, 
sex, associated AE group identification, time from last dose of study drug to death (if participant 
had discontinued study drug), and primary cause of death. 
Additional deaths that are reported outside of the study period will be obtained from the Lilly 
Safety System (LSS), which will be provided by Global Patient Safety.   
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4.6.3.2. 
Other Serious Adverse Events  
The counts and percentages of randomized participants who experienced at least 1 SAE 
(including deaths and SAEs temporally associated with or preceding deaths) during the 
postbaseline period will be summarized by treatment using MedDRA PT nested within SOC. 
Events will be ordered by decreasing frequency within SOC. The SOC will be in alphabetical 
order.  
A listing of all SAEs will be provided. The listing will include (not limited to) treatment, 
participant identification including the site number, participant number, date of event, age at the 
time of enrollment, sex, MedDRA SOC and PT, reported term, severity, outcome, relationship to 
study drug, time from first dose of study drug to the event, AE start date, AE end date, and action 
taken related to study treatment.  
4.6.3.3. 
Other Significant Adverse Events  
The counts and percentages of participants who discontinued from study treatment or study due 
to an AE during the double-blind treatment period may be summarized by treatment group using 
MedDRA PT nested within SOC. Events will be ordered by decreasing frequency within SOC. 
4.6.3.4. 
Vital Signs  
In the case that multiple measurements of an individual vital sign (eg, sitting SBP) are collected 
at the same visit, the mean of these measurements will be used for the analysis.   
Vital signs (SBP, DBP, and pulse) will be summarized by treatment group at each planned visit. 
Change from baseline to postbaseline values for vital signs will be summarized for participants 
who have both a baseline and at least 1 postbaseline result. Treatment differences in mean 
change from baseline for vital signs will be assessed using analysis model described in 
Section 4.6. Only planned measurements will be included in the mean change analyses.  
The counts and percentages of participants with treatment-emergent abnormal (high or low) vital 
signs (sitting SBP, DBP, and pulse) will be evaluated for patients randomized to the Tirzepatide 
treatment group and have both a baseline and at least 1 postbaseline result during the double-
blind treatment period (including the off-drug follow-up time period). The baseline for treatment 
emergent abnormal vital signs is the same as the safety outcome baseline defined in open label 
period Table GPHN.6.1. A treatment-emergent high result is defined as a change from a value 
less than or equal to the high limit at baseline to a value greater than the high limit at any time 
that meets the specified change criteria during the postbaseline period. A treatment-emergent low 
result is defined as a change from a value greater than or equal to the low limit at baseline to a 
value less than the low limit at any time that meets the specified change criteria during the 
postbaseline period. Both planned and unplanned measurements will be included in the analysis. 
The criteria for identifying participants with treatment-emergent vital signs abnormalities are 
listed in Table GPHN.4.5. 
Table GPHN.4.5. 
Categorical Criteria for Treatment-Emergent Abnormal Blood 
Pressure and Pulse Measurement for Adults 
Parameter 
Low 
High 
Systolic BP (mmHg)  
≤90 and decrease from baseline ≥20 
≥140 and increase from baseline ≥20 
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(Supine or sitting – 
forearm at heart level) 
≥129 and increase from baseline ≥20 
Diastolic BP (mmHg)  
(Supine or sitting – 
forearm at heart level) 
≤50 and decrease from baseline ≥10 
≥90 and increase from baseline ≥10 
Pulse (bpm)  
(Supine or sitting) 
<50 and decrease from baseline ≥15 
>100 and increase from baseline ≥15 
Abbreviations: BP = blood pressure; bpm = beats per minute.  
In addition, for patients randomized to the Tirzepatide treatment group during the double-blind 
treatment period, the following analyses will be conducted, note that baseline for analyses listed 
below is the same as the safety outcome baseline defined in open label period Table GPHN.6.1: 
 counts and percentages of participants who had resting pulse increases from baseline at 2 
or more consecutive visits of more than 10 bpm and/or 20 bpm 
 counts and percentages of participants who had resting pulse at any postbaseline visit 
increases from maximum baseline ≥20 bpm 
In addition, the following analyses will be conducted by treatment group during the double-blind 
treatment period:  
 counts and percentages of participants who had at least 1 resting pulse at any postbaseline 
visit exceeding 100 bpm 
 counts and percentages of participants who had at least 1 resting pulse exceeding 
100 bpm occurring at 2 or more consecutive study visits 
4.6.3.5. 
Electrocardiograms  
Summary statistics by treatment and by nominal visit will be provided for electrocardiogram 
(ECG) parameters (heart rate, PR interval, QRS, QT, and Fridericia’s corrected QT interval 
(QTcF) [QTcF = QT/RR0.333]). When the QRS is prolonged (eg, a complete bundle branch 
block), QT and corrected QT (QTc) should not be used to assess ventricular repolarization. Thus, 
for the analysis purposes, the QT and QTcF value will be set to missing when QRS is ≥120 msec 
for a particular ECG.  
Change from baseline to postbaseline values for ECG parameters (heart rate and PR interval) 
will be summarized for participants who have both a baseline and at least 1 postbaseline result. 
Only scheduled measurements will be included in the mean change analyses.   
The counts and percentages of participants who meet the following criteria at any time during the 
double-blind treatment period (including the safety follow up time period) will be summarized 
by treatment group:  
 QT >500 msec  
 QTcF >500 msec  
 QTcF >480 msec 
For patients randomized to Tirzepatide treatment group, the counts and percentages of 
participants who meet the following treatment-emergent criteria during the double-blind 
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treatment period (including the safety follow up time period) will be summarized. The baseline 
for treatment emergent abnormal ECG parameters is the same as the safety outcome baseline 
defined in open label period (Table GPHN.6.1): 
 Treatment-emergent ECG abnormalities as listed in Table GPHN.4.6. 
 Treatment-emergent increase from the maximum baseline in QTcF interval of >30 msec, 
60 msec, or 75 msec. Maximum baseline (see Table GPHN.4.1 for details) will be the 
maximum non-missing observation in the baseline period. The maximum value during 
the double-blind treatment period will be analyzed. Scheduled and unscheduled 
measurements will be included.   
Table GPHN.4.6. 
Selected Categorical Limits for ECG Data 
 
