Efficacy and Safety of LY3298176 Once Weekly Versus Insulin Glargine in Patients With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4)
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: Eli Lilly and Company

Protocol I8F-MC-GPGM (b) 
 
Efficacy and Safety of LY3298176 Once Weekly versus Insulin Glargine in Patients with Type 2 
Diabetes and Increased Cardiovascular Risk (SURPASS-4) 
 
NCT03730662 
Approval Date: 10-Jul-2020 

I8F-MC-GPGM(b) Clinical Protocol
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LY3298176
Protocol I8F-MC-GPGM(b)
Efficacy and Safety of LY3298176 Once Weekly versus 
Insulin Glargine in Patients with Type 2 Diabetes and 
Increased Cardiovascular Risk (SURPASS-4)
2018-002618-11
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 
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.
LY3298176 
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 18 JUL 2018
Amendment (a) Electronically Signed and Approved by Lilly: 28 Sep 2018
Amendment (b) Electronically Signed and Approved by Lilly on approval date provided 
below: 
Approval Date: 10-Jul-2020 GMT

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Table of Contents
Section
Page
Protocol I8F-MC-GPGM(b) Efficacy and Safety of LY3298176 Once 
Weekly versus Insulin Glargine in Patients with Type 2 Diabetes and 
Increased Cardiovascular Risk (SURPASS-4).....................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................13
3.
Introduction ......................................................................................................................23
3.1.
Study Rationale............................................................................................................23
3.2.
Background..................................................................................................................23
3.3.
Benefit/Risk Assessment..............................................................................................24
4.
Objectives and Endpoints..................................................................................................25
5.
Study Design.....................................................................................................................27
5.1.
Overall Design .............................................................................................................27
5.2.
Number of Participants.................................................................................................31
5.3.
End of Study Definition ...............................................................................................31
5.4.
Scientific Rationale for Study Design...........................................................................31
5.5.
Justification for Dose ...................................................................................................31
6.
Study Population...............................................................................................................33
6.1.
Inclusion Criteria..........................................................................................................33
6.2.
Exclusion Criteria ........................................................................................................35
6.3.
Lifestyle Restrictions....................................................................................................37
6.4.
Screen Failures.............................................................................................................38
7.
Treatments........................................................................................................................39
7.1.
Treatments Administered .............................................................................................39
7.1.1.
Packaging and Labeling .......................................................................................40
7.1.2.
Medical Devices...................................................................................................40
7.2.
Method of Treatment Assignment ................................................................................40
7.2.1.
Selection and Timing of Doses.............................................................................40
7.2.1.1.
LY3298176 ....................................................................................................40
7.2.1.2.
Insulin Glargine..............................................................................................40
7.3.
Blinding .......................................................................................................................41
7.4.
Dosage Modification....................................................................................................41
7.4.1.
Study Drugs .........................................................................................................41

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7.4.2.
Reduction and/or Discontinuation of Concomitant 
Antihyperglycemic Medications...........................................................................41
7.5.
Preparation/Handling/Storage/Accountability...............................................................42
7.6.
Treatment Compliance .................................................................................................42
7.7.
Concomitant Therapy...................................................................................................43
7.7.1.
Management of Patients with Gastrointestinal Symptoms.....................................43
7.8.
Treatment after the End of the Study............................................................................44
7.8.1.
Treatment after Study Completion........................................................................44
7.8.2.
Special Treatment Considerations ........................................................................45
8.
Discontinuation Criteria ....................................................................................................46
8.1.
Discontinuation from Study Treatment.........................................................................46
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................46
8.1.2.
Temporary Interruption of Study Treatment .........................................................47
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................47
8.2.
Discontinuation from the Study....................................................................................47
8.3.
Lost to Follow-up.........................................................................................................48
9.
Study Assessments and Procedures ...................................................................................49
9.1.
Efficacy Assessments...................................................................................................49
9.1.1.
Primary Efficacy Assessments and Procedures.....................................................49
9.1.2.
Secondary Efficacy Assessments and Procedures.................................................49
9.1.3.
Exploratory Efficacy Assessments and Procedures...............................................49
9.1.4.
Appropriateness of Assessments ..........................................................................50
9.2.
Adverse Events ............................................................................................................50
9.2.1.
Serious Adverse Events........................................................................................51
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................52
9.2.2.
Adverse Events of Special Interest .......................................................................52
9.2.2.1.
Hypoglycemia ................................................................................................52
9.2.2.2.
Severe, Persistent Hyperglycemia...................................................................53
9.2.2.3.
Pancreatitis.....................................................................................................54
9.2.2.4.
Thyroid Malignancies and C-Cell Hyperplasia................................................55
9.2.2.5.
Major Adverse Cardiovascular Events............................................................56
9.2.2.6.
Supraventricular Arrhythmias and Cardiac Conduction 
Disorders........................................................................................................56
9.2.2.7.
Hypersensitivity Events..................................................................................56
9.2.2.7.1.
Injection Site Reactions ............................................................................56
9.2.2.7.2.
Anti-Drug Antibodies ...............................................................................56
9.2.2.8.
Diabetic Retinopathy Complications...............................................................57
9.2.2.9.
Hepatobiliary Disorders..................................................................................57

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9.2.2.10.
Severe Gastrointestinal Adverse Events..........................................................57
9.2.2.11.
Acute Renal Events ........................................................................................57
9.2.2.12.
Metabolic Acidosis, Including Diabetic Ketoacidosis .....................................57
9.2.2.13.
Amputation/Peripheral Revascularization .......................................................58
9.2.2.14.
Major Depressive Disorder/Suicidal Ideation..................................................58
9.2.3.
Complaint Handling.............................................................................................58
9.3.
Treatment of Overdose.................................................................................................58
9.4.
Safety...........................................................................................................................58
9.4.1.
Electrocardiograms ..............................................................................................58
9.4.2.
Vital Signs ...........................................................................................................59
9.4.3.
Laboratory Tests ..................................................................................................59
9.4.4.
Immunogenicity Assessments ..............................................................................59
9.4.5.
Safety Monitoring ................................................................................................60
9.4.5.1.
Hepatic Safety Monitoring..............................................................................60
9.5.
Pharmacokinetics .........................................................................................................60
9.6.
Pharmacodynamics ......................................................................................................61
9.7.
Pharmacogenomics ......................................................................................................61
9.7.1.
Whole Blood Samples for Pharmacogenetic Research..........................................61
9.8.
Biomarkers...................................................................................................................61
9.9.
Health Economics ........................................................................................................62
9.9.1.
European Quality of Life (EQ-5D-5L)..................................................................62
9.9.2.
Ability to Perform Physical Activities of Daily Living 
(APPADL)...........................................................................................................63
9.9.3.
Impact of Weight on Self-Perception Questionnaire (IW-SP)...............................63
9.9.4.
Diabetes Treatment Satisfaction Questionnaire (DTSQ).......................................63
10.
Statistical Considerations ..................................................................................................64
10.1. Sample Size Determination ..........................................................................................64
10.2. Populations for Analyses..............................................................................................65
10.3. Statistical Analyses ......................................................................................................65
10.3.1.
General Statistical Considerations ........................................................................65
10.3.2.
Treatment Group Comparability...........................................................................66
10.3.2.1.
Patient Disposition..........................................................................................66
10.3.2.2.
Patient Characteristics ....................................................................................66
10.3.2.3.
Concomitant Therapy .....................................................................................66
10.3.2.4.
Treatment Compliance....................................................................................67
10.3.3.
Efficacy Analyses ................................................................................................67
10.3.3.1.
Primary Analyses ...........................................................................................67
10.3.3.2.
Secondary Analyses........................................................................................68

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10.3.3.3.
Tertiary/Exploratory Analyses ........................................................................68
10.3.4.
Safety Analyses....................................................................................................68
10.3.4.1.
Hypoglycemic Events.....................................................................................69
10.3.4.2.
Gastrointestinal Events...................................................................................69
10.3.4.3.
Adjudicated Cardiovascular Events ................................................................69
10.3.4.4.
Central Laboratory Measures, Vital signs, and 
Electrocardiograms.........................................................................................69
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................69
10.3.6.
Evaluation of Immunogenicity .............................................................................70
10.3.7.
Other Analyses.....................................................................................................70
10.3.7.1.
Health Economics...........................................................................................70
10.3.7.2.
Subgroup Analyses.........................................................................................70
10.3.8.
Interim Analyses..................................................................................................70
10.3.8.1.
Interim Safety CV Analysis ............................................................................71
11.
References ........................................................................................................................72
12.
Appendices .......................................................................................................................74

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List of Tables
Table
Page
Table GPGM.1. Schedule of Activities....................................................................................14
Table GPGM.2. Objectives and Endpoints...............................................................................25
Table GPGM.3. LY3298176 Treatment Regimens ..................................................................39
Table GPGM.4. Titration of Insulin Glargine ..........................................................................41
Table GPGM.5. Description of Analysis Sets ..........................................................................65

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List of Figures
Figure
Page
Figure GPGM.1. Illustration of study design for Clinical Protocol I8F-MC-GPGM. .................28

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................75
Appendix 2.
Clinical Laboratory Tests...............................................................................80
Appendix 3.
Study Governance Considerations..................................................................82
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................86
Appendix 5.
World Health Organization Classification of Diabetes and Diagnostic 
Criteria ..........................................................................................................87
Appendix 6.
Classification of Contraceptive Methods........................................................88
Appendix 7.
Management of Patients with Severe, Persistent Hyperglycemia during 
the Treatment Period......................................................................................89
Appendix 8.
Changes to Study Procedures due to the COVID-19 Pandemic ......................90
Appendix 9.
Protocol Amendment I8F-MC-GPGM(b)
Efficacy and Safety of LY3298176 Once Weekly versus Insulin 
Glargine in Patients with Type 2 Diabetes and Increased Cardiovascular
Risk (SURPASS-4)........................................................................................91

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1. Synopsis
Title of Study:
Efficacy and Safety of LY3298176 Once Weekly versus Insulin Glargine in Patients with Type 2 Diabetes and 
Increased Cardiovascular Risk.
Rationale: 
Patients with type 2 diabetes mellitus (T2DM) need antihyperglycemic treatment. As the disease progresses, 
multiple drug treatments are warranted to manage the disease.  When oral therapies are insufficient to reach target 
glycemia, injectable therapies are added.  Basal insulins, such as glargine, are frequently used as the first injectable 
after failure of the oral therapy.  Adequately titrated glargine therapy, in combination with oral treatment, frequently 
achieves the target glycemic level; however, it is frequently associated with weight increase and eventual 
hypoglycemia.  LY3298176 is a 39-amino acid synthetic peptide with agonist activity at both the GIP (glucose-
dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptors.  Its structure is based on the 
GIP sequence and includes a C20 fatty di-acid moiety.  It is administered once weekly (QW) by subcutaneous 
administration. The aim of the present study is to compare the glycemic effect of glargine and LY3298176 in 
patients with T2DM and elevated risk for cardiovascular disease.  The study will also compare the effect of these 
drugs on weight and their safety profile.
Study I8F-MC-GPGM (GPGM) is a Phase 3, open-label comparator, multicenter, parallel-arm, randomized study to 
compare the safety and efficacy of 3 maintenance doses of LY3298176 with insulin glargine in patients with T2DM
with increased cardiovascular (CV) risk. The primary endpoint will be the mean change in hemoglobin A1c 
(HbA1c) levels from baseline to 52 weeks.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary

To demonstrate that QW LY3298176 10 mg
and/or 15 mg is noninferior to insulin 
glargine for change from baseline in HbA1c
at 52 weeks

Mean change in HbA1c 
Key Secondary (controlled for type 1 error)
Efficacy

To demonstrate that QW LY3298176 5 mg is 
noninferior to insulin glargine for change 
from baseline in HbA1c at 52 weeks 

Mean change in HbA1c 

To demonstrate that QW LY3298176 5 mg, 
10 mg, and/or 15 mg is superior to insulin 
glargine for change from baseline in weight 
at 52 weeks 

To demonstrate that QW LY3298176 5 mg, 
10 mg, and/or 15 mg is superior to insulin 
glargine for change from baseline in HbA1c
at 52 weeks

To demonstrate that QW LY3298176 5 mg, 
10 mg, and/or 15 mg is superior to insulin 

Mean change in body weight 

Mean change in HbA1c 

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Objectives
Endpoints
glargine for the proportion of patients with 
HbA1c target values of <7.0% (53 
mmol/mol) at 52 weeks

HbA1c
Additional Secondary (not controlled for type 1 
error)
Efficacy

To demonstrate that QW LY3298176 5 mg, 
10 mg, and/or 15 mg is superior to insulin 
glargine at 52 weeks 

The mean change in fasting serum glucose
(central laboratory) from baseline

The proportion of patients achieving an HbA1c 
target value of ≤6.5% (48 mmol/mol) and 
<5.7% (39 mmol/mol)

Mean change in 7-point self-monitored blood 
glucose profiles from baseline

Proportion of patients who achieved weight 
loss of ≥5%, >10%, and >15% from baseline 
Safety

To compare the safety of LY3298176 5 mg, 
10 mg, and 15 mg LY3298176 to insulin 
glargine at 52 weeks and at the end of the 
safety follow-up period, with respect to the 
following outcomes

Treatment-emergent adverse events (TEAEs)

Early discontinuations of study drug due to 
adverse events (AEs)

Adjudicated deaths and nonfatal major CV 
events

Adjudicated pancreatic AEs

Medullary thyroid carcinoma (MTC), C-cell 
hyperplasia, and serum calcitonin 

Incidence of treatment-emergent LY3298176
anti-drug antibodies and systemic 
hypersensitivity reactions 

Mean change in systolic and diastolic blood
pressure and heart rate from baseline 

Occurrence of hypoglycemic events

Time to initiation of rescue therapy for severe, 
persistent hyperglycemia
Pharmacokinetics

To characterize the pharmacokinetics (PK) of 
LY3298176 5 mg, 10 mg, and 15 mg and 
evaluate the relationships between 
LY3298176 exposure and safety, tolerability,
and efficacy measures

Population PK and PD parameters

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Summary of Study Design:  
Study GPGM is a Phase 3, open-label comparator, multicenter, parallel-arm, randomized study to compare the 
safety and efficacy of 3 maintenance doses of LY3298176 with insulin glargine in patients with T2DM with 
increased CV risk. The primary endpoint will be the mean change in HbA1c from baseline to 52 weeks. 
Treatment Arms and Duration:  
Patients will be randomized in a 1:1:1:3 ratio to receive 5 mg LY3298176, 10 mg LY3298176, 15 mg LY3298176, 
or insulin glargine.  The randomization will be stratified by country, baseline HbA1c concentration (≤8.5%, ˃8.5% 
[≤69, ˃69 mmol/mol]), and sodium-glucose co-transporter-2 inhibitors (SGLT-2i) use (Yes or No). 
The study will continue until all of the following criteria are fulfilled.
1)
At least 52 weeks from the time of the last patient randomized 
2)
At least 300 patients assigned to the combined LY3298176 arms reach at least 78 weeks of treatment
3)
Approximately 110 patients in this study experience at least 1 component event of the composite CV 
endpoint of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina
Number of Patients:
Approximately 1878 patients will be randomized in a 1:1:1:3 ratio to 5 mg LY3298176 (313 patients), 10 mg 
LY3298176 (313 patients), 15 mg LY3298176 (313 patients), and insulin glargine (939 patients).  
Statistical Analysis:
Efficacy Analyses:
Efficacy and safety will be assessed using the modified intention-to-treat population, which consists of all randomly 
assigned participants who are exposed to at least 1 dose of study drug. There will be 2 estimands of interest in 
comparing efficacy of LY3298176 doses with insulin glargine relative to the primary measure of mean change in 
HbA1c from baseline to 52-week visit. First estimand, the “efficacy” estimand, represents efficacy prior to 
discontinuation of study drug without confounding effects of rescue therapy for persistent severe hyperglycemia.  
Second estimand, the “treatment-regimen” estimand, represents the efficacy irrespective of adherence to 
investigational product or introduction of rescue therapy for persistent severe hyperglycemia.
For the FDA, the primary efficacy assessments will be guided by the “treatment-regimen” estimand.  This 
assessment will analyze change from baseline in HbA1c to 52-week visit using an analysis of covariance 
(ANCOVA) with terms, treatment, stratification factors: country, SGLT-2i use (Yes or No), and baseline HbA1c as 
a covariate. The ANCOVA analysis will be conducted using full analysis set (FAS) at 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 study drug or whether the participant had been given rescue medication.  
Additionally, data for subjects with missing values will be imputed based on observed data from subjects in the 
same treatment arm who had their efficacy measure at the Week 52 visit assessed after early discontinuation of 
study drug 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).

