A Phase 3 Study of Tirzepatide Monotherapy Compared to Dulaglutide 0.75 mg in Patients With Type 2 Diabetes Mellitus
Phase: PHASE3
Conditions: Type 2 Diabetes
Sponsor: Eli Lilly and Company

Clinical Study Protocol Amendment Version (a) I8F-JE-GPGO 
 
A Phase 3 Study of Tirzepatide Monotherapy Compared to Dulaglutide 0.75 mg in Patients with Type 
2 Diabetes Mellitus (SURPASS J-mono) 
NCT03861052 
Approval Date: 17-Jan-2019 

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Protocol I8F-JE-GPGO(a)
A Phase 3 Study of Tirzepatide Monotherapy Compared to 
Dulaglutide 0.75 mg in Patients with Type 2 Diabetes
Mellitus (SURPASS J-mono)
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of
tirzepatide (LY3298176), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Tirzepatide (LY3298176)
Eli Lilly Japan K.K
Kobe, Hyogo Japan
Protocol Electronically Signed and Approved by Lilly: 18 Dec 2018
Amendment (a) Electronically Signed and Approved by Lilly 
on approval date provided below.
Approval Date: 17-Jan-2019 GMT

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Table of Contents
Section
Page
Protocol I8F-JE-GPGO(a) A Phase 3 Study of Tirzepatide Monotherapy 
Compared to Dulaglutide 0.75 mg in Patients with Type 2 Diabetes 
Mellitus (SURPASS J-mono)..............................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................13
3.
Introduction ......................................................................................................................17
3.1.
Study Rationale............................................................................................................17
3.2.
Background..................................................................................................................17
3.3.
Benefit/Risk Assessment..............................................................................................18
4.
Objectives and Endpoints..................................................................................................20
5.
Study Design.....................................................................................................................22
5.1.
Overall Design .............................................................................................................22
5.2.
Number of Participants.................................................................................................24
5.3.
End of Study Definition ...............................................................................................25
5.4.
Scientific Rationale for Study Design...........................................................................25
5.5.
Justification for Dose ...................................................................................................25
6.
Study Population...............................................................................................................27
6.1.
Inclusion Criteria..........................................................................................................27
6.2.
Exclusion Criteria ........................................................................................................28
6.3.
Lifestyle Restrictions....................................................................................................31
6.4.
Screen Failures.............................................................................................................31
7.
Treatments........................................................................................................................32
7.1.
Treatments Administered .............................................................................................32
7.1.1.
Packaging and Labeling .......................................................................................32
7.1.2.
Medical Devices...................................................................................................32
7.2.
Method of Treatment Assignment ................................................................................33
7.2.1.
Selection and Timing of Doses.............................................................................33
7.3.
Blinding .......................................................................................................................33
7.4.
Dosage Modification....................................................................................................34
7.5.
Preparation/Handling/Storage/Accountability...............................................................34
7.6.
Treatment Compliance .................................................................................................34
7.7.
Concomitant Therapy...................................................................................................35
7.7.1.
Management of Patients with Gastrointestinal Symptoms.....................................35

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7.8.
Treatment after the End of the Study............................................................................36
7.8.1.
Treatment after Study Completion........................................................................36
7.8.2.
Special Treatment Considerations ........................................................................36
8.
Discontinuation Criteria ....................................................................................................37
8.1.
Discontinuation from Study Treatment.........................................................................37
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................37
8.1.2.
Temporary Interruption of Study Treatment .........................................................38
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................38
8.2.
Discontinuation from the Study....................................................................................38
8.3.
Lost to Follow-Up........................................................................................................39
9.
Study Assessments and Procedures ...................................................................................40
9.1.
Efficacy Assessments...................................................................................................40
9.1.1.
Primary Efficacy Assessments .............................................................................40
9.1.2.
Secondary Efficacy Assessments..........................................................................40
9.1.2.1.
7-Point Self-Monitored Blood Glucose Profiles ..............................................40
9.1.3.
Appropriateness of Assessments ..........................................................................40
9.2.
Adverse Events ............................................................................................................41
9.2.1.
Serious Adverse Events........................................................................................41
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................42
9.2.2.
Adverse Events of Special Interest .......................................................................43
9.2.2.1.
Hypoglycemia ................................................................................................43
9.2.2.2.
Severe, Persistent Hyperglycemia...................................................................44
9.2.2.3.
Pancreatitis.....................................................................................................45
9.2.2.4.
Thyroid Malignancies and C-Cell Hyperplasia................................................46
9.2.2.5.
Major Adverse Cardiovascular Events............................................................46
9.2.2.6.
Supraventricular Arrhythmias and Cardiac Conduction 
Disorders........................................................................................................46
9.2.2.7.
Hypersensitivity Events..................................................................................46
9.2.2.7.1.
Injection Site Reactions ............................................................................47
9.2.2.7.2.
Anti-Drug Antibodies ...............................................................................47
9.2.2.8.
Diabetic Retinopathy Complications...............................................................47
9.2.2.9.
Hepatobiliary Disorders..................................................................................47
9.2.2.10.
Severe Gastrointestinal Adverse Events..........................................................47
9.2.2.11.
Acute Renal Events ........................................................................................47
9.2.2.12.
Amputation/Peripheral Revascularization .......................................................47
9.2.2.13.
Major Depressive Disorder/Suicidal Ideation..................................................48
9.2.2.14.
Individual Clinical Events Adjudication..........................................................48
9.2.3.
Complaint Handling.............................................................................................48

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9.3.
Treatment of Overdose.................................................................................................48
9.4.
Safety...........................................................................................................................48
9.4.1.
Electrocardiograms ..............................................................................................48
9.4.2.
Vital Signs ...........................................................................................................49
9.4.3.
Laboratory Tests ..................................................................................................49
9.4.4.
Immunogenicity Assessments ..............................................................................49
9.4.5.
Safety Monitoring ................................................................................................50
9.4.5.1.
Hepatic Safety Monitoring..............................................................................50
9.5.
Pharmacokinetics .........................................................................................................51
9.6.
Pharmacodynamics ......................................................................................................51
9.7.
Pharmacogenomics ......................................................................................................51
9.7.1.
Whole Blood Samples for Pharmacogenetic Research..........................................51
9.8.
Biomarkers...................................................................................................................52
9.9.
Health Economics ........................................................................................................52
9.9.1.
European Quality of Life (EQ-5D-5L)..................................................................52
9.9.2.
Diabetes Treatment Satisfaction Questionnaire (DTSQ).......................................53
10.
Statistical Considerations ..................................................................................................54
10.1. Sample Size Determination ..........................................................................................54
10.2. Populations for Analyses..............................................................................................54
10.3. Statistical Analyses ......................................................................................................55
10.3.1.
General Statistical Considerations ........................................................................55
10.3.2.
Treatment Group Comparability...........................................................................56
10.3.2.1.
Patient Disposition..........................................................................................56
10.3.2.2.
Patient Characteristics ....................................................................................56
10.3.2.3.
Concomitant Therapy .....................................................................................56
10.3.2.4.
Treatment Compliance....................................................................................56
10.3.3.
Efficacy Analyses ................................................................................................56
10.3.3.1.
Primary Analyses ...........................................................................................56
10.3.3.2.
Secondary Analyses........................................................................................57
10.3.3.3.
Tertiary/Exploratory Analyses ........................................................................57
10.3.4.
Safety Analyses....................................................................................................57
10.3.4.1.
Hypoglycemic Events.....................................................................................58
10.3.4.2.
Gastrointestinal Events...................................................................................58
10.3.4.3.
Adjudicated Cardiovascular Events ................................................................58
10.3.4.4.
Central Laboratory Measures, Vital Signs, and 
Electrocardiograms.........................................................................................58
10.3.5.
Evaluation of Immunogenicity .............................................................................59
10.3.6.
Other Analyses.....................................................................................................59

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10.3.6.1.
Health Economics...........................................................................................59
10.3.6.2.
Subgroup Analyses.........................................................................................59
10.3.7.
Interim Analyses..................................................................................................59
11.
References ........................................................................................................................60
12.
Appendices .......................................................................................................................62

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List of Tables
Table
Page
Table GPGO.1.
Schedule of Activities....................................................................................14
Table GPGO.2.
Objectives and Endpoints...............................................................................20
Table GPGO.3.
Treatment Regimens......................................................................................32

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List of Figures
Figure
Page
Figure GPGO.1. Illustration of study design for Clinical Protocol I8F-JE-GPGO.....................24

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................63
Appendix 2.
Clinical Laboratory Tests...............................................................................68
Appendix 3.
Study Governance Considerations..................................................................70
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................74
Appendix 5.
World Health Organization Classification of Diabetes and Diagnostic 
Criteria ..........................................................................................................75
Appendix 6.
Classification of Contraceptive Methods........................................................76
Appendix 7.
Management of Patients with Severe, Persistent Hyperglycemia during 
the Treatment Period......................................................................................77
Appendix 8.
Protocol Amendment I8F-JE-GPGO(a) Summary A Phase 3 Study of 
Tirzepatide Monotherapy Compared to Dulaglutide 0.75 mg in Patients 
with Type 2 Diabetes Mellitus (SURPASS J-mono) ......................................78

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1. Synopsis
Title of Study:
A Phase 3 Study of Tirzepatide Monotherapy Compared to Dulaglutide 0.75 mg in Patients with 
Type 2 Diabetes Mellitus (SURPASS J-mono).
Rationale: 
Tirzepatide is a once-weekly (QW) dual glucose-dependent insulinotropic polypeptide 
(GIP)/glucagon like peptide-1 (GLP-1) receptor agonist.  Tirzepatide is a 39-amino acid 
synthetic peptide with agonist activity at both the GIP and GLP-1 receptors.  The structure of 
tirzepatide is based on the GIP sequence and includes a C20 fatty di-acid moiety 
 
.  Tirzepatide is administered by subcutaneous (SC) administration.
Study I8F-JE-GPGO (GPGO) is a multicenter, randomized, double-blind, parallel, active-
controlled, 52-week Phase 3 study designed to assess the efficacy and safety of SC administered 
QW tirzepatide (5, 10, and 15 mg), compared to dulaglutide 0.75 mg in patients with type 2 
diabetes mellitus (T2DM) who have discontinued oral antihyperglycemic medication (OAM) 
monotherapy or are OAM-naïve. The primary endpoint will be to demonstrate that QW 
tirzepatide 5 mg, and/or 10 mg, and/or 15 mg are superior to dulaglutide 0.75 mg in glycated 
hemoglobin (HbA1c) change from baseline to 52 weeks, based on Guideline for Clinical 
Evaluation of Oral Hypoglycemic Agents (Pharmaceutical and Food Safety Bureau/Evaluation 
and Licensing Division Notification No. 0709-1. 2012).
Objectives/Endpoints:  
Objectives
Endpoints
Primary

To demonstrate that once-weekly tirzepatide 5 
mg, and/or 10 mg, and/or 15 mg are superior to 
dulaglutide 0.75 mg in HbA1c change from 
baseline to 52 weeks in patients with T2DM who 
have discontinued OAM monotherapy or are 
OAM-naïve

Mean change in HbA1c from baseline at 
Week 52
Secondary
Efficacy

To compare the efficacy of once-weekly
tirzepatide versus dulaglutide 0.75 mg at
52 weeks

Mean change in HbA1c 

Proportion of patients who achieve HbA1c 
<7%, ≤6.5%, and <5.7%

Mean change in FSG

Mean change in daily average 7-point 
SMBG profiles

Mean change in body weight

Proportion of patients who achieve weight 
loss of ≥5%, ≥10%, and ≥15% from baseline

Mean change in fasting insulin

Mean change in fasting C-peptide

Mean change in HOMA-2
CCI

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Objectives
Endpoints
Safety

To compare the safety of once-weekly
tirzepatide versus dulaglutide 0.75 mg at
52 weeks

Incidence of TEAEs

Early discontinuations of investigational 
product due to AEs

Adjudicated all deaths and nonfatal major 
CV events

Adjudicated pancreatic AEs

Serum calcitonin 

Incidence of allergic and hypersensitivity 
reactions 

Incidence of injection site reactions

Incidence of treatment-emergent ADAs to 
tirzepatide

The change in systolic and diastolic blood 
pressure, and heart rate from baseline 

Occurrence of hypoglycemic episodes

Time to initiation of rescue therapy for 
severe persistent hyperglycemia
Abbreviations:  ADAs = anti-drug antibodies; AE = adverse event; CV = cardiovascular; FSG = fasting serum 
glucose; HbA1c = hemoglobin A1c; OAM  = oral antihyperglycemic medication; SAE = serious adverse event; 
SMBG = self-monitored blood glucose; T2DM = type 2 diabetes mellitus; TEAE = treatment-emergent adverse 
event.
Summary of Study Design:  
Study GPGO is a multicenter, randomized, double-blind, parallel, active-controlled, 52-week 
Phase 3 study which will assess the safety and efficacy of tirzepatide (5, 10, and 15 mg)
compared to dulaglutide 0.75 mg in approximately 636 randomized patients with T2DM who 
have discontinued OAM monotherapy or are OAM-naïve.
Treatment Arms and Duration:  
Study GPGO will consist of 3 periods:  a 4-week (OAM-naïve) or 10-week (at least 8-week 
OAM washout) screening/lead-in period, followed by a 52-week treatment period, and a 4-week 
safety follow-up period.  Patients will be randomized in a 1:1:1:1 ratio (tirzepatide [5, 10, 15 
mg], and dulaglutide 0.75 mg).  
Patients will be stratified based on baseline HbA1c (≤8.5% or >8.5%), baseline body mass index 
(BMI) (<25 or ≥25 kg/m2), and washout of antidiabetic medication (yes or no).
Number of Patients:
A total of approximately 636 patients (159 patients per treatment group) will be randomized. 

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Statistical Analysis:
Sample size
The trial is powered to assess superiority of tirzepatide doses (5 mg, and/or 10 mg, and/or 15 
mg), versus dulaglutide 0.75 mg, relative to mean change from baseline in HbA1c at 52 weeks,
under the following assumptions: use of 2-sample t-test to compare treatment means utilizing 
HbA1c data collected before initiation of any rescue medication and premature treatment 
discontinuation; up to 15% subjects initiating any rescue medication or premature treatment 
discontinuation; at least 0.5%, 0.5%, and 0.4% superior mean reduction in HbA1c from baseline 
at 52 weeks for tirzepatide 15, 10, and 5 mg, respectively, compared to dulaglutide 0.75 mg; and 
a common standard deviation (SD) of 1.0%.  On the basis of these assumptions, randomizing 636 
subjects using a 1:1:1:1 randomization ratio to tirzepatide 5 mg (159 patients), tirzepatide 10 mg 
(159 patients), tirzepatide 15 mg (159 patients), and dulaglutide 0.75 mg (159 patients) is 
required to ensure at least 90% power to establish superiority of tirzepatide 10-mg and/or 15-mg 
doses, compared to dulaglutide 0.75 mg at a 2-sided significance level of 0.025, followed by 
superiority of tirzepatide 5 mg, compared to dulaglutide 0.75 mg only if superiority of tirzepatide
10 mg or 15 mg is declared.  Tirzepatide 5 mg will be tested at a 2-sided significance level of 
0.05 if superiorities of both 10 mg and 15 mg are declared.  Tirzepatide 5 mg will be tested at a 
2-sided significance level of 0.025 if superiority of either 10 mg or 15 mg is declared.  This 
parallel gatekeeping procedure controls family-wise Type 1 error rate at a 2-sided 0.05 level 
(Dmitrienko et al. 2003).  
Efficacy Analyses
Efficacy and safety will be assessed using the modified intention-to-treat (mITT) population, 
which consists of all randomly assigned participants who are exposed to at least 1 dose of 
investigational product. The primary efficacy of tirzepatide versus dulaglutide 0.75 at 52 weeks 
will be guided by the “efficacy” estimand. The “efficacy” estimand represents efficacy prior to 
discontinuation of investigational product without confounding effects of rescue therapy for 
persistent severe hyperglycemia.  
The primary efficacy assessment, guided by the “efficacy” estimand, will use the Efficacy 
Analysis Set (EAS), which consists of data obtained before the initiation of any rescue therapy 
and before premature treatment discontinuation. The analysis model for change from baseline in 
HbA1c assessed over time up to the 52-week visit, will be a mixed-model for repeated measures 
(MMRM), with terms: treatment, visit, and treatment-by-visit interaction, stratification factors: 
baseline BMI group (<25 or ≥25 kg/m2) and washout of antidiabetic medication (yes or no) as
fixed effects, baseline HbA1c as a covariate.  An unstructured covariance structure will model 
relationship of within-patient errors.  
A robustness of the primary efficacy assessment, guided by the “treatment-regimen” estimand, 
will be conducted.  This assessment will analyze change from baseline in HbA1c to 52-week 
visit using an analysis of covariance (ANCOVA) with terms, treatment, baseline BMI group 
(<25 or ≥25 kg/m2), washout of antidiabetic medication (yes or no), and baseline HbA1c as a 
covariate.  The ANCOVA analysis will be conducted using the Full Analysis Set (FAS) at the

