Clinical trial NCT03131687
Conditions: Type 2 Diabetes Mellitus
Sponsor: Eli Lilly and Company
Start date: 2017-05-24; Completion date: 2018-08-01
Enrollment: 318 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy of the study drug tirzepatide in participants with type 2 diabetes mellitus.

Detailed description:

Arms: arm 1: Tirzepatide placebo and dulaglutide placebo administered subcutaneously (SC) once weekly. arm 2: 1 milligrams (mg) tirzepatide administered SC once weekly. Dulaglutide placebo administered SC once weekly. arm 3: 5 mg tirzepatide administered SC once weekly. Dulaglutide placebo administered SC once weekly. arm 4: 10 mg tirzepatide administered SC once weekly. Dulaglutide placebo administered SC once weekly. arm 5: 15 mg tirzepatide administered SC once weekly. Dulaglutide placebo administered SC once weekly. arm 6: 1.5 mg Dulaglutide administered SC once weekly. Tirzepatide placebo administered SC once weekly.
Interventions: intervention 1: tirzepatide intervention 2: Dulaglutide intervention 3: Placebo
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC intervention 3: Administered SC

Protocol documents:
Prot_000.pdf: 
 
Protocol I8F-MC-GPGB (a) 
 
A Phase 2 Study of Once-Weekly LY3298176 Compared with Placebo and Dulaglutide in 
Patients with Type 2 Diabetes 
Mellitus 
NCT03131687 
Approval Date: 28-Nov-2017 


I8F-MC-GPGB(a) Clinical Protocol
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LY3298176
Approval Date: 17-Mar-2017 GMT
Protocol I8F-MC-GPGB(a)
A Phase 2 Study of Once-Weekly LY3298176 Compared with 
Placebo and Dulaglutide in Patients with Type 2 Diabetes 
Mellitus
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
This is a randomized, double-blind, parallel, placebo- and active comparator-controlled, 
Phase 2, multicenter, multi-country study in patients with type 2 diabetes.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 28-Nov-2017 GMT


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LY3298176
Table of Contents
Section
Page
Protocol I8F-MC-GPGB(a) A Phase 2 Study of Once-Weekly LY3298176 
Compared with Placebo and Dulaglutide in Patients with Type 2 
Diabetes Mellitus ................................................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................16
3.1.
Study Rationale............................................................................................................16
3.2.
Background..................................................................................................................16
3.3.
Benefit/Risk Assessment..............................................................................................18
4.
Objectives and Endpoints..................................................................................................19
5.
Study Design.....................................................................................................................21
5.1.
Overall Design .............................................................................................................21
5.2.
Number of Participants.................................................................................................22
5.3.
End of Study Definition ...............................................................................................22
5.4.
Scientific Rationale for Study Design...........................................................................22
5.5.
Justification for Dose ...................................................................................................23
6.
Study Population...............................................................................................................24
6.1.
Inclusion Criteria..........................................................................................................24
6.2.
Exclusion Criteria ........................................................................................................25
6.3.
Lifestyle Restrictions....................................................................................................29
6.4.
Screen Failures.............................................................................................................29
7.
Treatments........................................................................................................................30
7.1.
Treatments Administered .............................................................................................30
7.1.1.
Packaging and Labeling .......................................................................................32
7.1.2.
Medical Devices...................................................................................................33
7.2.
Method of Treatment Assignment ................................................................................33
7.2.1.
Selection and Timing of Doses.............................................................................33
7.2.2.
Specific Restrictions/Requirements......................................................................34
7.3.
Blinding .......................................................................................................................34
7.4.
Dosage Modification....................................................................................................35
7.5.
Preparation/Handling/Storage/Accountability...............................................................35
7.6.
Treatment Compliance .................................................................................................35
7.7.
Concomitant Therapy...................................................................................................36