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For all other purposes, the primary efficacy assessments will be guided by the “efficacy” estimand.  This assessment 
will use 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 will be a mixed model for repeated measures (MMRM), with terms: treatment, visit, and treatment-by-visit 
interaction, stratification factors: country, SGLT-2i use (Yes or No), as fixed effects, and baseline HbA1c as a 
covariate. An unstructured covariance structure will model relationship of within-patient errors.
Since the two estimands are intended for different purposes, no multiplicity adjustments will be made. For each 
estimand, the overall type I error rate of primary and key secondary efficacy endpoint assessments relative to each 
estimand will be controlled at 2-sided 0.05 level.  
Additional details, including analysis methods for key secondary endpoints and the strategy for controlling overall 
type 1 error rate in evaluating primary and key secondary endpoint evaluation to a 2-sided 0.05 significance level,
will be provided in the statistical analysis plan (SAP).
Safety Analyses:
Unless specified otherwise, safety assessments will be based on all available data, irrespective of whether they were 
obtained after the participants had discontinued the study drug or whether the participant had been given rescue 
medication. Summary statistics will be provided for incidence of TEAEs, serious adverse events, and study 
discontinuation due to AEs or death during the treatment period. 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 an MMRM analysis.  Selected safety analysis (for example, hypoglycemia) 
will be conducted after excluding data while on rescue therapy.  Additional details, including analysis of AEs of 
special interest, will be provided in the SAP.

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2.
Schedule of Activities
The Schedule of Activities described below should be followed for all patients enrolled in 
Study GPGM.  However, for those patients whose participation in this study is affected by severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the novel 
Coronavirus Disease 2019 (COVID-19), please refer to Appendix 8 for additional instructions.

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Table GPGM.1.
Schedule of Activities
Study 
Period I
Study Period II
52 Weeks
Study Period III
Variable
Study 
Period 
IV
Screening 
Lead in
Treatment Period
Safety 
F/U
Visit
1
2
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
FT
V
z
ETb
801
Week of 
Treatment
-3
-2
0
1
2
3
4
5
6
7
8
10
12
15
16
20
23
24
28
32
35
36
42
52
62
72
78
88
104
4 week 
post 
end of 
tx
Allowable 
Deviation 
(days)c
-
±3
±7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
-
±3
±3
±3
-
±3
±7
±7
±7
±7
±7
±7
±7
±3
Fasting Visitd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK only Visit
X
X
Telephone Visit
X
X
X
X
Informed 
consent
X
Randomization
X
Clinical Assessments
Medical historye
X
Physical
X
X
X
Height
X
X
Weightf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist 
circumference
X
X
X
X
X
X
X
X
X
X
ECGg
X
X
X
X
X
X
X
X
Vital signs (2 
sitting BP and 
HR)g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dilated 
fundoscopic 
examh
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

I8F-MC-GPGM(b) Clinical Protocol
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LY3298176
Study 
Period I
Study Period II
52 Weeks
Study Period III
Variable
Study 
Period 
IV
Screening 
Lead in
Treatment Period
Safety 
F/U
Visit
1
2
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
FT
V
z
ETb
801
Week of 
Treatment
-3
-2
0
1
2
3
4
5
6
7
8
10
12
15
16
20
23
24
28
32
35
36
42
52
62
72
78
88
104
4 week 
post 
end of 
tx
Allowable 
Deviation 
(days)c
-
±3
±7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
-
±3
±3
±3
-
±3
±7
±7
±7
±7
±7
±7
±7
±3
Fasting Visitd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK only Visit
X
X
Telephone Visit
X
X
X
X
Hypoglycemic 
events review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient Education
Diabetes 
educationI I, j
X
BG meter, 
SMBG trainingj
X
Dispense BG 
meter/
supplies as 
needed
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug 
injection 
trainingj
X
X
Hand out diary 
and instruct on 
use
X
X
X
X
X
Remind patient 
about 7-point 
SMBGk
X
X
X
Review 7-point 
SMBG values 
collected in the 
diary
X
X
X
Dispense study 
drug
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Observe patient 
Administer 
LY3298176,l,m
X

I8F-MC-GPGM(b) Clinical Protocol
Page 16
LY3298176
Study 
Period I
Study Period II
52 Weeks
Study Period III
Variable
Study 
Period IV
Screening 
Lead in
Treatment Period
Safety 
F/U
Visit
1
2
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
FT
V
z
ETb
801
Week of 
Treatment
-3
-2
0
1
2
3
4
5
6
7
8
10
12
15
16
20
23
24
28
32
35
36
42
52
62
72
78
88
104
4 weeks 
post end 
of tx
Allowable 
Deviation 
(days)c
-
±3
±7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
-
±3
±3
±3
-
±3
±7
±7
±7
±7
±7
±7
±7
±3
Fasting 
Visitd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK only 
Visit
X
X
Telephone 
Visit
X
X
X
X
Patient 
returns 
study drugs 
and 
injection 
supplies
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess 
study drug 
compliance 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review 
insulin dose 
and 
adjustment 
per TTT 
algorithmn,o
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess 
compliance 
with insulin 
dose 
adjustment 
TTT 
algorithmo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

I8F-MC-GPGM(b) Clinical Protocol
Page 17
LY3298176
Study 
Period I
Study Period II
52 Weeks
Study Period III
Variable
Study 
Period IV
Screening 
Lead in
Treatment Period
Safety F/U
  Visit
1
2
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
FTV
z
ETb
801
Week of 
Treatment
-3
-2
0
1
2
3
4
5
6
7
8
10
12
15
16
20
23
24
28
32
35
36
42
52
62
72
78
88
104
4 weeks 
post end of 
tx
Allowable 
Deviation 
(days)c
-
±3
±
7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
-
±3
±3
±3
-
±3
±7
±7
±7
±7
±7
±7
±7
±3
Fasting 
Visitd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK only 
Visit
X
X
Telephone 
Visit
X
X
X
X
Laboratory Tests
Serum 
pregnancy 
testp
X
Urine 
pregnancy 
testq
X
X
X
X 
X
X
X
X
X
X
Follicle-
stimulating 
hormone 
testr
X
Chemistry 
panel
Xs
X
X
X
X
X
X
X
X
X
Fasting 
serum 
glucose
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lipid panel
X
X
X
X
X
X
X
X

I8F-MC-GPGM(b) Clinical Protocol
Page 18
LY3298176
Study 
Period I
Study Period II
52 Weeks
Study Period III
Variable
Study 
Period 
IV
Screening 
Lead in
Treatment Period
Safety 
F/U
   Visit
1
2
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
FTV
z
ETb
801
Week of 
Treatment
-3
-2
0
1
2
3
4
5
6
7
8
10
12
15
16
20
23
24
28
32
35
36
42
52
62
72
78
88
104
4 weeks 
post 
end of 
tx
Allowable 
Deviation 
(days)c
-
±3
±7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
-
±3
±3
±3
-
±3
±7
±7
±7
±7
±7
±7
±7
±3
Fasting Visitd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK only Visit
X
X
Telephone 
Visit
X
X
X
X
Urinary 
albumin/
creatinine 
ratio
X
X
X
X
X
X
X
X
Serum 
creatinine, 
eGFR (CKD-
EPI)t
Xs
Xu
X
X
X
X
X
X
X
X
X
Calcitonin
Xs
X
X
X
X
X
X
X
X
X
Hematology
Xs
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pancreatic 
amylase, 
lipase
Xs
X
X
X
X
X
X
X
X
X
Immuno-
genicityv
X
X
X
X
X
X
X
X
X
X
X

I8F-MC-GPGM(b) Clinical Protocol
Page 19
LY3298176
Study 
Period I
Study Period II
52 Weeks
Study Period III
Variable
Study 
Period 
IV
Screening 
Lead in
Treatment Period
Safety 
F/U
Visit
1
2
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
FTV
z
ETb
801
Week of 
Treatment
-3
-2
0
1
2
3
4
5
6
7
8
10
12
15
16
20
23
24
28
32
35
36
42
52
62
72
78
88
104
4 
weeks 
post 
end of 
tx
Allowable 
Deviation 
(days)c
-
±3
±
7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
-
±3
±3
±3
-
±3
±7
±7
±7
±7
±7
±7
±7
±3
Fasting Visitd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK only Visit
X
X
Telephone 
Visit
X
X
X
X
PK sample for 
Immuno-
genicityw
X
X
X
X
X
X
X
X
X
X
Anti-GAD 
antibody
X
LY  PKx
X
X
X
X
X
  Pharmaco-
  genetic stored
  sample
X
Non-
 Pharmaco-
genetic          
stored sample
X
X
X
X
X
X

I8F-MC-GPGM(b) Clinical Protocol
Page 20
LY3298176
Study 
Period I
Study Period II
52 Weeks
Study Period III
Variable
Study 
Period 
IV
Screening 
Lead in
Treatment Period
Safety 
F/U
   Visit
1
2
3a
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
FTV
z
ETb
801
Week of 
Treatment
-3
-2
0
1
2
3
4
5
6
7
8
10
12
15
16
20
23
24
28
32
35
36
42
52
62
72
78
88
104
4 
weeks 
post 
end of 
tx
Allowable 
Deviation 
(days)c
-
±3
±7
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
-
±3
±3
±3
-
±3
±7
±7
±7
±7
±7
±7
±7
±3
Fasting 
Visitd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK only 
Visit
X
X
Telephone 
Visit
X
X
X
X
Patient-Reported Outcomes (PROs)y
APPADL
X
X
X
EQ-5D-5L
X
X
X
IW-SP
X
X
X
DTSQs 
X
DTSQc
X
X
Abbreviations: ADA = anti-drug antibodies; APPADL = Ability to Perform Physical Activities of Daily Living; BG = blood glucose; BP = blood pressure; 
CKD-EPI = Chronic Kidney Disease-Epidemiology; DTSQc = Diabetes Treatment Satisfaction Questionnaire change; DTSQs = Diabetes Treatment 
Satisfaction Questionnaire status; ECG = electrocardiogram;; eGFR = estimated glomerular filtration rate; EQ-5D-5L = European Qualtiy of Life-
dimensions; ET = early termination; FTV = final treatment visit; F/U = follow-up; GAD = glutamic acid decarboxylase; HbA1c = hemoglobin A1c; HR = 
heart rate; IW-SP = Impact of Weight on Self Perception; LY=LY3298176; PK = pharmacokinetics; PRO = patient-reported outcome; SGLT-2i = sodium-
glucose co-transporter-2 inhibitor; SMBG = self-monitored blood glucose; SU = sulfonylurea; TTT = treat-to-target; Tx = treatment.

I8F-MC-GPGM(b) Clinical Protocol
Page 21
LY3298176
a
Baseline assessments must be completed before processing in the interactive web-response system (IWRS).
b
Patients who are unable or unwilling to continue in the study for any reason will perform an ET visit. If the patient is discontinuing during an unscheduled 
visit, that visit should be performed as the ET visit. If the patient is discontinuing during a scheduled visit, that visit should be performed as an ET visit. 
Visit 801 (safety follow-up visit) should be performed 4 weeks after the ET visit as the final study visit.
c
The visit date is determined in relation to the date of the randomization visit (± the allowed visit window). 
d
On visits 3, 5, 7, 11, 13, 15, 16, 18, 23, 24, 27, 29, ET, and at follow-up (801), 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 study drug(s), metformin (if 
used), SGLT-2i (if used), SU (if used).
e
Medical history includes assessment of preexisting conditions (including history of gall bladder disease, cardiovascular disease, and medullary thyroid 
carcinoma) and substance usage (such as, alcohol and tobacco).
f
Weight measurements should be obtained per the detailed guidance in the Manual of Operations.
g
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.
h
Dilated fundoscopic exam 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 exam will be recorded on a specific retinopathy eCRF as a baseline 
measure of retinopathy.  A follow-up dilated fundoscopic exam should be performed when clinically indicated by any adverse event suspected of worsening
retinopathy, and the findings should be recorded on the retinopathy eCRF.
i
Includes counseling on diet and exercise, management of hypoglycemia and hyperglycemia, etc.
j
All training should be repeated as needed to ensure patient compliance. 
k
Patient is required to collect two 7-point SMBGs on nonconsecutive days prior to the next visit. A 7-point SMBG consists of measurements before and 2 
hours after each of 3 main meals within the same day and at bedtime. These SMBG profiles will be collected by the patient within 2 weeks prior to the 
assigned visits. If 7-point SMBG is not performed, then data from the most recent nonconsecutive 4-point SMBG profiles can be used. If more than 2 SMBG 
profiles are available, the 2 most recent nonconsecutive profiles should be used.
l
Patients should administer their first dose of LY3298176 at the end of this visit, after other study procedures and randomization. 
m LY3298176 patients only.
n
During the first 8 weeks, the dose adjustment will be determined by the investigator in discussion with the patient by following a TTT algorithm. After 
Week 8, the dose adjustment will be determined by the patient in a weekly manner and will be reviewed by the investigator at each office visit. Patient will 
have weekly visits (clinic or phone) in the first 8 weeks and then visits every 2-3 weeks (clinic or phone) until Week 16 in order to improve compliance with 
the TTT algorithm.
o
Insulin glargine patients only. A review of the patient’s compliance to the TTT algorithm will still be conducted during the telephone Visits 6, 8, 9, and 12, 
but the patient’s compliance for these visits will be collected in the eCRF at Visits 7, 10 and 13 for the period since the previous visit.
p
A serum pregnancy test will be performed at Visit 1 for women of childbearing potential only.
q
A urine pregnancy test must be performed at Visit 3 with the result available prior to randomization and first injection of study drug(s) for women of 
childbearing potential only.  Additional pregnancy tests may be performed at the investigator’s discretion during the study.  If required per local regulations 
and/or institutional guidelines, pregnancy testing can also occur at other times during the study treatment period.

I8F-MC-GPGM(b) Clinical Protocol
Page 22
LY3298176
r
Follicle-stimulating hormone test performed at Visit 1 for postmenopausal women at least 50 years of age with an intact uterus, without a history of 
oophorectomy or bilateral tubal ligation, not on hormone therapy, and who have had spontaneous amenorrhea for more than 6 months and less than 12 
months.
s
Screening visit assessment will serve as baseline.
t
The CKD-EPI equation will be used by the central lab to estimate and report eGFR. For patients who meet inclusion criterion [4] based solely on history of 
chronic kidney disease and eGFR <60 mL/min/1.73m2, the eGFR value must be confirmed to be <60 mL/min/1.73m2 at Visit 2.  
u
This sample is required only for patients who meet inclusion criterion [4] based solely on history of chronic kidney disease and eGFR <60 mL/min/1.73m2.
v
In the event of systemic drug hypersensitivity reactions (immediate or nonimmediate), additional blood samples will be collected including ADA, PK, and,
exploratory biomarker sample.  
w
PK sample for immunogenicity must be collected prior to drug administration.
x
PK samples will not be collected from patients who were randomized to insulin glargine since it is an open-label study.  PK samples will be collected at these 
visits at time windows of 1 to 24 hours, 24 to 96 hours, OR 120 to 168 hours post dose, as assigned by IWRS. Dependent on the time-windows to which a 
patient gets assigned, they may be required to come to site for PK-specific visits. Draw PK at ET visit only if patient discontinues study prior to Week 35.
Visits 10 and 14 are for all patients, but only those patients assigned to PK will get a PK blood draw. Visits 17 and 21 are for patients assigned to a PK blood 
draw only.
y
PROs should be completed before any other study procedures if the patient is not adversely affected by the fasting condition or completed after the patient has 
sufficiently recovered from the preceding visit procedures.
z
When the sponsor determines that the study has met the completion criteria, all patients remaining in the study will return to the site for a FTV within 
approximately 30 days.  The safety follow-up visit will be approximately 30 days after the FTV.
Note: Patients will be required to collect a daily BG and a weekly 4-point SMBG.