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52-week visit, which consists of all available change from baseline in HbA1c data at the 52-week 
visit, irrespective of whether they were obtained while the participants had discontinued the 
investigational product or whether the participant had been given rescue medication.  
Additionally, data for subjects with missing values will be imputed based on observed data in the 
same treatment arm from subjects who had their efficacy measure at the Week 52 visit assessed 
after early discontinuation of investigational product and/or initiation of rescue medication 
(retrieved drop outs).  Analysis will be conducted with multiple imputations and statistical 
inference over multiple imputations will be guided by the method proposed by (Rubin 1987).  No 
multiplicity adjustments will be made for conducting 2 efficacy assessments for different 
estimands.
Safety Analysis
Safety assessments will be based on all available data, irrespective of whether they were 
obtained while the participants had discontinued the investigational product or whether the 
participant had been given rescue medication.  Summary statistics will be provided for incidence 
of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), study 
discontinuation due to adverse events (AEs), investigational product discontinuation due to AEs 
and deaths from first dose to end of safety follow-up.  Counts and proportions of subjects 
experiencing AEs will be reported for each treatment group, and Fisher’s exact test will be used 
to compare the treatment groups.  For continuous laboratory analytes, summary statistics will be 
provided by visit, with statistical comparisons among treatment at each visit conducted using a 
MMRM analysis.  Selected safety analysis (eg, hypoglycemia) will be conducted after excluding 
data while on rescue therapy or data after starting another antihyperglycemic medication, which 
is allowed after the permanent discontinuation of investigational product.  Additional details, 
including analysis of AEs of special interest, will be provided in the statistical analysis plan 
(SAP).

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2. Schedule of Activities

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Table GPGO.1.
Schedule of Activities
Screening
Lead-in
Treatment
Follow-
up
Study Visit
1a
2
3
4
5
6
7
8
9
10
11
12
13
ETb
801c
Week of Treatment
-4 or -10
-2
0
4
8
12
16
20
24
32
40
48
52
―
56
Visit Window (days)
±7
±7
―
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
―
±7
Fasting Visit d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Assessments
Informed consent
X
Medical history
X
Demographics
X
Previous diabetes therapy
X
Physical examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dilated Fundoscopic Examinatione
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (2 sitting BP and HR)f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Single 12-lead ECGg
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypoglycemic events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Tests
Pregnancy test (serum)h
X
Pregnancy test (urine) i
X
X
X
X
X
X
Follicle-stimulatinghormone test, estradiolj
X
HbA1c
X
X
X
X
X
X
X
X
X
Fasting Serum Glucose
X
X
X
X
X
X
X
Insulin
X
X
X
X
X
X
C-peptide
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
Chemistry panel
X
X
X
X
X
X
X
X
Lipid panel
X
X
X
X
X
X
X
Urinary albumin/creatinine ratio
X
X
X
X
X
eGFR (CKD-EPI)
X
X
X
X
Lipase, pancreatic amylase
X
X
X
X
X
X
X
X
Calcitonin
X
X
X
X
X
X
X
Review screening lab test results
X

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Schedule of Activities
Screening
Lead-in
Treatment
Follow-
up
Study Visit
1a
2
3
4
5
6
7
8
9
10
11
12
13
ETb
801c
Week of Treatment
-4 or -10
-2
0
4
8
12
16
20
24
32
40
48
52
―
56
Visit Window (days)
±7
±7
―
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
―
±7
Fasting Visit d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Tests
Pharmacogenetics samplek
X
Immunogenicity (ADAs)l
X
X
X
X
X
X
X
X
PK sample for immunogenicitym
X
X
X
X
X
X
X
X
Nonpharmacogenetic samples for storage
X
X
X
X
X
X
X
Patient Education and Supplies
Dispensing of SMBG meter/supplies
X
X
X
X
X
X
X
X
X
X
X
SMBG meter training
X
Weekly fasting SMBG measurementn
X
X
X
X
X
X
X
X
X
X
X
X
7-point SMBG measuremento
X
X
Dispensing of study diary and instruct in use
X
X
X
X
X
X
X
X
X
X
X
X
Study diary review
X
X
X
X
X
X
X
X
X
X
X
X
X
Subcutaneous injection training/ injection site 
inspection/ review of technique
X
Dispensing of investigational product and injection 
supplies
X
X
X
X
X
X
X
X
X
X
Return of used investigational product containers, 
unused study medication and study diary
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of investigational product compliance
X
X
X
X
X
X
X
X
X
X
X
X
Patient-Reported Outcomes
EQ-5D-5L
X
X
X
X
DTSQs
X
DTSQc
X
X
X

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Schedule of Activities
Abbreviations: ADAs = antidrug antibodies; BP = blood pressure; CKD-EPI = Chronic Kidney Disease-Epidemiology; DTSQc = Diabetes Treatment 
Satisfaction Questionnaire (change); DTSQs = Diabetes Treatment Satisfaction Questionnaire (status); ECG = electrocardiogram; eCRF = electronic case 
report form; eGFR = estimated glomerular filtration rate; EQ-5D-5L = European Quality of Life – dimensions; ET = early termination; FBG = fasting blood
glucose; FSH = follicle stimulating hormone; HbA1c = glycated hemoglobin; HR = heart rate; OAM = oral antihyperglycemic medication;
PK = pharmacokinetics; SMBG = self-monitored blood glucose.
a
Visit 1 should be 4 weeks (OAM-naïve) or 10 weeks (at least 8-week OAM washout and extra 2 weeks before Visit 3) prior to Visit 3. For OAM washout, 
patients must complete the 8-week washout period prior to Visit 2.  
b
ET visit is conducted within 14 days after the decision of study discontinuation.
c
Visit 801 should be 4 weeks after Visit 13 or 4 weeks after early termination.  
d
Patients should be reminded to report to the site in a fasting condition, after a period of approximately 8 hours without eating, drinking (except water), or any 
significant physical activity and before taking investigational product.
e
Dilated fundoscopic examination will be performed by an eye-care professional (ophthalmologist or optometrist) for all patients between Visit 2 and Visit 3 to
exclude patients with proliferative diabetic retinopathy and/or diabetic maculopathy or nonproliferative diabetic retinopathy that requires acute treatment. The
results from this examination will be recorded on a specific retinopathy eCRF as a baseline measure of retinopathy. Follow up dilated fundoscopic
examination should be performed when clinically indicated, and, the results recorded on the retinopathy eCRF (See exclusion criterion #11 Section 6.2).
f
Vital sign measurements should be taken before obtaining an ECG tracing and before collection of blood samples for laboratory testing, at visits where 
required. The participant should sit quietly for 5 minutes before vital sign measurements are taken. For each parameter, 2 measurements will be taken using 
the same arm; the recordings should be taken at least 1 minute apart. BP must be taken with an automated blood pressure machine.
g
A single 12-lead ECG will be recorded, after the patient has been lying supine for 5 minutes.  A local ECG will be performed at screening.  The ECGs during 
the treatment period will be electronically transmitted via modem to the centralized ECG vendor designated by Lilly.
h
Serum pregnancy test to be performed by the central laboratory at Visit 1 for women of childbearing potential only.  
i
Urine pregnancy tests can be performed as required at local laboratories.  A urine pregnancy test must be performed at Visit 3 with the result available prior to 
randomization and first injection of investigational product (s) for women of childbearing potential only. Additional pregnancy tests will be performed at 
Visits 6, 9, 11,13, and ET. Pregnancy tests may also be performed at the investigator’s discretion during the study.
j
FSH test performed at Visit 1 for postmenopausal women at least 45 years of age with an intact uterus, not on hormone therapy, and who have had spontaneous 
amenorrhea for more than 6 months and less than 12 months and estradiol levels consistent with a postmenopausal state (FSH ≥40 mIU/mL and estradiol 
<30 pg/mL).
k
The blood sample should be collected at Visit 3 before any investigational product has been given to the patient.
l
In the event of systemic drug hypersensitivity reactions (immediate or nonimmediate), additional blood samples will be collected including ADAs, PK, and 
exploratory immune safety sample.
m PK samples for immunogenicity must be taken prior to drug administration.
n
The patients are required to measure their fasting (pre-breakfast) blood glucose (FBG) concentration at least once a week at approximately the same time of 
day before OAMs have been taken.  By the investigator’s decision, the frequency of measurement of FBG could be increased.
o
7-point SMBG profiles (glucose measurements before breakfast, lunch, dinner, and bedtime and 2-hours after breakfast, lunch, and dinner) should be 
performed on 2 days within the 2 weeks prior to Visit 3 (0 weeks), and Visit 13 (52 weeks).

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3. Introduction
3.1.
Study Rationale
Tirzepatide is a once-weekly (QW) dual glucose-dependent insulinotropic polypeptide 
(GIP)/glucagon like peptide-1 (GLP-1) receptor agonist.  Tirzepatide is a 39-amino acid 
synthetic peptide with agonist activity at both the GIP and GLP-1 receptors.  The structure of 
tirzepatide is based on the GIP sequence and includes a C20 fatty di-acid moiety 
 
.  Tirzepatide is administered by subcutaneous (SC) administration.  Study 
I8F-JE-GPGO (GPGO) is a Phase 3 study designed to assess the safety and efficacy of SC
administered QW tirzepatide (5, 10, and 15 mg), compared to dulaglutide 0.75 mg in patients 
with type 2 diabetes mellitus (T2DM) who have discontinued oral antihyperglycemic medication 
(OAM) monotherapy or are OAM-naïve. The primary endpoint will be to demonstrate that QW 
tirzepatide 5 mg, and/or 10 mg, and/or 15 mg are superior to dulaglutide 0.75 mg as measured by 
the change from baseline in glycated hemoglobin (HbA1c) after 52 weeks of treatment, based on 
Guideline for Clinical Evaluation of Oral Hypoglycemic Agents (Pharmaceutical and Food 
Safety Bureau/Evaluation and Licensing Division Notification No. 0709-1. 2012).
The data from this trial, together with the data from other Phase 3 trials, are expected to provide 
robust benefit/risk profiles of individual doses of tirzepatide, as required by regulatory agencies 
for regulatory submission and marketing approval.
3.2.
Background
Tirzepatide is currently being investigated for its potential use in the treatment of hyperglycemia 
in T2DM. In normal physiology, the incretins GIP and GLP-1 are secreted from enteroendocrine 
cells in the gut following a meal, and these incretins enhance the physiological response to food, 
including sensation of satiety, insulin secretion, and nutrient disposal (Baggio and Drucker 
2007). Patients with T2DM have impaired incretin responses (Baggio and Drucker 2007).  
Incretin-based treatments that are currently available fall within 2 classes: GLP-1 receptor
agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors (Neumiller 2015). Most GLP-1 receptor
agonists have a beneficial effect on glucose metabolism through the enhancement of glucose-
dependent insulin secretion, reduction of inappropriately elevated glucagon levels, and a delay in 
gastric emptying. Dipeptidyl peptidase-4 inhibitors indirectly exert an incretin effect by 
preventing the proteolytic breakdown and inactivation of endogenous agonists of gastric 
inhibitory polypeptide receptor (GIPR) and the GLP-1 receptor. Each class has its therapeutic 
limitations.  For example, dosing of GLP-1 receptor agonists may be limited by gastrointestinal 
(GI) adverse effects and DPP-4 inhibitors are limited in efficacy by the fact that they inhibit 
degradation of endogenous incretins, but even when protected from degradation the endogenous 
incretins do not reach plasma levels similar to what is attained with exogenous incretin analog 
treatment. As a dual receptor agonist, tirzepatide binds both GIP and GLP-1 receptors and 
combines the signaling of each receptor for improved glycemic control. By virtue of being a
GIP/GLP dual receptor agonist, tirzepatide has the potential of reaching higher efficacy in target 
tissues such as the insulin-producing pancreatic ß-cells that express both the GIPR and GLP-1
receptors before reaching its therapeutic limitation. Tirzepatide may furthermore attain 
CCI

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additional efficacy by recruiting metabolically active tissues not targeted by classical GLP-1 
analogs (for example, adipose tissue as indicated by the observation of increased energy 
utilization [Baggio and Drucker 2007]).
Three tirzepatide clinical trials have completed dosing and analysis:  a Phase 1 study, 
Study I8F-MC-GPGA (GPGA), and 2 Phase 2 studies, Study I8F-MC-GPGB (GPGB) and 
I8F-MC-GPGF (GPGF).  One Phase 1 study, Study I8F-JE-GPGC (GPGC) is ongoing in Japan.
The safety and tolerability and pharmacokinetic (PK)/pharmacodynamic (PD) profiles of 
tirzepatide at doses and escalation regimens administered in Study GPGA supported further 
development of tirzepatide for QW dosing in patients with T2DM.
Phase 2 studies have evaluated the efficacy, tolerability, and safety of tirzepatide in patients with 
T2DM with inadequate glycemic control on diet and exercise alone or on a stable dose of 
metformin monotherapy.
Study GPGB, a 26-week Phase 2 study compared the efficacy, tolerability, and safety of 4 doses 
(1, 5, 10, and 15 mg [titrated]), of QW tirzepatide, compared with QW dulaglutide 1.5 mg and QW
placebo in 318 patients with T2DM, with inadequate glycemic control on diet and exercise alone or 
on a stable dose of metformin monotherapy.  Tirzepatide 5 mg, 10 mg, and 15 mg significantly 
lowered HbA1c and body weight in a dose-dependent manner in comparison to placebo.  In addition, 
reductions in HbA1c for the tirzepatide 5-, 10-, and 15-mg doses were greater than with dulaglutide 
1.5 mg QW.  Similar to adverse events (AEs) observed with the GLP-1 receptor agonist class and the 
Phase 1 Study GPGA, most of the tirzepatide AEs were GI-related, consisting mainly of nausea, 
vomiting, and diarrhea, which were mild-to-moderate in intensity and dose-dependent. Serious AEs 
(SAEs) were balanced across the treatment groups and none of the groups in the study reported 
severe hypoglycemia (Frias et al. 2018).
Study GPGF, a 3-month, Phase 2 study, was designed to examine the efficacy, and tolerability of 
3 different titration schemes (longer time intervals between dose escalations and different dose 
escalations), to reach the highest tirzepatide planned doses of 12 mg and 15 mg, compared with 
placebo in patients with T2DM who have inadequate glycemic control with diet and exercise 
alone or with a stable dose of metformin monotherapy. Study GPGF was designed to support the 
evaluation of optimized dosing regimen(s) in Phase 3.
In addition, the safety, tolerability, and PK/PD of tirzepatide are being evaluated in the ongoing 
Study GPGC; a Phase 1, 8-week multiple ascending dose (MAD) study in Japanese patients with 
T2DM. This study involves a comparison of 3 once-weekly SC dose levels of tirzepatide
(2.5-mg to 10-mg titration regimen for Cohort 1; 5-mg to 15-mg titration regimen for Cohort 2;
and 5-mg fixed dose for Cohort 3), or placebo.  The interim safety and tolerability data of Study 
GPGC supports the use of doses up to 15 mg of tirzepatide in Japanese patients.  
3.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of tirzepatide are to be found in the Investigator’s Brochure (IB).

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More detailed information about the known and expected benefits and risks of dulaglutide may 
be found in the Package Insert.