Low 
High 
Parameter 
Males 
Females 
Males 
Females 
Heart Rate (bpm) 
<50 and decrease 
≥15 
<50 and decrease 
≥15 
>100 and increase 
≥15 
>100 and increase 
≥15 
PR Interval (msec) 
<120 
<120 
≥220 
≥220 
QRS Interval (msec) 
<60 
<60 
≥120 
≥120 
QTcF (msec) 
<330 
<340 
>450 
>470 
Abbreviations: bpm = beats per minute; ECG = electrocardiogram; QTcF = Fridericia’s corrected QT interval. 
4.6.3.6. 
Clinical Laboratory Evaluation  
Descriptive summaries at each planned visit by treatment group will be provided for the baseline 
and postbaseline values and change from baseline values. The associated descriptive summaries 
will be presented in SI units and in CN units. Limits from the performing laboratory will be used 
to define low and high.   
Observed and change from baseline to each visit will be displayed for participants who have both 
a baseline and at least 1 postbaseline planned measurement. Baseline is defined in 
Table GPHN.4.1.   
A shift table will be provided including unscheduled measurements. The shift table will include 
the number and percentage of participants within each baseline category (low, normal, high, or 
missing) versus each postbaseline category (low, normal, high, or missing) by treatment. The 
proportion of participants shifted will be compared between treatments using Fisher’s exact test. 
For qualitative laboratory analytes, the number and percentage of participants with normal and 
abnormal values will be summarized by treatment. 
A listing of abnormal findings will be created for laboratory analyte measurements, including 
qualitative measures. The listing will include participant identification, treatment group, 
laboratory collection date, study day, analyte name, and analyte finding. 
The MMRM model or ANCOVA (if MMRM model is not applicable) will be used for the 
analysis during the double-blind treatment period for the continuous measurements for selected 
lab tests.  
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4.6.4. 
Patient Narratives  
The following are “notable” events, from start of study drug through end of study participation 
(or data cutoff for the submission if earlier):  
 deaths 
 SAEs 
 permanent discontinuations of study treatment due to AEs, and 
 pregnancy. 
Patient narratives (patient-level data and descriptive paragraph) will be provided for participants 
in the enrolled population with at least 1 notable event. 
4.6.5. 
Special Safety Topics  
For AESI or special safety topics, the counts and percentages of participants will be summarized 
by treatment and PT with decreasing frequency. Individual participant-level data may be 
presented. Displays with individual patient-level data may be created using various formats such 
as a customized listing and/or a customized graphical patient profile. Adverse events of special 
interest are defined in each section of special safety topics, where applicable. Listing will be 
generated for each AESI. 
4.6.5.1. 
Exocrine Pancreas Safety  
4.6.5.1.1. Pancreatic Enzymes  
Observed pancreatic enzyme data (p-amylase and lipase) will be summarized by treatment. 
The counts and percentages of participants with maximum postbaseline pancreatic enzyme value 
exceeding the following thresholds will be provided by baseline pancreatic enzyme value 
(≤ ULN, > ULN), and postbaseline: ≤1 × ULN, (>1 to ≤3) × ULN, (>3 to ≤5) × ULN, (>5 to 
≤10) × ULN, >10 × ULN.  
An MMRM analysis will be used to analyze each pancreatic enzyme with a log transformed 
(postbaseline measure/baseline measure) response variable and treatment, nominal visit, 
treatment-by-nominal visit interaction as fixed effects. 
4.6.5.1.2. Pancreatitis Events  
Summaries of adjudicated and investigator-reported pancreatic events will be provided by 
treatment. Detailed search criteria can be found in Appendix 6. 
Treatment-emergent adjudication confirmed pancreatitis will be considered as an AESI. Listing 
of participants with adjudicated pancreatitis may be provided if deemed necessary.  
4.6.5.2. 
Gastrointestinal Adverse Events  
4.6.5.2.1. Nausea, Vomiting, and Diarrhea  
Summaries and analyses for incidence and severity of nausea, vomiting (including “vomiting” 
and “vomiting projectile”), diarrhea (including “diarrhea” and “diarrhoea”), and 3 events 
combined will be provided by each treatment group. Summary of the prevalence over time for 
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nausea, vomiting, and diarrhea will also be presented. Time to the first onset of nausea, vomiting, 
and diarrhea will be plotted. 
4.6.5.2.2. Severe Gastrointestinal Events  
Severe GI AEs (GI SOC) will be captured with AE-CRF form and serious cases will be captured 
with the SAE form. The PTs in the GI SOC from the most recent MedDRA version at the time of 
database lock will be used to identify GI AEs, and only the PTs with severe/serious cases will be 
considered as AESIs.   
The counts and percentages of participants with severe/serious GI events will be summarized by 
treatment.   
4.6.5.3. 
Hepatobiliary Disorders  
4.6.5.3.1. Hepatic Events  
Severe/serious hepatic events will be considered as AESI and summarized separately. The counts 
and percentages of participants with treatment-emergent potentially drug-related hepatic events 
will be summarized by treatment using the MedDRA PTs. Detailed searching criteria can be 
found in Appendix 7.  
4.6.5.3.2. Acute Gallbladder Disease  
Events related to acute gallbladder disease will also be summarized by treatment groups by PT 
with decreasing frequency. Detailed searching criteria can be found in Appendix 7). 
Severe/serious acute gallbladder disease will be considered as AESIs and summarized separately.  
4.6.5.3.3. Liver Enzymes  
Common analyses for laboratory analyte measurements described in Section 4.6.3.3 are 
applicable for the liver enzyme-related measurements. This section provides additional analyses 
for liver enzymes. 
The counts and percentages of participants with the following elevations in hepatic laboratory 
tests at any time during the double-blind treatment period and during double-blind treatment 
period including follow up period will be summarized between treatment groups: 
 The counts and percentages of participants with an ALT measurement ≥3 ×, 5 ×, and 
10 × ULN for the central lab will be summarized for all participants with a postbaseline 
value and for subsets based on the following levels of baseline value:   
o participants whose nonmissing maximum baseline value is ≤1 × ULN  
o participants whose maximum baseline is >1 × ULN, and  
o participants whose baseline values are missing.   
 The counts and percentages of participants with an aspartate aminotransferase) 
measurement ≥3 ×, 5 ×, and 10 × ULN for the central lab will be summarized for all 
patients with a postbaseline value and for subsets based on various levels of baseline, as 
described above for ALT. 
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 The counts and percentages of participants with a total bilirubin measurement ≥2 × ULN 
for the central lab will be summarized for all participants with a postbaseline value, and 
for subsets based on the following levels of baseline values:   
o participants whose nonmissing maximum baseline value is ≤1 × ULN, 
o participants whose maximum baseline is >1 × ULN, but <2 × ULN, 
o participants whose maximum baseline value is ≥2 × ULN, and  
o participants whose baseline values are missing. 
 The counts and percentages of participants with a serum alkaline phosphatase 
measurement ≥2 × ULN for the central lab will be summarized for all participants with a 
postbaseline value, and for subsets based on various levels of baseline, as described for 
total bilirubin. 
Maximum baseline will be the maximum nonmissing observation in the baseline period. The 
maximum postbaseline value will be the maximum nonmissing value from the postbaseline 
period. Planned and unplanned measurements will be included. 
4.6.5.4. 
Hypoglycemia  
The following categories in accordance with the American Diabetes Association position 
statement on glycemic targets (ADA 2020) will be defined in the database. 
Glucose Alert Value (Level 1): 
 Documented symptomatic hypoglycemia is defined as any time a participant 
feels that he/she is experiencing symptoms and/or signs associated with 
hypoglycemia, and has a PG level of <70 mg/dL (<3.9 mmol/L). 
 Documented asymptomatic hypoglycemia is defined as any event not 
accompanied by typical symptoms of hypoglycemia, but with a measured PG 
<70 mg/dL (<3.9 mmol/L). 
 Documented unspecified hypoglycemia is defined as any event with no 
information about symptoms of hypoglycemia available, but with a measured PG 
<70 mg/dL (<3.9 mmol/L). 
Documented Clinically Significant Hypoglycemia (Level 2):   
 Documented symptomatic hypoglycemia is defined as any time a participant feels that 
he/she is experiencing symptoms and/or signs associated with hypoglycemia and has a 
blood glucose (BG) level of <54 mg/dL (<3.0 mmol/L). 
 Documented asymptomatic hypoglycemia is defined as any event not accompanied by 
typical symptoms of hypoglycemia but with a measured BG <54 mg/dL (<3.0 mmol/L). 
 Documented unspecified hypoglycemia is defined as any event with no information 
about symptoms of hypoglycemia available but with a measured BG <54 mg/dL 
(<3.0 mmol/L). 
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Severe Hypoglycemia (Level 3): 
Severe hypoglycemia is defined as an episode with severe cognitive impairment requiring the 
assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative 
actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or 
coma. Plasma glucose measurements may not be available during such an event, but neurological 
recovery attributable to the restoration of PG to normal is considered sufficient evidence that the 
event was induced by a low PG concentration.  
Other hypoglycemia categories: 
 Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs 
between bedtime and waking. 
If a hypoglycemic event meets the criteria of severe, the event would specifically be collected as 
an SAE. Serious hypoglycemia is defined by pharmacovigilance criteria and will also be 
captured with an SAE form.  
To avoid duplicate reporting, all consecutive hypoglycemic events occurring within a 1-hour 
period will be considered to be a single hypoglycemic event.   
Both the incidence (percent of participants experiencing ≥1 episode) and the rate 
(episodes/patient/year) of Level 2 or Level 3 hypoglycemia, and Level 3 hypoglycemia will be 
reported.   
Severe/serious hypoglycemia will be considered as AESIs. The summaries of severe/serious 
hypoglycemia will be provided by treatment group. A listing of all events of severe/serious 
hypoglycemia may be provided, if deemed necessary. This listing will provide treatment, and 
clinical characteristics of the hypoglycemic event. 
4.6.5.5. 
Immunogenicity  
4.6.5.5.1. Definitions of Sample ADA Status  
At a high level, an individual sample is potentially examined multiple times, in a hierarchical 
procedure, to produce a sample ADA assay result and potentially multiple cross-reactive 
antibodies assay results and multiple NAb assay results. The cut points used, the drug tolerance 
of each assay, and the possible values of titers are operating characteristics of the assay.  
Figure GPHN.4.1 details a flow chart that reflects the multitiered testing approach. 
 
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Abbreviations: ADA = anti-drug antibodies; CP = cut point; GIPR = glucose-dependent 
insulinotropic polypeptide receptor; GLP-1R = glucagon-like peptide-1 receptor; 
LY = LY3298176 (tirzepatide); NAb = neutralizing antibody; nGIP = native glucose-
dependent insulinotropic polypeptide; nGLP-1 = native glucagon-like peptide-1.  
Figure GPHN.4.1. 
Flowchart of immunogenicity multitiered testing approach. 
 
Table GPHN.4.7 outlines results as reported from Tier 2a of the multitiered testing approach. 
Tier 4 results are reported similarly. 
 