I8F-MC-GPGM(b) Clinical Protocol
Page 23
LY3298176
3.
Introduction
3.1.
Study Rationale
Type 2 diabetes mellitus (T2DM) is a metabolic condition characterized by impaired glycemic 
control caused by increased insulin resistance and successive beta-cell failure and consequently 
inadequate insulin secretion. Type 2 diabetes mellitus is frequently associated with 
comorbidities such as increased weight or obesity, hypertension, and increased blood lipoprotein 
concentrations.  Patients with T2DM have a higher risk for cardiovascular diseases (CVDs)
particularly arteriosclerotic diseases in the heart and in the central nervous system.  In case of 
prevalent arteriosclerotic diseases and/or chronic kidney diseases (CKD) of T2DM patients, the 
likelihood of a subsequent, life-threatening major cardiovascular (CV) event is very high, up to 
2% to 4%/year (Haffner et al. 1998).  To prevent these, complex medical therapy is warranted 
beyond the necessary changes in lifestyle and diet.  Among others, patients have to achieve a 
tight glycemic control by combination of various antihyperglycemic medications (American 
Diabetes Association 2017).  The diabetes therapy usually starts with lifestyle and diet changes 
followed by 1 or more oral medications.  When oral antihyperglycemic therapies are insufficient 
to reach the therapy goal of target glycemia, injectable therapies are added to them.  Insulins, 
especially basal insulins, like glargine, are basic injectable treatments after failure of the oral 
therapy.  Adequately titrated glargine therapy, in combination with oral treatment, frequently 
achieves the target glycemic level.  Glargine therapy, however, is frequently associated with 
weight increase and eventual hypoglycemia.  LY3298176 is a 39-amino acid synthetic peptide 
with agonist activity at both the GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 
(glucagon-like peptide-1) receptors.  Its structure is based on the GIP sequence and includes a 
C20 fatty di-acid moiety.  It is administered once weekly (QW) by subcutaneous (SC) 
administration. The aim of the present study is to compare the glycemic effect of glargine and 
LY3298176 in patients with T2DM and elevated risk for CVD. In addition, the number of major 
cardiovascular outcome events (MACE-4) to be collected in the study with high CV risk 
patients, will largely contribute to establishing the cardiovascular safety of LY3298176 prior to 
submission for license, as requested by the regulatory agencies. The study could also compare 
the effect of these drugs on weight loss and their safety profile.
Study I8F-MC-GPGM (GPGM) is a Phase 3, open-label comparator, multicenter, parallel-arm, 
randomized study to compare the safety and efficacy of 3 maintenance doses of LY3298176 with 
insulin glargine in patients with T2DM with increased CV risk. The primary endpoint will be 
the mean change hemoglobin A1c (HbA1c) from baseline to 52 weeks.
3.2.
Background
Three LY3298176 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).  
Phase 1 Study GPGA was a combination of single ascending dose (SAD) and multiple ascending
dose study in healthy subjects and a multiple dose study in patients with T2DM.  Study GPGA 
investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of 

I8F-MC-GPGM(b) Clinical Protocol
Page 24
LY3298176
LY3298176 administered as SC injections.  A total of 142 subjects (89 healthy subjects and 
53 patients with T2DM) received at least 1 dose of treatment.  Doses of LY3298176 ranged from 
0.25 mg to 8 mg in the SAD (with maximum tolerated dose achieved at 5 mg); multiple doses 
from 0.5 mg to 4.5 mg QW; and titrated doses up to 10 mg QW for 4 weeks in healthy subjects; 
and multiples doses at 0.5 mg and 5 mg QW and titrated to 15 mg QW for 4 weeks in T2DM 
patients.  
LY3298176 was better tolerated by patients with T2DM than healthy subjects. Doses higher 
than 5 mg were better tolerated when attained via escalation. Maximum tolerated dose of 
LY3298176 in healthy subjects following single-dose administration was 5 mg. A dose of 15 mg 
LY3298176 was administered in patients with T2DM by accelerated dose escalation over 4 
weeks (5/5/10/15 mg) and while considered to be safe, was associated with high incidence of GI 
events.
Gastrointestinal (GI) adverse events (AEs) (nausea, vomiting, diarrhea, decreased appetite, 
abdominal distension) were the most frequently reported events by both healthy subjects and 
patients with T2DM and were dose related.  Most AEs were mild in severity, few were moderate, 
and none were reported as severe.  There were no apparent trends in chemistry, hematology, or 
urinalyses.  A few subjects experienced elevations in lipase and/or amylase levels, but these 
episodes were not associated with drug-related risk of pancreatitis.
The safety and tolerability and PK/PD profiles of LY3298176 at doses and escalation regimens 
administered in this phase 1 study supported further development of LY3298176 for QW dosing 
in patients with T2DM.
Phase 2 studies have evaluated the efficacy, tolerability, and safety of LY3298176 in patients 
with T2DM with inadequate glycemic control on diet and exercise alone or on a stable dose of 
metformin monotherapy.
3.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated AEs of LY3298176 are to be found in the Investigator’s Brochure 
(IB).
In addition, detailed information about the known and expected benefits and risks of insulin 
glargine may be found in the insulin glargine package insert (Basaglar USPI, 2015 [WWW]).

I8F-MC-GPGM(b) Clinical Protocol
Page 25
LY3298176
4.
Objectives and Endpoints
Table GPGM.2 shows the objectives and endpoints of the study.
Table GPGM.2.
Objectives and Endpoints
Objectives
Endpoints
Primary

To demonstrate that QW LY3298176 10 mg
and/or 15 mg is noninferior to insulin glargine 
for change from baseline in HbA1c at 52
weeks

Mean change in HbA1c
Key Secondary (controlled for type 1 error)
Efficacy

To demonstrate that QW LY3298176 5 mg is 
noninferior to insulin glargine for change from 
baseline in HbA1c at 52 weeks 

Mean change in HbA1c 

To demonstrate that QW LY3298176 5 mg, 
10 mg, and/or 15 mg is superior to insulin 
glargine for change from baseline in weight at 
52 weeks

To demonstrate that QW LY3298176 5 mg, 
10 mg, and/or 15 mg is superior to insulin 
glargine for change from baseline in HbA1c at 
52 weeks 

To demonstrate that QW LY3298176 5 mg, 
10 mg, and/or 15 mg is superior to insulin 
glargine for the proportion of patients with 
HbA1c target values of <7.0 (53 mmol/mol) at 
52 weeks.

Mean change in body weight 

Mean change in HbA1c

HbA1c
Additional Secondary (not controlled for type 1 
error)
Efficacy

To demonstrate that QW LY3298176 5 mg, 
10 mg, and/or 15 mg is superior to insulin 
glargine at 52 weeks

The mean change in fasting serum glucose
(central laboratory) from baseline

The proportion of patients achieving an 
HbA1c target value of ≤6.5% (48 mmol/mol), 
and <5.7% (39 mmol/mol)

Mean change in 7-point self-monitored blood 
glucose (SMBG) profiles from baseline

Proportion of patients who achieved weight 
loss of ≥5%, >10%, and >15% from baseline 
Safety

I8F-MC-GPGM(b) Clinical Protocol
Page 26
LY3298176

To compare the safety of LY3298176 5 mg, 
10 mg, and 15 mg LY3298176 to insulin 
glargine at 52 weeks, and at the end of the 
safety follow-up period, with respect to the 
following outcomes: 

Treatment-emergent adverse events (TEAEs)

Early discontinuations of study drug due to 
AEs

Adjudicated deaths and nonfatal major CV 
events

Adjudicated pancreatic AEs

Medullary thyroid carcinoma (MTC) and 
serum calcitonin 

Incidence of treatment-emergent (TE) 
LY3298176 anti-drug antibodies (ADA) and 
systemic hypersensitivity reactions

Mean change in systolic and diastolic blood 
pressure and heart rate from baseline

Occurrence of hypoglycemic events 

Incidence of initiation of rescue therapy for 
severe, persistent hyperglycemia
Pharmacokinetics

To characterize the PK of LY3298176 5 mg, 
10 mg, and 15 mg and evaluate the 
relationship between LY3298176 exposure 
and safety, tolerability, and efficacy measures

Population PK and PD parameters
Tertiary/Exploratory

To characterize long-term glycemic control 
with LY3298176 5 mg, 10 mg, and 15 mg

To compare LY3298176 5 mg, 10 mg, and 
15 mg to insulin glargine with respect to the 
following:

HbA1c

Change in lipids (total cholesterol, high-
density lipoproteins, low-density lipoproteins, 
very low-density lipoproteins, and 
triglycerides) from baseline

Changes from baseline in mean body mass 
index (BMI)

Change in waist circumference

Biomarkers

Patient-Reported Outcomes (European 
Quality of Life – dimensions [EQ-5D-5L], 
Ability to Perform Physical Activities of Daily 
Living [APPADL], Impact of Weight on Self-
Perception [IW-SP], status (s) and change (c) 
versions of Diabetes Treatment Satisfaction 
Questionnaire (DTSQ)

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5.
Study Design
5.1.
Overall Design
Study GPGM is a Phase 3, open-label comparator, multicenter, parallel-arm, randomized study 
to compare the safety and efficacy of 3 maintenance doses of LY3298176 with insulin glargine 
in patients with T2DM with increased CV risk.  The primary endpoint will be the mean change 
HbA1c from baseline to 52 weeks. 
Patients should be on a stable dose (no dose change for at least 90 days) of at least 1 and no more 
than 3 oral antihyperglycemic medications: metformin, sodium-glucose co-transporter-2
inhibitors (SGLT-2is), or sulfonylureas. Patients will be randomized in a 1:1:1:3 ratio to receive 
5 mg LY3298176, 10 mg LY3298176, 15 mg LY3298176, or insulin glargine.  The 
randomization will be stratified by country, baseline HbA1c concentration (≤8.5%, ˃8.5% [≤69, 
˃69 mmol/mol]), and SGLT-2i use (Yes or No). 
The study will continue until all of the following criteria are fulfilled:
1) At least 52 weeks from the time of the last patient randomized,
2) At least 300 patients assigned to the combined LY3298176 arms reach at least 78 
weeks of treatment,
3) Approximately 110 patients in this study experience at least 1 component event of the 
composite CV endpoint of cardiovascular death, myocardial infarction, stroke, or 
hospitalization for unstable angina.
The starting dose of insulin glargine will be 10 IU/day at bedtime, titrated to a fasting blood 
glucose (FBG) <100 mg/dL, following a treat-to-target algorithm (Riddle et al. 2003).  Patients 
will titrate the insulin glargine dose in a weekly manner and will make the dose decision with the 
investigator for the first 8 weeks (phone or clinic visit).  From Week 8 to Week 16, patients will
have a phone or clinic visit every other week.
Figure GPGM.1 illustrates the study design.  

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Abbreviations:  QD = once daily; QW = once weekly; SGLT-2i = sodium-glucose 
co-transporter-2 inhibitor; SU = sulfonylurea.
a
Patients will be on study drug for at least 12 months and will receive no more 
than months of treatment.
b
All patients will perform a Visit 801 4 weeks after their last treatment visit.
c
The starting dose of insulin glargine will be 10 IU/day at bedtime, titrated to a 
FBG <100 mg/dL, following a TTT algorithm (Riddle et al. 2003).
d
Patients will titrate insulin glargine dose in a weekly manner and will make the 
dose decision with the investigator for the first 8 weeks (phone or  clinic 
visit). From Week 8 to Week 16, patients will continue the titration by a phone 
consultation or clinic visit every other week, with 3 weeks between Visits 13 
and 14.
Figure GPGM.1.
Illustration of study design for Clinical Protocol I8F-MC-GPGM.
Study Period I (screening and lead-in)
Screening (Visit 1)
The purpose of screening procedures at Visit 1 is to establish initial eligibility and to obtain 
blood samples for laboratory assessments needed to confirm eligibility at Visit 2.  Patients who 
meet all applicable inclusion criteria and none of the applicable exclusion criteria at Visit 1 will 
continue on their prestudy therapy until Visit 2.

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Lead-in (Visit 2 to Visit 3)
At Visit 2, the screening laboratory results will be reviewed and patient eligibility will be 
established.  For those patients meeting all other eligibility requirements, a dilated fundoscopic
exam, performed by an ophthalmologist or optometrist, must be completed between Visit 2 and 
Visit 3 to ensure patients with proliferative retinopathy or maculopathy are identified and not 
enrolled.  During the lead-in period, eligible patients should continue their prestudy therapy (all 
oral medications at the same dose), in order to allow reliable assessment of HbA1c at baseline 
(Visit 3).  During this period, patients will be trained on disease monitoring and disease 
management procedures, study diaries, and study procedures.  
Study Period II (52-week treatment period)
Randomization (Visit 3)
At Visit 3, patients will perform all required baseline study procedures (including the collection 
of all baseline laboratory measures) prior to randomization and prior to taking the first dose of 
study drug.  Patients will be randomized in a 1:1:1:3 ratio to receive 5 mg LY3298176, 10 mg 
LY3298176, 15 mg LY3298176, or insulin glargine.  The randomization will be stratified by 
country, baseline HbA1c concentration (≤8.5%, ˃8.5% [≤69, ˃69 mmol/mol]), and SGLT-2i use 
(Yes or No).
Immediately after randomization, the patient will inject the first dose of LY3298176 at the study 
site, according to the dose escalation regimen described below.  Patients randomized to the 
insulin glargine arm will administer insulin glargine per the investigators’ discretion.  The date 
and time of the first dose of study drug should be recorded on the electronic case report form 
(eCRF).
Following randomization, patients will participate in a 52-week treatment period.  
Postrandomization period (end of Visit 3 to Visit 24):
The starting dose of LY3298176 will be 2.5 mg QW for 4 weeks, followed by an increase to 5 
mg QW, for the duration of the study low-dose arm.  For the 10-mg arm, the starting dose of 
LY3298176 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 LY3298176 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 12.5-15 
mg) until the 15-mg dose is reached and maintained for the duration of the study.  
The initial dose of insulin glargine will be 10 IU/day at bedtime, titrated to a FBG <100 mg/dL, 
following a treat-to-target (TTT) algorithm (Riddle et al. 2003) (see Section 7.2.1.2, Table 
GPGM.4).

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Study Period III (variable treatment period)
Long-term safety period (Visit 25 to Visit 29):
Some patients will continue to receive LY3298176 or insulin glargine for up to, but not longer 
than, 24 months, as determined by the sponsor. 
When the sponsor determines that the study completion criteria have been met, all patients will 
return to the site for a final treatment visit (FTV) within approximately 30 days.  Patients who 
attend Visit 29 (24 months) or the FTV are considered to have completed the treatment period.
Study Period IV (safety follow-up period)
Safety follow-up (Visit 801) visits:
All patients who complete the treatment period are required to complete Visit 801, a safety 
follow-up visit approximately 4 weeks after their last visit.  Patients discontinuing the study early 
and performing an early termination (ET) visit will also be asked to perform the safety follow-up 
visit, so that the safety follow-up visit will be their final visit.  During the safety follow-up 
period, patients will not receive study drug.  Patients will be treated with another 
glucose-lowering intervention decided upon by the investigator.  Initiation of new 
antihyperglycemic therapy for the safety follow-up period will not be classified as “rescue 
therapy.”  All antihyperglycemic medications will be entered on the eCRF specified for this 
purpose.  Patients are also required to return any remaining study diaries to the study site at the 
end of this period.
Study Procedures
Patients will perform study procedures listed in the Schedule of Activities (Section 2).  
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 GLP-1 receptor agonists,
amylin analogs, and dipeptidyl peptidase-4 (DPP-4) inhibitors (see Section 7.7).  
Pharmacokinetic samples will be collected from the first 150 patients at each LY3298176 dose, 
all patients aged ≥70 years, and all patients with severe renal impairment or end-stage renal 
disease (ESRD) (estimated glomerular filtration rate [eGFR] <30 mL/min) (see Section 9.5).
Patients who develop severe, persistent hyperglycemia based on prespecified thresholds (see 
Sections 7.2.1.2 and 9.2.2.2) will receive a new glucose-lowering intervention (“rescue therapy”) 
and will also continue to administer study drug.  Patients who need hyperglycemic rescue 
therapy will continue in the trial until they complete all study visits.  
Study governance considerations are described in detail in Appendix 3.