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4.
Objectives and Endpoints
Table GPGO.2 shows the objectives and endpoints of the study.
Table GPGO.2.
Objectives and Endpoints
Objectives
Endpoints
Primary

To demonstrate that once-weekly tirzepatide 5 
mg, and/or 10 mg, and/or 15 mg are superior to 
dulaglutide 0.75 mg in HbA1c change from 
baseline to 52 weeks in patients with T2DM 
who have discontinued OAM monotherapy or 
are OAM-naïve

Mean change in HbA1c from baseline at Week 
52
Secondary
Efficacy

To compare the efficacy of once-weekly 
tirzepatide versus dulaglutide 0.75 mg at 52 
weeks

Mean change in HbA1c 

Proportion of patients who achieve HbA1c 
<7%, ≤6.5%, and <5.7%

Mean change in FSG

Mean change in daily average 7-point SMBG 
profiles

Mean change in body weight

Proportion of patients who achieve weight loss 
of ≥5%, ≥10%, and ≥15% from baseline

Mean change in fasting insulin

Mean change in fasting C-peptide

Mean change in HOMA-2
Safety

To compare the safety of once-weekly 
tirzepatide versus dulaglutide 0.75 mg at 52 
weeks

Incidence of TEAEs

Early discontinuations of investigational 
product due to AEs

Adjudicated all deaths and nonfatal major CV 
events

Adjudicated pancreatic AEs

Serum calcitonin 

Incidence of allergic and hypersensitivity 
reactions 

Incidence of injection site reactions

Incidence of treatment-emergent ADAs to 
tirzepatide

The change in systolic and diastolic blood 
pressure, and heart rate from baseline 

Occurrence of hypoglycemic episodes

Time to initiation of rescue therapy for severe 
persistent hyperglycemia

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Abbreviations:  ADAs = anti-drug antibodies; AE = adverse event; CV = cardiovascular; FSG = fasting serum 
glucose; HbA1c = hemoglobin A1c; OAM  = oral antihyperglycemic medication; SAE = serious adverse event; 
SMBG = self-monitored blood glucose; T2DM = type 2 diabetes mellitus; TEAE = treatment-emergent adverse 
event.

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5. Study Design
5.1.
Overall Design
Study GPGO is a multicenter, randomized, double-blind, parallel, active-controlled, 52-week 
Phase 3 study which will assess the safety and efficacy of tirzepatide (5, 10, and 15 mg),
compared to dulaglutide 0.75 mg in approximately 636 randomized patients with T2DM who 
have discontinued OAM monotherapy or are OAM-naïve.
Study GPGO will consist of 3 periods:  

a 4-week (OAM-naïve) or 10-week (at least 8-week OAM washout) screening/lead-in 
period 

a 52-week treatment period

a 4-week safety follow-up period  
Patients will be randomized in a 1:1:1:1 ratio (tirzepatide 5, 10, 15 mg, and dulaglutide 0.75 mg). 
Patients will be stratified based on baseline HbA1c (≤8.5% and ˃8.5%), baseline BMI (<25 or 
≥25 kg/m2), and washout of antidiabetic medication (yes or no) (see Figure GPGO.1).
Screening procedures and patient training (disease monitoring and management procedures, 
study diaries, and study procedures) will be performed at Visits 1 and 2 (screening and lead-in 
periods).  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 at Visit 2.  
A patient who has been taking OAM monotherapy must complete the 8-week washout period 
prior to Visit 2.
At Visit 2, the screening laboratory results will be reviewed.  For those patients meeting all other 
eligibility requirements, a dilated fundoscopic examination performed by an ophthalmologist or 
optometrist, must be completed between Visit 2 and Visit 3 to ensure patients with proliferative 
diabetic retinopathy, diabetic maculopathy, or nonproliferative diabetic retinopathy that requires 
acute treatment, are identified and excluded.  
At Visit 3, patients will perform all required baseline study procedures (including the collection 
of all baseline laboratory measures and electrocardiograms [ECGs]) and confirm all eligibility 
criteria prior to randomization and prior to taking the first dose of investigational product.  
Following randomization, the patient will inject the first dose of investigational product at the 
study site, according to the dose escalation regimen.  The date and time of the first dose of 
investigational product should be recorded on the electronic case report form (eCRF).  Beginning 
at randomization, all patients will receive investigational product according to the randomized
treatment arm for the duration of the 52-week treatment period.  A safety follow-up visit will 
occur approximately 4 weeks following the last dose of the investigational product.
The starting dose of tirzepatide will be 2.5 mg QW for 4 weeks, followed by an increase to 5 mg 
QW for the duration of the study in the tirzepatide 5-mg arm.  For the 10-mg arm, the starting 
dose of tirzepatide will be 2.5 mg QW for 4 weeks, then the dose will be increased by 2.5 mg 

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every 4 weeks (2.5 to 5 to 7.5 to 10 mg) until the 10-mg dose is reached and maintained for the 
duration of the study.  For the 15-mg arm, the starting dose of tirzepatide will be 2.5 mg QW for 
4 weeks, then the dose will be increased by 2.5 mg every 4 weeks (2.5 to 5 to 7.5 to 10 to 12.5 to 
15 mg) until the 15-mg dose is reached and maintained for the duration of the study.  Patients 
will be permitted to use concomitant medications that they require during the study, except 
certain medications that may interfere with the assessment of efficacy and safety characteristics 
of the study treatments (Section 7.7).  
Investigative site staff will inform patients 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
patient will inform the investigator or a designated site staff member as soon as possible.  Any 
additional medication initiated during the course of the study (including over-the-counter [OTC] 
drugs) must be documented, and the name of the drug(s) and the date(s) of administration must 
be recorded in the patient’s diary and on the “Concomitant Medications” section of the eCRF.  
Antihyperglycemic medications other than investigational products are not allowed at any time 
during the study, except as allowed for rescue therapy, after early investigational product
discontinuation. An additional therapeutic intervention should be considered in patients who 
develop severe, persistent hyperglycemia after randomization at the discretion of investigator in 
accordance with American Diabetes Association/European Association for the Study of Diabetes 
guidance.  Rescue therapy with antihyperglycemic medications, including insulins, will be 
allowed in certain situations after randomization due to severe, persistent hyperglycemia. In this 
case, GLP-1 receptor agonists and DPP-4 inhibitors are not allowed as rescue therapies.
After early discontinuation of study treatment, any antihyperglycemic medications, except for 
GLP-1 receptor agonists may be allowed. Short-term insulin use for up to 14 days is allowed for 
certain clinical situations (eg, elective surgery, during hospitalization, hyperosmolar states). If 
insulin is prescribed as a rescue therapy, it must be differentiated from short-term use of insulin 
therapy for medical emergencies when reported in the eCRF.
All nonstudy medications will be recorded on source documents at all visits.
Study governance considerations are described in detail in Appendix 3.
Figure GPGO.1 illustrates the study design.  

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Abbreviation:  D/E = diet and exercise therapy; OAM = oral antihyperglycemic 
medication; QW = once weekly.
a
At least 8-weeks or more OAM monotherapy washout must be completed prior 
to V2.
Note:  All doses will be administered QW subcutaneously using single-use pens.
Figure GPGO.1.
Illustration of study design for Clinical Protocol I8F-JE-GPGO.
5.2.
Number of Participants
The trial is powered to assess superiority of tirzepatide doses versus dulaglutide 0.75 mg relative 
to mean change from baseline in HbA1c at 52 weeks under the following assumptions: use of 
2-sample t-test to compare treatment means utilizing HbA1c data collected before initiation of 
any rescue medication and premature treatment discontinuation; up to 15% subjects initiating 
any rescue medication or premature treatment discontinuation; at least 0.5%, 0.5% and 0.4% 
superior mean reduction in HbA1c from baseline at 52 weeks for tirzepatide 15, 10, and 5 mg, 
respectively, compared to dulaglutide 0.75 mg; and a common standard deviation (SD) of 1.0%.  
On the basis of these assumptions, randomizing 636 subjects using a 1:1:1:1 randomization ratio 
to tirzepatide 5 mg (159 patients), tirzepatide 10 mg (159 patients), tirzepatide 15 mg 
(159 patients) and dulaglutide 0.75 mg (159 patients) is required to ensure at least 90% power to 
establish superiority of tirzepatide 10 mg and/or 15 mg doses compared to dulaglutide 0.75 mg at 
a 2-sided significance level of 0.025, followed by superiority of tirzepatide 5 mg, compared to 
dulaglutide 0.75 mg, only if superiority of tirzepatide 10 mg or 15 mg is declared.  Tirzepatide
5 mg will be tested at a 2-sided significance level of 0.05 if superiorities of both 10 mg and 
15 mg are declared.  Tirzepatide 5 mg will be tested at a 2-sided significance level of 0.025 if 
2.5 mg
5 mg
2.5 mg
5 mg
7.5 mg
10 mg
2.5 mg
5 mg
7.5 mg 10 mg
12.5 mg
15 mg
Dulaglutide 0.75 mg
Week
0
24
Lead-in
Randomization
Follow-up
2 weeks
Tirzepatide 10 mg QW
52
Dulaglutide 0.75 mg QW
Tirzepatide 5 mg QW
Visit
-10 or -4
-2
1
2
3
5
6
7
8
4
8
12
16
20
40
48
9
10
11
13
801
56
2 weeks
or
8 weeks a
Screening
Washout 
OAM or 
D/E only
Study Period I
Study Period II
Study Period III
52 weeks
4 weeks
End of treatment period
Primary endpoint
32
12
Tirzepatide 15 mg QW
4

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superiority of either 10 mg or 15 mg is declared.  This parallel gatekeeping procedure controls 
family-wise Type 1 error rate at a 2-sided 0.05 level (Dmitrienko et al. 2003).  
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
The primary objective of this trial is to compare the effect of tirzepatide and dulaglutide on 
overall glycemic control over a 52-week treatment period, as measured by change in HbA1c
from baseline, in patients with T2DM who have discontinued OAM monotherapy or are OAM-
naïve.  Tirzepatide will be investigated in this population to better understand its effect on 
glycemic control in patients who remain hyperglycemic despite OAM monotherapy or 
diet/exercise only.  Dulaglutide was selected as an incretin-mimetic comparator because it has a 
similar mechanism of action and it is a marketed compound in Japan for monotherapy of T2DM, 
to determine the comparative benefits and risks of QW tirzepatide.  The doses of tirzepatide
(5, 10, and 15 mg) have been chosen for this study, based on safety and efficacy data from 
Phase 1 and 2 studies.  The dose of dulaglutide (0.75 mg) was selected, based upon the approved 
label in Japan.
The trial design and visit schedule is expected to allow patients to stabilize on their glycemic 
status and to minimize the potential confounding effect of previous OAM therapy during the 
lead-in period, assuring that the treatment groups are balanced at randomization.  The parallel-
group design for treatment comparison was chosen to avoid any interaction between treatments 
that may interfere with the interpretation of the trial outcome.  The frequency of clinic visits 
postrandomization is intended to encourage patients and investigators interaction for frequent 
assessment of study treatments.  
The efficacy measure, HbA1c, was chosen for the primary objective because it is an accepted 
surrogate endpoint for a clinically relevant outcome.  Other measures of blood glucose (BG)
control (eg, daily profiles, variability of BG) will also be assessed.
5.5.
Justification for Dose
Tirzepatide doses of 5 mg, 10 mg, and 15 mg administered SC QW will be evaluated in this 
study.  
These doses and associated escalation schemes were selected based on assessment of safety, 
efficacy (glycemic and weight loss benefit), and GI tolerability data followed by exposure 
response modeling of data in T2DM patients in Phase 1 and 2 studies.  Dosing algorithms 
starting at a low dose of 2.5 mg accompanied by dose escalation of 2.5 mg increments every 
4 weeks would permit adequate time for development of tolerance to GI events and are predicted 
to minimize GI tolerability concerns.
The maximum proposed dose of 15 mg maintains an exposure multiple of 1.6 to 2.4 to the 
no-observed-adverse-effect level doses in 6-month monkey and rat toxicology studies.

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The selected dose and escalation scheme would enable further evaluation of benefit/risk 
considerations for 5-, 10-, and 15-mg doses of tirzepatide.
Based on interim data in Study GPGC, there were no clinically meaningful differences in the PK, 
PD, and safety profile between Japanese patients and non-Japanese patients.  Hence, the doses 
and associated escalation schemes chosen for this Phase 3 study GPGO are the same as that 
chosen for global studies.

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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria.  
Subjects who do not qualify, based upon Visit 1 laboratory measurements, will have an 
opportunity to have 1 additional screening visit with repeat screening laboratory tests.
Type of Patient and Disease Characteristics
[1]
Have been diagnosed with T2DM based on the World Health Organization 
classification at least 8 weeks prior to the screening visit (Visit 1).
Patient Characteristics
[2]
Are OAM-naïve (diet and exercise only) or are taking OAM monotherapy 
except for thiazolidinedione (TZD) and are willing to discontinue this 
medication.  Patients taking OAM monotherapy must complete an 8-week 
washout period prior to Visit 2.
[3]
Have HbA1c meeting the following criteria, as determined by the central 
laboratory at Visit 1 and Visit 2:
[3a] for patients who are OAM-naïve at Visit 1, ≥7.0% to ≤10.0% at both 
Visit 1 and Visit 2.
[3b] for patients who have been taking OAM monotherapy at Visit 1, 
≥6.5% to ≤9.0% at Visit 1, and ≥7.0% to ≤10.0% at Visit 2.
[4]
Are of stable weight (±5%) during the 3 months preceding Visit 1; and agree 
to not initiate an intensive diet and/or exercise program during the study with 
the intent of reducing body weight other than the lifestyle and dietary 
measures for diabetes treatment.
[5]
Have body mass index (BMI) of ≥23 kg/m2 at Visit 1.
[6]
20 years or older at the time of signing informed consent:
[6a] Male patients (see Appendix 6 for more details):
Male patients should be willing to use reliable contraceptive methods 
throughout the study and for at least 3 months after last injection.
[6b] Female patients:
Female patients not of childbearing potential due to surgical sterilization 
(hysterectomy or bilateral oophorectomy or tubal ligation) congenital 
anomaly (ie, Müllerian agenesis) or menopause.

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Women with an intact uterus are deemed postmenopausal if they are 
45 years old, and

have not taken hormones or oral contraceptives within 
the last year and had cessation of menses for at least 1 year.
OR

have had at least 6 months of amenorrhea with follicle-
stimulating hormone (FSH) and estradiol levels consistent 
with a postmenopausal state (FSH ≥40 mIU/mL and estradiol 
<30 pg/mL).
Female patients of child-bearing potential (not surgically sterilized and
between menarche and 1-year postmenopausal) must:

test negative for pregnancy at Visit 1 based on a serum 
pregnancy test.
AND

if sexually active, agree to use 2 forms of effective 
contraception, where at least 1 form is highly effective for the 
duration of the trial and for 30 days, thereafter.

not be breastfeeding.
[7]
In the investigator’s opinion, are well-motivated, capable, and willing to: 
a) perform 7-point self-monitored blood glucose (SMBG) testing.
b) learn how to self-inject treatment (tirzepatide or dulaglutide), 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 investigational product; persons with 
physical limitations who are not able to perform the injections must 
have the assistance of an individual trained to inject the investigational 
product).
c) are willing and able to inject investigational products QW.
d) maintain a study diary, as required, for this protocol.
e) Have a sufficient understanding of the primary language of the country 
such that they will be able to complete the patient questionnaires.
[8]
Have given written informed consent to participate in this study in accordance 
with local regulations and the Ethical Review Board (ERB) governing the 
study site. 
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria:
Medical Conditions
[9]
Have type 1 diabetes mellitus (T1DM).
[10] Had chronic or acute pancreatitis any time prior to study entry (Visit 1).