 
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Table GPHN.4.7. 
Sample ADA Assay Results  
Sample Laboratory Result 
Explanation 
Detected 
ADA are detected and confirmed. 
Not Detected 
The raw result as reported from the laboratory indicates not detected. The 
clinical interpretation of such results depends on other factors (see 
Table GPHN.4.8). 
NO TEST, QNS, etc. 
Sample exists but was unevaluable by the assay. 
Abbreviations: ADA = anti-drug antibodies; QNS = quantity not sufficient. 
 
It can be the case that the presence of high concentrations of tirzepatide will affect ADA 
immunoassays, and conversely high levels of antibodies may affect the measurement of 
tirzepatide concentration. Thus, a tirzepatide drug concentration, assessed from a sample drawn 
at the same time as the ADA sample, plays a key role in clinical interpretation of a sample when 
the laboratory result is Not Detected (see Table GPHN.4.8).  
Table GPHN.4.8. 
Sample Clinical ADA Interpretation Results  
Sample Clinical Interpretation 
Explanation 
ADA Present 
ADA assay result is Detected 
ADA Not Present 
ADA assay result is Not Detected and simultaneous drug concentration is at 
a level that has been demonstrated to not interfere in the ADA detection 
method (ie, drug concentration is below the assay’s drug tolerance level). 
 
For participants receiving placebo, drug concentration is not assessed and is 
assumed to be below the assay’s drug tolerance level. 
 
If drug concentration was planned but is not available for a treatment-period 
sample, a Not Detected sample will be declared ADA Not present.  
ADA Inconclusive 
ADA assay result is Not Detected but drug concentration in the sample is 
≥ the assay’s drug tolerance level, which may cause interference in the 
ADA detection method. 
Abbreviation: ADA = anti-drug antibodies. 
All ADA present samples will be evaluated for cross-reactivity to native GIP (Tier 2b), cross-
reactivity to native GLP-1 (Tier 2c), NAb LY (tirzepatide) on GIPR (Tier 4a), and NAb LY 
(tirzepatide) on GLP-1R (Tier 4b). If cross-reactive ADA against native GIP is detected, the in 
silico assessment for cross-reactive NAb against native GIP is evaluated. If cross-reactive ADA 
against native GLP-1 is detected, the in silico assessment for cross-reactive NAb against native 
GLP-1 is evaluated (Figure GPHN.4.1).  
Similar terminology to Table GPHN.4.8 applies for each type of cross-reactive and NAb assay. 
Importantly, each of these are distinct assays and, in general, have different assay operating 
characteristics.  
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The following are considered inconclusive for the NAb result: 
 NAb LY on GIPR: if NAb result is not detected, and PK concentration is ≥ drug 
tolerance limit of the NAb LY on GIPR assay 
 NAb LY on GLP-1R: if NAb result is not detected, and PK concentration is ≥ drug 
tolerance limit of the NAb LY on GLP-1R assay  
To mitigate inconclusive cross-reactive neutralizing antibody interpretations against native GIP 
and GLP-1 due to potential tirzepatide concentrations above the drug tolerance limit of the NAb 
GIP on GIP-R (Tier 4c) and NAb GLP-1 on GLP-1R (Tier 4d) assays. 
An in silico method utilizing results from Tiers 2b and 2c, Tiers 4a and 4b, and tirzepatide 
concentrations is used to determine cross-reactive NAb against native GIP and GLP-1. The in 
silico method is outlined in the following table: 
Table GPHN.4.9. 
In Silico Classification for Cross-Reactive NAb  
In Silico 
Classification 
Cross-Reactive ADA 
Result 
NAb Result 
Circulating 
Tirzepatide 
Level (ng/mL) 
In Silico Cross-
Reactive NAb 
Interpretation 
Cross-Reactive 
NAb to nGIP 
Tier 2b: “Not Detected” 
 Tier 4a: “Not 
Detected” 
or  
Tier 4a: “Detected” or 
N/A or Missing 
Any value or 
missing 
Not Present 
 
Tier 2b: “Detected” 
Tier 4a: “Not Detected” 
< drug tolerance 
limit of Tier 4a 
assay 
Not Present 
 
Tier 2b: “Detected” 
Tier 4a: “Not Detected” 
≥ drug tolerance 
limit of Tier 4a 
assay 
Inconclusive 
 
Tier 2b: “Detected” 
Tier 4a: “Detected” 
< drug tolerance 
limit of Tier 4a 
assay 
Present 
 
Tier 2b: “Detected” 
Tier 4a: “Detected” 
≥ drug tolerance 
limit of Tier 4a 
assay 
Present 
Cross-Reactive 
NAb to nGLP-1  
Tier 2c: “Not Detected” 
Tier 4b: “Not Detected” 
or  
Tier 4b: “Detected” or 
N/A or Missing 
Any value or 
missing 
Not Present 
 
Tier 2c: “Detected” 
Tier 4b: “Not Detected” 
< drug tolerance 
limit of Tier 4b 
assay 
Not Detected 
 
Tier 2c: “Detected” 
Tier 4b: “Not Detected” 
≥ drug tolerance 
limit of Tier 4b 
assay 
Inconclusive 
 
Tier 2c: “Detected” 
Tier 4b: “Detected” 
< drug tolerance 
limit of Tier 4b 
assay 
Detected 
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In Silico 
Classification 
Cross-Reactive ADA 
Result 
NAb Result 
Circulating 
Tirzepatide 
Level (ng/mL) 
In Silico Cross-
Reactive NAb 
Interpretation 
 
Tier 2c: “Detected” 
Tier 4b: “Detected” 
≥ drug tolerance 
limit of Tier 4b 
assay 
Detected 
Abbreviations: ADA = anti-drug antibodies; NAb = neutralizing antibody; nGIP = native glucose-dependent 
insulinotropic polypeptide; nGLP-1 = native glucagon-like peptide-1; Tier 2b = cross-reactive ADA to nGIP; 
Tier 4a = NAb LY (tirzepatide) on GIPR; Tier 4b = NAb LY (tirzepatide) on GLP-1R. 
 
Note that in the case of an ADA Inconclusive sample, each of the NAb and Cross-Reactive NAb 
assay results is taken to be Inconclusive. 
Note also that any reference to an assay cut point and/or drug tolerance is population specific, 
and is subject to modification to study-specific parameters per regulatory guidance. 
4.6.5.5.2. Definitions of Immunogenicity Assessment Periods  
Immunogenicity Baseline Observations: Baseline period for immunogenicity assessment for 
each participant includes all observations prior to first dose of study treatment. In instances 
where multiple baseline observations are collected, to determine participant ADA status the last 
nonmissing immunogenicity assessment prior to first administration of study drug is used to 
determine treatment-emergent status (see below).  
Immunogenicity Postbaseline Period Observations: Postbaseline period observations for each 
participant includes all observations after the first administration of study drug. There are 
2 different periods listed below:  
 The planned treatment period is defined as from the first dose of treatment to end of the 
treatment period. 
 The entire postbaseline period is defined as from the first dose of treatment to the end of 
safety follow-up visit or date of study withdrawal  
4.6.5.5.3. Definitions of Participant ADA Status  
Participant evaluable for TE ADA: a participant has a nonmissing baseline ADA result, and at 
least 1 nonmissing postbaseline ADA result. 
Treatment-emergent ADA-unevaluable participant: any participant who does not meet the 
evaluable criteria. 
Baseline ADA Present (preexisting antibody): ADA detected in a sample collected up to the first 
dose date and time. 
Baseline ADA Not Present: ADA is not detected, and the corresponding PK concentration is 
missing or below the drug tolerance limit in a sample collected up to the first dose date and time. 
Treatment-emergent ADA positive (TE ADA+) participant: A participant who is evaluable for 
TE ADA is TE ADA+ if either of the following holds:  
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 The participant has baseline status of ADA Not Present and at least 1 postbaseline status 
of ADA Present with titer ≥2× MRD of the ADA assay. 
 The participant has baseline and postbaseline status of ADA Present, with the 
postbaseline titer being 2 dilutions (4-fold) greater than the baseline titer. That is, the 
participant has baseline (B) status of ADA Present, with titer 1:B, and at least 
1 postbaseline (P) status of ADA Present, with titer 1:P, with P/B ≥4.  
As shown in Figure GPHN.4.1, a titer is expected when ADA assay result is detected. On 
occasion, the corresponding assay cannot be performed, in which case a titer value will be 
imputed for the purpose of TE ADA determination. A baseline sample with detected ADA and 
no titer is imputed to be the MRD (1:10), and a postbaseline sample with ADA detected and no 
titer is imputed to be 1 dilution above the MRD (1:20). 
Treatment-emergent ADA inconclusive participant: A TE ADA-evaluable participant is TE 
ADA inconclusive if ≥20% of the participant’s postbaseline samples are ADA inconclusive and 
all remaining postbaseline samples are ADA not present. 
Treatment-emergent ADA negative (TE ADA-) participant: A TE ADA evaluable participant is 
TE ADA- when the participant is not TE ADA+ and not TE ADA inconclusive.  
For each NAb assay, the following are defined: 
NAb-positive (NAb+) participant: A participant who is TE ADA+ and has a NAb+ sample in the 
postbaseline period. 
NAb-inconclusive participant: A participant who is TE ADA+, is not NAb+, and all samples that 
have TE ADA+ titer have a NAb-inconclusive sample result. 
NAb-negative (NAb-) participant: A participant who is neither NAb+ nor NAb inconclusive. 
Unless specified otherwise, the above-mentioned definitions of NAb are applicable to all NAb 
analyses, including cross-reactive NAb analyses, and cross-reactive antibodies. 
4.6.5.5.4. Analyses to be Performed  
Two analysis sets will be considered: 
 mITT analysis set: refer to Section 3. Note that for mITT population, only time during 
tirzepatide exposure will be summarized.  
 For participants who randomized to tirzepatide MTD arm. 
The analysis period was defined in Section 4.6.5.5.2. The count and proportion of participants 
who are TE ADA+ will be tabulated, where proportion are relative to the number of participants 
who are TE ADA evaluable, as defined above. The tabulation will include the number and 
proportion of participants with ADA Present at baseline, and the number and proportion of 
TE ADA+ participant exhibiting each type of cross-reactive antibodies and NAb. In silico 
classification for cross-reactive NAb will be summarized.   
A summary will be provided of the count and percentage of tirzepatide-treated participants 
experiencing specific TEAE (see Table GPHN.4.10) by participant TE ADA status (TE ADA+, 
TE ADA-, TE ADA inconclusive) during the planned treatment period.  
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Table GPHN.4.10. 
Adverse Events for Analysis with Immunogenicity Results  
TEAE category 
Criteria 
Hypersensitivity reactions 
Anaphylactic reaction SMQ (narrow or algorithm) 
Hypersensitivity SMQ (narrow) 
Angioedema SMQ (narrow) 
Severe Cutaneous Adverse Reaction SMQ (narrow) 
Vasculitis SMQ (narrow) 
Injection site reactions 
Injection site reaction HLT  
Infusion site reaction HLT  
Administration site reaction HLT 
Abbreviations: HLT = High Level Term; MedDRA = Medical Dictionary for Regulatory Activity; 
SMQ = Standardized MedDRA Query; TEAE = treatment-emergent adverse event. 
 