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5.2.
Number of Participants
A total of approximately 1878 patients will be randomized in a 1:1:1:3 ratio to 5 mg LY3298176
(313 patients), 10 mg LY3298176 (313 patients), 15 mg LY3298176 (313 patients), and insulin 
glargine (939 patients).
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
Study GPGM is designed to determine the comparative benefits and risks of QW LY3298176
5 mg, 10 mg, or 15 mg versus insulin glargine in patients with T2DM with increased CV risk. 
An active comparator rather than placebo was selected for this trial because it includes patients 
with uncontrolled T2DM despite of oral antihyperglycemic therapies (7.5% [58 mmol/mol] to 
10.5% [91 mmol/mol], inclusive) and increased risk for CVDs who will be studied for a longer 
period, up to 2 years.  To ensure a valid comparison of the randomized study treatments, it is 
important that insulin glargine is titrated optimally throughout the entire study.  Patients will be 
required to use a TTT algorithm, which has been shown to be effective in enabling a high 
proportion of patients with T2DM to achieve their therapeutic targets when treated with insulin 
glargine (Riddle et al. 2003) as described in Section 7.2.1.2.
To minimize the potential confounding effect of changes to concomitant medications, patients 
will be permitted to use concomitant medications that they require during the study. Medications 
that may interfere with the assessment of efficacy and safety characteristics of the study 
treatments will not be allowed (see Section 7.7).  
The planned duration of treatment for the primary endpoint at 52 weeks is considered appropriate 
to assess the full effects and benefit/risk of each maintenance dose of LY3298176 compared with 
the other LY3298176 doses on both glycemic control and body weight.  The variable treatment 
duration of up to, but not longer than 104 weeks, will provide sufficient 18-month patient 
exposures to meet regulatory requirements and to provide sufficient numbers of patients with a 
major adverse CV event (MACE-4:  CV death, myocardial infarction, stroke, or hospitalization 
for unstable angina) for the meta-analysis to rule out excess CV risk.
5.5.
Justification for Dose
LY3298176 doses of 5 mg, 10 mg, and 15 mg administered subcutaneously 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-week would permit time for development of tolerance to GI events and are predicted to 
minimize GI tolerability concerns.

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The maximum proposed dose of 15 mg maintains an exposure multiple of 1.6 to 2.4 to the 
no-observed adverse effect level doses in 6-month monkey and rat toxicology studies.
The selected dose and escalation scheme would enable further evaluation of benefit/risk 
considerations for 5 mg, 10 mg, and 15 mg doses of LY3298176.

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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 at 
screening:
Type of Patient and Disease Characteristics
[1]
Have been diagnosed with T2DM based on the World Health Organization
classification or other locally applicable diagnostic standards
Patient Characteristics
[2]
Have HbA1c between ≥7.5% (58 mmol/mol) and ≤10.5% (91 mmol/mol) at 
screening as determined by the central laboratory at Visit 1
[3]
On stable treatment with unchanged dose of at least 1 and no more than 3 oral 
antihyperglycemic drugs, which may only include metformin, SGLT-2i, 
and/or sulfonylurea for at least 3 months before Visit 1
[4]
Increased risk of CV events as defined by at least 1 of the following (a – e):
a) Coronary heart disease documented as having any of the following:
1) History of acute myocardial infarction (ST elevation or non-ST 
elevation) 
2) Stenosis of ≥50% in at least 1 major (left main, left anterior 
descending, ramus intermedius, left circumflex, right) coronary artery 
as determined by cardiac imaging
3) Coronary calcium score ≥300
4) Stable angina pectoris treated with anti-anginal medication
5) Asymptomatic cardiac ischemia documented by cardiac imaging on 
exercise or pharmacological stress test
6) History of coronary revascularization (percutaneous coronary 
intervention or coronary artery bypass surgery)
OR
b) Peripheral arterial disease presumed to be of atherosclerotic origin 
documented as a history of any of the following:
1) Current or intermittent claudication
2) Resting limb ischemia
3) Stenosis of >50% in an iliac, femoral, popliteal, or subclavian artery
4) An ankle-brachial index ≤0.90
5) Peripheral arterial revascularization or amputation due to 
atherosclerotic vascular disease
6) Asymptomatic carotid artery stenosis ≥70%
7) Carotid artery revascularization

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8) Abdominal aortic aneurysm
OR
c) Cerebrovascular disease presumed to be of atherosclerotic origin 
documented as a history of ischemic stroke or transient ischemic attack 
(TIA).  Patients with a history of TIA must be age ≥50 years.
NOTE:  Does not include stroke or TIA due to nonatherosclerotic causes, 
for example, hypertension, embolism, or hemorrhagic stroke
OR
d) Age ≥50 years, history of CKD, and an estimated glomerular filtration rate 
<60 mL/min/1.73m2 (CKD-Epidemiology[CKD-EPI]) on consecutive 
measurements (Visit 1 and Visit 2) 
OR
e) Age ≥50 years and congestive heart failure (CHF) documented as a history 
of CHF by the New York Heart Association Functional Classification II to
III
[5]
Are of stable weight (± 5%) ≥3 months prior to 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 
[6]
Have a BMI ≥25 kg/m2 at Visit 1
[7]
Eighteen years or older at the time of signing informed consent
Male patients:
Male patients should be willing to use reliable contraceptive methods throughout 
the study and for at least 3 months after last injection 
Female patients:
Female patients not of childbearing potential due to surgical sterilization 
(hysterectomy, bilateral oophorectomy, or tubal ligation) or menopause.
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 childbearing potential (not surgically sterilized and 
between menarche and 1-year postmenopausal) must

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
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
[8]
In the investigator’s opinion, are well motivated, capable, and willing to

perform SMBG (up to 7 measures in a day)

learn how to self-inject treatment (LY3298176 or insulin glargine), as 
required for this protocol (visually impaired persons who are not able to 
perform the injections must have the assistance of a sighted individual 
trained to inject the study drug; persons with physical limitations who are 
not able to perform the injections must have the assistance of an individual 
trained to inject the study drug) 

are willing and able to inject study drug QW/once daily 

maintain a study diary, as required for this protocol

have a sufficient understanding of one of the provided languages of 
the country such that they will be able to complete the patient 
questionnaires
Informed Consent
[9]
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 at
screening:
Medical Conditions
[10] Have type 1 diabetes mellitus (T1DM)
[11] Had chronic or acute pancreatitis any time prior to study entry (Visit 1)
[12] Have a history of proliferative diabetic retinopathy or diabetic maculopathy (a 
dilated fundoscopic exam, performed by an ophthalmologist or optometrist
between Visit 2 and Visit 3, is required to confirm eligibility) or 
nonproliferative diabetic retinopathy that requires acute treatment
[13] Have a history of ketoacidosis or hyperosmolar state/coma 
[14] Have had 1 or more episode of severe hypoglycemia and/or 1 or more episode 
of hypoglycemia unawareness within the 6 months prior to Visit 1

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[15] Have a known clinically significant gastric emptying abnormality (for 
example, severe diabetic gastroparesis or gastric outlet obstruction), have 
undergone gastric bypass (bariatric) surgery or restrictive bariatric surgery 
(for example, Lap-Band®), or chronically take drugs that directly affect GI 
motility
[16] New York Heart Association Functional Classification IV congestive heart failure
[17] Have any of the following CV conditions within 2 months prior to Visit 1:
acute myocardial infarction, cerebrovascular accident (stroke), or 
hospitalization for CHF
[18] Have acute or chronic hepatitis, signs or symptoms of any other liver disease, 
or an alanine aminotransferase (ALT) level >3.0 the upper limit of normal 
(ULN) for the reference range, as determined by the central laboratory.  
Patients with nonalcoholic fatty liver disease are eligible to participate only if 
their ALT level is ≤3.0 the ULN for the reference range
[19] Have evidence of a significant, uncontrolled endocrine abnormality (for 
example, 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
[21] Have a serum calcitonin level of
(a) ≥20 ng/L at Visit 1, if eGFR ≥60 mL/min/1.73m2
(b) ≥35 ng/L at Visit 1, if eGFR <60 mL/min/1.73m2
[22] Have evidence of significant, active autoimmune abnormality (for example, 
lupus, rheumatoid arthritis) that, in the opinion of the investigator, is likely to 
require concurrent treatment with systemic glucocorticoids in the next 12 
months.
[23] Known or suspected hypersensitivity to trial product(s) or related products
[24] History of hypersensitivity to insulin glargine
[25] Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or 
awaiting an organ transplant
[26] Have a history of an active or untreated malignancy or are in remission from a 
clinically significant malignancy (other than basal or squamous cell skin 
cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 
5 years
[27] Have a history of any other condition (such as known drug, alcohol abuse, or 
psychiatric disorder) that, in the opinion of the investigator, may preclude the 
patient from following and completing the protocol
[28] Have any hematological condition that may interfere with HbA1c 
measurement (for example, hemolytic anemias, sickle cell disease)

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Prior/Concomitant Therapy
[29] Have a history of insulin therapy except for the use of insulin for treatment of 
gestational diabetes or acute, temporary use of insulin (≤14 days), for 
example, for acute illness, hospitalization, elective surgery
[30] Treatment with any glucose-lowering agent(s) other than stated in the 
inclusion criteria (including DPP-4 inhibitors and GLP-1 receptor agonists) in 
a period of 3 months before screening prior to Visit 1   
[31] 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 of Visit 1
[32] Have been treated with drugs that promote weight loss (for example, Saxenda 
[liraglutide 3.0 mg], Xenical® [orlistat], Meridia® [sibutramine], Acutrim®
[phenylpropanolamine], Sanorex® [mazindol], Apidex® [phentermine], 
BELVIQ® [lorcaserin], Qsymia™[phentermine/topiramate combination], 
Contrave® [naltrexone/bupropion], or similar other body weight loss 
medications including over-the-counter [OTC] medications [for example, 
allī®]) within 3 months prior to Visit 1 and/or between study entry (Visit 1) 
and randomization (Visit 3)
Prior/Concurrent Clinical Trial Experience
[33] 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
[34] Have participated, within the last 30 days, in a clinical study involving an 
investigational product.  If the previous investigational product has a long 
half-life, 5 half-lives or 30 days (whichever is longer) should have passed
[35] Have previously completed or withdrawn from this study or any other study 
investigating LY3298176
Other Exclusions
[36] 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
[37] Are Lilly employees 
[38] Are unwilling or unable to comply with completing a diary to record data 
from the subject
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.  

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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 [5] (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
Individuals who do not meet the criteria for participation in this study (screen failure) must not 
be rescreened.  

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7.
Treatments
7.1.
Treatments Administered
Patients will be randomized in a 1:1:1:3 ratio to receive LY3298176 5 mg, LY3298176 10 mg, 
LY3298176 15 mg, or insulin glargine.  LY3298176 will be administered QW as SC injection in 
patients with T2D who are already treated with a stable dose of at least 1 and no more than 3 oral 
antihyperglycemic medications: metformin, sodium-glucose co-transporter-2 inhibitors, or 
sulfonylureas.  
Table GPGM.3 shows the randomized treatments for the entire treatment period.
The starting dose of LY3298176 will be 2.5 mg QW for 4 weeks, followed by an increase to 5 
mg QW, for the duration of the study low-dose arm.  For the 10-mg arm, the starting dose of 
trizepatide 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 LY3298176 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 starting dose of insulin glargine will be 10 IU/day at bedtime, titrated to a FBG <100 mg/dL, 
following a treat-to-target algorithm (Riddle et al. 2003).  Patients will titrate the insulin glargine 
dose in a weekly manner and will make the dose decision with the investigator for the first 
8 weeks (phone or clinic visit).  For further dose titration, from Week 8 to Week 16, patients will 
have a phone or clinic visit every other week.
Table GPGM.3.
LY3298176 Treatment Regimens
Treatment 
Group
Treatment Period Interval
Weeks
0 to 3
Weeks
4 to 7
Weeks
8 to 11
Weeks
12 to 15
Weeks
16 to 19
Weeks
20 to 104
15 mg 
LY3298176
2.5 mg
5 mg
7.5 mg
10 mg
12.5 mg
15 mg
10 mg 
LY3298176
2.5 mg
5 mg
7.5 mg
10 mg
5 mg 
LY3298176
2.5 mg
5 mg
Note:  All doses will be administered QW using a single-dose prefilled syringe.
The investigator or his or her designee is responsible for the following:

explaining the correct use of the investigational agent(s) 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 study drug administration

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
patient should be instructed to discard all used syringes for LY3298176 or pens 
for insulin glargine in a closeable, puncture-resistant container and dispose 
according to local regulations
7.1.1. Packaging and Labeling
The sponsor will provide LY3298176 in prefilled syringes and insulin glargine in prefilled pens.  
These will be dispensed via an interactive web-response system (IWRS).  Prefilled syringes and 
prefilled pens will be packaged in cartons to be dispensed.  Clinical trial materials will be labeled 
according to the country’s regulatory requirements.  
7.1.2. Medical Devices 
The combination products provided for use in the study are LY3298176 investigational prefilled 
syringe and a marketed insulin glargine prefilled pen.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to 1 of the study treatment arms 
at Visit 3.  Assignment to treatment arms will be determined by a computer-generated random 
sequence using an IWRS.  Patients will be randomized in a 1:1:1:3 ratio to receive 5 mg 
LY3298176, 10 mg LY3298176, 15 mg LY3298176, or insulin glargine.  The randomization 
will be stratified by country, baseline HbA1c concentration (≤8.5%, ˃8.5% [≤69, ˃69 
mmol/mol]), and baseline SGLT-2i use (Yes or No). 
7.2.1. Selection and Timing of Doses
7.2.1.1.
LY3298176
Assignment to LY3298176 (3 doses) or insulin glargine will occur at randomization.  
There are no restrictions on the time of day each weekly dose of LY3298176 is given, but it is 
advisable to administer the SC injections on the same day and same time each week.  The actual 
date and time of all dose administrations will be recorded by the patient.  If a dose of 
LY3298176 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 should be taken at 
the appropriate time.  
7.2.1.2.
Insulin Glargine
Dosing for patients randomized to insulin glargine will start at 10 units once daily. Patients 
should administer their daily doses at the time of day agreed upon between the patient and the 
investigator, typically before bedtime.  Patients assigned to the insulin glargine treatment arm 
will be instructed to adjust insulin glargine doses to a target FBG of <100 mg/dL (5.6 mmol/L) 
based on the median value of the last 3 self-monitored fasting blood glucose (SMBG) values 
according to the schedule below (Riddle et al. 2003).  Insulin glargine dose adjustments should 
occur once in a week. After Week 8, patients will continue to adjust insulin glargine per the 
titration algorithm; the insulin glargine dose will be also reviewed and revised, as needed, at 
subsequent office visits. There will be no central oversight of insulin glargine titration. Add-on 