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[11] Have a history of:

proliferative diabetic retinopathy.
or 

diabetic maculopathy.
or 

nonproliferative diabetic retinopathy that requires acute treatment.  
(A dilated fundoscopic examination, performed by an ophthalmologist or 
optometrist between Visit 2 and Visit 3, is required to confirm eligibility.)
[12] Have a history of severe hypoglycemia and/or hypoglycemia unawareness 
within the 6 months prior to Visit 1.
[13] Have had 1 or more episodes of ketoacidosis or hyperosmolar state/coma 
requiring hospitalization within the 6 months prior to Visit 1.
[14] Have a known clinically significant gastric emptying abnormality (eg, severe 
diabetic gastroparesis or gastric outlet obstruction), have undergone or plan to 
have during the course of the study:  gastric bypass (bariatric) surgery, or 
restrictive bariatric surgery (eg, Lap-Band®), or chronically take drugs that 
directly affect GI motility.
[15] Have any of the following cardiovascular (CV) conditions within 2 months 
prior to Visit 1: acute myocardial infarction, cerebrovascular accident 
(stroke), or hospitalization due to heart failure.
[16] Have a history of New York Heart Association Functional Classification IV 
congestive heart failure.
[17] Have acute or chronic hepatitis, signs and symptoms of any other liver disease 
other than nonalcoholic fatty liver disease (NAFLD), or alanine 
aminotransferase (ALT) level >3.0 times the upper limit of the reference 
range, as determined by the central laboratory at study entry; patients with 
NAFLD are eligible to participate only if their ALT level is ≤3.0 times the 
upper limit of normal (ULN) for the reference range
[18] Have an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2
(or lower than the country-specific threshold for discontinuing metformin 
therapy per local label), calculated by Chronic Kidney Disease-Epidemiology 
(CKD-EPI), as determined by central laboratory at Visit 1.
[19] Have evidence of a significant, uncontrolled endocrine abnormality 
(eg, thyrotoxicosis or adrenal crises), in the opinion of the investigator.
[20] Have family or personal history of medullary thyroid carcinoma or multiple 
endocrine neoplasia syndrome type 2 (MEN-2).
[21] Have a serum calcitonin level of ≥35 ng/L at Visit 1.

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[22] Have evidence of a significant, active autoimmune abnormality (eg, lupus or 
rheumatoid arthritis) that, in the opinion of the investigator, is likely to require 
concurrent treatment with systemic glucocorticoids in the next 12 months.
[23] Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or 
are awaiting an organ transplant.
[24] 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.
[25] Have a history of any other condition (such as known drug or alcohol abuse or 
psychiatric disorder) that, in the opinion of the investigator, may preclude the 
patient from following and completing the protocol.
[26] Have any hematological condition that may interfere with HbA1c 
measurement (eg, hemolytic anemias, sickle-cell disease).
Prior/Concomitant Therapy
[27] Have history of use of any injectable therapy for T2DM treatment 
(pramlintide, GLP-1 receptor agonists, and insulin) except for the use of 
insulin for treatment of gestational diabetes, or short term use (14 days) for 
acute conditions, such as acute illness, hospitalization or elective surgery.
[28] Are receiving chronic (>2 weeks or 14 days) systemic glucocorticoid therapy 
(excluding topical, intra-ocular, intranasal, or inhaled preparations) or have 
received such therapy within 1 month prior to Visit 1 and/or between study 
entry (Visits 1) and randomization (Visit 3).
[29] Have been treated with drugs that promote weight loss (eg, Sanorex®
[mazindol]) within 3 months prior to Visit 1 and/or between study entry 
(Visit 1) and randomization (Visit 3).
Prior/Concurrent Clinical Trial Experience
[30] Are currently enrolled in, or discontinued within the last 30 days from, a 
clinical trial involving any other clinical study involving an investigational 
product or investigational drug or device or off-label use of a drug or device 
(other than the investigational product/device used in this study), or are 
currently enrolled in any other clinical study involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study.
[31] Have participated, within the last 30 days in a clinical trial involving an 
investigational product.  If the previous investigational product has a long 
half-life, 30 days or 5 half-lives (whichever is longer) should have passed.
[32] Have previously completed or withdrawn from this study or any other study 
investigating tirzepatide.

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Other Exclusions
[33] 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.
[34] Are Lilly employees.
6.3.
Lifestyle Restrictions
Per the Schedule of Activities (Section 2), qualified medical staff will provide diabetes 
management counseling, which will include instructions on diet and exercise and education
about the signs, symptoms, and treatment of hypoglycemia, should it occur.  
Patients should continue their usual exercise habits and generally follow a healthy meal plan 
(with consistent meal size and time of day) throughout the course of the study.  Dietary 
counseling may be reviewed throughout the study, as needed.  Per inclusion criterion [4] 
(Section 6.1), patients should not initiate during the study an organized diet and/or exercise 
weight reduction program other than the lifestyle and dietary measures for diabetes treatment.
Study participants should be instructed not to donate blood or blood products during the study.
6.4.
Screen Failures
Subjects who do not qualify, based upon Visit 1 laboratory measurements, will have an 
opportunity to have 1 additional screening visit with repeat screening laboratory tests.

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7. Treatments
7.1.
Treatments Administered
In this study, patients will receive treatment with 1 of the 3 doses of tirzepatide (5 mg, 10 mg,
and 15 mg) or with dulaglutide 0.75 mg, each administered QW as SC injection(s) in patients 
with T2DM.  Patients will receive 1 administration of double-blinded investigational product at a 
time throughout the study.
Table GPGO.3 shows the randomized treatments for the entire treatment period.
Table GPGO.3.
Treatment Regimens
Name of Drug
Dosage
Frequency
Drug Formulation
Route of
Administration
Investigational Compound
Tirzepatide
5 mga
QW
Single-use pen
SC
10 mga
QW
Single-use pen
SC
15 mga
QW
Single-use pen
SC
Comparator
Dulaglutide
0.75 mg
QW
Single-use pen
SC
Abbreviations:  QW = once weekly; SC = subcutaneous.
a
The starting dose of tirzepatide will be 2.5 mg QW for 4 weeks, followed by an increase to 5 mg QW, for the 
duration of the study in the tirzepatide 5-mg arm.  For the 10-mg arm, the starting dose of tirzepatide will be 
2.5 mg QW for 4 weeks, then the dose will be increased by 2.5 mg every 4 weeks (2.5 to 5 to 7.5 to 10 mg) until 
the 10-mg dose is reached and maintained for the duration of the study.  For the 15-mg arm, the starting dose of 
tirzepatide will be 2.5 mg QW for 4 weeks, then the dose will be increased by 2.5 mg every 4 weeks (2.5 to 5 to 
7.5 to 10 to 12.5 to 15 mg) until the 15-mg dose is reached and maintained for the duration of the study.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational product to the patient 

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection,
as well as records of interruptions in investigational product administration

instructing patient to discard all used single-use pens for tirzepatide in a closeable, 
puncture-resistant container and to dispose according to local regulations
7.1.1. Packaging and Labeling
Clinical trial materials will be labeled according to the country’s regulatory requirements.  
Tirzepatide 5 mg, 10 mg, 15 mg, and dulaglutide 0.75 mg will be supplied by Lilly in single-use
pens.
7.1.2. Medical Devices
The manufactured medical devices provided for use in the study are the tirzepatide and 
dulaglutide single-use pens.

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7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to 1 of the double-blinded
treatment arms at Visit 3.  Assignment to treatment arms will be determined by a computer-
generated random sequence using an interactive web-response system (IWRS).  Patients will be 
randomized in a 1:1:1:1 ratio to receive 5 mg tirzepatide, 10 mg tirzepatide, 15 mg tirzepatide, or 
0.75 mg dulaglutide.  The randomization will be stratified by baseline HbA1c (≤8.5% or >8.5%), 
baseline BMI (<25 or ≥25 kg/m2), and washout of antidiabetic medication (yes or no).
7.2.1. Selection and Timing of Doses
Assignment to 1 of the 3 tirzepatide doses or dulaglutide 0.75-mg dose will occur at 
randomization.  There are no restrictions on the time of day each weekly dose is given, but it is 
advisable to administer SC injections on the same day and same time each week.  The actual date 
and time of all dose administrations will be recorded in the subject’s eCRF.  If a dose of 
investigational product, including tirzepatide 5 mg, 10 mg, 15 mg or dulaglutide 0.75 mg, is 
missed, the patient 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 taken at the appropriate time.
7.3.
Blinding
This is a double-blind study.
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomization table and treatment assignments before the study is complete.
Emergency codes, generated by a computer drug-labeling system, will be available to the 
investigator.  These codes, which reveal the patient’s treatment group when opened, may be 
opened during the study ONLY if the patient’s well-being requires knowledge of the patient’s 
treatment assignment.
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computerized drug-labeling system.  This 
option may be used ONLY if the patient’s well-being requires knowledge of the patient’s 
treatment assignment.  All calls resulting in an unblinding event are recorded and reported by the 
IWRS.
If an investigator, site personnel performing assessments, or patient is unblinded, the patient 
must be discontinued from the study.  In cases where there are ethical reasons to have the patient 
remain in the study, the investigator must obtain specific approval from a Lilly clinical research 
physician (CRP)/clinical research scientist (CRS) for the patient to continue in the study.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event.  The 
patient safety must always be the first consideration in making such a determination.  If a 
patient’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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Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dosage Modification
No adjustment in investigational product doses (tirzepatide 5mg, 10 mg, 15 mg, or dulaglutide 
0.75 mg) will be allowed.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or his/her designee is responsible for the following:

Confirming that appropriate temperature conditions have been maintained during 
transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment.

Ensuring that only participants enrolled in the study may receive study treatment 
and only authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff.

Ensuring that the investigator, institution, or the head of the medical institution 
(where applicable) is responsible for study treatment accountability, 
reconciliation, and record maintenance (such as receipt, reconciliation, and final 
disposition records).
The study site must store the investigational product in a locked and secure environment.  Please 
refer to the investigational product label for specific storage conditions.  Patients will receive 
insulated bags with cooling gel packs for use in transporting the investigational product from the 
site to home.
Temperature logs must be maintained to verify correct storage conditions at the investigator site
and throughout the study.  Patients should be instructed to store the investigational product in 
their refrigerator, but are not required to maintain temperature logs. 
Study site staff must regularly assess whether the patient is correctly administering the assigned 
investigational product and storing the investigational product according to the provided 
instructions. 
7.6.
Treatment Compliance
Investigational product compliance will be determined by the following: 

Investigational product administration data will be recorded by the patient and 
reviewed by the investigator at each study visit.

The patients will be instructed to return any unused investigational product and/or 
empty cartons at the next visit to the study site for the purpose of performing drug 
accountability.
In the 3 tirzepatide treatment arms, as well as the dulaglutide arm, treatment compliance overall
is defined as taking at least 75% of the total required doses of investigational product.  Similarly, 

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a patient will be considered significantly noncompliant if he/she is judged by the investigator to 
have intentionally or repeatedly taken more than the prescribed amount of medication.  
In addition to the assessment of a patient’s compliance with the investigational product
administration, other aspects of compliance with the study treatments will be assessed at each 
visit, based on the patient’s adherence to the visit schedule, completion of study diaries, the 
results of home BG monitoring, and any other parameters the investigator considers necessary.
Initially, patients 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. 
7.7.
Concomitant Therapy
Patients will be permitted to use concomitant medications that they require during the study, 
except certain medications that may interfere with the assessment of efficacy and safety 
characteristics of the study treatments. Prohibited medications include following;

Any antihyperglycemic medications, except for concomitant OAMs

Any medications that promote weight loss (eg, Sanorex® [mazindol])

Any chronic (>2 weeks or 14 days) systemic glucocorticoid therapy (excluding topical, 
intra-ocular, intranasal, or inhaled preparations)
Short-term insulin use is allowed for certain clinical situations (eg, elective surgery, during 
hospitalization, hyperosmolar states).  Rescue therapy with antihyperglycemic medications,
including insulins, may be medically indicated in certain situations after randomization, due to 
severe, persistent hyperglycemia (see Appendix 7).  In this case, GLP-1receptor agonists and 
DPP-4 inhibitors are not allowed as rescue therapies.  After early discontinuation of study 
treatment, any antihyperglycemic medications, except for GLP-1receptor agonists may be 
allowed.  If insulin is prescribed as a rescue therapy, it must be differentiated from short-term use 
of insulin therapy for medical emergencies when reported in the eCRF.
Investigative site staff will inform patients 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 
patient will inform the investigator or a designated site staff member as soon as possible.  Any 
additional medication initiated during the course of the study (including OTC drugs) must be 
documented, and the name of the drug and the date(s) of administration must be recorded in the 
patient’s diary and on the “Concomitant Medications” section of the eCRF. 
All nonstudy medications will be recorded on the eCRF at all visits.
Nonstudy medications taken by patients who are screened, but not randomized, will not be 
reported to Lilly, unless an SAE occurs.
7.7.1. Management of Patients with Gastrointestinal Symptoms
In the Phase 2 program, the most commonly reported treatment-emergent adverse events 
(TEAEs) for patients receiving tirzepatide were nausea, vomiting, and diarrhea.  The tirzepatide

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dose escalation scheme has been designed to improve GI tolerability. The escalation period is 
considered to be 24 weeks, which allows 20 weeks to escalate to 15 mg and an additional 
4 weeks to reach steady state. During the dose escalation period, every effort should be made by 
the investigator to be able to escalate and maintain patients on the corresponding investigational 
product dosage.
To mitigate GI symptoms and manage patients with intolerable GI AEs, the investigator should:

Advise patients to eat smaller meals, (eg, splitting 3 daily meals into 4 or more smaller 
meals), and to stop eating when they feel full.

Prescribe symptomatic medication (eg, antiemetic or antidiarrheal medication) per local 
country availability and individual patient needs.  Use of symptomatic medication should 
be captured as concomitant medication in the eCRF.

Temporarily interrupt tirzepatide or dulaglutide (eg, omit 1 dose).  The data related to 
temporary interruption of study treatment should be documented in source documents 
and entered on the eCRF.

After the interruption, restart investigational product with the patient taking medication to 
alleviate his/her GI symptoms (Section 8.1.2).

If intolerable GI symptoms or events persist despite the above measures, the investigator 
may decide to discontinue investigational products. De-escalation of investigational 
products will not be allowed.  Patients who stop the investigational product permanently 
will receive another glucose-lowering intervention and will continue participating in the 
study, according to the protocol, to collect all planned efficacy and safety measurements.  
The new glucose-lowering intervention will be recorded on the eCRF specified for 
collecting antihyperglycemic medications.
In the event that intolerable persistent GI symptoms occur after the escalation period (after 
Week 24), the investigator should take the above measures to keep the patient on study 
treatment before stopping the investigational product permanently and initiate another 
glucose-lowering intervention. 
7.8.
Treatment after the End of the Study
7.8.1. Treatment after Study Completion 
Tirzepatide will not be made available to patients after the conclusion of the study.
7.8.2. Special Treatment Considerations 
An additional therapeutic intervention should be considered for patients with persistent 
hyperglycemia, as described in Appendix 7.

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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of investigational product:

Patient Decision
o
the patient requests to discontinue investigational product.

Discontinuation due to a hepatic event or liver test abnormality.  Patients who are 
discontinued from investigational product due to a hepatic event or liver test abnormality 
should have additional hepatic safety data collected via the eCRF.
Discontinuation of the investigational product for abnormal liver tests should be
considered by the investigator when a patient meets 1 of the following conditions after 
consultation with the Lilly designated medical monitor:
o
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8X 
upper limit of normal (ULN)
o
ALT or AST >5X ULN for more than 2 weeks
o
ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or 
international normalized ratio (INR) >1.5
o
ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
o
alkaline phosphatase (ALP) >3X ULN
o
ALP >2.5X ULN and TBL >2X ULN
o
ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

In addition, patients will be discontinued from the investigational product in the 
following circumstances:
o
If a patient is inadvertently enrolled and it is determined that continued treatment with 
investigational product would not be medically appropriate (see Section 8.1.3)
o
Acute or chronic pancreatitis 
o
If a patient is diagnosed with medullary thyroid carcinoma (MTC) after 
randomization
o
If a patient is diagnosed with an active or untreated malignancy (other than basal or 
squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) 
after randomization
o
Any significant investigational product-related hypersensitivity reaction

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o
Any other TEAE, SAE, or clinically significant laboratory value for which the 
investigator believes that permanent investigational product discontinuation is the 
appropriate measure to be taken
o
If female patient becomes pregnant
o
If a patient is diagnosed with T1DM
o
The patient misses ≥3 consecutive weekly injections of the investigational product
Patients who stop the investigational product permanently may receive another 
antihyperglycemic medication except for GLP-1receptor agonists, and will continue participating 
in the trial, according to the protocol, to collect all planned efficacy and safety measurements.
Patients discontinuing from the investigational product prematurely for any reason should 
complete AE and other follow-up procedures per Section 2 (Schedule of Activities), Section 9.2
(Adverse Events), and Section 9.4 (Safety) of this protocol.
8.1.2. Temporary Interruption of Study Treatment
In certain situations, after randomization, the investigator may need to temporarily interrupt 
investigational product. Every effort should be made by the investigator to maintain patients on 
investigational product and to restart investigational product after any temporary interruption, as 
soon as it is safe to do so.  