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7.8.
Treatment after the End of the Study............................................................................37
7.8.1.
Special Treatment Considerations (Rescue Therapy)............................................37
8.
Discontinuation Criteria ....................................................................................................38
8.1.
Discontinuation from Study Treatment.........................................................................38
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................38
8.1.2.
Temporary Discontinuation from Study Treatment...............................................39
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................39
8.2.
Discontinuation from the Study....................................................................................39
8.3.
Lost to Follow-Up........................................................................................................40
9.
Study Assessments and Procedures ...................................................................................41
9.1.
Efficacy Assessments...................................................................................................41
9.1.1.
Primary Efficacy Assessments .............................................................................41
9.1.2.
Secondary Efficacy Assessments..........................................................................41
9.1.2.1.
Exploratory Efficacy Assessments..................................................................41
9.1.3.
Appropriateness of Assessments ..........................................................................42
9.2.
Adverse Events ............................................................................................................42
9.2.1.
Serious Adverse Events........................................................................................43
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................44
9.2.1.2.
Adverse Events of Special Interest..................................................................44
9.2.1.2.1.
Injection Site Reactions ............................................................................44
9.2.1.2.2.
Hypersensitivity Reactions........................................................................44
9.2.1.2.3.
Hypoglycemia...........................................................................................44
9.2.1.2.4.
Nausea, Vomiting, and Diarrhea ...............................................................45
9.2.1.2.5.
Acute Pancreatitis .....................................................................................45
9.2.1.2.6.
Major Adverse Cardiovascular Events ......................................................46
9.2.1.2.7.
Thyroid C-Cell Hyperplasia and C-Cell Neoplasms ..................................47
9.2.2.
Complaint Handling.............................................................................................47
9.3.
Treatment of Overdose.................................................................................................47
9.4.
Safety...........................................................................................................................47
9.4.1.
Electrocardiograms ..............................................................................................47
9.4.2.
Vital Signs ...........................................................................................................49
9.4.3.
Laboratory Tests ..................................................................................................49
9.4.4.
Safety Monitoring ................................................................................................49
9.5.
Pharmacokinetics .........................................................................................................50
9.6.
Pharmacodynamics ......................................................................................................50
9.7.
Pharmacogenetics.........................................................................................................50
9.7.1.
Whole Blood Samples for Pharmacogenetic Research..........................................50
9.8.
Biomarkers...................................................................................................................51


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9.8.1.
Samples for Immunogenicity Research.................................................................51
9.9.
Health Economics ........................................................................................................52
10.
Statistical Considerations ..................................................................................................54
10.1. Sample Size Determination ..........................................................................................54
10.2. Populations for Analyses..............................................................................................54
10.3. Statistical Analyses ......................................................................................................55
10.3.1.
General Statistical Considerations ........................................................................55
10.3.2.
Treatment Group Comparability...........................................................................56
10.3.2.1.
Patient Disposition..........................................................................................56
10.3.2.2.
Patient Characteristics ....................................................................................56
10.3.2.3.
Concomitant Therapy .....................................................................................56
10.3.2.4.
Treatment Compliance....................................................................................56
10.3.3.
Efficacy Analyses ................................................................................................56
10.3.3.1.
Primary Analyses ...........................................................................................56
10.3.3.2.
Supporting Analyses of Primary Outcome ......................................................57
10.3.3.3.
Secondary Analyses........................................................................................57
10.3.3.3.1.
Secondary Analysis on Primary Efficacy Endpoint ...................................57
10.3.3.3.2.
Analyses on Secondary Efficacy Endpoints...............................................58
10.3.4.
Safety Analyses....................................................................................................59
10.3.4.1.
Clinical Evaluation of Safety..........................................................................59
10.3.4.2.
Adverse Events...............................................................................................59
10.3.4.3.
Vital Signs......................................................................................................60
10.3.4.4.
Laboratory Measures ......................................................................................60
10.3.4.5.
Evaluation of Immunogenicity........................................................................60
10.3.4.6.
Electrocardiograms.........................................................................................60
10.3.4.7.
Adverse Events of Special Interest..................................................................61
10.3.4.8.
Hypoglycemic Episodes .................................................................................61
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................62
10.3.6.
Other Analyses.....................................................................................................62
10.3.6.1.
Health Outcome/Quality of Life Analyses ......................................................62
10.3.6.2.
Subgroup Analyses.........................................................................................62
10.3.6.3.
Exploratory Analyses .....................................................................................62
10.3.7.
Interim Analyses..................................................................................................63
11.
References ........................................................................................................................64