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glycemic rescue therapy should be initiated for patients who met prespecified criteria for severe, 
persistent hyperglycemia, and further titration of glargine cannot control the condition (see Table 
GPGM.4).
Table GPGM.4.
Titration of Insulin Glargine
Median Fasting Blood Glucosea
Adjustment of Insulin Glargine
mg/dL
mmol/L
≤70
≤3.9
Decrease by 2 to 4 unitsb,c
71 to 99
4.0 to 5.5
No adjustment
100 to 119
5.6 to 6.6
Increase by 2 units
120 to 139
6.7 to 7.7
Increase by 4 units
140 to 179
7.8 to 9.9
Increase by 6 units
≥180
≥10.0
Increase by 8 units
Abbreviation:  SMBG = self-monitored blood glucose.
a
Based on the last 3 self-monitored fasting blood glucose (SMBG) values.
b
Dose should also be decreased by 2 to 4 units in the following situations:

If multiple episodes of nonsevere hypoglycemia were recorded during the assessment period at any time 
during the day; and/or

If at least 1 episode that met the criteria for severe hypoglycemia (events requiring assistance to administer 
therapy) or was associated with self-monitored blood glucose (SMBG) value <54 mg/dL (<3.0 mmol/L) 
was recorded during the assessment period.
c
If only 1 hypoglycemic episode with SMBG value ≥54 mg/dL (≥3.0 mmol/L) and ≤70 mg/dL (≤3.9 mmol/L) was 
recorded, insulin dose should not be changed.
Source:  Riddle et al. 2003.
7.3.
Blinding
This trial is open-label due to the differences in dosing schedule, titration, and devices between 
QW LY3298176 and once-daily insulin glargine.
7.4.
Dosage Modification
7.4.1. Study Drugs
Details about dose administration of LY3298176 during the study are described in Sections 7.2.1
and 8.1.2.
Insulin glargine will be adjusted according to the TTT method (see Section 7.2.1.2,
Table GPGM.4).
7.4.2. Reduction and/or Discontinuation of Concomitant 
Antihyperglycemic Medications
Temporary discontinuation of concomitant antihyperglycemic medications <14 consecutive days 
is allowed for certain clinical situations (for example, severe dehydration, elective surgery, or 
need for radiologic exam involving IV iodinated contrast dye).
In the event of a hypoglycemic episode(s) (clinical symptoms of hypoglycemia and/or blood 
glucose (BG)-confirmed symptomatic BG hypoglycemia [glucose concentration ≤3.1 mmol/L 

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[{56 mg/dL}]), in patients on any oral treatment combination containing sulfonylurea, the 
sulfonylurea dosage should be reduced or discontinued. In patients not on sulfonylurea 
(anymore) but on dual oral treatment of metformin and SGLT-2i, in case of (further) 
hypoglycemic episode(s), the dose of metformin should be reduced or discontinued prior to 
reducing/discontinuing SGLT-2i. When hypoglycemia develops in patients on any oral 
monotherapies, the dose of this oral medication should be reduced or discontinued. For further 
information see Section 9.2.2.1.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or his or her designee is responsible for the following:

confirming 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.

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 study drug in a locked and secure environment. Please refer to the 
study drug label for specific storage conditions. Patients will receive insulated bags with cooling 
gel packs for use in transporting the study drug carton from the site to home. 
Study site staff must regularly assess whether the patient is correctly administering the assigned 
study drug and storing the study drug according to the provided instructions. 
7.6.
Treatment Compliance
Study drug compliance will be determined by the following:

Study drug 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 study drug and/or empty 
cartons at the next visit to the study site for the purpose of performing drug 
accountability.
In the 3 LY3298176 treatment arms, as well as the insulin glargine arm, treatment compliance 
for each visit interval is defined as taking at least 75% of the required doses of study drug. 
Similarly, a patient will be considered significantly noncompliant if he or she is judged by the 
investigator to have intentionally or repeatedly taken more than the prescribed amount of 
medication.  

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In addition to the assessment of a patient’s compliance with the study drug 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.
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 GLP-1 receptor agonists, 
amylin agonists, and DPP-4 inhibitors.  The list of excluded medications and procedures is 
provided in the Manual of Operations.  Other medications for glycemic control for patients 
meeting severe persistent hyperglycemia criteria for rescue may be added during the study at the 
investigator’s discretion. Patients on the insulin glargine arm should receive other 
antihyperglycemic medication only when further dose adjustment of glargine cannot control the 
persistent hyperglycemia.
Short-term insulin use is allowed for certain clinical situations (for example, elective surgery, 
during hospitalization, hyperosmolar states).  Rescue therapy with other glucose-lowering agents, 
including basal or rapid acting insulins, may be medically indicated in certain situations after 
randomization due to severe, persistent hyperglycemia or early discontinuation of study 
treatment. 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, such as 
paracetamol or aspirin) must be documented, and the name of the drug and the date(s) of 
administration must be recorded 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 or AE occurs that the investigator believes may have been 
caused by a study procedure.
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 LY3298176 were nausea, vomiting, and diarrhea.  

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The LY3298176 dose escalation scheme has been designed to minimize the development of 
intolerable GI symptoms.  The escalation period is considered to be 24 weeks, which allows 20 
weeks to escalate to 15 mg and 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 study drug dosage. 
To mitigate GI symptoms and manage patients with intolerable GI AEs, the investigator should:

Advise patients to eat smaller meals, for example, splitting 3 daily meals into 4 or more 
smaller meals, and to stop eating when they feel full.

Prescribe symptomatic medication (for example, anti-emetic or anti-diarrheal medication) 
per local country availability and individual patient needs. Use of symptomatic 
medication should be captured as concomitant medication in the eCRF.

Temporarily interrupt LY3298176 (omit 1 dose, the patient will take 3 of 4 doses at that 
dose level).  The data related to temporary interruption of study treatment should be 
documented in source documents and entered on the eCRF.

After the interruption, restart at the same dose with the patient taking medication to 
alleviate their GI symptoms (Section 8.1.2).
If intolerable GI symptoms or events persist despite the above measures, the investigator may 
decide to continue treatment at a lower, tolerated maintenance dose of LY3298176 (5 mg or 
10 mg).  

Patients at 5 mg or lower will be discontinued from LY3298176.

Patients at 7.5 mg or 10 mg will decrease the dose to 5 mg.

Patients at 12.5 mg or 15 mg will decrease the dose to 10 mg.
If de-escalation of the LY3298176 dose is necessary, the investigator will use the IWRS to 
receive the appropriate LY3298176 dispensing information.  If de-escalation is needed between 
scheduled visits, the IWRS will have unscheduled visits (for example, Visit 13a) dedicated to 
provide dispensing information for patients whose dose has been de-escalated. Those patients 
who have their dose de-escalated, will not be escalated again. The dose can be de-escalated only 
once.  After that, the patients will have to discontinue LY3298176 if intolerable GI AE persists.  
Please see the Manual of Operations for more detailed instructions.
If intolerable persistent GI symptoms occur after 24 weeks, the investigator should take the 
above measures to keep the patient on study treatment.  However, after the escalation period 
(Week 24), dose decreases will not be permitted.
7.8.
Treatment after the End of the Study
7.8.1. Treatment after Study Completion
LY3298176 will not be made available after conclusion of the study to patients.

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7.8.2. Special Treatment Considerations
Investigators will be trained on how to apply decision criteria for the timing and method of 
intervention in patients who do not reach glycemic targets during the treatment period.  An 
additional therapeutic intervention should be considered for patients with persistent 
hyperglycemia as described in Section 9.2.2.2.

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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 electronic case report form 
(eCRF).
Discontinuation of the investigational product for abnormal liver tests should be
considered by the investigator when a patient meets one of the following conditions after 
consultation with the Lilly designated medical monitor:
o
ALT or aspartate aminotransferase (AST) >8X 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 
study drug would not be medically appropriate (see Section 8.1.3)
o
Acute or chronic pancreatitis 
o
If a patient is diagnosed with 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 study drug-related hypersensitivity reaction
o
Any other TEAE, SAE, or clinically significant laboratory value for which the 
investigator believes that permanent study drug discontinuation is the appropriate 
measure to be taken

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o
If female patient becomes pregnant
o
If a patient is diagnosed with T1DM
Patients who stop the study drug permanently may receive another glucose-lowering intervention
(Section 7.4.2) 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 study 
drug. Every effort should be made by the investigator to maintain patients on study drug and to 
restart study drug after any temporary interruption, as soon as it is safe to do so.

If the number of doses missed is ≤2, the treatment can be restarted at the same dose, if the 
drug was well tolerated prior to discontinuation.

If the number of missed doses is ≥3, then the treatment should be restarted at 5 mg 
irrespective of the dose the patient was receiving before the interruption and 
subsequently, escalated as required by protocol (See Manual of Operations for further 
details).
If study drug 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.  If the study drug interruption is due to 
intolerable persistent GI AE (for example, nausea, vomiting, or diarrhea), the patients should be 
treated as suggested in Section 7.7.1.  
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 identifies 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 clinical research physician (CRP) agree that
it is medically appropriate to continue, the investigator must obtain documented approval from 
the sponsor CRP 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:

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
adherence to study drug

adherence to visit schedule

missing assessments

study drug 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

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 study drug and will have end-of-
study procedures (ET visit) performed as shown in the Schedule of Activities (Section 2).  
During the ET visit, the patient may be prescribed an appropriate glucose-lowering regimen 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 AE 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 or 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 and Procedures
The primary efficacy measurement in this study is mean change in HbA1c from baseline to 
52 weeks, as determined by the central laboratory.  Blood samples for HbA1c measurements will 
be collected at specific clinic visits as summarized in the Study Schedule.
9.1.2. Secondary Efficacy Assessments and Procedures
The following secondary efficacy measures will be collected at the times shown in the Study 
Schedule.

Change in HbA1c from baseline

Change in weight from baseline

Proportion of patients achieving a target HbA1c <7% (53 mmol/mol)
9.1.3. Exploratory Efficacy Assessments and Procedures
The following secondary efficacy measures will be collected at the times shown in the Study 
Schedule.

Fasting serum glucose measured in the central laboratory (actual values and change from 
baseline)

Seven-point SMBG profile (actual values and change from baseline to prespecified time 
points). Patients will be asked to perform two 7-point SMBG profiles over a 24-hour 
period, on nonconsecutive days, during the 14-day period prior to each visit, according to 
the Study Schedule. The 7-point profile consists of pre-meal and 2-hour postprandial 
SMBG measurements for the morning, midday, and evening meals in one day, and at 
bedtime. Pre-meal measurements should be taken before the patient begins eating the 
meal. Patients should record their glucose measurements in their patient diaries, which 
are considered source documents and are to be returned to the investigator at each study 
visit. Values from the 7-point SMBG profile will be transferred from the diary and 
recorded on the eCRF.

Change waist circumference from baseline

I 8 F-M C - G P G M( b) Cli ni c al Pr ot o c ol
P a g e 5 0
L Y 3 2 9 8 1 7 6
9. 1. 4.
A p pr o pri at e n e s s of A s s e s s m e nt s
Efficac y a n d safet y assess me nts i ncl u de d i n t his st u d y are ge nerall y re gar de d as relia ble a n d 
acc urate wit h res pect t o t he efficac y a n d safet y assess me nts i n i n di vi d uals a n d p o p ulat i ons wit h 
T 2 D M.
9. 2.
A d v er s e E v e nt s
I n vesti gat ors are res p o nsi ble f or m o nit ori n g t he safet y of pat ient s w h o ha ve e ntere d t his st u d y  
a n d f or alerti n g Lill y or its desi g nee t o a n y e ve nt t hat see ms u n us ual, e ve n if t his e ve nt ma y be 
c o nsi dere d a n u na nt ici pate d be nefit t o t he pati e nt .
T he i n vest i gat or is res p o nsi ble f or t he a p pr o priate me dical care of pat ient s d uri n g t he st u d y.
I n vesti gat ors m ust d oc u me nt t heir re vie w of eac h la b orat or y safet y re p ort.
T he i n vest i gat or re mai ns res p o nsi ble f or f oll owi n g, t hr o u g h a n a p pr o priate healt h care o pti o n, 
A Es t hat are seri o us or ot her wise me dicall y i m p orta nt, c o nsi dere d re late d t o t he i n vest i gati onal 
pr o d uct or t he st u d y , or t hat ca use d t he patie nt t o disc o nti n ue t he i n vesti gati onal pr o d uct bef ore 
c o mplet i n g t he st u d y.  T he pati e nt s h o uld be f ol l owe d u nt il t he e ve nt res ol ves or sta bilizes wit h 
a p pr o priate dia g n ostic e val uat i on.   T he fre q ue nc y of f o ll ow- u p e val uat i ons o f t he A E is left t o 
t he discret i on of t he i n vest i gat or.
Lac k of dr u g effect is n ot a n A E i n cli nical st u dies, beca use t he p ur p ose of t he cli nical st u d y is t o 
esta blis h treat me nt effect.
After t he i nf or me d c o nse nt f or m (I C F) is si g ne d, st u d y site pers o n nel will rec or d via t he 
ele ctr o nic case re p ort f or m ( eC R F ) t he occ urre nce a n d nat ure of eac h pati e nt ’s pree xisti n g 
c o n ditio ns, i ncl u di n g cli nicall y  sig nifica nt si g ns a n d s y m pt o m s of t he disease u n der treat me nt i n 
t he st u d y.  I n a d diti o n, site pers o n nel will rec or d a n y c ha n ge i n t he c o n dit i on(s) a n d a n y ne w 
c o n ditio ns as A Es . F or eac h A E, t he o nset a n d d urati o n, t he seri o us ness a n d se verit y,  a n d t he 
actio ns ta ke n wi t h res pect t o st u d y treat me nt will be rec or de d.
I n vesti gat ors s h o ul d rec or d t heir 
assess me nt of t he p ote ntial relate d ness of eac h A E t o pr ot oc ol pr oce d ure, i n vesti gat i onal pr o d uct, 
via t he C R F .
Pr oce d ures a n d assess me nts perf or me d pri or t o Visit 3 are c o nsi dere d scree ni n g pr oce d ures . T he 
res ults of t hese pr oce d ures a n d assess me nts s h o uld be c o nsi dere d pre -e xist i n g c o n diti ons a n d 
s h o uld be re p orte d as m e dical hist or y or c o nc o mita nt ill ness.  
T he i n vest i gat or will i nter pret a n d d oc u me nt w het her or n ot a n A E has a reas o na ble p ossi bilit y 
of  bei n g relate d t o st u d y treat me nt, st u d y de vice, or a st u d y pr oce d ure, ta kin g i nt o acc o u nt t he 
di sease, c o nc o mita nt treat me nt, or pat h ol o gies.
A “reas o na ble p ossi bilit y” mea ns t hat t here is a ca use a n d effect relat i ons hi p bet wee n t he 
i n vesti gati onal pr o d uct, st u d y  de vice, a n d/ or st u d y pr oce d ure a n d t he A E.
T he i n vest i gat or a ns wers Yes or N o w he n ma ki n g t his assess me nt.
Pl a n ne d s ur geries a n d n o ns ur gical i nter ve nt i ons s h o ul d n ot be re p orte d as A Es u nless t he 
u n derl yi n g me dical c o n dit i on has w orse ne d d ur i n g t he c o urse of t he st u d y.

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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 the CRF, clarifying if possible, the circumstances 
leading to any dosage modifications or 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

a life-threatening experience (that is, 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 AE should have additional data collected using the 
eCRFs (Section 9.4.5.1).
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 or she considers the event reasonably possibly related to 
the study treatment or study participation, the investigator must promptly notify Lilly.

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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 guidance or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the 
identification, recording, and expedited reporting of SUSARs that are consistent with global 
regulations and the associated detailed guidances.
9.2.2. Adverse Events of Special Interest
9.2.2.1.
Hypoglycemia 
Patients will collect information on episodes of hypoglycemia starting from Visit 2 until the last 
study visit (Follow-up Visit or Early Termination 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.  
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the PG 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
or she is experiencing symptoms and/or signs associated with hypoglycemia and has a 
BG level of ≤70 mg/dL (≤3.9 mmol/L).

Documented asymptomatic hypoglycemia is defined as any event not accompanied by 
typical symptoms of hypoglycemia but with a measured BG ≤70 mg/dL (≤3.9 mmol/L).