If the number of consecutive doses missed is ≤2, the treatment can be restarted at the 
dose defined in the protocol, if the drug was well-tolerated prior to discontinuation. 
If investigational product interruption is due to an AE, the event is to be documented and 
followed according to the procedures in Section 9.2 of this protocol.  The data related to 
temporary interruption of study treatment will be entered on the eCRF.
8.1.3. Discontinuation of Inadvertently Enrolled Patients
If the Sponsor or investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment, unless there 
are extenuating circumstances that make it medically necessary for the patient to continue on 
study treatment.  If the investigator and the Sponsor CRP/CRS agree it is medically appropriate 
to continue, the investigator must obtain documented approval from the Sponsor CRP/CRS to 
allow the inadvertently enrolled patient to continue in the study with or without treatment with 
investigational product. Safety follow up is as outlined in Section 2 (Schedule of Activities), 
Section 9.2 (Adverse Events), and Section 9.4 (Safety) of the protocol.
8.2.
Discontinuation from the Study
In order 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 patients in the study,
irrespective of the following:

adherence to investigational product

adherence to visit schedule

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
missing assessments

investigational product discontinuation due to AE (Section 8.1.1)

development of comorbidities

development of clinical outcomes
The circumstances listed above are not valid reasons for discontinuation from the study. 
Patients will be discontinued in the following circumstances:

enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study

participation in the study needs to be stopped for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and good clinical 
practice (GCP)

if a female patient becomes pregnant 

if a patient is diagnosed with T1DM

investigator decision
o
the investigator decides that the patient should be discontinued from the study

patient decision
o
the patient requests to be withdrawn from the study
Patients who agree to provide information relevant to any trial endpoint at the end of the study 
are not considered to have discontinued from the study.
A patient who withdraws consent and clearly indicates that there will be no further contact of any 
kind with the site will be considered to have discontinued from the study.
Prior to early study discontinuation, the patient will discontinue investigational product and will 
have end-of-study procedures (early termination [ET] visit) performed as shown in the Schedule 
of Activities (Section 2).  During the ET visit, the patient will be prescribed an appropriate 
antihyperglycemic medication and glucose self-monitoring plan. Visit 801 (safety follow-up 
visit) should be performed approximately 4 weeks after the ET visit as the final study visit.
Patients discontinuing from the study prematurely for any reason should complete adverse event 
and other safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events),
and Section 9.4 (Safety) of this protocol.
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Every attempt will be made to minimize 
the number of patients considered lost to follow-up at the end of the study.  Patients will be 
informed about the importance of completing the study and providing updated contact 
information to the study site, when necessary.

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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
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.
9.1.
Efficacy Assessments
9.1.1. Primary Efficacy Assessments
The primary efficacy measurement in this study is mean change in HbA1c from baseline at 
Week 52, as determined by the central laboratory.
9.1.2. Secondary Efficacy Assessments
The following secondary efficacy measures will be evaluated at Week 52:

Mean change in HbA1c 

Proportion of patients who achieve HbA1c <7%, ≤6.5%, and <5.7%

Mean change in fasting serum glucose (FSG)

Mean change in daily average 7-point SMBG profiles

Mean change in body weight

Proportion of patients who achieve weight loss of ≥5%, ≥10%, and ≥15% from baseline

Mean change in fasting insulin

Mean change in fasting C-peptide

Mean change in Updated Homeostasis Model Assessment (HOMA-2)
9.1.2.1.
7-Point Self-Monitored Blood Glucose Profiles
Patients will be asked to perform a 7-point SMBG profile on 2 days during the 2 weeks before 
Visits 3, and 13 (refer to the Schedule of Activities in Section 2). Patients will test and record 
SMBG concentrations in their study diaries before each meal (breakfast, lunch, and dinner),
approximately 2 hours after the start of each meal, and at bedtime. The 7-point SMBG profiles 
will be entered into eCRF and analyzed.
9.1.3. Appropriateness of Assessments
Efficacy and safety assessments included in this study are generally regarded as reliable and 
accurate with respect to the efficacy and safety assessments in individuals and populations with 
T2DM.

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9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate healthcare option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the informed consent form (ICF) is signed, study site personnel will record via eCRF the 
occurrence and nature of each patient’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  In addition, site personnel will 
record any change in the condition(s) and any new conditions as AEs. Investigators should 
record their assessment of the potential relatedness of each AE to study procedure and
investigational product via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to investigational product or a study procedure, taking into account the disease, 
concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs, unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF, clarifying, if possible, the circumstances 
leading to discontinuations of treatment.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

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
a life-threatening experience (ie, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug 
abuse.
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  The SAE reporting to the Sponsor begins after the patient has signed the ICF and has 
received investigational product.  However, if an SAE occurs after signing the ICF, but prior to 
receiving investigational product, the SAE should be reported to the Sponsor as per SAE 
reporting requirements and timelines (see Section 9.2) if it is considered reasonably possibly 
related to study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a Sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.  Patients with a serious hepatic adverse event should have additional data collected 
using the eCRF.
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements, any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient disposition eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs. Lilly has procedures that will be followed for the 
identification, recording and expedited reporting of SUSARs that are consistent with global 
regulations and the associated detailed guidances.

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9.2.2. Adverse Events of Special Interest
9.2.2.1.
Hypoglycemia 
Patients will collect information in the study diary on episodes of hypoglycemia starting from 
Visit 1 until the last study visit.  For that purpose, patients will be trained about signs and 
symptoms of hypoglycemia, how to treat hypoglycemia, and how to collect appropriate 
information for each episode of hypoglycemia in the study according to the Schedule of 
Activities (Section 2).  
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the blood glucose [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 2017 American Diabetes Association position statement on glycemic targets (American 
Diabetes Association 2017):
Glucose Alert Value (Level 1):

Documented symptomatic hypoglycemia is defined as any time a patient feels that 
he/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 patient feels that 
he/she is experiencing symptoms and/or signs associated with hypoglycemia, and has a 
BG level of <54 mg/dL (<3.0 mmol/L).

Documented asymptomatic hypoglycemia is defined as any event not accompanied by 
typical symptoms of hypoglycemia, but with a measured BG <54 mg/dL (<3.0 mmol/L).

Documented unspecified hypoglycemia is defined as any event with no information 
about symptoms of hypoglycemia available, but with a measured BG <54 mg/dL 
(<3.0 mmol/L).
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.

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Nocturnal hypoglycemia:

Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs between 
bedtime and waking.
If a hypoglycemic event meets the criteria of severe, it should be recorded as serious on the AE 
eCRF and reported to Lilly as an SAE.
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).
9.2.2.2.
Severe, Persistent Hyperglycemia
Add-on glycemic rescue therapy will be allowed for patients who meet any of the following 
prespecified criteria for severe, persistent hyperglycemia.  In this case, the investigator 
determines if a new intervention is warranted, after noncompliance with the assigned therapeutic 
regimen is ruled out as the reason for hyperglycemia.  Patients should continue administering 
assigned investigational products .  The criteria are as follows: 
a) Blood glucose concentration measured by weekly 1-point SMBG before breakfast
>270 mg/dL (>15.0 mmol/L) over at least a consecutive 2-week period any time during 
the first 8 weeks postrandomization
OR 
b) Blood glucose concentration measured by weekly 1-point SMBG before breakfast
>240 mg/dL (>13.3 mmol/L) over at least a consecutive 2-week period at any time 9-
16 weeks postrandomization 
OR 
c) Blood glucose concentration measured by weekly 1-point SMBG before breakfast
>200 mg/dL (>11.1 mmol/L) over a consecutive 2-week period at any time beyond the 
first 16 weeks postrandomization 
OR 
d) HbA1c ≥8.5% (69 mmol/mol) at 24 weeks, with inadequate response to the existing 
regimen, defined as improvement in HbA1c over the last 3 months (Week 12 to 
Week 24) that is <0.3%.  
Investigators should first confirm that the patient is fully compliant with the assigned therapeutic 
regimen and that he/she does not have an acute condition that is raising his/her BG.  For patients 
who meet criteria for severe persistent hyperglycemia, the investigator will decide, in 
consultation with the patient, on an appropriate antihyperglycemic medication (rescue therapy). 
Investigators should follow national standards of care for diabetes management in respective 
participating countries or the American Diabetes Association/ European Association for the 
Study of Diabetes guidance (Inzucchi et al. 2015). Antihyperglycemic medications, including 
insulin, will be allowed as the rescue intervention. In this case, GLP-1 receptor agonists and 

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DPP-4 inhibitors are not allowed as rescue therapies. Patients who receive a new intervention 
should also continue administering investigational products for the remaining period in the trial.
9.2.2.3.
Pancreatitis
Acute pancreatitis is defined as an AE of interest in all trials with tirzepatide, including this trial.  
Acute pancreatitis is an acute inflammatory process of the pancreas that may also involve 
peripancreatic tissues and/or remote organ systems (Banks and Freeman 2006).  The diagnosis of 
acute pancreatitis requires 2 of the following 3 features:

abdominal pain, characteristic of acute pancreatitis (generally located in the 
epigastrium and radiates to the back in approximately one-half of the cases 
[Banks and Freeman 2006; Koizumi et al. 2006]; the pain is often associated with 
nausea and vomiting)

serum amylase (total and/or pancreatic) and/or lipase ≥3×ULN

characteristic findings of acute pancreatitis on computed tomography (CT) scan or 
magnetic resonance imaging (MRI).
If acute pancreatitis is suspected, appropriate laboratory tests (including levels of pancreatic 
amylase and lipase) should be obtained via the central laboratory (and locally, if needed).  
Imaging studies, such as abdominal CT scan with or without contrast, MRI, or gallbladder 
ultrasound, should be performed.  If laboratory values and/or abdominal imaging support the 
diagnosis of acute pancreatitis, the patient must discontinue therapy with tirzepatide, but will 
continue in the study on another antihyperglycemic medication.  The most appropriate diabetes 
therapeutic regimen will be decided by the investigator, based on the patient’s clinical status.  
A review of the patient’s concomitant medications should be conducted to assess any potential 
causal relationship with pancreatitis.
Each AE of pancreatitis must be reported.  If typical signs and/or symptoms of pancreatitis are 
present and confirmed by laboratory values (lipase or amylase [total and/or pancreatic]) and 
imaging studies, the event must be reported as an SAE.  For a potential case that does not meet 
all of these criteria, it is up to the investigator to determine the seriousness of the case (AE or 
SAE) and the relatedness of the event to investigational products.
Each patient will have measurements of pancreatic amylase and lipase (assessed at the central 
laboratory) as shown on the Schedule of Activities (Section 2) to assess the effects of the 
investigational doses of tirzepatide on pancreatic enzyme levels.  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; Steinberg et al. 2017b).  Thus, further 
diagnostic follow-up of cases of asymptomatic pancreatic hyperenzymemia (lipase and/or 
pancreatic lipase ≥3X ULN) is not mandated, but may be performed, based on the investigator’s 
clinical judgment and assessment of the patient’s overall clinical condition.  Only cases of 
pancreatic hyperenzymemia that undergo additional diagnostic follow-up and/or are 
accompanied by symptoms suggestive of pancreatitis will be submitted for adjudication.
All suspected cases of acute or chronic pancreatitis will be adjudicated by an independent 
clinical endpoint committee (CEC). In addition, AEs of severe or serious abdominal pain of 
unknown etiology will also be submitted to the adjudication committee to assess for possible 

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pancreatitis or other pancreatic disease. Relevant data from patients with acute or chronic 
pancreatitis and those with severe or serious abdominal pain will be entered into a specifically 
designed eCRF page by study site. The adjudication committee representative will enter the 
results of adjudication in a corresponding eCRF page.
9.2.2.4.
Thyroid Malignancies and C-Cell Hyperplasia
Individuals with personal or family history of MTC and/or MEN-2 will be excluded from the 
study.  The assessment of thyroid safety during the trial will include reporting of any case of 
thyroid malignancy, including MTC, papillary carcinoma, and measurements of calcitonin. This 
data will be captured in specific eCRFs. The purpose of calcitonin measurements is to assess the 
potential of tirzepatide to affect thyroid C-cell function, which may indicate development of C-
cell hyperplasia and neoplasms. 
Tirzepatide should be discontinued (after first confirming the value) if postrandomization 
calcitonin value is ≥35 ng/mL and has increased at least 50% over baseline.  A consultation with 
a thyroid specialist (if not available, an endocrinologist) should be obtained. If the increased 
calcitonin value (≥35 ng/mL and increases by ≥50%, compared with baseline) is observed in a 
patient who has administered a medication that is known to increase serum calcitonin, this 
medication should be stopped and calcitonin levels should be measured after an appropriate 
washout period. If the confirmed calcitonin value is <35 ng/mL, tirzepatide should be restarted 
when it is safe to do so.
9.2.2.5.
Major Adverse Cardiovascular Events
Deaths and nonfatal CV AEs will be adjudicated by a committee of physicians, external to Lilly,
with cardiology expertise.  The nonfatal CV AEs to be adjudicated include:  myocardial 
infarction (MI); 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.  Relevant data from patients who experienced death or nonfatal CV AEs will be entered 
into a specifically designed eCRF page by study site.
9.2.2.6.
Supraventricular Arrhythmias and Cardiac Conduction Disorders
Treatment-emergent cardiac conduction disorders will be further evaluated. Patients who 
develop any event from this group of disorders should undergo an ECG, which should be 
submitted to the central reading center. Additional diagnostic tests to determine the 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 9.2.1, must be reported as 
SAEs. 
9.2.2.7.
Hypersensitivity Events
All allergic or hypersensitivity reactions will be reported by the investigator as either AEs or, if 
any serious criterion is met, as SAEs.  Additional data, such as type of reaction and treatment 
received, will be collected on any AEs or SAEs that the investigator deems related to 
investigational product(s), via an eCRF created for this purpose.  Additional samples should also 
be collected, as outlined in Section 9.4.4.  Investigational product should be temporarily 

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interrupted in any individual suspected of having a severe or serious allergic reaction to 
investigational product.  Investigational product may be restarted when/if it is safe to do so, in 
the opinion of the investigator.  If investigational product is permanently discontinued, the 
patient will receive another glucose-lowering treatment, judged by the investigator to be
appropriate, based on the patient’s clinical status, and will continue in the trial to collect all 
planed efficacy and safety measurements.
9.2.2.7.1. Injection Site Reactions
Injection site reactions will be collected on the eCRF, separate from the hypersensitivity reaction 
eCRF. At the time of AE occurrence, samples will be collected for measurement of tirzepatide
anti-drug antibodies (ADAs) and tirzepatide concentration.
9.2.2.7.2. Anti-Drug Antibodies
The occurrence of ADA formation will be assessed, as outlined in Section 9.4.4.
9.2.2.8.
Diabetic Retinopathy Complications
Dilated retinal fundoscopic examination will be performed by an eye-care professional 
(ophthalmologist or optometrist) for all patients between Visit 2 and Visit 3 to exclude patients 
with proliferative retinopathy and/or maculopathy.  The results from this examination will be 
recorded on a specific retinopathy eCRF as a baseline measure of retinopathy.  
A follow-up, dilated fundoscopic examination should be performed when clinically indicated by 
any AE suspected of worsening retinopathy, and the findings should be recorded on the 
retinopathy eCRF.  
9.2.2.9.
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 9.4.5.1 and Appendix 4.
9.2.2.10. Severe Gastrointestinal Adverse Events
Tirzepatide may cause severe GI AEs, such as nausea, vomiting, and diarrhea.  Information 
about severe GI AEs, as well as antiemetic/antidiarrheal use, will be collected in the eCRF.  For 
detailed information concerning the management of GI AEs, please refer to Section 7.7.1.
9.2.2.11. Acute Renal Events
Renal safety will be assessed based on repeated renal functional assessment as well as 
assessment of AEs suggestive of acute or worsening of chronic renal failure.  Gastrointestinal
AEs have been reported with tirzepatide, including nausea, diarrhea, and vomiting. This is 
consistent with other GLP-1 receptor agonists (Aroda and Ratner 2011). The events may lead to 
dehydration, which could cause a deterioration in renal function, including acute renal failure.
Patients should be advised to notify investigators in case of severe nausea, frequent vomiting, or 
symptoms of dehydration.
9.2.2.12. Amputation/Peripheral Revascularization
All cases of amputation and peripheral revascularization should be reported as an AE.