A listing will be provided for all participants who had ADA Present at any time (including 
baseline) or had any specific TEAE (see Table GPHN.4.10). This listing includes a time course 
of ADA (clinical interpretation result plus flags for samples meeting TE ADA+ criteria and for 
samples with cross-reactive antibodies and NAb present) along with the TEAE.   
Cases of TE ADA that are associated with AEs of either severe/serious hypersensitivity or 
severe/serious ISR will be classified as AESIs.  
Additional immunogenicity analyses as determined later may be presented. The relationship 
between antibody titers, the PK parameters, and PD response to tirzepatide may also be assessed.  
4.6.5.6. 
Hypersensitivity Reactions  
Two main analyses are performed in support of assessment of potential immediate 
hypersensitivity, including anaphylaxis, and as well as potential non-immediate hypersensitivity.   
Time Period A, of potential immediate hypersensitivity, includes all TEAEs occurring from start 
of study drug administration up to 24 hours after end of study drug administration. For events 
without the hypersensitivity eCRF, only date (no time) information is collected; if such events 
occurred on the same date as the study drug injection date, they will be included in Time 
Period A. 
Time Period B, of potential non-immediate hypersensitivity, includes all TEAEs occurring more 
than 24 hours after the end of study drug administration, but prior to subsequent drug 
administration. 
The counts and percentages of participants who experienced a hypersensitivity TEAE will be 
summarized by PT with decreasing frequency by treatment.  
Analyses for both time periods are based on the following: 
 Narrow and algorithm terms in Anaphylactic reaction standardized MedDRA query 
(SMQ) (20000021) (Note that Anaphylactic reaction SMQ algorithm will only be 
summarized for Time Period A) 
 Narrow terms in Angioedema SMQ (20000024) 
 Narrow terms in Severe cutaneous adverse reactions SMQ (20000020) 
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 Narrow terms in Hypersensitivity SMQ (20000214), and 
 Narrow terms in Vasculitis SMQ (20000174)   
Additionally, for the Anaphylactic reaction SMQ in Time Period A, the algorithmic query (per 
the MedDRA Maintenance and Support Services Organization SMQ guide) will be performed. 
An algorithmic case must include either: 
 A narrow term from the SMQ (Category A of the SMQ); 
 Multiple terms from the SMQ, from the same administration of study drug, comprising 
terms from at least 2 of the following categories from the SMQ: 
o Category B - (Upper Airway/Respiratory) 
o Category C - (Angioedema/Urticaria/Pruritus/Flush) 
o Category D - (Cardiovascular/Hypotension) 
Where algorithm is mentioned below, this applies only to Time Period A. 
The counts and percentages of participants who experienced a TEAE for the following will be 
analyzed for each of the 2 time periods:  
 Any narrow or algorithm term from any 1 of the 5 SMQs indicated above (ie, combined 
search across narrow and algorithmic portions of all 5 SMQs) 
 Any narrow or algorithm term within each SMQ, separately (ie, narrow SMQ search). 
Within query, individual PTs that satisfied the queries will be summarized. For Time Period A 
analysis, the Anaphylactic reaction SMQ algorithm will be summarized. Also, a single event 
may satisfy multiple SMQs, in which case the event contributes to every applicable SMQ.  
4.6.5.6.1. Severe/Serious Hypersensitivity Reactions  
The severe/serious cases of hypersensitivity will be considered as AESIs. Summary with 
severe/serious hypersensitivity reactions may be provided, if deemed necessary.   
4.6.5.7. 
Injection Site Reaction  
Injection site reaction, incidence and rates, and related information reported via “Injection Site 
Reactions” eCRF will be summarized by treatment. Information to be summarized includes 
location of the reaction, timing of reaction relative to study drug administration, and 
characteristics of the injection site reaction: erythema, induration, pain, pruritus, and edema.  
Patient-based analysis and event-based analysis may be provided if necessary. The patient-based 
analysis summarizes all ISR questionnaire forms for an individual participant with a single 
statistic, typically an extreme value. This analysis allows each participant to contribute only once 
for each parameter, at the expense of a focus on the most extreme events. By contrast, the event-
based analysis summarizes all ISR questionnaire forms received, without regard to individual 
participants. This provides characteristics of ISR events as a proportion of all events for which 
questionnaire responses were provided, at the expense of some potential bias due to differential 
contribution of individual participants to the analysis.   
The counts and percentages of participants with treatment-emergent injection site reaction will 
be summarized by treatment using the MedDRA PTs. Detailed searching criteria can be found in 
Appendix 7. 
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The PT will be summarized within each category in decreasing order of incidence for tirzepatide-
treated participants. 
4.6.5.7.1. Severe/Serious Injection Site Reactions  
The severe/serious treatment-emergent injection site reactions based on TEAE search criteria 
specified in Appendix 7 will be considered as AESIs. The counts and percentages of participants 
with severe/serious injection site reactions will be summarized by treatment. A listing of 
participants with treatment-emergent severe/serious ISRs may be provided, if deemed necessary.  
4.6.5.8. 
Major Adverse Cardiovascular Events  
The following positively adjudicated MACE will be considered as AESI:  
 death due to cardiovascular AEs 
 myocardial infarction  
 hospitalization for unstable angina  
 hospitalization for heart failure  
 coronary interventions (such as coronary artery bypass graft or percutaneous coronary 
intervention), and 
 cerebrovascular events, including cerebrovascular accident (stroke) and transient 
ischemic attack.  
The counts and percentages of participants with positively adjudicated MACE may be 
summarized by treatment.  
A listing of participants reporting MACE events, either reported by investigator or identified by 
the Clinical Evaluation Committee, may be provided.  
In addition, MACE reported by investigator may be summarized although a MACE reported by 
investigator and not positively adjudicated is not considered as AESI. 
4.6.5.9. 
Major Depressive Disorder / Suicidal Ideation or Behavior  
The severe/serious major depressive disorder/suicidal ideation or behavior will be captured as 
AESI. Adverse events will be searched using MedDRA PT terms. Detailed searching criteria can 
be found in Appendix 7. 
The counts and percentages of participants with TEAEs will be summarized by treatment group 
using MedDRA PT nested within SMQ. Events will be ordered by decreasing frequency nested 
within SMQ. A listing of participants with major depressive disorder/suicidal ideation or 
behavior may be provided if deemed necessary. 
In addition to spontaneously reported AEs assessed by the investigator, suicidal ideation and 
behavior and depression will be assessed through the use of the C-SSRS and the PHQ-9, 
respectively. 
4.6.5.9.1. Patient Health Questionnaire  
Total scores for the PHQ-9 range from 0 to 27 with total scores being categorized as follows:  
 None (not depressed) 0 – 4 
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 Mild 5 – 9 
 Moderate 10 – 14 
 Moderately Severe 15 – 19, and 
 Severe 20 – 27. 
Shift tables will be provided showing the counts and percentages of participants within each 
baseline category (maximum value) versus each postbaseline category (maximum value) by 
treatment. 
Additionally, the following 3 outcomes of interest will be compared between treatments (based 
on the maximum value during baseline and postbaseline): 
 Any increase in depression category (ie, worsening of depression); includes participants 
in the none, mild, moderate, or moderately severe category during baseline and with at 
least 1 postbaseline measurement; 
 Increase from No or Mild Depression to Moderate, Moderately Severe, or Severe 
Depression; includes participants in the none or mild depression category during baseline 
and with at least 1 postbaseline measurement; and 
 Increase from Mild or Moderate Depression to Moderately Severe or Severe Depression; 
includes participants in the mild or moderate depression category during baseline and 
with at least 1 postbaseline measurement. 
4.6.5.9.2. Suicidal Ideation and Behavior Solicited Through C-SSRS  
Suicide-related thoughts and behaviors occurring during the double-blind study period, based on 
the C-SSRS, will be summarized by treatment group. In particular, for each of the following 
suicide-related events, the counts and percentages of participants with the event will be 
summarized by treatment group: 
 Died by suicide 
 Nonfatal suicide attempt 
 Interrupted attempt 
 Aborted attempt 
 Preparatory acts or behavior 
 Active suicidal ideation with specific plan and intent 
 Active suicidal ideation with some intent to act without specific plan 
 Active suicidal ideation with any methods (no plan) without intent to act 
 Nonspecific active suicidal thoughts 
 Wish to be dead, and 
 Non-suicidal, self-injurious behavior. 
In addition, the counts and percentages of participants who experienced at least 1 of the 
composite measures will be presented. The participants with at least 1 postbaseline C-SSRS 
assessment are included. The composite measure is determined at each assessment by the “yes” 
or “no” responses in C-SSRS categories by the study participant:   
 Category 1 – Wish to be Dead 
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 Category 2 – Non-specific Active Suicidal Thoughts 
 Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
 Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
 Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
 Category 6 – Preparatory Acts or Behavior 
 Category 7 – Aborted Attempt 
 Category 8 – Interrupted Attempt 
 Category 9 – Actual Attempt (non-fatal), and 
 Category 10 – Completed Suicide. 
Composite endpoints of suicidal ideation and suicidal behavior based on the above categories are 
defined below: 
 Suicidal ideation: A “yes” answer at any time during the double-blind treatment period 
of the study to any 1 of the 5 suicidal ideation questions (Categories 1 – 5) on the 
C-SSRS 
 Suicidal behavior: A “yes” answer at any time during double-blind treatment period of 
the study to any 1 of the 5 suicidal behavior questions (Categories 6 – 10) on the 
C-SSRS, and 
 Suicidal ideation or behavior: A “yes” answer at any time during double-blind 
treatment period of the study to any 1 of the 10 suicidal ideation and behavior questions 
(Categories 1 – 10) on the C-SSRS.  
A listing containing data for each participant with suicidal ideation, suicidal behavior, or non-
suicidal self-injurious behavior during the double-blind treatment period of the study by 
treatment and visit may be provided. Data from all visits are displayed, regardless of a “yes” or 
“no” answer, for participants with any “yes” answer for suicidal ideation, suicidal behavior, or 
self-injurious behavior without suicidal intent.  
4.6.5.10. Malignancy  
Malignancy will be considered as AESI. The counts and percentages of participants with 
treatment-emergent malignancy will be summarized by treatment and PT ordered by decreasing 
frequency. Detailed searching criteria can be found in Appendix 7. 