Documented unspecified hypoglycemia is defined as any event with no information 
about symptoms of hypoglycemia available but with a measured BG ≤70 mg/dL 
(≤3.9 mmol/L).
Clinically Significant Hypoglycemia (Level 2):

Documented symptomatic hypoglycemia is defined as any time a patient feels that he
or she is experiencing symptoms and/or signs associated with hypoglycemia and has a 
BG level of <54 mg/dL (<3.0 mmol/L).

Documented asymptomatic hypoglycemia is defined as any event not accompanied by 
typical symptoms of hypoglycemia but with a measured BG <54 mg/dL (<3.0 mmol/L).

Documented unspecified hypoglycemia is defined as any event with no information 
about symptoms of hypoglycemia available but with a measured BG <54 mg/dL 
(<3.0 mmol/L).
Severe hypoglycemia (Level 3):

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
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.
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 study drugs (insulin glargine or LY3298176). The criteria are as follows:
a) average daily BG from the QW 4-point SMBG 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) average daily BG from the QW 4-point SMBG profile >240 mg/dL (>13.3 mmol/L) 
over a consecutive 2-week period at any time 8 to 16 weeks post randomization; 
OR
c) average daily BG from the QW 4-point SMBG profile >200 mg/dL (>11.1 mmol/L) 
over a consecutive 2-week period at any time beyond the first 16 weeks post
randomization.
OR
d) HbA1c ≥8.5% (69 mmol/mol) on 2 consecutive measurements separated by at least 
8 weeks at any time beyond the first 24 weeks post randomization
Investigators should first confirm that the patient is fully compliant with the assigned therapeutic 
regimen and that they do not have an acute condition that is raising their BG. For patients in the 
insulin glargine arm, the above-described criteria for severe, persistent hyperglycemia will only 
be applicable after Week 12. The first choice before initiating any rescue therapy for those 
patients during the initial 12 weeks will be to follow the TTT algorithm and to increase the dose 

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of insulin glargine. This approach is recommended as first measure during the entire study 
course.  For patients who meet criteria for severe persistent hyperglycemia, the investigator will 
decide, in consultation with the patient, on an appropriate glucose-lowering intervention (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).  Glucagon-like peptide-1 receptor 
agonists, basal insulins, amylin analogs, and DPP-4 inhibitors are prohibited medications and 
must not be included in the rescue intervention (with the exception of basal insulin in the 
LY3298176 arm).  Patients who receive a new intervention should also continue administering 
study drugs 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 LY3298176, including this 
trial.  Acute pancreatitis is an acute inflammatory process of the pancreas that may also involve 
peripancreatic tissues and/or remote organ systems (Banks and Freeman 2006).  The diagnosis of 
acute pancreatitis requires 2 of the following 3 features:

abdominal pain, characteristic of acute pancreatitis (generally located in the 
epigastrium and radiates to the back in approximately half the cases) (Banks 
and Freeman 2006; Koizumi et al. 2006); the pain is often associated with 
nausea and vomiting)

serum amylase (total and/or pancreatic) and/or lipase ≥3X ULN

characteristic findings of acute pancreatitis on computed tomography (CT) 
scan or magnetic resonance imaging (MRI).
If acute pancreatitis is suspected, appropriate laboratory tests (including levels of pancreatic 
amylase and lipase) should be obtained via the central laboratory (and locally, if needed).  
Imaging studies, such as abdominal CT scan with or without contrast, MRI, or gallbladder 
ultrasound, should be performed.  If laboratory values and/or abdominal imaging support the 
diagnosis of acute pancreatitis, the patient must discontinue therapy with LY3298176 but will 
continue in the study on another glucose-lowering regimen.  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 study drug(s).
Each patient will have measurements of p-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 LY3298176 on pancreatic enzyme levels. Serial measures of pancreatic enzymes have 
limited clinical value for predicting episodes of acute pancreatitis in asymptomatic patients 

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(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 
amylase ≥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 
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 and papillary carcinoma and measurements of calcitonin. 
This data will be captured in specific eCRFs. The purpose of calcitonin measurements is to 
assess the potential of LY3298176 to affect thyroid C-cell function, which may indicate 
development of C-cell hyperplasia and neoplasms. 
Patients with eGFR ≥60 mL/min/1.73m2 at Baseline
Patients who develop serum calcitonin increases ≥50% over the screening value AND an 
absolute value ≥20 ng/L and <35 ng/L will be asked to repeat the measurement within 1 month.  
If this repeat value is increasing (≥10% increase), the patient will be encouraged to undergo 
additional endocrine assessment and longer term follow-up by an endocrinologist to exclude a 
serious adverse effect on the gland.  
Patients with an increase in serum calcitonin ≥50% over the screening value AND an absolute 
value ≥35 ng/L will be recommended to immediately undergo additional endocrine assessments 
and longer term follow-up by an endocrinologist.  If a patient’s labs meet this criteria, these 
clinically significant labs should be recorded as an AE.  
For patients who require additiona QC Did not see in Amendment summary nor Revised 
Protocol Sections l endocrine assessment because of increased calcitonin concentration per 
criteria provided in this section, data from the follow-up assessment will be collected in the 
specific section of the eCRF.
Patients with eGFR <60 mL/min/1.73m2 at Baseline
LY3298176 should be discontinued (after first confirming the value) if postrandomization
calcitonin value is ≥35 ng/L and has increased at least 50% over baseline. A consultation with a 
thyroid specialist (if not available, an endocrinologist) should be obtained. 

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If the increased calcitonin value (≥35 ng/L and increases by ≥50% compared to baseline) is 
observed in a patient who has been administered a medication that is known to increase serum 
calcitonin, then this medication should be stopped and calcitonin levels should be measured after 
an appropriate washout period.
For patients who require additional endocrine assessment because of increased calcitonin 
concentration per criteria provided in this section, data from the follow-up assessment will be 
collected in the specific section of the eCRF.
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.  This committee will be blinded to treatment assignment.  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.
9.2.2.6.
Supraventricular Arrhythmias and Cardiac Conduction Disorders
Treatment-emergent cardiac conduction disorders will be further evaluated. Patients who 
develop any event from these groups of disorders should undergo an electrocardiogram (ECG)
which should be submitted to the central reading center. Additional diagnostic tests to determine 
exact diagnosis should be performed, as needed. The specific diagnosis will be recorded as an 
AE. Events that meet criteria for serious conditions as described in Section 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 study 
drug(s) via the eCRF created for this purpose.  Additional samples should also be collected as 
outlined in Section 9.4.4.  Study drug(s) should be temporarily interrupted in any individual 
suspected of having a severe or serious allergic reaction to study drug(s).  Study drug(s) may be 
restarted when/if it is safe to do so, in the opinion of the investigator.  If study drug(s) 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 planned 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 in the LY3298176 arm, samples will be collected for 
measurement of LY3298176 ADA and LY3298176 concentration.
9.2.2.7.2. Anti-Drug Antibodies
The occurrence of ADA formation will be assessed as outlined in Section 9.4.4. 

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9.2.2.8.
Diabetic Retinopathy Complications
Dilated retinal fundoscopic exam 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 exam will be recorded on a specific
retinopathy eCRF as a baseline measure of retinopathy.  
A follow-up, dilated fundoscopic exam should be performed when clinically indicated by any 
adverse event suspected of worsening retinopathy, and the findings should be recorded on the 
retinopathy eCRF.  
9.2.2.9.
Hepatobiliary Disorders
All events of TE biliary colic, cholecystitis, or other suspected events related to gallbladder 
disease should be evaluated and additional diagnostic tests performed, as needed.  In cases of 
elevated liver markers, hepatic monitoring should be initiated as outlined in Section 9.4.5.1 and
Appendix 4.
9.2.2.10. Severe Gastrointestinal Adverse Events
LY3298176 may cause severe GI AEs, such as nausea, vomiting, and diarrhea.  Information 
about severe GI AEs as well as antiemetic/antidiarrheal use will be collected in the eCRF/AE 
form.  For detailed information concerning the management of GI AEs, please refer to
Section 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. GI AEs have been 
reported with LY3298176, 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. Metabolic Acidosis, Including Diabetic Ketoacidosis 
Ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, has been 
reported rarely in patients with T2DM.  Patients who present with signs and symptoms consistent 
with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood 
glucose levels, as ketoacidosis may be present even if blood glucose levels are less than 250 
mg/dL. If ketoacidosis is suspected, SGLT2is should be discontinued (if used), patients should 
be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require 
insulin, fluid, and carbohydrate replacement.
Lactic acidosis has been reported rarely in patients with T2DM associated with use of 
metformin, excessive alcohol intake, and decreased renal function. Routine bicarbonate 
assessment will be performed during the course of the study.  If lactic acidosis is suspected, 
metformin should temporarily be discontinued (if used) until the resolution of the event.

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9.2.2.13. Amputation/Peripheral Revascularization
All cases of amputation and peripheral revascularization should be reported as an AE.
9.2.2.14. Major Depressive Disorder/Suicidal Ideation
The prevalence of depressive symptoms and disorders is increased in patients with T1DM or 
T2DM (ADA 2017). Any AE of major depressive disorder or suicidal ideation should be 
reported.
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, to monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
Study drug overdose (more than the specified number and dose of injections) will be reported as 
an AE. In the event of overdose, refer to the IB for LY3298176 and/or Product Label for insulin 
glargine (Basaglar USPI, 2015 [WWW]).
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 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.
All digital ECGs will be obtained using centrally provided ECG machines and will be 
electronically transmitted to a designated central ECG laboratory. The central ECG laboratory 
will perform a basic quality control check (for example, demographics and study details) and 
then store the ECGs in a database. At a future time, the stored ECG data may be overread by a 
cardiologist at the central ECG laboratory for further evaluation of machine-read measurements 
or to meet regulatory requirements. The machine-read ECG intervals and heart rate may be used 
for data analysis and report-writing purposes, unless a cardiologist overreading of the ECGs is 
conducted prior to completion of the final study report (in which case, the overread data would 
be used).

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9.4.2. Vital Signs
For each patient, vital signs measurements 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 the 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 LY3298176 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 the LY3298176.  To interpret the 
results of immunogenicity, a PK sample will be collected at the same time points as the 
immunogenicity sample.  All samples for immunogenicity should be taken predose when 
applicable and possible.  In the event of systemic drug hypersensitivity reactions (immediate or 
nonimmediate), additional samples will be collected (including ADA, 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 onset of the event.  Instructions for the collection and handling 
of blood samples will be provided by the sponsor.  The actual date and time (24-hour clock time) 
of each sampling will be recorded.  Immunogenicity will be assessed by a validated assay 
designed to detect ADAs in the presence of the LY3298176 at a laboratory approved by the 
sponsor.  Sample collected at Visit 801 will assess immunogenicity at washout of LY3298176 (5 
half-lives post end of treatment).
Treatment-emergent ADAs are defined in Section 10.3.6.
Samples with LY3298176 ADA detected will be titered and evaluated for their ability to
neutralize the activity of assigned treatment (LY3298176-neutralizing antibodies). Samples with 
LY3298176 ADA detected will also be tested for cross-reactive binding to native GIP and GLP-

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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 Ethical Review Boards (ERBs) allow, at a facility selected by the 
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to 
LY3298176.  Any samples remaining after 15 years will be destroyed.
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 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
9.5.
Pharmacokinetics
Pharmacokinetic samples will be collected from the first 150 patients in each LY3298176 arm,
all patients aged ≥70 years, and all patients with severe renal impairment or ESRD
(eGFR<30 mL/min). 
Plasma LY3298176 concentrations will be determined from blood samples obtained from 
patients receiving LY3298176 treatment. Blood samples for PK assessment will be collected 
after 7, 15, 23, and 35 weeks of LY3298176 treatment per the Study Schedule or at early 
termination (reference to SoA).  Each patient will be assigned via IWRS to one of the sampling 
PK time windows of 1 to 24 hours, 24 to 96 hours, or 120 to 168 hours post dose at Weeks 7, 15, 
23, and 35.

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The date and time of the most recent SC injection administered prior to collecting the sample 
must be recorded on the eCRF from the study diaries.
The date and time at which each sample was drawn must be recorded on the laboratory accession 
page. 
Concentrations of LY3298176 will be assayed using a validated liquid chromatography mass 
spectrometry (LC/MS) method.
Bioanalytical samples collected to measure LY3298176 concentrations will be retained for a 
maximum of 1 year following last patient visit for the study.
9.6.
Pharmacodynamics
Samples to assess the PD properties of LY3298176 are included in the efficacy measures and not 
applicable in this section.
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 LY3298176 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 Ethical 
Review Boards (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 
LY3298176 or after LY3298176 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 
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 

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clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including 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 
LY3298176, pathways associated with T2DM, mechanism of action of LY3298176, 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 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 course of the development and commercialization of both study drugs.
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 their 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 their fasting condition.
9.9.1. European Quality of Life (EQ-5D-5L)
Generic HR-QoL will be assessed using the EQ-5D-5L (EQ-5D; EuroQoL Group 2015).  The 
EQ-5D-5L is a standardized 5-item instrument for use as a measure of health outcome.  It 
provides a simple descriptive profile and a single index value for health status that can be used in 
the clinical and economic evaluation of health care as well as population health surveys.  The 
EQ-5D-5L comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression).  The 5L version, introduced in 2005, scores each 
dimension at 5 levels (no problems, slight problems, moderate problems, severe problems, 
unable to perform/extreme problems), for a total of 3251 possible health states.  In addition to the 
health profile, a single health state index value can be derived based on a formula that attaches 
weights to each of the levels in each dimension. This index value ranges between 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 records the respondent’s self-rated 
health status on a vertical graduated (0 to 100) visual analog scale.  In conjunction with the 
health state data, it provides a composite picture of the respondent’s health status.  

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The EQ-5D-5L is used worldwide and is available in more than 170 different languages.  Details 
on the instrument, and scoring, organizing, and presenting the data collected can be found in the 
EQ-5D-5L User Guide (EuroQoL Group 2015). 
9.9.2. Ability to Perform Physical Activities of Daily Living (APPADL) 
The Ability to Perform Physical Activities of Daily Living (APPADL) questionnaire contains 7 
items that assess how difficult it is for patients to engage in certain activities considered to be 
integral to normal daily life, such as walking, standing, and climbing stairs (Hayes et al. 2011; 
Hayes et al. 2012).  Items are scored on a 5-point numeric rating scale, where 5 = “not at all 
difficult” and 1 = “unable to do.”  A raw overall score is calculated by simply summing the 
scores of the 7 items, and a transformed overall score is obtained by linearly transforming the 
raw overall score to a 0 to 100 scale.  A higher raw overall score and a higher transformed 
overall score are indicative of better ability to perform activities of daily living.  
9.9.3. Impact of Weight on Self-Perception Questionnaire (IW-SP)
The Impact of Weight on Self-Perception (IW-SP) questionnaire contains 3 items that assess 
how often the patients’ body weight affects how happy they are with their appearance and how 
often they feel self-conscious when out in public (Hayes and DeLozier 2015).  Each item is rated 
on a 5-point scale ranging from “always” to “never.”  Total scores for the IW-SP are derived by 
summing the item scores and dividing by the number of items.  The score can also be 
transformed to a range from 0 to 100.  Higher IW-SP scores correspond to better self-perception 
(Hayes and DeLozier 2015).
9.9.4.
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
Patients will be randomized in a 1:1:1:3 ratio to 5 mg LY3298176, 10 mg LY3298176, 15 mg 
LY3298176, and insulin glargine to optimize CV risk assessment of LY3298176.
Although the primary objective is to establish noninferiority, sample size selection is guided by 
the objective of establishing superiority of each LY3298176 dose to insulin glargine relative to 
the reduction in mean HbA1c change from baseline at 52 weeks from randomization irrespective
of adherence to investigational product or introduction of rescue therapy for persistent severe 
hyperglycemia (“treatment-regimen” estimand).  
The sample size determination assumes that evaluation of superiority of 10 mg LY3298176 and 
15 mg LY3298176 to insulin glargine will be conducted in parallel, each at a 2-sided 
significance level of 0.025 using a 2-sample t-test.  Additionally, a 0.30% superior mean HbA1c 
reduction from baseline at 52 weeks from randomization for 10 mg LY3298176 and 15 mg 
LY3298176 compared to insulin glargine and a common standard deviation (SD) of 1.3% are 
assumed for statistical power calculations.  Under the assumptions above, randomizing 1878 
patients in a 1:1:1:3 ratio to 5 mg LY3298176 (313 patients), 10 mg LY3298176 (313 patients),
15 mg LY3298176 (313 patients), and insulin glargine (939 patients) provides 90% power to 
demonstrate superiority of each LY3298176 dose to insulin glargine. 
The chosen sample size and randomization ratio also provides >90% power to establish 
superiority of 10 mg LY3298176 and 15 mg LY3298176 doses to insulin glargine in absence of 
confounding effects of rescue therapy for persistent severe hyperglycemia (“efficacy” estimand).  
For comparison of each LY3298176 dose to insulin glargine using data collected prior to the 
initiation of any rescue medication or premature treatment discontinuation, conducted in parallel 
using a 2-sample t-test, each at a 2-sided significance level of 0.025, a 0.30% superior mean 
HbA1c reduction compared to insulin glargine, a common SD of 1.1%, and no more than 28% 
initiate of any rescue antihyperglycemic medication or prematurely discontinue study drug by 52
weeks are assumed.
The trial is designed to contribute toward a meta-analysis across Phase 3 trials demonstrating that 
LY3298176 treatment is not associated with excessive CV risk.  The anticipated treatment 
allocation of pooled LY3298176 versus pooled comparator is 3:1 in other LY3298176 Phase 3 
clinical trials. The primary measure of CV risk is the hazard rate of CEC that confirmed 4-
component MACE-4: CV death, myocardial infarction (MI), stroke, and hospitalization for 
unstable angina.  Under the assumption of no increase or decrease in CV risk with LY3298176
compared to pooled comparator, approximately 133 patients with MACE-4 events are required 
to have 90% power to ensure that the upper 95% confidence limit for the hazard ratio is less than 
1.8 in the meta-analysis.  Assuming 33 to 40 patients with MACE-4 events per 1000 patient 
years of exposure and 2% reduced exposure due to lost to follow-up, patients followed for an 
average of 18 to 22 months is expected to result in 110 patients with MACE-4 events. 