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9.2.2.13. Major Depressive Disorder/Suicidal Ideation 
The prevalence of depressive symptoms and disorders is increased in patients with T1DM or 
T2DM (American Diabetes Association 2017).  Any AE of major depressive disorder or suicidal 
ideation should be reported. 
9.2.2.14. Individual Clinical Events Adjudication 

All AEs of acute or chronic pancreatitis, as well as cases of pancreatic hyperenzymemia 
only, that undergo additional diagnostic follow-up and/or are accompanied by symptoms 
suggestive of pancreatitis will be adjudicated by an independent committee of expert 
physicians.  

Deaths and nonfatal CV AEs will be adjudicated by a committee of physicians, external 
to Lilly, with cardiology expertise.  The nonfatal CV AEs to be adjudicated include:  MI; 
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.
9.2.3. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if they have complaints
or problems with the investigational product or drug delivery system, so that the situation can be 
assessed.
9.3.
Treatment of Overdose
Investigational product overdose (more than the specified number of injections) will be reported 
as an AE.  In the event of overdose, refer to the IB for tirzepatide and to the package insert for 
dulaglutide.
9.4.
Safety
9.4.1. Electrocardiograms
For each patient, ECGs should be collected, according to the Schedule of Activities (Section 2).  
Electrocardiograms should be recorded according to the study-specific recommendations 
included in the Manual of Operations for the study.  
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 patient is still present, for immediate subject management, should any clinically 
relevant findings be identified.  Any clinically significant findings from ECGs that result in a 
diagnosis and that occur after the patient receives the first dose of the investigational treatment 
should be reported to Lilly or its designee as an AE via the eCRF.

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All digital ECGs will be obtained using centrally provided ECG machines and will be 
electronically transmitted to a designated central ECG laboratory except for the screening ECG 
which will be performed by a local laboratory.  The central ECG laboratory will perform a basic 
quality control check (eg, demographics and study details) and then store the ECGs in a 
database.  At a future time, the stored ECG data may be overread by a cardiologist at the central 
ECG laboratory for further evaluation of machine-read measurements or to meet regulatory 
requirements.  The machine-read ECG intervals and heart rate may be used for data analysis and 
report-writing purposes, unless a cardiologist overreading of the ECGs is conducted prior to 
completion of the final study report (in which case, the overread data would be used).  
9.4.2. Vital Signs
For each patient, vital signs measurements (systolic blood pressure, diastolic blood pressure, and 
heart rate), height, weight, and waist circumference, should be conducted according to the 
Schedule of Activities (Section 2) and following the study-specific recommendations included in 
the Manual of Operations for the study.
Any clinically significant findings from vital signs measurement that result in a diagnosis and 
that occur after the patient receives the first dose of study treatment should be reported to Lilly or 
its designee as an AE via the eCRF.
9.4.3. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). 
With the exception of laboratory test results that may unblind the study, Lilly or its designee will 
provide the investigator with the results of laboratory tests analyzed by a central vendor, if a 
central vendor is used for the clinical trial.  
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of investigational product should be reported to Lilly or its 
designee as an AE via eCRF.
9.4.4. 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 Schedule of 
Activities (Section 2).  
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected to determine antibody production against tirzepatide.  To interpret the results of 
immunogenicity, a PK sample will be collected at the same time points as the immunogenicity 
sample. All samples for immunogenicity should be taken predose, when applicable and possible. 
In the event of drug hypersensitivity reactions (immediate or nonimmediate), additional samples 
will be collected (including ADAs, PK, and, exploratory immune safety sample), as close to the 
onset of the event as possible, at the resolution of the event, and 30 days following the event.  
Instructions for the collection and handling of blood samples will be provided by the Sponsor.  

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The actual date and time (24-hour clock time) of each sampling will be recorded.  
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of the tirzepatide at a laboratory approved by the Sponsor.  Samples collected at Visit 801 will 
assess immunogenicity at washout of tirzepatide (5 half-lives post-end of treatment).
Treatment-emergent ADAs are defined in Section 10.3.5.  
Samples with tirzepatide ADAs detected will be titered and evaluated for their ability to 
neutralize the activity of assigned treatment (tirzepatide-neutralizing antibodies).  Samples with 
tirzepatide ADAs detected will also be tested for cross-reactive binding to native GIP and 
GLP-1, and, if such is detected, then, for neutralizing antibodies against native GIP and GLP-1, 
respectively.
Samples will be retained for a maximum of 15 years after the last patient 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. Immunogenicity information that would unblind the 
study will not be reported to investigative sites or blinded personnel (until the study has been 
unblinded).
9.4.5. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
9.4.5.1.
Hepatic Safety Monitoring
If a study patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X ULN,
liver testing (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, ALP, 
TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator and in 
consultation with the study medical monitor. Monitoring of ALT, AST, TBL, and ALP should 
continue until levels normalize or return to approximate baseline levels. 
Hepatic Safety Data Collection
Additional safety data should be collected via the eCRF if 1 or more of the following conditions 
occur: 

elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥ 2X ULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests

patient discontinued from treatment due to a hepatic event or abnormality of 
liver tests

hepatic event considered to be a SAE

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9.5.
Pharmacokinetics
A PK sample will be collected at the same time points as the immunogenicity sample per the 
Study Schedule of Activities (Section 2).  All samples for PK assessment should be taken 
predose.  PK samples will be collected from patients allocated to the dulaglutide arm, but the 
samples will not be assayed for dulaglutide concentration.
The date and time of SC injection must be recorded on the eCRF from the study diaries.
The date and time at which each sample was drawn must be recorded on the laboratory 
requisition form. 
Concentrations of tirzepatide will be assayed using a validated liquid chromatography mass 
spectrometry (LC/MS) method.
Bioanalytical samples collected to measure tirzepatide concentrations will be retained for a 
maximum of 1 year following last patient visit for the study.
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel (until the study has been unblinded).
9.6.
Pharmacodynamics
Pharmacodynamics will not be evaluated in this study. 
9.7.
Pharmacogenomics
9.7.1. Whole Blood Samples for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in the 
Schedule of Activities (Section 2) 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 T2DM.  Assessment of variable response 
may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigator site personnel.  
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last patient visit for the study, or for a shorter period if local regulations and/or 
ERBs/investigational review boards (IRBs) impose shorter time limits. This retention period 
enables use of new technologies, response to regulatory questions, and investigation of variable 
response that may not be observed until later in the development of tirzepatide or after 
tirzepatide become(s) commercially available.
Molecular technologies are expected to improve during the 15-year storage period and, therefore,
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, and candidate gene studies.  Regardless of 

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technology utilized, genotyping data generated will be used only for the specific research scope 
described in this section.
9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of patient response (including safety), and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), proteins, lipids, and other cellular elements.
Serum and plasma samples for nonpharmacogenetic biomarker research will be collected at the 
times specified in the Schedule of Activities (Section 2), where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
tirzepatide, pathways associated with T2DM, mechanism of action of tirzepatide, and/or research 
method or in validating diagnostic tools or assay(s) related to T2DM.  
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigator site personnel.  
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last patient 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.  Any 
samples remaining after 15 years will be destroyed. 
9.9.
Health Economics
The following questionnaires will be completed by the patients at specific clinic visits, according 
to the Schedule of Events (Section 2).  At these visits, the questionnaires should be completed 
before the patient has discussed his/her medical condition or progress in the study with the 
investigator and/or site staff, and before any other study procedures if the patient is not adversely 
affected by his/her fasting condition.
9.9.1. European Quality of Life (EQ-5D-5L)
Generic health-related quality of life (HR-QoL) will be assessed using the European Quality of 
Life – 5 Dimensions – 5 Level (EQ-5D-5L) (EuroQoL Group 2015).  The EQ-5D-5L is a 
standardized 5-item instrument for use as a measure of health outcome.  It provides a simple 
descriptive profile and a single index value for health status that can be used in the clinical and 
economic evaluation of healthcare, as well as population health surveys.  The EQ-5D-5L 
comprises 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression).  The 5L version, introduced in 2005, scores each dimension at 5 levels (no 
problems, slight problems, moderate problems, severe problems, unable to perform/extreme 
problems), for a total of 3125 possible health states.  In addition to the health profile, a single 
health state index value can be derived based on a formula that attaches weights to each of the 

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levels in each dimension.  This index value ranges between less than 0 (where 0 is a health state 
equivalent to death; negative values are valued as worse than dead) to 1 (perfect health).  In 
addition, the EQ Visual Analog Scale (VAS) records the respondent’s self-rated health status on 
a vertical graduated (0 to 100) VAS.  In conjunction with the health state data, it provides a 
composite picture of the respondent’s health status.  
The EQ-5D-5L is used worldwide and is available in more than 170 different languages.  Details 
on the instrument, and on scoring, organizing, and presenting the data collected can be found in 
the EQ-5D-5L User Guide (EuroQoL Group 2015).
9.9.2. Diabetes Treatment Satisfaction Questionnaire (DTSQ)
The status (s) and change (c) versions of the Diabetes Treatment Satisfaction Questionnaire 
(DTSQ) will be used during the study to assess the patients’ satisfaction with their diabetes 
treatment and the perceived frequency of hyperglycemia and hypoglycemia.  The questionnaire 
contains 8 items (Bradley 1994).  Each item is rated on a 7-point Likert scale.  Six items (1, and 
4 through 8) are summed to produce a measure of treatment satisfaction ranging from 0 “very 
dissatisfied” to 6 “very satisfied.”  The remaining 2 items (2 and 3) are treated individually.  
Item 2 measures the perceived frequency of hyperglycemia on a scale ranging from 0 “none of 
the time” to 6 “most of the time,” and Item 3 measures the perceived frequency of hypoglycemia 
on the same scale.  The change version has the same 8 items as the status version with a small 
alteration of the wording of Item 7. The DTSQc response options differ from those of the 
DTSQs to produce measures of relative change rather than absolute satisfaction.  

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10. Statistical Considerations
10.1. Sample Size Determination
The trial is powered to assess superiority of tirzepatide doses (5 mg, and/or 10 mg, and/or 15 
mg), versus dulaglutide 0.75 mg, relative to mean change from baseline in HbA1c at 52 weeks, 
under the following assumptions:  use of 2 sample t-test to compare treatment means utilizing 
HbA1c data collected before initiation of any rescue medication and premature treatment 
discontinuation; up to 15% subjects initiating any rescue medication or premature treatment 
discontinuation; at least 0.5%, 0.5%, and 0.4% superior mean reduction in HbA1c from baseline 
at 52 weeks for tirzepatide 15, 10, and 5 mg, respectively, compared to dulaglutide 0.75 mg; and 
a common standard deviation (SD) of 1.0%.  On the basis of these assumptions, randomizing 636 
subjects using a 1:1:1:1 randomization ratio to tirzepatide 5 mg (159 patients), tirzepatide 10 mg 
(159 patients), tirzepatide 15 mg (159 patients), and dulaglutide 0.75 mg (159 patients) is 
required to ensure at least 90% power to establish superiority of tirzepatide 10-mg and/or 15-mg 
doses, compared to dulaglutide 0.75 mg at a 2-sided significance level of 0.025, followed by 
superiority of tirzepatide 5 mg, compared to dulaglutide 0.75 mg only if superiority of tirzepatide 
10 mg or 15 mg is declared.  Tirzepatide 5 mg will be tested at a 2-sided significance level of 
0.05 if superiorities of both 10 mg and 15 mg are declared.  Tirzepatide 5 mg will be tested at a 
2-sided significance level of 0.025 if superiority of either 10 mg or 15 mg is declared.   This 
parallel gatekeeping procedure controls family-wise Type 1 error rate at a 2-sided 0.05 level 
(Dmitrienko et al. 2003).  
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined:
Analysis Set
Description
Screened patients
All participants who sign informed consent
Randomized patients
All patients who are randomly assigned a treatment arm
Modified intention-to-treat (mITT) set
All randomly assigned participants who are exposed to at least 1 dose of 
investigational product.
Efficacy analysis set (EAS)
Data obtained during Study Period II from mITT, excluding data after 
initiating rescue antihyperglycemic medication or stopping investigational 
product (last dose date + 7 days). In the event of a treatment error, 
participants will be analyzed according to the treatment they were 
randomized.
Full analysis set (FAS)
Data obtained during Study Period II from mITT, regardless of adherence 
to investigational product or initiation of rescue antihyperglycemic 
medication. 
Safety analysis set (SAS)
Data obtained during both Study Period II and III from mITT, regardless 
of adherence to investigational product or initiation of rescue 
antihyperglycemic medication.

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10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.  Any change to 
the data analysis methods described in the protocol will require an amendment ONLY if it 
changes a principal feature of the protocol.  Any other change to the data analysis methods 
described in the protocol, and the justification for making the change, will be described in the 
statistical analysis plan (SAP) or the clinical study report (CSR). Additional exploratory data 
analyses may be conducted, as deemed appropriate.
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and the confidence interval (CI) will be calculated at 95%, 2-sided.  In statistical 
summaries and analyses, patients will be analyzed as randomized.
Efficacy and safety will be assessed using the modified intention-to-treat (mITT) population, 
which consists of all randomly assigned participants who are exposed to at least 1 dose of 
investigational product.  The primary efficacy of tirzepatide versus dulaglutide 0.75 at 52 weeks 
will be guided by the “efficacy” estimand using the efficacy analysis set (EAS).  The “efficacy” 
estimand represents efficacy prior to discontinuation of investigational product without 
confounding effects of rescue therapy for persistent severe hyperglycemia.
Summary statistics for continuous measures will include sample size, mean, SD, median, 
minimum, and maximum.  The analysis model for comparisons among treatment arms relative to 
continuous measurements assessed over time will be an MMRM, with terms: treatment, visit, 
and treatment-by-visit interaction as stratification factors; baseline HbA1c (≤8.5% or >8.5%), 
baseline BMI group (<25 or ≥25 kg/m2), and washout of antidiabetic medication (yes or no) as 
fixed effects; 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.
Summary statistics for categorical measures (including categorized continuous measures) will 
include sample size, frequency, and percentages.  Fisher’s exact test will be used to examine the 
treatment difference in categorical outcomes. Logistic regression may be used to examine the 
treatment difference in binary efficacy outcomes.  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. 
A multiplicity adjustment will be applied to control the overall type I error rate of primary 
efficacy endpoint assessments controlling at a 2-sided 0.05 level.  
Other statistical methods may be used, as appropriate, and details will be documented in the 
SAP.