4.6.5.11. Renal Safety  
Laboratory measures related to renal safety will be analyzed as specified for laboratory 
measurements in Section 4.6.3.3. 
Additionally, 2 shift tables examining renal function will be created. A min-to-min shift table of 
estimated glomerular filtration rate estimated by the Chronic Kidney Disease Epidemiology 
Collaboration equation with units mL/min/1.73m2, using categories (<30, ≥30 to <45, ≥45 to 
<60, ≥60 to <90, and ≥90 mL/min/1.73m2). A max-to-max shift table of UACR, using the 
categories UACR<30 mg/g, 30 mg/g ≤UACR≤300 mg/g, UACR>300 mg/g (respectively, these 
represent normal, microalbuminuria, and macroalbuminuria).   
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Mixed model repeated measure analyses for estimated glomerular filtration rate and UACR will 
be provided. Log transformation will be performed for UACR.   
4.6.5.11.1. Acute Renal Events  
Acute renal events, including those associated with chronic renal failure exacerbation, will also 
be captured.  
Severe/serious renal events from the SMQ search below will be considered as AESI.  
The counts and percentages of participants with renal events will be summarized by treatment by 
using the MedDRA PTs contained in any of the following SMQs: 
 Acute renal failure:  
o Narrow terms in Acute renal failure SMQ (20000003) 
 Chronic kidney disease: 
o Narrow terms in Chronic kidney disease SMQ (20000213)  
In addition, a listing of participants with treatment-emergent acute renal events may be provided, 
if deemed necessary. 
4.6.5.11.2. Dehydration  
Dehydration events will be captured in the following SMQ and summarized. Severe/serious 
dehydration events will be considered as AESI:  
 Narrow terms in Dehydration SMQ (20000232) 
The counts and percentages of participants with dehydration will be summarized by treatment 
and PT and ordered by decreasing frequency. A listing of participants with treatment-emergent 
dehydration events may be provided, if deemed necessary. 
4.6.5.12. Thyroid Safety Monitoring  
4.6.5.12.1. Calcitonin  
The number and proportion of participants with a maximum postbaseline calcitonin value in the 
following thresholds will be provided by treatment and baseline calcitonin value: (≤20 ng/L, 
>20 ng/L to ≤35 ng/L, >35 ng/L); postbaseline: ≤20 ng/L, >20 ng/L to ≤35 ng/L, >35 ng/L to 
≤50 ng/L, >50 ng/L to ≤100 ng/L, and >100 ng/L. 
4.6.5.12.2. C-Cell Hyperplasia and Thyroid Malignancies  
Thyroid malignancies and C-cell hyperplasia will be considered as AESI.    
The counts and percentages of participants with treatment-emergent thyroid C-cell hyperplasia 
and malignancies will be summarized by treatment and PT ordered with decreasing frequency. In 
addition, a listing of participants with treatment-emergent thyroid C-cell hyperplasia and 
neoplasms may be provided if deemed necessary.   
4.6.5.13. Treatment-Emergent Arrhythmias and Cardiac Conduction Disorders  
Severe/serious treatment-emergent arrhythmias and cardiac conduction disorders will be 
considered as AESI.  
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The treatment-emergent arrhythmias and cardiac conduction disorders events will be included 
using the MedDRA PTs. Detailed search criteria can be found in Appendix 7. 
The counts and percentages of participants with treatment-emergent arrhythmias and cardiac 
conduction disorders will be summarized by treatment and PT nested within SMQ. The PT will 
be ordered with decreasing frequency within SMQ. A listing of participants with treatment-
emergent arrhythmias and cardiac conduction disorders may be provided if deemed necessary. 
4.6.5.14. Treatment of Overdose  
Overdose is defined as taking more than 15 mg of tirzepatide in less than 72 hours. Overdosing 
of tirzepatide will be summarized by treatment group, and a listing of participants with 
tirzepatide overdosing may be provided. 
In addition, a listing of participants reporting AEs related to overdosing of tirzepatide may be 
provided. 
4.6.5.15. Abuse Potential  
To identify AE terms suggestive of abuse liability potential, narrow terms from the SMQ Drug 
abuse and dependence (20000101) will be used. The counts and percentages of participants will 
be summarized by treatment group with decreasing frequency. 
4.7. 
Other Analyses  
4.7.1. 
Health Outcomes  
The patient-reported outcome questionnaires will be analyzed using the mITT population on the 
EAS, unless specified otherwise. 
Item-level missingness is dealt with as per the instrument developers’ instruction. 
Additional psychometric analyses may be performed by Value Evidence Outcomes group at 
Lilly and documented in a separate analysis plan. 
4.7.1.1. 
Patient Global Impression of Status for Physical Activity  
The counts and percentages of participants endorsing each PGIS response category will be 
summarized by nominal visit and by treatment. A shift table from baseline to postbaseline of 
5 PGIS response categories at each postbaseline visit by treatment will be created.  
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4.7.1.2. 
Short-Form-36 Health Survey Version 2, Acute Form  
Per copyright owner, the QualityMetric Health Outcomes™ Scoring Software 4.5 will be used to 
derive the following domain and component scores: 
 Mental Component Summary (MCS) 
 Physical Component Summary (PCS) 
 Physical Functioning domain (PF) 
 Role-Physical domain (RP) 
 Bodily Pain domain (BP) 
 General Health domain (GH) 
 Vitality domain (VT) 
 Social Functioning domain (SF) 
 Role-Emotional domain (RE), and 
 Mental Health domain (MH). 
For each above domain and component summary scores parameter, the raw scores will be 
transformed into the domain scores (t-scores) and the following analyses for the actual value and 
change from baseline value will be conducted:  
 descriptive summaries by treatment group, and 
 analysis described in Table GPHN.4.3 and Table GPHN.4.4.  
The empirical cumulative distribution function curves of the change from randomization to 
Week 88 in SF-36 physical function domain score will be provided by treatment group. 
If data allowed, analysis for SF-36 physical function domain score analysis described in 
Table GPHN.4.3 will be conducted to evaluate the treatment effect in participants who have 
limitations in physical function at baseline, which is defined as PGIS response at baseline of 
“moderately limited,” “very much limited,” or “extremely limited.”  
4.7.1.3. 
Impact of Weight on Quality of Life-Lite Clinical Trials  
The following parameters will be included from IWQOL-Lite-CT: 
 IWQOL-Lite-CT total score (all items: items 1 through 20) 
 Physical Function composite score (5 items: Items 1 through 3, 16, 17) 
 Physical composite score (7 items: Item 1 through 5, 16, 17), and 
 Psychosocial composite score (13 items: Item 6 through 15, 18, 19, 20). 
IWQOL-Lite-CT total and composite scores range from 0 to 100, with higher scores reflecting 
better levels of functioning. 
IWQOL-Lite-CT scores are computed according to the IWQOL-Lite scoring rules (Kolotkin et 
al. 2002) as following: 
 Each composite raw score will be calculated if a minimum of 50% of the items for that 
composite has a nonmissing value; the total score will be calculated if a minimum of 75% 
of all 20 items has a nonmissing value.   
 If the minimum required number of items is answered for a composite domain then:  
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o Calculate the average of the valid non-missing responses corresponding to the items 
in the total or each composite (1 = “never” or “not at all true” and 5 = “always” or 
“completely true”). 
o The composite score is then calculated by transforming the raw composite score to 
the 0 (worst)-to-100 (best) metric using the following formula for every patient at 
each time point: 
100 (𝑆𝑚𝑎𝑥−𝐶𝑎𝑣𝑔)/(𝑆𝑚𝑎𝑥−𝑆𝑚𝑖𝑛) 
▪ 𝐶𝑎𝑣𝑔 is the raw average score of all nonmissing item responses in the composite; 
this average must be a number between 1 and 5, inclusive 
▪ 𝑆𝑚𝑎𝑥 is the maximum possible raw score value (i.e., 5) 
▪ 𝑆𝑚𝑖𝑛 is the minimum possible raw score value (i.e., 1) 
▪ Inserting the maximum and minimum possible score values, the formula is 
reduced to 100 (5 −𝐶𝑎𝑣𝑔)/4. 
For total and each composite score, the following analyses for the actual value and change from 
baseline value will be conducted:  
 descriptive summaries by treatment group, and 
 ANCOVA analysis described in Table GPHN.4.3 and Table GPHN.4.4. 
If data allows, analysis for IWQOL-Lite-CT physical function composite score analysis 
described in Table GPHN.4.3 and Table GPHN.4.4 will be conducted to evaluate the treatment 
effect in participants who have limitations in physical function at baseline (as defined in Section 
4.7.1.3).  
4.7.1.4. 
EQ-5D-5L  
For the utility score and the Visual Analog Scale scores, the following analyses of the actual 
value and change from baseline value will be conducted: 
 descriptive summaries by treatment group, and 
 analyses described in Table GPHN.4.4.  
4.7.2. 
Subgroup Analyses  
Efficacy subgroup analyses will be guided by the treatment-regimen estimand in FAS and the 
efficacy estimand in EAS.   
Subgroup analyses may be done by country to support local regulatory registrations. 
4.7.2.1. 
Subgroup Analysis of Body Weight Change  
Subgroup analyses by the following baseline characteristics will be provided:   
 age (<65 years and ≥65 years) 
 sex (female and male) 
 race  
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 ethnicity (Hispanic/Latino, non-Hispanic/non-Latino) 
 BMI at study entry (<30, ≥30 and <35, ≥35 and <40, ≥40 kg/m2)  
 BMI at randomization (<25, ≥25 and <30, ≥30 and <35, ≥35 and <40, ≥40 kg/m2) 
 Percent body weight loss at 36 weeks (<10% and ≥10%), and  
 Region of enrollment (US, outside of US).  
The outcome measure for the subgroup analyses will include percent change in body weight 
from randomization at 88 weeks. 
For the percentage change in body weight from randomization at 88 weeks, for each subgroup 
analysis aforementioned, the following analyses will be conducted:  
For treatment regimen estimand: ANCOVA model will be used; for efficacy estimand: MMRM 
model will be used. The detail of analytical approach is documented in Section 4.4.1. For each 
estimand, 2 models will be considered:  
 model on each stratum of the subgroup, and 
 full model with use subgroup as a covariate.  
4.8. 
Interim Analyses  
No interim analyses are planned for this study.  
A database lock will occur after all enrolled participants complete or discontinue the 36-week 
open-label lead-in treatment period. This is not considered an interim lock since the enrolled 
participants who complete the 36-week open-label lead-in treatment period will be randomized 
to a double-blind, placebo-controlled treatment period, and there is no plan to modify the study 
based on the results from this open-label lead-in database lock. 
4.8.1. 
Data Monitoring Committee  
Not Applicable. 
4.9. 
Changes to Protocol-Planned Analyses  
To provide data on efficacy of the investigational product that would be valuable to better inform 
clinical decisions in management of people living with obesity, protocol-planned objectives are 
changed as below. 
Key secondary objectives: 
 Moving percentage of study participants who achieve >20% body weight reduction at 
Week 88 from Visit 2 (Week 0) from exploratory endpoint to a key secondary endpoint. 
 Moving percentage of study participants who achieve >15% body weight reduction at 
Week 88 from Visit 2 (Week 0) from additional secondary endpoint to a key secondary 
endpoint. 
 