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10.2. Populations for Analyses
For purposes of analysis, the following analysis sets are defined in Table GPGM.5 below:
Table GPGM.5.
Description of Analysis Sets
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 study 
drug.
Efficacy analysis set (EAS)
Data obtained during Study Period II and III from mITT, excluding data after 
initiating rescue antihyperglycemic medication or stopping study drug (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 and III from mITT, regardless of 
adherence to study drug or initiation of rescue antihyperglycemic medication. 
Safety analysis set (SAS)
Data obtained during both Study Period II, III, and IV from mITT, regardless 
of adherence to study drug or initiation of rescue antihyperglycemic
medication.
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.
There will be 2 estimands of interest in comparing efficacy of LY3298176 doses with insulin 
glargine. First estimand, the “efficacy” estimand, represents efficacy prior to discontinuation of 
study drug without confounding effects of antihyperglycemic rescue therapy.  Second estimand, 
the “treatment-regimen” estimand, represents the efficacy irrespective of adherence to study drug 
or initiation of rescue antidiabetic drugs.  
The primary efficacy assessment, guided by the “efficacy” estimand, will be conducted using 
EAS. The primary efficacy assessment, guided by the “treatment-regimen” estimand, will be 
conducted using FAS. As they are intended for different purposes, no multiplicity adjustments 
will be made for conducting 2 primary efficacy assessments.
Unless specified otherwise, safety assessments will be guided by an estimand comparing safety 
of LY3298176 doses with insulin glargine irrespective of adherence to study drug or initiation of 

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antihyperglycemic rescue therapy. Thus, safety analysis will be conducted using safety analysis 
set (SAS).  Selected safety analysis may be conducted after excluding data on rescue therapy.  
Summary statistics for continuous measures will include sample size, mean, SD, median, 
minimum, and maximum.  The analysis model to make comparisons among treatment arms 
relative to continuous measurements assessed over time will be a mixed model for repeated 
measures (MMRM), with terms: treatment, visit, and treatment-by-visit interaction, country, 
SGLT-2i use (Yes or No), and baseline measurement as a covariate. An unstructured covariance
structure will model relationship of within-patient errors.
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. 
Other statistical methods may be used, as appropriate, and details will be documented in the 
SAP.
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 study drug will be presented by treatment groups.  A listing of randomized patients not 
receiving study drug will be provided. Of the patients in modified intention-to-treat (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.  
10.3.2.2. Patient Characteristics
Demographic, medical history, and concomitant illness will be summarized by treatment group, 
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 incidence of initiation of rescue therapy for severe, persistent hyperglycemia will 
be analyzed as an exploratory safety endpoint. Dose modifications of oral antihyperglycemic 
therapy will also be compared between treatment arms.

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10.3.2.4. Treatment Compliance 
Of the patients in mITT set, frequency counts and percentages of patients prematurely 
discontinuing study drug, including reason for premature discontinuation, will be presented by 
treatment groups.  A Kaplan-Meier analysis of time from randomization to premature study drug 
discontinuation by treatment group will be provided.
Treatment compliance for each visit interval is defined as taking at least 75% of required
injections of study drugs. Frequency counts and percentages of patients compliant to study drug 
will be summarized by treatment arms and visits using the mITT set.
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
As indicated in Section 10.3.1, there will be 2 primary efficacy analyses conducted to establish 
noninferiority of 10 mg LY3298176 and 15 mg LY3298176 to insulin glargine relative to mean 
change in HbA1c from baseline to 52-week visit.
For the FDA, the primary efficacy analysis will be guided by the “treatment-regimen” estimand 
defined in Section 10.3.1.  This assessment will analyze change in HbA1c values obtained at 
52-week visit using an analysis of covariance (ANCOVA) with terms, treatment, stratification 
factors, and baseline HbA1c as a covariate.  Missing change in HbA1c from baseline values at 
52-week visit will be imputed based on observed changes in HbA1c from baseline values at the 
visit from patients in the same treatment arm who had their efficacy assessed after early 
discontinuation of study drug and/or initiation of rescue antihyperglycemic medication.  With the 
aid of the ANCOVA, 2-sided 97.5% CI for the difference in mean change in HbA1c from 
baseline to 52-week visit between 10 mg LY3298176 and insulin glargine as well as between 
15 mg LY3298176 and insulin glargine will be constructed.  Analysis will be conducted with 
multiple imputations, and statistical inference over multiple imputations will be guided by the 
method proposed by Rubin (1987).  If the upper limit of the CI is below 0.3%, LY3298176 dose 
will be declared noninferior to insulin glargine.
For all other purposes, the primary efficacy analysis will be guided by the “efficacy” estimand 
defined in Section 10.3.1. This assessment will be conducted using EAS. The primary analysis
model for HbA1c measurements over time will be an MMRM. The response variable of 
MMRM will be change in HbA1c from baseline values obtained at each scheduled postbaseline 
visit.  The independent variables of the MMRM model are treatment group (5 mg LY3298176, 
10 mg LY3298176, 15 mg LY3298176, and insulin glargine), visit, and treatment-by-visit 
interaction, country, SGLT-2i use (Yes or No), and baseline HbA1c as a covariate.  An 
unstructured covariance structure will model relationship of within-patient errors. If the analysis 
fails to converge, the following variance-covariance matrix will be used (in order) until 
convergence is achieved: heterogeneous compound symmetry, compound symmetry, and first-
order autoregressive.  The Kenward-Roger approximation will be used to estimate denominator 
degrees of freedom. With the aid of the MMRM analysis, 2-sided 97.5% CI for the difference in 
mean change in HbA1c from baseline to 52-week visit between 10 mg LY3298176 and insulin 
glargine as well as between 15 mg LY3298176 and insulin glargine will be constructed.  If the 

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upper limit of the CI is below 0.3%, LY3298176 dose will be declared noninferior to insulin 
glargine.
10.3.3.2. Secondary Analyses
The secondary study objectives subject to type 1 error rate control are as follows: 

noninferiority of 5 mg LY3298176 dose to insulin glargine relative to mean change in 
HbA1c from baseline to 52-week visit

superiority of each LY3298176 dose to insulin glargine relative to mean change in 
HbA1c from baseline to 52-week visit

superiority of each LY3298176 dose to insulin glargine relative to mean change in body 
weight from baseline to 52-week visit

superiority of each LY3298176 dose to insulin glargine relative to proportion of patients 
achieving target value of HbA1c <7% at 52-week visit
Type 1 error-controlled strategy for primary and secondary endpoints will be described in the 
SAP.  All type 1 error-controlled secondary efficacy analyses will be conducted relative to both
estimands, the “efficacy” estimand and the “treatment-regimen” estimand.  
Analysis of change from baseline in body weight at 52-week visit will be conducted in a manner 
similar to the primary efficacy analyses with change in body weight from baseline as the 
response variable, baseline HbA1c category (≤8.5%, ˃8.5%) in place of baseline HbA1c, and 
baseline body weight as a covariate.  
Comparisons among treatments relative to proportion of patients achieving HbA1c target value 
of <7.0% (53 mmol/mol) at 52-week visit will be conducted using a logistic regression analysis 
with terms treatment, country, SGLT-2i use (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 52-week visit will be excluded.  In the analysis of patients 
achieving HbA1c target value relative to the “treatment-regimen” estimand, missing values at 
52-week visit will be imputed based on observed data at respective visits from patients in the 
same treatment arm who had their efficacy assessed after early discontinuation of study drug 
and/or initiation of rescue medication.  Analysis will be conducted with multiple imputations and 
statistical inference over multiple imputations will be guided by the method proposed by Rubin 
(1987).  
10.3.3.3. Tertiary/Exploratory Analyses 
All exploratory efficacy analysis will be guided by “efficacy” estimand and will be conducted 
using 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 LY3298176 doses with insulin glargine irrespective of adherence to study drug or initiation of 
rescue therapy. Thus, safety analysis will be conducted using Safety Analysis Set.  Selected 
safety analysis will be conducted after excluding data on rescue therapy.  

I 8 F-M C - G P G M( b) Cli ni c al Pr ot o c ol
P a g e 6 9
L Y 3 2 9 8 1 7 6
A d verse e ve nts will be c o de d fr o m t he act ual ter m usi n g t he Me dical Dict i onar y  for Re g ul at or y
Act i vities ( Me d D R A) a n d re p orte d wit h preferre d ter ms a n d s yste m or ga n class.  Selecte d
n ota bl e A Es of i nterest ma y be re p orte d usi n g hi g h -level ter ms or Sta n dar dize d Me d D R A 
Q ueri es.  S u m mar y statistics will be pr o vi de d f or i nci de nce of T E A Es, serio us a d verse e ve nts 
( S A Es), st u d y disc o nti n uatio n d ue t o A Es, stu d y dr u g disc o nt i n uati on d ue t o A Es , deat hs, a n d 
ot her C V e n d p oi nts.  C o u nts a n d pr o p orti o ns o f s u bjects e x perie nci n g A Es will be re p orte d f or 
eac h treat me nt gr o u p, a n d Fis her’s e xact test will be use d t o c o m pare t he treat me nt gr o u ps.  
1 0. 3. 4. 1. H y p o gl y c e mi c E v e nt s
I nci de nce of d oc u me nte d s y m pt o matic h y p o gl yce mia e ve nts a n d se vere h y p o gl yce mia i n eac h 
cate g or y ( eit her t otal or n oct ur nal) will be c o m pare d bet wee n L Y 3 2 9 8 1 7 6 d oses a n d i ns uli n
gl ar gi ne usi n g ne gat i ve bi n o mial re gressi o n a nal ysis. S u m m aries a n d a nal ysis will be re peate d 
e xcl u di n g data f o ll owi n g i nit iati on of resc ue a nt ih y per gl yce mic t hera p y.
1 0. 3. 4. 2. G a str oi nt e sti n al E v e nt s
S u m maries a n d a nal yses f or i nci de nce a n d se verit y of na usea , v o mit i n g, a nd diarr hea will be 
pr o vi de d b y eac h treat me nt.  
1 0. 3. 4. 3. A dj u di c at e d C ar di o v a s c ul ar E v e nt s
List i n g of deat hs, m y ocar dial i nfarcti ons, str o kes, a n d h os pitalizat i on f or u nsta ble a n gi na 
c o nfir me d b y a n i n de pe n de nt C E C will be pr o vi de d. T he dates of ra n d o mizat i on, e ve nt, first 
d ose a n d l ast d ose of st u d y dr u g, a n d ti me fr o m ra n d omizat i on t o e ve nt will be liste d.  
1 0. 3. 4. 4. C e ntr al L a b or at or y M e a s ur e s , Vit al si g n s, a n d El e ctr o c ar di o gr a m s
V alu es a n d c ha n ge fr o m baseli ne t o p ost baseli ne val ue s of  ce ntral la b orat or y meas ures, vital 
sig ns, a n d s e lecte d E C G para meters will be s u m mari ze d at eac h sc he d ule d visit. T he a nal ysis 
m o d el  t o ma ke c o m par is o ns a m on g treat me nt ar ms relat i ve t o c o nti n u o us c ha n ge fr o m baseli ne 
val ues assesse d o ver ti me will  be a n M M R M, wi t h ter ms: treat me nt, visit, a n d treat me nt - b y-visit 
i nteract i on, c o u ntr y , baseli ne S G L T - 2i use ( Yes or N o), a n d baseli ne meas ure me nt as a 
c o variate. A n u nstr uct ure d c o varia nce str uct ure will m o del relati o ns hi p of wit hi n -pat ient  err ors.
T he per ce nta ges of pat ient s wit h treat me nt -e mer ge nt a b n or mal, hi g h, or lo w l a b orat or y meas ures
at a n y ti me will be s u m marize d a n d c o m pare d bet wee n treat me nt gr o u ps b y usi n g Fis her’s e xact
test.  A treat me nt-e mer ge nt a b n or mal val ue is defi ne d as a c ha n ge fr om n or m al v al u e at baseli ne 
t o a n a b n or mal v al u e at a n y ti me d uri n g t he f oll ow- u p. A treat me nt -e mer ge nt hi g h res ult is 
defi ne d as a c ha n ge fr o m a val ue less t ha n or e q ual t o t he hi g h li mit at baseli ne t o a val ue greater 
t ha n t he hi g h li mit at a n y ti me d uri n g P erio d s II, III, a n d I V. A treat me nt -e mer ge nt lo w res ul t is 
defi ne d as a c ha n ge fr o m a val ue greater t ha n or e q ual t o t he l o w li mit at baseli ne t o a val ue less 
t ha n t he l o w li mit at a n y time d uri n g P erio ds II, III, a n d I V .  Hi g h li mit a n d l o w li mit will be
pr o vi de d i n S A P.
1 0. 3. 5. P h ar m a c o ki n eti c/ P h ar m a c o d y n a mi c A n al y s e s
L Y 3 2 9 8 1 7 6 c o nce ntrati o n data will be a nal yze d usi n g a p o p ulat i on P K a p pr oac h via n o nli near
mi xe d -effects mo deli n g wi t h t he N O N M E M s oft ware.  T he relati o ns hi ps bet wee n L Y 3 2 9 8 1 7 6
d ose a n d/ or c o nce ntr atio n a n d efficac y , t olera bilit y, a n d safety e n d p o i nts will be c haracterize d.