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List of Tables
Table
Page
Table GPGB.1.
Objectives and Endpoints...............................................................................19
Table GPGB.2.
Investigational Product Administration and Treatment Regimens ..................31
Table GPGB.3.
Recommended Dose Titration Schedulea........................................................31
Table GPGB.4.
Dose–Response Assumption Used in Sample Size Determination..................54
Table GPGB.5.
Definitions of Populations to Be Analyzed in Study GPGB ...........................54


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List of Figures
Figure
Page
Figure GPGB.1. Illustration of study design for Clinical Protocol I8F-MC-GPGB. ..................21


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List of Appendices
Appendix
Page
Abbreviations and Definitions........................................................................66
Appendix 1.
Clinical Laboratory Tests...............................................................................70
Appendix 2.
Study Governance Considerations..................................................................72
Appendix 3.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................76
Appendix 4.
World Health Organization Classification for Diabetes..................................77
Appendix 5.
Pharmacokinetics Schedule of Events ............................................................78
Appendix 6.
Contraceptive Methods..................................................................................79
Appendix 7.
World Health Organization Standardized Protocols for the 
Appendix 8.
Measurement of Height and Weight...............................................................80
Protocol Amendment I8F-MC-GPGB(a) Summary:  A Phase 2 Study of 
Appendix 9.
Once-Weekly LY3298176 Compared with Placebo and Dulaglutide in 
Patients with Type 2 Diabetes Mellitus ..........................................................81


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1.
Synopsis
Title of Study:
A Phase 2 Study of Once-Weekly LY3298176 Compared with Placebo and Dulaglutide in Patients with 
Type 2 Diabetes Mellitus
Rationale: 
Study I8F-MC-GPGB is a 26-week Phase 2 study designed to examine the safety, efficacy, and pharmacokinetics 
(PK)/pharmacodynamics (PD) of 4 dose levels of once weekly (QW) LY3298176 compared with QW dulaglutide 
1.5 mg and QW placebo in patients with type 2 diabetes mellitus (T2DM) who have inadequate glycemic control 
with diet and exercise with or without a stable dose of metformin.  The primary endpoint will be the effect on 
hemoglobin A1c (HbA1c).  These data will support dose selection for Phase 3.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary
To demonstrate a dose–response relationship of QW 
subcutaneous injections of LY3298176 on HbA1c 
change from baseline relative to placebo, in patients 
with T2DM inadequately controlled with diet and 
exercise alone or treated with a stable dose of 
metformin.
The change in HbA1c from baseline to 26 weeks
Secondary
To determine the effect of LY3298176 versus 
dulaglutide (and to compare the effect of each versus 
placebo) on:

The mean body weight change from baseline 
to 12 and 26 weeks

The percentage of patients with 5% or 
greater body weight loss at 26 weeks

The change in mean body weight from 
baseline to 12 and 26 weeks

The percentage of patients with 5% or 
greater body weight loss from baseline to 
26 weeks

The change from baseline of HbA1c at 
12 weeks

The change in HbA1c from baseline to 
12 weeks

The percentage of patients with 10% or 
greater body weight loss at 26 weeks

The percentage of patients reaching the 
HbA1c target of 6.5% and of 7.0%

The percentage of patients with 10% or 
greater body weight loss from baseline to 
26 weeks

The percentage of patients reaching the 
HbA1c target of 6.5% and of 7.0%

The change from baseline of fasting blood 
glucose (FBG) at 12 and 26 weeks

The change from baseline to 26 weeks in 
high-density lipoprotein cholesterol, total 
cholesterol, triglycerides, and low-density 
lipoprotein cholesterol

The change in FBG from baseline to 12 and 
26 weeks

The change in lipids from baseline to 
26 weeks

The waist circumference

The change from baseline to 12 and 
26 weeks


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Objectives
Endpoints
Secondary (continued)
Safety and tolerability, including gastrointestinal
tolerability, incidence and rate of hypoglycemia, 
hypersensitivity reactions, and pancreatic safety

Adverse events and glucose data
To evaluate the development of treatment-emergent 
anti-drug antibodies to LY3298176