 
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5. 
Sample Size Determination  
Approximately 1000 participants will be screened and 750 participants enrolled into the 36-week 
open-label tirzepatide lead-in treatment period for approximately 600 participants to be 
randomized in a 1:1 ratio to tirzepatide MTD (300 participants) or placebo (300 participants). 
The sample size determination assumes that evaluation of superiority of tirzepatide MTD to 
placebo will be conducted at a 2-sided significance level of 0.05 using a 2-sample t-test. 
Additionally, a difference of at least 6% mean body weight percentage change from 
randomization (36 weeks) to 88 weeks between tirzepatide MTD and placebo, a common SD of 
8%, and a dropout rate of 25% are assumed for statistical power calculations. Under the 
assumptions above, randomizing 600 participants in a 1:1 ratio to tirzepatide MTD 
(300 participants) and placebo (300 participants) provides more than 90% power to demonstrate 
superiority of tirzepatide MTD to placebo.  
 
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6. 
Supporting Documentation  
6.1. 
Appendix 1: Demographic and Other Characteristics of Study 
Population  
6.1.1. 
Patient Characteristics  
Summary tables will be generated for participant demographics and baseline disease 
characteristics for randomized population. Variables to be included (but not limited to) are: age, 
sex, race, ethnicity, weight, BMI, waist circumference, age groups, and BMI groups.   
6.1.2. 
Historical Illnesses and Preexisting Conditions  
The number and percentage of participants with historical illnesses and preexisting conditions 
will be summarized by treatment group using MedDRA PTs nested within SOC. System Organ 
Class will be in alphabetical order. Conditions (ie, PTs) will be ordered by decreasing frequency 
within SOC. A preexisting condition is defined as the condition/event recorded on the 
Preexisting Conditions and Medical History eCRF page or on the Prespecified Medical History 
eCRF page with a start date prior to the date of informed consent, and no end date (ie, the event 
is ongoing) or an end date on or after the date of informed consent. A historic illness is defined 
as an event with start date and stop date that are prior to the informed consent. The AEs 
occurring prior to first dose of study treatment will be included in the preexisting condition for 
reporting purpose. 
6.1.3. 
Concomitant Medications  
Summaries of Preferred Names of concomitant medications with number and percentage of 
patients sorted by decreasing frequency will be generated by treatment group.   
Additionally, concomitant medications of interest (as defined below) will be summarized. 
Concomitant medications of interest include the following: 
 baseline antihypertensive therapy, by type/class 
 baseline lipid lowering therapy, by type/class 
 changes to baseline medication in post-randomization: 
o antihypertensive therapy, and 
o lipid lowering therapy 
 utilization after randomization: 
o medicines that cause weight gain 
o antihyperglycemic medication for the treatment of diabetes for participants who 
develop T2DM during the study (antihyperglycemic medication for the treatment 
of prediabetes is not allowed pre protocol) 
o antidiarrheal medication, and 
o antiemetic medication. 
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The analysis of concomitant medication for the open-label period is provided in Appendix 4. 
6.2. 
Appendix 2: Treatment Compliance  
Treatment compliance will be defined as taking at least 75% of the required doses of study drug. 
Compliance at each treatment visit and over the corresponding study period will be calculated 
using the number of doses administered (regardless of the actual dose in mg administered) 
divided by the total number of doses expected to be administered ×100 at the specific visit or 
over the corresponding study period, respectively. Treatment compliance will be summarized 
descriptively at each treatment visit and over the double-blind treatment period by treatment 
using the mITT population.  
For the open-label period, the analysis of treatment compliance is provided in Appendix 4. 
6.3. 
Appendix 3: Important Protocol Deviations  
Important protocol deviations are identified in the Trial Issues Management Plan. A listing of all 
important protocol deviations will be provided at the end of the study. For the double-blind 
treatment period, a summary of important protocol deviations will be provided for all 
randomized participants by treatment. 
6.4. 
Appendix 4: Analyses for the Open-Label Lead-in Period  
6.4.1. 
General consideration  
Unless specified otherwise, all analyses for open-label lead-in period will be based on all 
enrolled patients who are exposed to at least one dose of study drug.  
Table GPHN.6.1. 
Baseline and Postbaseline Definitions in Open-Label Period 
Population 
Analysis Type 
Baseline  
Postbaseline  
All enrolled 
participants 
1.1) Treatment-
Emergent Adverse 
Events 
The baseline period is defined 
as the start of screening and 
ends prior to the first dose of 
tirzepatide treatment (typically 
at Week 0). 
Starts after the first dose of tirzepatide 
treatment and ends prior to the 
randomization (typically at Week 36).   
All enrolled 
participants 
1.2) Treatment-
Emergent 
Abnormal Labs, 
Vital Signs, and 
ECGs. 
Baseline will include all 
scheduled and unscheduled 
measurements during the 
baseline period as defined 
above (1.1). 
Postbaseline is defined as above (1.1). 
All scheduled and unscheduled 
measurements will be included. 
All enrolled 
participants 
1.3) Change from 
Last Baseline to 
Week xx and to 
Last Postbaseline 
for Labs, Vital 
Signs, and ECGs. 
The last scheduled and 
unscheduled non-missing 
assessment recorded during the 
baseline period defined above 
(1.1). 
Postbaseline is defined as above (1.1). 
Only scheduled visits will be included. 
The ED visits are considered scheduled 
visits. 
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Population 
Analysis Type 
Baseline  
Postbaseline  
All enrolled 
participants 
Other outcomes 
(efficacy, PROs, 
questionnaires, etc.) 
Baseline is defined as the last 
nonmissing data collected 
prior to or at study entry 
(Week 0) 
Postbaseline is defined as data collected 
after the study entry (Week 0) and prior 
to or at the randomization (Week 36)  
Abbreviations: ECG = electrocardiogram; ED = early discontinuation; PRO = patient-reported outcome.  
 