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10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
Frequency counts and percentages of all patients screened, randomized, and receiving at least 
1 dose of investigational product will be presented by treatment groups.  A listing of randomized 
patients not receiving investigational product will be provided.  Of the patients in the mITT set, 
frequency counts and percentages of patients completing the study, prematurely discontinuing 
the study, including reason for premature discontinuation, will be presented by treatment groups.  
A Kaplan-Meier analysis of time from randomization to premature discontinuation from study,
by treatment group, will be provided.  Patients with important protocol deviations will be listed.
10.3.2.2. Patient Characteristics
Demographic, medical history, and preexisting conditions will be descriptively summarized, by 
treatment groups, using the mITT set.
10.3.2.3. Concomitant Therapy 
Concomitant medications, including previous therapy for diabetes, will be summarized by 
Anatomical Therapeutic Chemical classification and treatment arm, using the mITT set.  In 
particular, the time to initiation of rescue therapy for severe, persistent hyperglycemia will be 
analyzed as an exploratory safety endpoint.  
10.3.2.4. Treatment Compliance 
Treatment compliance, overall, is defined as taking at least 75% of the total required injections 
of investigational product.  Frequency counts and percentages of patients compliant to 
investigational product will be summarized by treatment arms and visits, using the mITT set. 
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary efficacy measure is HbA1c change from baseline at 52 weeks, and the primary 
comparison is to compare tirzepatide doses versus dulaglutide 0.75 mg. Superiority of each 
tirzepatide dose will be demonstrated if the upper limit of the 97.5% or 95% CI for the difference 
between tirzepatide dose and dulaglutide 0.75 mg is below 0.  
The statistical analyses for the primary efficacy measure of HbA1c change from baseline at 
52 weeks will examine the following 3 hypotheses:

H1: the 15-mg dose of tirzepatide is superior to dulaglutide 0.75 mg

H2: the 10-mg dose of tirzepatide is superior to dulaglutide 0.75 mg

H3: the 5-mg dose of tirzepatide is superior to dulaglutide 0.75 mg
H1 and H2 will be tested at a 2-sided significance level of 0.025, followed by testing H3 only if 
H1 and/or H2 are declared.  H3 will be tested at a 2-sided significance level of 0.05 if H1 and H2
are declared.  H3 will be tested at a 2-sided significance level of 0.025 if either H1 or H2 is 
declared. This parallel gatekeeping procedure controls family-wise Type 1 error rate at a 2-sided 
0.05 level (Dmitrienko et al. 2003).

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The primary efficacy assessment, guided by the “efficacy” estimand, will use the EAS, which 
consists of data obtained before the initiation of any rescue therapy and before premature 
treatment discontinuation.  The analysis model for change from baseline in HbA1c assessed over 
time up to the 52-week visit will be an MMRM, with terms: treatment, visit, and treatment-by-
visit interaction as stratification factors; baseline BMI group (<25 or ≥25 kg/m2) and washout of 
antidiabetic medication (yes or no) as fixed effects; and baseline HbA1c as a covariate.  An 
unstructured covariance structure will model the relationship of within-patient errors.  
A robustness of the primary efficacy assessment, guided by the “treatment-regimen” estimand, 
will be conducted.  This assessment will analyze change from baseline in HbA1c to the 52-week 
visit using an analysis of covariance (ANCOVA) with terms, treatment, baseline BMI group 
(<25 or ≥25 kg/m2), washout of antidiabetic medication (yes or no), and baseline HbA1c as a 
covariate.  The ANCOVA analysis will be conducted using the Full Analysis Set (FAS) at the
52-week visit, which consists of all available changes from baseline in HbA1c data at the 
52-week visit, irrespective of whether they were obtained while the participants had discontinued 
the investigational product or whether the participant had been given rescue medication.  
Additionally, data for subjects with missing values will be imputed, based on observed data in 
the same treatment arm from subjects who had their efficacy measure at the Week 52 visit 
assessed after early discontinuation of investigational product and/or initiation of rescue 
medication (retrieved dropouts).  Analysis will be conducted with multiple imputations and 
statistical inference over multiple imputations will be guided by the method proposed by 
(Rubin 1987).  No multiplicity adjustments will be made for conducting 2 efficacy assessments 
for different estimands.
10.3.3.2. Secondary Analyses
Analysis of change from baseline in body weight at the 52-week visit will be conducted in a 
manner similar to the primary efficacy analyses with change in weight from baseline as the 
response variable and baseline body weight as a covariate.  
Comparisons among treatments relative to the proportion of patients achieving HbA1c target 
value of <7.0% (53 mmol/mol), ≤6.5%, and <5.7% at the 52-week visit will be conducted using 
a logistic regression analysis with terms: treatment, baseline BMI group (<25 or ≥25 kg/m2),
washout of antidiabetic medication (yes or no), and baseline HbA1c as a covariate.  In the 
analysis of patients achieving HbA1c target value relative to the “efficacy” estimand, subjects 
with missing values at the 52-week visit will be excluded.  
10.3.3.3. Tertiary/Exploratory Analyses 
All exploratory efficacy analyses will be guided by the “efficacy” estimand and will be 
conducted using the EAS.  Details will be provided in the SAP.
10.3.4. Safety Analyses
Unless specified otherwise, safety assessments will be guided by an estimand comparing safety 
of tirzepatide doses with dulaglutide 0.75 mg, irrespective of adherence to investigational 
product or initiation of rescue therapy. Thus, the safety analysis will be conducted using the 

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Safety Analysis Set (SAS).  A selected safety analysis will be conducted after excluding data on 
rescue therapy.
Adverse events will be coded from the actual term using the Medical Dictionary for Regulatory 
Activities (MedDRA) and reported with preferred terms and system organ class.  Selected 
notable AEs of interest may be reported using high-level terms or Standardized MedDRA 
Queries.  Summary statistics will be provided for incidence of TEAEs, SAEs, study 
discontinuation due to AEs, investigational product discontinuation due to AEs, and deaths.  
Counts and proportions of subjects experiencing AEs will be reported for each treatment group, 
and Fisher’s exact test will be used to compare the treatment groups.  
A selected safety analysis (eg, hypoglycemia) will be conducted after excluding data while on 
rescue therapy or data after starting another antihyperglycemic medication, which is allowed 
after the permanent discontinuation of investigational product.  Additional details, including 
analysis of AEs of special interest, will be provided in the SAP.
10.3.4.1. Hypoglycemic Events
Incidence of documented symptomatic hypoglycemia events and severe hypoglycemia in each 
category (either total or nocturnal) will be compared between tirzepatide doses and dulaglutide 
0.75 mg, using negative binomial regression analysis.  Summaries and analysis will be repeated,
excluding data following initiation of rescue antihyperglycemic medication.
10.3.4.2. Gastrointestinal Events
Summaries and analyses for incidence and severity of nausea, vomiting, and diarrhea will be 
provided by each treatment.  
10.3.4.3. Adjudicated Cardiovascular Events
Listing of deaths, myocardial infarctions, strokes, and hospitalization for unstable angina 
confirmed by an independent CEC will be provided.  The dates of randomization, event, first 
dose, and last dose of investigational product, and time from randomization to event will be 
listed.  
10.3.4.4. Central Laboratory Measures, Vital Signs, and Electrocardiograms
Values and change from baseline to postbaseline values of central laboratory measures, vital 
signs, and selected ECG parameters will be summarized at each scheduled visit.  The analysis 
model to make comparisons among treatment arms, relative to continuous change from baseline 
values assessed over time, will be an MMRM, with terms: treatment, baseline HbA1c (≤8.5% or 
>8.5%), baseline BMI group (<25 or ≥25 kg/m2), washout of antidiabetic medication (yes or no);
baseline measurement will be used as a covariate. An unstructured covariance structure will 
model relationship of within-patient errors.
The percentages of patients with treatment-emergent abnormal, high, or low laboratory measures 
at any time will be summarized and compared between treatment groups by using Fisher’s exact 
test.  A treatment-emergent abnormal value is defined as a change from normal value at baseline 
to an abnormal value at any time during the follow-up.  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 

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than the high limit at any time during Periods II and III.  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 during Periods II and III.  High limit and low limit will be 
provided in the SAP.
10.3.5. Evaluation of Immunogenicity
The frequency and percentage of patients with preexisting ADAs, with treatment-emergent
ADAs, and with treatment-emergent neutralizing antibodies to tirzepatide will be tabulated by 
tirzepatide dose.  Treatment-emergent ADAs are defined as those with a titer 2-fold (1 dilution) 
greater than the minimum required dilution if no ADAs were detected at baseline (treatment-
induced ADAs) or those with a 4-fold (2 dilutions) increase in titer compared to baseline if 
ADAs were detected at baseline (treatment-boosted ADAs).  For the treatment-emergent ADA 
patients, the distribution of maximum titers will be described by tirzepatide dose. The frequency 
of neutralizing antibodies to tirzepatide and/or cross-reactive and neutralizing antibodies to 
endogenous counterparts will be tabulated in treatment-emergent ADA-positive patients.
The relationship between the presence of antibodies and and tirzepatide PK and PD response
including safety and efficacy to tirzepatide may be assessed.
10.3.6. Other Analyses
10.3.6.1. Health Economics
Analyses of actual and change from baseline in patient-reported outcome (PRO) scores will be 
conducted using linear models with baseline PRO scores, treatment, and other factors that may 
be considered relevant.  These variables will be specified in the SAP.  
10.3.6.2. Subgroup Analyses 
Subgroup analyses of mean change in HbA1c, mean change in body weight, AEs, and 
hypoglycemic events will be provided by age, gender, baseline BMI group (<25 or ≥25 kg/m2), 
duration of diabetes, and baseline HbA1c (≤8.5%, ˃8.5%).  Additional details will be provided in 
the SAP.
10.3.7. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly medical director, or designee, will be consulted to determine 
whether it is necessary to amend the protocol.

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11.
References
Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its 
complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a 
WHO consultation. Diabet Med. 1998;15(7):539-553.
American Diabetes Association. Glycemic Targets. Sec 6. In Standards of Medical Care in 
Diabetes—2017. Diabetes Care. 2017;40(Suppl 1):S48-S56. Available at: 
http://care.diabetesjournals.org/content/40/Supplement_1/S48. Accessed September 26, 2018.
Aroda VR, Ratner R. The safety and tolerability of GLP-1 receptor agonists in the treatment of 
type 2 diabetes : a review. Diabetes Metab Res Rev. 2011;27(6):528-542. 
Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 
2007;132(6):2131-2157.
Banks PA, Freeman ML; Practice Parameters Committee of the American College of 
Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol.
2006;101(10):2379-2400.
Bradley C. The diabetes treatment satisfaction questionnaire: DTSQ. In: Bradley C, editor. 
Handbook of Psychology and Diabetes: a guide to psychological measurement in diabetes 
research and practice. Chur, Switzerland: Harwood Academic Publishers; 1994.
Danne T, Philotheou A, Goldman D, Guo X, Ping L, Cali A, Johnston P. A randomized trial 
comparing the rate of hypoglycemia--assessed using continuous glucose monitoring--in 
125 preschool children with type 1 diabetes treated with insulin glargine or NPH insulin (the 
PRESCHOOL study). Pediatr Diabetes. 2013;14(8):593-601. 
Dmitrienko A, Offen WW, Westfall PH. Gatekeeping strategies for clinical trials that do not
require all primary effects to be significant. Stat Med. 2003;22(15):2387-2400.
EuroQoL Group. EQ-5D-5L User guide: basic information on how to use the EQ-5D-5L 
instrument. Version 2.1. 2015. Available at: https://euroqol.org/wp-
content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf. Accessed October 17, 2018.
Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Milicevic Z, 
Robins D, Haupt A. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor 
agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active 
comparator-controlled phase 2 trial. Lancet. 2018;392(10160):2180-2193.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, 
Tsapas A, Wender R, Matthews DR. Management of hyperglycemia in type 2 diabetes, 2015: 
a patient-centered approach: update to a position statement of the American Diabetes 
Association and the European Association for the Study of Diabetes. Diabetes Care.
2015;38(1):140-149.
Koizumi M, Takada T, Kawarada Y, Hirata K, Mayumi T, Yoshida M, Sekimoto M, Hirota M, 
Kimura Y, Takeda K, Isaji S, Otsuki M, Matsuno S; JPN. JPN guidelines for the management 
of acute pancreatitis: diagnostic criteria for acute pancreatitis. J Hepatobiliary Pancreat Surg. 
2006;13(1):25-32.

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Nauck MA, Frossard JL, Barkin JS, Anglin G, Hensley IE, Harper KD, Milicevic Z. Assessment 
of pancreas safety in the development program of once-weekly GLP-1 receptor agonist 
dulaglutide. Diabetes Care. 2017;40(5):647-654.
Neumiller JJ. Incretin-based therapies. Med Clin North Am. 2015;99(1):107-129.
Rubin DB. Multiple imputation for nonresponse in surveys. New York: John Wiley & Sons Inc.;
1987.
Steinberg WM, Buse JB, Ghorbani ML, Ørsted DD, Nauck MA; LEADER Steering Committee;
LEADER Trial Investigators. Amylase, lipase, and acute pancreatitis in people with type 2 
diabetes treated with liraglutide: results from the LEADER Randomized Trial. Diabetes Care.
2017a;40(7):966-972.
Steinberg WM, Rosenstock J, Wadden TA, Donsmark M, Jensen CB, DeVries JH. Impact of 
liraglutide on amylase, lipase, and acute pancreatitis in participants with overweight/obesity 
and normoglycemia, prediabetes, or type 2 diabetes: secondary analyses of pooled data from 
the SCALE clinical development program. Diabetes Care. 2017b;40(7):839-848.
Weinberg ME, Bacchetti P, Rushakoff RJ. Frequently repeated glucose measurements 
overestimate the incidence of inpatient hypoglycemia and severe hyperglycemia. J Diabetes 
Sci Technol. 2010;4(3):577-582.

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12.
Appendices

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Appendix 1.
Abbreviations and Definitions
Term
Definition
ADA
anti-drug antibodies
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BG
blood glucose
BMI
body mass index
CEC
Clinical Events Classification
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CKD-EPI
Chronic Kidney Disease-Epidemiology
COA
clinical outcome assessment
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
CRF
case report form
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.
CRS
clinical research scientist
CSR
clinical study report

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Term
Definition
CT
computed tomography
CV
cardiovascular
DNA
deoxyribonucleic acid
DPP-4
dipeptidyl-peptidase-4
DTSQc
Diabetes Treatment Satisfaction Questionnaire (change)
DTSQs
Diabetes Treatment Satisfaction Questionnaire (status)
EAS
efficacy analysis set
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture system 
eGFR
estimated glomerular filtration rate
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
EQ-5D-5L
European Quality of Life – 5 Dimension -5 Level Questionnaire
ERB
ethical review board
ET
early termination
FAS
full analysis set
FBG
fasting blood glucose
FSG
fasting serum glucose
FSH
follicle-stimulating hormone
GCP
good clinical practice
GI
gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide
GIPR
gastric inhibitory polypeptide receptor
GLP-1
glucagon like peptide-1 

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Term
Definition
HbA1c
glycated hemoglobin
HOMA-2
Updated Homeostasis Model Assessment
HR-QoL
health-related quality of life
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
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.
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
Institutional Review Board
ITT
intention to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IWRS
interactive web-response system
LC/MS
liquid chromatography/mass spectrometry
MAD
multiple ascending dose
MedDRA
Medical Dictionary for Regulatory Activities
MEN-2
multiple endocrine neoplasia syndrome type 2
MI
myocardial infarction
mITT
modified intention-to-treat
MMRM
mixed-model repeated measures

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Term
Definition
MRI
magnetic resonance imaging
MTC
medullary thyroid carcinoma
NAFLD
nonalcoholic fatty liver disease
OAM
oral antihyperglycemic medication
OTC
over the counter
PD
pharmacokinetics
PK
pharmacokinetics
PRO
patient-reported outcomes
QW
once weekly administration
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set
SC
subcutaneous
SD
standard deviation
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. 
SGLT-2i
sodium-glucose cotransporter type 2 inhibitor
SMBG
self-monitored blood glucose
SUSAR
suspected unexpected serious adverse reaction
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TBL
total bilirubin
TE
treatment-emergent
TEAE
treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.