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Additionally, the impact of intrinsic and extrinsic patient factors such as age, weight, gender, and
renal function on PK and/or PD parameters may be examined as needed. If anti-drug antibody
titers are detected from immunogenicity testing, then the impact of immunogenicity titers on 
LY3298176 PK or any relevant PD parameters may also be examined.
10.3.6. Evaluation of Immunogenicity 
The frequency and percentage of patients with preexisting ADA, with TE ADA, and with 
neutralizing TE ADA to LY3298176 will be tabulated by LY3298176 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 ADA) or those with a 
4-fold (2 dilutions) increase in titer compared to baseline if ADAs were detected at baseline 
(treatment-boosted ADA).  For the TE ADA patients, the distribution of maximum titers will be 
described by LY3298176 dose. The frequency of neutralizing antibodies to LY3298176 and/or 
cross-reactive and neutralizing antibodies to endogenous counterparts will be tabulated in TE
ADA+ patients.
The relationship between the presence of antibodies and the PK parameters and PD response 
including safety and efficacy to LY3298176 may be assessed.
10.3.7. Other Analyses
10.3.7.1. 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.  
10.3.7.2. Subgroup Analyses 
Subgroup analyses of mean change in HbA1c from baseline to Visit 18 will be provided by age, 
race, ethnicity, gender, duration of diabetes, baseline HbA1c (≤8.5%, ˃8.5%), and baseline 
SGLT-2i use (Yes or No).
10.3.8. Interim Analyses
No interim analyses of efficacy (eg, HbA1c and body weight) are planned for this study.  
A data monitoring committee (DMC) will have the responsibility to review unblinded interim 
analysis results in order to monitor the safety of the patients in the study.  A sponsor statistical 
analysis group external to the study team will perform the data analysis for the DMC.  As no 
efficacy analyses are planned by the DMC, the family-wise error rate for the efficacy analysis of 
the current protocol will not be affected by any of these interim analyses; hence, no alpha 
spending is necessary.  The DMC will perform safety reviews periodically.  Detailed information 
regarding safety reviews will be described in the program DMC Charter.
Study sites will receive information about interim results ONLY if deemed necessary for the 
safety of their patients.

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10.3.8.1. Interim Safety CV Analysis
This study is designed to contribute approximately 110 patients with MACE-4 endpoint towards
the accrual of approximately 133 patients with MACE-4 endpoint demonstrating that 
LY3298176 treatment is not associated with excessive CV risk.  Interim analysis of the CV 
safety meta-analysis is to be conducted when all the following conditions are met:
1. At least 100 patients have reached MACE-4 endpoint confirmed by the CEC across 
all trials included in the CV meta-analysis
2. All trials included in the CV meta-analysis SAP except for the current trial have 
achieved their database lock
3. All patients in the current trial who have not discontinued the study before 12 months 
complete the 12-month primary endpoint assessment
4. At least 300 patients in the current trial receive 18 months or longer of exposure to
tirzepatide
An interim data extraction from the current trial will be conducted when all the conditions above 
are met to aid with the conduct of the interim safety CV meta-analysis.  If the interim safety CV 
meta-analysis results in discharging excessive CV risk with tirzepatide, then close-out of the 
current trial will be initiated regardless of number of patients with MACE-4 in this study.  If the 
interim safety CV meta-analysis does not result in discharging excessive CV risk with 
tirzepatide, then the current trial will continue until approximately 133 patients experience 
MACE-4 across all the trials included in the CV safety meta-analysis.

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11.
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Rubin DB. Multiple imputation for nonresponse in surveys. New York: John Wiley & Sons Inc.;
1987.
Steinberg WM, Buse JB, Ghorbani MLM, 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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Abbreviations and Definitions 
Appendix 1.
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 
APPADL 
Ability to Perform Physical Activities of Daily Living 
AST 
aspartate aminotransferase 
BG 
blood glucose 
BMI 
body mass index 
CEC 
clinical endpoint committee 
CHF 
congestive heart failure 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical 
Sciences 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease-Epidemiology 
companion diagnostic  
An in vitro diagnostic device (assay or test) that 
provides information that is essential for the safe and 
effective use of a corresponding therapeutic product 

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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. 
COVID-19 
Coronavirus Disease 2019 
CRF 
case report form 
CRP 
clinical research physician:  Individual responsible for 
the medical conduct of the study.  Responsibilities of 
the CRP may be performed by a physician, clinical 
research scientist, global safety physician, or other 
medical officer. 
CSR 
clinical study report 
CT 
computed tomography 
CV 
Cardiovascular 
CVD 
cardiovascular disease 
DMC 
data monitoring committee 
DPP-4 
dipeptidyl-peptidase-4 
DTSQ 
Diabetes Treatment Satisfaction Questionnaire 
EAS 
efficacy analysis set 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
enroll 
The act of assigning a patient to a treatment.  Patients 
who are enrolled in the study are those who have been 
assigned to a treatment. 
enter 
Patients entered into a study are those who sign the 
informed consent form directly or through their legally 
acceptable representatives. 
EQ-5D-5L 
European Quality of Life 
ERB 
ethical review board 
ESRD 
end stage renal disease 

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ET 
early termination 
FAS 
full analysis set 
FBG 
fasting blood glucose 
FSH 
follicle-stimulating hormone 
FTV 
final treatment visit 
GCP 
good clinical practice 
GI 
Gastrointestinal 
GIP 
glucose-dependent insulinotropic polypeptide 
GLP 
glucagon-like peptide-1 
HbA1c 
hemoglobin A1c 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
informed consent 
A process by which a patient voluntarily confirms his 
or her willingness to participate in a particular study, 
after having been informed of all aspects of the study 
that are relevant to the patient’s decision to participate.  
Informed consent is documented by means of a written, 
signed, and dated informed consent form. 
interim analysis 
An interim analysis is an analysis of clinical study data, 
separated into treatment groups, that is conducted 
before the final reporting database is created/locked. 
INT 
International normalized ratio 
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. 

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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 
IW-SP 
Impact of Weight on Self-Perception 
MACE 
major adverse cardiovascular events 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEN-2 
multiple endocrine neoplasia type 2 
mITT 
modified intention-to-treat 
MMRM 
mixed-model for repeated measures 
MRI 
magnetic resonance imaging 
MTC 
medullary thyroid carcinoma 
OTC 
over the counter 
PK/PD 
pharmacokinetics/pharmacodynamics 
PRO 
patient-reported outcome 
QW 
once weekly 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
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.  

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SGLT-2 
sodium-glucose co-transporter-2 
SGLT-2i 
sodium-glucose co-transporter-2 inhibitor 
SMBG 
self-monitored blood glucose 
SUSARs 
suspected unexpected serious adverse reactions 
T1DM 
type 1 diabetes mellitus 
T2DM 
type 2 diabetes mellitus 
TBL 
total bilirubin level 
TE 
treatment-emergent 
TEAE 
treatment-emergent adverse event:  An untoward 
medical occurrence that emerges during a defined 
treatment period, having been absent pretreatment, or 
worsens relative to the pretreatment state, and does not 
necessarily have to have a causal relationship with this 
treatment. 
TTT 
treat-to-target 
ULN 
upper limit of normal 

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Clinical Laboratory Tests  
Appendix 2.
Clinical Laboratory Testsa 
 
Hematology 
Clinical Chemistry 
Hemoglobin 
Serum Concentrations of: 
Hematocrit 
Sodium 
Erythrocyte count (RBC) 
Potassium 
Bicarbonate 
Mean cell volume 
Total bilirubin 
Mean cell hemoglobin concentration 
Direct bilirubin 
Leukocytes (WBC) 
Alkaline phosphatase 
Neutrophils, segmented 
Alanine aminotransferase (ALT) 
Lymphocytes 
Aspartate aminotransferase (AST) 
Monocytes 
Blood urea nitrogen (BUN) 
Eosinophils 
Creatinine 
Basophils 
Uric acid 
Platelets 
Calcium 
 
Glucose, fasting 
Urinalysis 
Albumin 
Albumin 
Cholesterol 
Creatinine 
Creatine kinase (CK) 
 
Nonpharmacogenetic Stored Samples 
 
Serum 
EDTA plasma 
P800 plasma 
Pregnancy Test (females only)b 
 
 
 
eGFR (calculated by CKD-EPI equation)c 
 
 
 
Pancreas (exocrine) 
 
Serum pancreatic amylase 
HbA1c 
Serum lipase 
 
 
Endocrine 
Immunogenicity 
Calcitonin 
LY3298176 anti-drug antibody 
Follicle-stimulating hormone 
 
  
Anti-GAD Antibodies 
 
Lipid Panel (fasting) 
   
Total cholesterol 
   
LDL 
 
HDL 
Samples for PK analysis 
 
Pharmacogentics Sample 
VLDL 
 
Triglycerides 
 
 

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Abbreviations:  CKD-EPI = Chronic Kidney Disease-Epidemiology; eGFR = estimated glomerular filtration rate; 
HbA1c = hemoglobin A1c; HDL = high-density lipoprotein cholesterol; LDL = low-density lipoprotein 
cholesterol; PK = pharmacokinetics; VLDL = very low-density lipoprotein cholesterol. 
a All tests will be performed by a Lilly-designated central laboratory, unless otherwise noted. 
b Serum pregnancy test will be performed by central laboratory at Visit 1 for women of childbearing potential; 
urine pregnancy tests may be performed at the investigator’s discretion during the study.  A local laboratory may 
be used for urine pregnancy tests. 
c Estimated glomerular filtration rate will be calculated by the central laboratory at all visits and included in lab 
result reports. 
 

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Study Governance Considerations 
Appendix 3.
Appendix 3.1. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Appendix 3.1.1. 
Informed Consent 
The investigator is responsible for the following: 
 ensuring that the patient understands the nature of the study, the potential risks 
and benefits of participating in the study, and that their 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 may have throughout the study and sharing in 
a timely manner any new information that may be relevant to the patient’s 
willingness to continue his or 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). 
The study site’s ERB(s) should be provided with the following: 
 the protocol and related amendments and addenda, current Investigator Brochure 
(IB), and updates during the course of the study 

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 informed consent form  
 other relevant documents (for example, curricula vitae, advertisements) 
 
Appendix 3.1.4. 
Regulatory Considerations 
This study will be conducted in accordance with the protocol and with the following points: 
 
consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of Medical 
Sciences 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 with clinical research experience 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 or 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 agreement that, to the best of his or 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 or her knowledge, the report accurately describes the 
conduct and results of the study. 
Appendix 3.2. 
Data Quality Assurance 
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following: 

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 provide instructional material to the study sites, as appropriate 
 provide sponsor start-up training to instruct the investigators and study 
coordinators.  This training will give instruction on the protocol, the completion 
of the eCRFs, and study procedures 
 make periodic visits to the study site 
 be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax 
 review and verify data reported to detect potential errors  
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 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. 
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. 

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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-MC-GPGM is described in Clinical Trial Agreement. 

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Hepatic Monitoring Tests for 
Appendix 4.
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, IgG 
Direct bilirubin 
Hepatitis E antibody, IgM 
Alkaline phosphatase 
 
ALT 
Anti-nuclear antibody 
AST 
 
GGT 
Alkaline Phosphatase Isoenzymesa 
CPK 
 
 
 
Anti-smooth muscle antibody (or anti-actin antibody)a 
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cells; WBC = white blood cells. 
a Assayed by Lilly-designated or local laboratory. 
b Reflex/confirmation dependent on regulatory requirements and/or testing availability. 

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World Health Organization 
Appendix 5.
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 (for example, severe infection or mesenteric 
artery thrombosis) due to an acute increase in insulin requirements, but spontaneous ketosis does 
not occur.  Some patients with type 2 diabetes later progress to a state of absolute insulin 
deficiency (Alberti and Zimmet 1998).  
 
 

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Classification of Contraceptive 
Appendix 6.
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 their preferred and usual lifestyle) or in a same-sex relationship 
with no sexual relationship with males (as part of their preferred and usual lifestyle).  
Note:  periodic abstinence (for example, 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 (must use combination of 2 methods): 
 Male condom with spermicide 
 Female condom with spermicide 
 Diaphragm with spermicide 
 Cervical sponge 
 Cervical cap with spermicide 
 
 
 

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Management of Patients with Severe, 
Appendix 7.
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 (ADA)/European Association for the Study 
of Diabetes (EASD) guidance (Inzucchi et al. 2015).  Rescue treatment with pramlintide, 
dipeptidyl peptidase-4 (DPP-IV) inhibitors, or glucagon-like peptide-1 (GLP-1) receptor agonists 
will not be allowed.  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) 
average daily blood glucose (BG) from the once-weekly 4-point self-monitored BG 
(SMBG) profile >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) 
average daily blood glucose from the once-weekly 4-point SMBG profile >240 mg/dL 
(>13.3 mmol/L) over at least a consecutive 2-week period at any time 9-16 weeks 
postrandomization;  
OR 
c) 
average daily blood glucose  from the once-weekly 4-point SMBG profile >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) on 2 consecutive measurements separated by at least 
8 weeks at any time beyond the first 24 weeks post randomization 
 
In the insulin glargine arm, the first step will be further titration of the insulin based on the 
corresponding Treat to-Target algorithm (until Week 16). 

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Changes to Study Procedures due to 
Appendix 8.
the COVID-19 Pandemic 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the novel 
COVID-19 pandemic, has caused numerous global restrictions to be enacted that may impact a 
patient’s ability and/or willingness to attend their onsite study visit as originally scheduled.  In 
such a situation, please follow the guidance below: 
1) Patients should come for the primary endpoint visit (Visit 24) at the originally planned 
52-week (±7 days) schedule whenever possible and safe to do so, at the investigator's 
discretion.  However, in order to maximize the ability for onsite visits for Visit 24, 
minimize missing data, and preserve the intended conduct of the study, the visit window 
for Visit 24 may be brought forward no sooner than 14 days (Week 50) or extended up to 
8 weeks (Week 60).   
2) The sites will need to identify and document the details of how all patients and visits 
were affected by the COVID-19 pandemic restrictions.  
3) Mobile (in home) healthcare visits may be performed at participants’ homes when 
participants cannot travel to the site due to extenuating circumstances.  These will be 
performed by a qualified home nursing service provider following sponsor approval, if 
permitted by local regulations.  Procedures performed may include, but are not limited to, 
taking blood samples, conducting physical assessments, administering PROs, and 
collecting health information.  Please note that requirements related to the reporting of 
SAEs remain unchanged.  Every effort should be made for the participant to return to 
onsite visits as soon as reasonably possible, while ensuring the safety of the participant 
and investigational site staff. 
4) Additional consent from the participant will be obtained for those who participate in 
home health services. 
 

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Protocol Amendment I8F-MC-
Appendix 9.
GPGM(b) 
Efficacy and Safety of LY3298176 Once Weekly 
versus Insulin Glargine in Patients with Type 2 
Diabetes and Increased Cardiovascular Risk 
(SURPASS-4) 
Overview 
Protocol I8F-MC-GPGM Efficacy and Safety of LY3298176 Once Weekly versus Insulin 
Glargine in Patients with Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4) has 
been amended.  The new protocol is indicated by amendment (b) 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 described in the 
following table.  Note that minor edits have been made throughout the protocol, which are not 
captured in the amendment summary table.

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Amendment Summary for Protocol I8F-MC-GPGM Amendment (b) 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 2 Schedule 
of Activities 
Added a final treatment visit (FTV) 
and corresponding activities related 
to this visit 
Addition of this visit will allow consistent collection 
of data as patients complete the treatment period. 
Section 5.1 Overall 
Design 
Changed visit numbers for the 
postrandomization period and Study 
Period III (variable treatment period) 
Correction/clarification. 
Section 5.1 Overall 
Design 
Added language related to the FTV 
Addition of this visit will allow consistent collection 
of data as patients complete the treatment period. 
Section 10.3.8 
Interim Analyses 
Added language for a Safety Interim 
Analysis for the program wide 
MACE-4 Meta-Analysis 
Based on regulatory interaction. 
Appendix 8 
Added language describing changes 
to the study procedures due to the 
COVID-19 pandemic 
The added language provides guidance when a 
patient’s ability and/or willingness to attend their 
onsite study visit is impacted by the global 
restrictions enacted in response to the COVID-19 
pandemic. 
 

Leo Document ID = a5cbc2ab-abd6-41f1-9bc9-b4fb6b412699
Approver: 
Approval Date & Time: 10-Jul-2020 15:14:01 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 10-Jul-2020 15:42:01 GMT
Signature meaning: Approved
PPD
PPD