For the open-label lead-in period, there will be no treatment comparison in summaries and 
analyses since all participants will be treated with tirzepatide. 
6.4.2. 
Patient Characteristics  
Summary tables will be generated for participant demographics and baseline disease 
characteristics for enrolled population. Variables to be included (but not limited to) are: age, sex, 
race, ethnicity, weight, BMI, waist circumference, age groups, and BMI groups.   
6.4.3. 
Disposition  
Summaries of study disposition and study drug disposition will be provided for the open-label 
lead-in period. Counts and percentages of all participants that are entered, enrolled, and 
discontinued from study or study drug will be summarized. A listing may also be provided if 
necessary. 
The study completion status for the open-label lead-in period is defined as  
 at the end of 36-week open-label lead-in period (when all enrolled participants complete 
or discontinue the open-label lead-in period). Participants with a nonmissing body weight 
measurement at 36 weeks (Visit 11) will be considered as completers; otherwise, will be 
considered as non-completers. 
Summary of prematurely discontinued study treatment (including discontinuation reason) will be 
provided for all enrolled participants. A time-to-event analysis of premature study treatment 
discontinuation will also be conducted.  
If data warrants, the counts and percentages of participants who follow the planned escalation 
scheme, have dose interruption, or have dose de-escalation/re-escalation, will be summarized for 
the open-label lead-in period. In addition, the proportion of participants receiving 2.5 mg, 5 mg, 
7.5 mg, 10 mg, 12.5 mg, or 15 mg may be presented by visit during the dose escalation period. 
6.4.4. 
Efficacy Analysis  
Unless otherwise noted, statistical tests will be conducted at a 2-sided alpha level of 0.05, and the 
confidence interval will be calculated at 95% 2-sided.  
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Table GPHN.6.2. 
Efficacy Analysis for the Open-Label Period 
Analysis Variable 
Analysis Set 
Analysis Method 
Additional 
Information 
Mean change in: 
-body weight 
-waist circumference 
-BMI  
Data from 
Week 0 to 
Week 36 
Change from baseline to 
postbaseline values at each 
scheduled visit will be 
summarized. Within treatment 
difference will be assessed by 
Wilcoxon signed-rank test 
Missing data at 
Week 36 will be 
imputed using LOCF. 
Mean change in: 
- Fasting glucose (mg/dL) 
- HbA1c (%)  
- fasting insulin (pmol/L) 
- Total cholesterol (mg/dL) 
- LDL-cholesterol (mg/dL) 
- Non-HDL-cholesterol (mg/dL) 
- HDL-cholesterol (mg/dL) 
- VLDL-cholesterol (mg/dL) 
- Triglycerides (mg/dL) 
- Free Fatty acids (mg/dL) 
-systolic blood pressure (mmHg) 
-diastolic blood pressure 
(mmHg) 
 
Mean change in health outcome 
measurements (Section 4.7.1)  
Percentage of study participants 
who achieve 
≥5/10/15/20/25%body weight 
reduction  
 
The counts and percentages will 
be summarized at each scheduled 
visit. 
 