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Term
Definition
TZD
thiazolidinedione
ULN
upper limit of normal

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Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Chloride
Mean cell volume (MCV)
Bicarbonate
Mean cell hemoglobin concentration (MCHC)
Total bilirubin
Leukocytes (WBC)
Direct bilirubin
Neutrophils
Alkaline phosphatase
Lymphocytes
Alanine aminotransferase (ALT/SGPT)
Monocytes
Aspartate aminotransferase (AST/SGOT)
Eosinophils
Gamma-glutamyl transferase (GGT)
Basophils
Blood urea nitrogen (BUN)
Platelets
Creatinine
Creatine kinase (creatine phosphokinase)d
Urinalysisa,b
Uric acid
Albumin
Calcium
Creatinine
Albumin
Lipid Panel (fasting)a
Total cholesterol
High-density lipoprotein-cholesterol (HDL-C)
Low-density lipoprotein-cholesterol (LDL-C)e
Nonpharmacogenetic Stored Samplesa
Very low-density lipoprotein-cholesterol (VLDL-C)
Triglycerides
Serum
EDTA plasma
Pharmacogenetics Samplea
P800 plasma
Pregnancy test (females only)a,f
Follicle-stimulating hormone (FSH)g
Estradiolg
Immunnogenicityj
HbA1ca
Anti-tirzepatide antibody 
Glucose, fastinga,h
Hepatitis Testinga,c
Pancreas (exocrine)a
Endocrinea
Pancreatic amylase
Calcitonin
Lipase
Pharmacokineticsj
C-peptidea
Tirzepatide plasma levels
Insulin, fastingh
eGFR (calculated by CKD-EPI equation)i

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Abbreviations: CKD-EPI = Chronic Kidney Disease-Epidemiology; EDTA = ethylenediaminetetraacetic acid;
eGFR = estimated glomerular filtration rate; FSH = follicle stimulating hormone; HbA1c = hemoglobin A1c; 
RBC = red blood cell; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic 
transaminase; WBC = white blood cell.
a
All tests will be performed or sample stored by the Lilly-designated central laboratory.
b
Urinary albumin and creatinine are measured at a central laboratory and the ratio is calculated.
c
As needed per hepatic monitoring criteria (refer to Appendix 4).
d
Creatine kinase MB (CK-MB) is to be assayed if creatine kinase result >1000 IU/L.
e
Low-density lipoprotein is calculated using the Friedwald equation.
f
A serum pregnancy test will be performed at Visit 1 for women of childbearing potential only and will be 
analyzed at a central laboratory. Pregnancy tests may be repeated at any time during the study and analyzed 
locally at the investigator’s discretion.  Urine pregnancy test will be performed by a local laboratory.
g
FSH test performed at Visit 1 for postmenopausal women at least 45years of age with an intact uterus, not on 
hormone therapy, and who have had spontaneous amenorrhea for more than 6 months and less than 12 months 
and estradiol levels consistent with a postmenopausal state (FSH ≥40 mIU/mL and estradiol <30 pg/mL).
h
Fasting serum glucose and insulin values will be used to calculate beta-cell function and insulin sensitivity using 
the updated Homeostasis Model Assessment (HOMA2).  Fasting serum glucose samples must be obtained after 
8 hours or more without eating, drinking (other than water) or performing any significant physical activity.
i
Estimated glomerular filtration rate will be calculated by the central laboratory at required visits and included in 
lab result reports.
j
Assayed by a Lilly-designated laboratory.

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Appendix 3.
Study Governance Considerations
Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for:

ensuring that the patient/patient’s legal representative understands the nature of 
the study, the potential risks and benefits of participating in the study, and that 
his/her participation is voluntary.

ensuring that informed consent is given by each patient or legal representative.  
This includes obtaining the appropriate signatures and dates on the informed 
consent form (ICF) prior to the performance of any protocol procedures and prior 
to the administration of investigational product.

answering any questions the patient/ patient’s legal representative may have 
throughout the study and sharing in a timely manner any new information that 
may be relevant to the patients/ patient’s legal representative’s willingness to 
continue his/her participation in the study.

ensuring that a copy of the ICF is provided to the participant or the participant’s 
legal representative and is kept on file.

ensuring that the medical record includes a statement that written informed 
consent was obtained before the participant was enrolled in the study and the date 
the written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF.
Appendix 3.1.2.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.
Appendix 3.1.3.
Ethical Review
The investigator or an appropriate local representative must give assurance that the ethical 
review board (ERB) was properly constituted and convened as required by International Council
for Harmonisation (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s).  All ICFs 
must be compliant with the ICH guideline on Good Clinical Practice (GCP).

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The study site’s ERB(s) should be provided with the following:

the protocol and related amendments and addenda, current Investigator’s
Brochure (IB) and updates during the course of the study

informed consent form 

other relevant documents (eg, curricula vitae, advertisements)
Appendix 3.1.4.
Regulatory Considerations
This study will be conducted in accordance with the protocol and with the:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the Sponsor will be assigned to a third party.
Appendix 3.1.5.
Investigator Information
Physicians with a specialty in diabetes/endocrinology, cardiology, nephrology, internal medicine, 
family medicine, general medicine, or any other specialty physician who has experience treating 
type 2 diabetes mellitus (T2DM) and clinical research experience in T2DM will participate as 
investigators in this clinical trial.
Appendix 3.1.6.
Protocol Signatures
The Sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his/her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.7.
Final Report Signature
The clinical study report (CSR) coordinating investigator will sign the final CSR for this study, 
indicating to the best of his/her knowledge, the report accurately describes the conduct and 
results of the study.
A qualified investigator will serve as the CSR coordinating investigator.  If this investigator is 
unable to fulfill this function, another investigator will be chosen by Lilly to serve as the CSR 
coordinating investigator.
The Sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his/her knowledge, the report accurately describes the 
conduct and results of the study.

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Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate.

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the case report 
forms (CRFs), and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax.

review and evaluate CRF data and use standard computer edits to detect errors in 
data collection.

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the Sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the Sponsor. 
An electronic data capture system (EDC) will be used in this study for the collection of the 
eCRF 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 electronic CRF (eCRF).
Additionally, clinical outcome assessment (COA) data (questionnaires, scales, self-reported diary 
data, rating scales, etc.) will be collected by the patient (investigator site personnel), via a paper 
source document and will be transcribed by the investigator site personnel into the EDC system.
Data collected via the Sponsor-provided data capture system(s) will be stored at third party.  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.

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Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system, and electronic transfers will be provided to the investigator 
for review and retention.  Data will subsequently be transferred from the central vendor to the 
Lilly data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent
with applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.
Appendix 3.4.
Publication Policy
The publication policy for Study I8F-JE-GPGO is described in the Letter of Agreement.

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Appendix 4.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly, or its designee, clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgGc
Direct bilirubin
Hepatitis E antibody, IgMc
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/Confirmation tests may be performed depending on regulatory requirements and/or testing availability.
c
Hepatitis E Virus testing in endemic areas only.

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Appendix 5.
World Health Organization Classification 
of Diabetes and Diagnostic Criteria 
Type 1 Diabetes:  Type 1 diabetes is judged to be present when the classical symptoms of 
diabetes (thirst, polyuria, wasting and stupor, or coma) are associated with readily detectable 
concentrations of glucose and ketone bodies in the blood and urine.  Insulin treatment is 
necessary not only to control hyperglycemia, but also to prevent spontaneous ketosis and death.
Type 2 Diabetes:  Type 2 diabetes, although often asymptomatic, may also present with 
classical hyperglycemic symptoms (thirst, polyuria, weight loss), but, despite hyperglycemia, 
ketone bodies are present in only low concentrations in the blood and urine.  Coma is rare in 
type 2 diabetes, but may result from extreme hyperglycemia and hyperosmolarity; lactic acidosis 
or ketoacidosis can also occur in fulminating illness (eg, severe infection or mesenteric artery 
thrombosis) due to an acute increase in insulin requirements, but spontaneous ketosis does not 
occur.  Some patients with type 2 diabetes later progress to a state of absolute insulin deficiency 
(Alberti and Zimmet 1998). 

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Appendix 6.
Classification of Contraceptive Methods
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 the preferred and usual lifestyle) or in a same-sex relationship 
with no sexual relationship with males (as part of the preferred and usual lifestyle).  
Note: periodic abstinence (eg, calendar, ovulation, symptothermal, 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 trials
Effective Methods of Contraception:

Male condom with spermicide

Female condom with spermicide

Diaphragm with spermicide

Cervical sponge

Cervical cap with spermicide
Men, regardless of their fertility status, with non-pregnant women of child bearing potential 
partners must agree to use 2 forms of effective contraception, where at least 1 form is highly 
effective for the duration of the study and for at least 3 months after the last injection.
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 in exclusively same sex relationships (as the preferred and usual lifestyle) are not 
required to use contraception.

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Appendix 7.
Management of Patients with Severe, 
Persistent Hyperglycemia during the Treatment Period 
Below are criteria for deciding when and how to intervene with patients who do not reach 
glycemic targets.  An additional therapeutic intervention should be considered in patients who 
develop severe, persistent hyperglycemia after randomization at the discretion of the investigator 
in accordance with American Diabetes Association/European Association for the Study of 
Diabetes guidance (Inzucchi et al. 2015).  Rescue treatment with antihyperglycemic medications,
including insulins, will be allowed.  In this case, GLP-1RA and DPP-4 inhibitors are not allowed 
as rescue therapies.  Rescue medication will be prescribed as add-on to randomized treatment,
and patients will continue to follow the protocol-specified visit schedule.  
Add-on glycemic rescue therapy will be allowed for patients based on the following criteria:  
1) The patient is fully compliant with the assigned therapeutic regimen
AND
2) Has no acute condition that raises blood glucose
AND
a)
Blood glucose concentration measured by weekly 1-point SMBG before breakfast profile 
>270 mg/dL (>15.0 mmol/L) over at least a consecutive 2-week period any time during 
the first 8 weeks post-randomization
OR 
b)
Blood glucose concentration measured by weekly 1-point SMBG before breakfast
>240 mg/dL (>13.3 mmol/L) over at least a consecutive 2-week period at any time 
9-16 weeks postrandomization
OR
c)
Blood glucose concentration measured by weekly 1-point SMBG before breakfast
>200 mg/dL (>11.1 mmol/L) over at least a consecutive 2-week period at any time 
beyond the first 16 weeks postrandomization
OR 
d)
HbA1c ≥8.5% (69 mmol/mol) at 24 weeks, with inadequate response to the existing 
regimen defined as improvement in HbA1c over the last 3 months (Week 12 to Week 24) 
that is <0.3%.

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Appendix 8.
Protocol Amendment I8F-JE-GPGO(a) 
Summary A Phase 3 Study of Tirzepatide Monotherapy 
Compared to Dulaglutide 0.75 mg in Patients with Type 2 
Diabetes Mellitus (SURPASS J-mono)
Overview
Protocol I8F-JE-GPGO A Phase 3 Study of Tirzepatide Monotherapy Compared to Dulaglutide 
0.75 mg in Patients with Type 2 Diabetes Mellitus (SURPASS J-mono) has been amended.  The 
new protocol is indicated by amendment (a) and will be used to conduct the study in place of any 
preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

Changes to the table of Objectives/Endpoints in section 1 and section 4 to delete some of 
abbreviations 

A change to section 3.2 to clarify the description of Phase 2 studies

A change to section 7.2.1 to correct the timing of administration of investigational product 
when missed

A change to section 7.6 to align with study procedure

Changes to section 7.7 to add prohibited comcomitant therapy

Changes to section 9.2 to align with study procedure

A change to section 9.2.2.2 for consistency with Appendix 7

A change to section 9.2.3 to align with study procedure

A change to section 9.9.1 to correct the number of health states used in EQ-5D-5L

Changes to section 10.3.3.1 to correct explanation of statistical testing procedure

Change to Appendix 6 for consistency with inclusion criterion [6b]

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
1.
Synopsis
Objectives/Endpoints:
Abbreviations:  ADAs = anti-drug antibodies; AE = adverse event; AUC = area under the 
concentration versus time curve; Cmax = maximum plasma concentration; CGM = continuous 
glucose monitoring; CV = cardiovascular; FSG = fasting serum glucose; HbA1c = hemoglobin 
A1c; MTC = Medullary Thyroid Carcinoma; OAM  = oral antihyperglycemic medication; SAE 
= serious adverse event; SMBG = self-monitored blood glucose; T2DM = type 2 diabetes 
mellitus; TEAE = treatment-emergent adverse event.
3.2.
Background
…..
Serious AEs (SAEs) were balanced across the treatment groups, and none of the groups in the
either study reported severe hypoglycemia (Frias et al. 2018).
…..
4.
Objectives and Endpoints
Abbreviations:  ADAs = anti-drug antibodies; AE = adverse event; AUC = area under the 
concentration versus time curve; Cmax = maximum plasma concentration; CGM = continuous 
glucose monitoring; CV = cardiovascular; FSG = fasting serum glucose; HbA1c = 
hemoglobin A1c; MTC = Medullary Thyroid Carcinoma; OAM  = oral antihyperglycemic 
medication; SAE = serious adverse event; SMBG = self-monitored blood glucose; T2DM = 
type 2 diabetes mellitus; TEAE = treatment-emergent adverse event.
7.2.1.
Selection and Timing of Doses
…..
If a dose of investigational product, including tirzepatide 5 mg, 10 mg, 15 mg or dulaglutide 
0.75 mg, is missed, the patient should take it as soon as possible, unless it is within 72 48 hours 
of the next dose, in which case that dose should be skipped and the next dose taken at the 
appropriate time.
7.6.
Treatment Compliance
…..
In addition to the assessment of a patient’s compliance with the investigational product
administration, other aspects of compliance with the study treatments will be assessed at each 
visit, based on the patient’s adherence to the visit schedule, compliance with the concomitant 
antihyperglycemic medication regimen, completion of study diaries, the results of home BG
monitoring, and any other parameters the investigator considers necessary.

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…..
7.7.
Concomitant Therapy
…..
Prohibited medications include following;

Any antihyperglycemic medications, except for concomitant OAMs

Any medications that promote weight loss (eg, Sanorex® [mazindol])

Any chronic (>2 weeks or 14 days) systemic glucocorticoid therapy (excluding topical, 
intra-ocular, intranasal, or inhaled preparations)
…..
9.2.
Adverse Event
…..
Investigators should record their assessment of the potential relatedness of each AE to study
procedure, and investigational product, and study device(s), via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to investigational product, study device(s), or a study procedure, taking into 
account the disease, concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device, and/or study procedure and the AE.
…..
9.2.2.2.
Severe, Persistent Hyperglycemia
…..
b)
Blood glucose concentration measured by weekly 1-point SMBG before breakfast
>240 mg/dL (>13.3 mmol/L) over at least a consecutive 2-week period at any time 9-
16 8 to 16 weeks post-randomization; 
…..
9.2.3.
Complaint Handling 
…..
Patients will be instructed to contact the investigator as soon as possible if they have complaints
or problems with the investigational product or drug delivery system, so that the situation can be 
assessed.
9.9.1.
European Quality of Life – 5 Demension – 5 Level (EQ-5D-5L)
…..

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The 5L version, introduced in 2005, scores each dimension at 5 levels (no problems, slight 
problems, moderate problems, severe problems, unable to perform/extreme problems), for a total 
of 3125 3251 possible health states.
…..
10.3.3.1
Primary Analyses
The primary efficacy measure is HbA1c change from baseline at 52 weeks, and the primary 
comparison is to compare tirzepatide doses versus dulaglutide 0.75 mg. Superiority of each 
tirzepatide dose will be demonstrated if the upper limit of the 97.5% or 95% CI for the difference 
between tirzepatide dose and dulaglutide 0.75 mg is below 0.  
The statistical analyses for the primary efficacy measure of HbA1c change from baseline at 
52 weeks will examine the following 3 hypotheses:

H1: the 15-mg dose of tirzepatide is superior to dulaglutide 0.75 mg

H2: the 10-mg dose of tirzepatide is superior to dulaglutide 0.75 mg

H3: the 5-mg dose of tirzepatide is superior to dulaglutide 0.75 mg
H1 and H2 will be tested at a 2-sided significance level of 0.025, followed by testing H3 only if 
H1 and/or H2 are declared.  H3 will be tested at a 2-sided significance level of 0.05 if H1 and H2
are declared.  H3 will be tested at a 2-sided significance level of 0.025 if either H1 or H2 is 
declared. This parallel gatekeeping procedure controls family-wise Type 1 error rate at a 2-sided 
0.05 level (Dmitrienko et al. 2003).
Appendix 6.
Classification of Contraceptive Methods
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 non-pregnant women of child bearing potential 
partners must agree to use 2 forms of effective contraception, where at least 1 form is highly 
effective either remain abstinent (if this is their preferred and usual lifestyle) or use condoms 
plus 1 additional highly effective (<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 at least 3 months after the last injection.

Leo Document ID = 9caf24ab-57dc-45da-8ad8-8ae004094393
Approver: 
Approval Date & Time: 17-Jan-2019 01:05:51 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 17-Jan-2019 03:32:25 GMT
Signature meaning: Approved
PPD
PPD