Abbreviations: BMI = body mass index; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; LDL = low-
density lipoprotein; LOCF = last observation carried forward; VLDL = very low-density lipoprotein. 
6.4.5. 
Treatment Compliance  
The definition of treatment compliance can be found in Section 6.2. It will be summarized 
descriptively at each treatment visit and over the open-label period for all enrolled participants.  
6.4.6. 
Medical History, Preexisting condition, and Concomitant Medicines  
Medical history, preexisting condition and concomitant medicines for all enrolled participants 
will be analyzed in a similar manner to Section 6.1 without performing treatment comparison. 
6.4.7. 
Extent of Exposure  
Summary of duration of open-label lead-in period (defined as time in days from date of Visit 2 to 
the date of randomization) and duration on study treatment (defined as time in days from date of 
first dose of study treatment on or after Visit 2 to date of last dose of study treatment during 
open-label period prior to randomization plus 7 days) will be provided for all enrolled 
participants.  
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For the summary of duration on study treatment, the frequency and percentage of participants in 
the following ranges will be summarized as well:  
 >4 weeks 
 ≥8 weeks 
 ≥12 weeks 
 ≥16 weeks 
 ≥20 weeks 
 ≥24 weeks, and 
 ≥36 weeks. 
In addition, the frequency and percentages of participants in the following study treatment 
exposure ranges may be summarized:  
 0 weeks  
 >0 to <4 weeks 
 ≥4 to <8 weeks  
 ≥8 to <12 weeks  
 ≥12 to <16 weeks  
 ≥16 to <20 weeks  
 ≥20 to <24 weeks  
 ≥24 to <36 weeks, and  
 ≥36 weeks.  
6.4.8. 
Adverse Events  
For the open-label lead-in period, a TEAE is defined as an event, based upon MedDRA LLT, 
that first occurred or worsened in severity after baseline. 
For events occurring on the day of first taking study medication, the CRF-collected information 
(eg, treatment-emergent flag, start time of study treatment and event) will be used to determine 
whether the event was pre- versus post-treatment if available. If the relevant information is not 
available, then the events will be counted as post-treatment. 
Treatment-emergent adverse event, common TEAE, deaths, SAE, and other significant AE will 
be summarized in a similar way of Section 4.6.2 without performing treatment comparison.  
6.4.9. 
Additional Safety Assessments  
Vital signs, ECG parameters, and clinical laboratory results during the entire open label period 
(including the off-drug follow-up time period for participants who discontinued the study during 
the open label period) will be summarized in a similar way of Section 4.6.3 without performing 
treatment comparison.  
6.4.10. 
Special Safety topics  
Adverse events of special interest will be summarized in a similar way of Section 4.6.4 without 
performing treatment comparison. 
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6.4.11. 
Important Protocol Deviations  
Important protocol deviations are identified in the Trial Issues Management Plan. A summary of 
important protocol deviations will be provided at the end of 36 weeks treatment (for all enrolled 
participants). 
6.5. 
Appendix 5: Clinical Trial Registry Analyses  
Additional analyses will be performed for the purpose of fulfilling the CTR requirements.   
Analyses provided for the CTR requirements include the following: 
 Summary tables of adverse events for the open-label period and the double-blind 
treatment period, provided as datasets which will be converted to XML files. For 
the open-label period, serious adverse events and ‘other’ non-serious adverse 
events are summarized by MedDRA preferred term. For the double-blind 
treatment period, they are summarized by treatment group and MedDRA 
preferred term. 
 An adverse event is considered ‘Serious’ whether or not it is a TEAE. 
 An AE is considered in the ‘Other’ category if it is both a TEAE and is not 
serious. For each Serious AE and ‘Other’ AE, for each term and treatment group, 
the following are provided: 
o the number of participants at risk of an event 
o the number of participants who experienced each event term, and 
o the number of events experienced 
 For each Serious AE, these additional terms are provided for EudraCT: 
o the total number of occurrences causally related to treatment 
o the total number of deaths, and 
o the total number of deaths causally related to treatment.   
Demographic table including the following age ranges required by EudraCT: 18 to 65 years, 
65 to 85 years, and 85 years and over. 
6.6. 
Appendix 6: Exceptional Circumstances Impact  
This section lists additional statistical analyses that may be performed at the final database lock 
to assess the impact of exceptional circumstances if the data warrant.   
6.6.1. 
General Consideration  
Percentage and count of randomized participants who followed the exceptional circumstances 
mitigation plan may be summarized by treatment group. This includes, but not limited to, 
participants rescreened, procedures conducted via remote visit or mobile home health visit, visits 
occurred using the extended visit windows, alternative way of investigator product 
shipment/dispensing, use of a local lab, etc.  
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Percentage and count of randomized participants who completely missed at least 1 study visit 
due to exceptional circumstances may also be summarized. 
Similar summaries during the open-label lead-in period may also be provided for all enrolled 
participants. 
6.6.2. 
Exposure  
A listing of enrolled participants who had study drug temporary interruption due to exceptional 
circumstances may be provided with information to indicate whether a participant is randomized 
(along with randomized treatment) and whether events occur post-randomization.  
6.6.3. 
Protocol Deviation  
Percentage and count of randomized participants having important protocol deviation related to 
exceptional circumstances will be summarized by treatment.  
Percentage and count of randomized participants with protocol deviation and mitigation related 
to exceptional circumstances may also be summarized by treatment.   
A listing of all randomized participants who had important protocol deviation and mitigation due 
to exceptional circumstances may be provided.  
Similar summaries during the open-label lead-in period may also be provided for all enrolled 
participants. 
6.6.4. 
Patient Disposition  
A summary table for all randomized participants that discontinue study or study treatment due to 
exceptional circumstances will be provided by treatment. A similar summary during the open-
label lead-in period may also be provided for all enrolled participants. 
A listing of all enrolled participants who discontinued the study or study treatment due to 
exceptional circumstances will be provided with information to indicate whether a participant is 
randomized (along with randomized treatment).  
6.6.5. 
Adverse Events  
A listing of all enrolled participants who had COVID-19 infection, including death due to 
COVID-19, will be provided with information to indicate whether a participant is randomized 
(along with randomized treatment), and whether events occur post-randomization.  
6.6.6. 
Major Depressive Disorder/Suicidal Ideation  
The counts and percentages of participants with TEAEs for major depression may be 
summarized by treatment group using MedDRA PT nested within SMQ by subgroup impacted 
by exceptional circumstances (ie, participants without impact versus with impact) for SS group.   
The suicidal ideation and behavior solicited through C-SSRS may be summarized by treatment 
group by subgroup impacted by exceptional circumstances (ie, participants without impact vs 
with impact) for SS group.   
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Similar summaries during the open-label lead-in period may also be provided for all enrolled 
participants. 
6.6.7. 
Local Lab  
Local lab due to exceptional circumstances will not be brought into the Lilly database at the time 
of primary database lock and final database lock per data collection system in Study GPHN, even 
though local laboratory is one of the options in exceptional circumstances. Therefore, this section 
is not applicable for analysis purposes. 
6.6.8. 
Missing Data Due to Exceptional Circumstances  
For the primary endpoints and key secondary endpoints, missing data due to exceptional 
circumstances will be handled as described in Section 4.1 and Section 4.3.2.3.  
6.7. 
Appendix 7: Searching Criteria for Special Safety Topics  
Pancreatitis Events  
Determination of investigator-reported events will be through the “Acute pancreatitis” 
standardized MedDRA query (SMQ) (20000022, narrow scope) and a “Pancreatitis Chronic” PT 
search of the AE database, while adjudication-confirmed pancreatitis events are from 
adjudication forms.   
Hepatic Events 
Treatment-emergent potentially drug-related hepatic events will be identified using the MedDRA 
PTs contained in any of the following SMQs: 
 Broad and narrow terms in the Liver related investigations, signs and symptoms 
SMQ (20000008) 
 Broad and narrow terms in the Cholestasis and jaundice of hepatic origin SMQ 
(20000009) 
 Broad and narrow terms in the Hepatitis non-infectious SMQ (20000010) 
 Broad and narrow terms in the Hepatic failure, fibrosis and cirrhosis and other 
liver damage SMQ (20000013)  
 Narrow terms in the Liver-related coagulation and bleeding disturbances SMQ 
(20000015) 
Acute Gallbladder Disease  
 Narrow PTs in Gallbladder related disorders SMQ (20000124) 
 Narrow PTs in Biliary tract disorders SMQ (20000125), and 
 Narrow PTs in Gallstone related disorders SMQ (20000127). 
Injection Site Reactions 
Treatment-emergent injection site reaction will be identified using the MedDRA PT in any of the 
following:  
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 MedDRA High Level Term (HLT) of Injection site reaction   
 HLT of Administration site reaction, and 
 HLT of Infusion Site Reactions.  
Major Depressive Disorder/Suicidal Ideation 
The major depressive disorder/suicidal ideation events will be identified using the PTs from the 
Depression and suicide/self-injury SMQ as defined in MedDRA (SMQs narrow scope: 20000037 
[Suicide/self-injury] and 20000167 [Depression (excl suicide and self injury)]).   
Malignancies 
The malignancy events will be identified using the MedDRA PT contained in Malignant tumours 
SMQ (20000194) narrow scope or Tumours of unspecified malignancy SMQ (20000195) narrow 
scope.  
Arrhythmias and Cardiac Conduction Disorders 
The treatment-emergent arrhythmias and cardiac conduction disorders events will be identified 
using the MedDRA PTs contained in any of the following SMQs: 
1) Arrhythmias: 
 For symptoms: Arrhythmia related investigations, signs and symptoms SMQ 
(20000051), narrow and broad terms 
 For arrhythmias: In Cardiac arrhythmia SMQ, under tachyarrhythmia sub SMQ 
i. 
Supraventricular tachyarrhythmia SMQ (20000057), broad and narrow terms 
ii. 
Tachyarrhythmia terms, nonspecific SMQ (20000164), narrow terms only 
iii. 
Ventricular tachyarrhythmia SMQ (20000058), narrow terms only 
2)  Cardiac Conduction Disorders  
 Conduction defects SMQ (20000056), narrow terms only 
 Cardiac conduction disorders HLT (10000032), all PTs. 
 
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7. 
References  
[ADA]. Glycemic targets: standards of medical care in diabetes- 2020. Diabetes Care. 
2020(suppl 1):S66–S76. https://doi.org/10.2337/dc20-S006  
[ICH] International Council for Harmonisation. Addendum on estimands and sensitivity analysis 
in clinical trials to the guideline principles for clinical trials: E9(R1). Published 20 November 
2019. Accessed August 31, 2022. https://www.gmp-compliance.org/files/guidemgr/E9-
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Signature Page for VV-CLIN-076401 v1.0
Signature Page for VV-CLIN-076401 v1.0
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Approved on 03 Feb 2023 GMT
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