Number of patients testing positive for 
anti-LY3298176 antibodies
To assess the PK and PD of LY3298176 and potential 
patient factors that may influence its PK and PD

PK and PD
To assess the relationship between LY3298176 dose 
and/or exposure and key efficacy and safety 
measures, where applicable

Dose-exposure–response analyses
Summary of Study Design:
Study GPGB is a multicenter, randomized, double-blind, parallel, placebo- and active comparator-controlled Phase 2 
trial in patients with T2DM who failed to achieve adequate glycemic control on diet and exercise alone or on a 
stable dose of metformin (1000 mg/day for at least 3 months prior to Visit 1).
Treatment Arms and Duration:
There are 6 treatment arms, including placebo, 4 dose levels of LY3298176, and dulaglutide 1.5 mg.
Number of Patients:
There will be 540 patients screened with the goal of randomizing 300 patients and having 45 patients per treatment 
arm who complete the study.
Statistical Analysis:
Efficacy:  The primary efficacy outcome of HbA1c change from baseline to the 26-week endpoint will be analyzed 
using a Bayesian dose–response model.  Analyses will be performed on the modified intent-to-treat (mITT) analysis 
set.  Supportive analysis of the primary efficacy outcome for the mITT dataset will be the mixed model for repeated 
measures (MMRM) with body mass index (<30, 30), metformin use, treatment, visit, and treatment-by-visit 
interaction as fixed effects, baseline HbA1c as a covariate, and patient as a random effect.  Additional covariates 
may be added and will be detailed in the statistical analysis plan.
The mean weight change from baseline at 12 and 26 weeks along with the mean change from baseline of HbA1c at 
12 weeks will be analyzed using similar dose–response models as the primary analysis. The percentage of patients 
with 5% (and with 10%) body weight loss, the percentage of patients reaching the HbA1c target of 6.5% (and of 
7.0%) at 26 weeks, and the proportion of patients requiring rescue therapy will be analyzed using a logistic 
regression analysis with fixed effects of treatment and strata, and baseline as a covariate.  The change from baseline 
of FBG, self-monitoring of blood glucose levels, waist circumference, mean percentage change in lipids and change 
from baseline to 12 and 26 weeks for fibroblast growth factor-21, adiponectin, -hydroxy butyrate, free fatty acids, 
glycerol, monocyte chemoattractant protein-1 (MCP-1), glucagon, C-peptide, and insulin levels will be calculated 


I8F-MC-GPGB(a) Clinical Protocol
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LY3298176
using a similar MMRM-based model to the one used for the supporting primary analysis.  Summaries will include 
descriptive statistics for continuous measures (sample size, mean, standard deviation [SD], median, minimum, and 
maximum) and for categorical measures (sample size, frequency, and percentage).
Pharmacokinetics/Pharmacodynamics:  LY3298176 concentration data will be analyzed using a population PK 
approach via nonlinear mixed-effects modeling with the NONMEM software.  The relationships between 
LY3298176 dose and/or concentration and efficacy, tolerability, and safety, as well as biomarkers, will be 
characterized if exploratory analyses of the PD data warrant further PK/PD analyses upon review.  Such analyses 
may include, but are not necessarily limited to, QTc interval, blood pressure, heart rate, glucose, HbA1c, insulin, 
nausea/vomiting, etc.  In addition, the relationship between biomarkers and LY3298176 efficacy will be analyzed, if 
deemed appropriate.  If positive antibody titers to LY3298176 are observed, the relationship between LY3298176
PK or any relevant PD parameters and antibody titer will be performed.
Safety:  The summary statistics for continuous variables will be sample size, mean, SD, median, minimum, and 
maximum.  The summary statistics for categorical variables will be sample size, frequency, and percentage.  
Exposure to each therapy during the treatment period of the study will be calculated for each patient and 
summarized by treatment group.  Additional analyses, such as concentration–safety lab plots, may be performed if 
warranted upon review of the data.


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2.
Schedule of Activities
Study Phase
Screen Lead -
in
Randomize
Treatment Phase
Follow
up
Early 
Term
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
801
Week of Treatment
3
2
0
1
1
2
2
4
4
8
12
12
16
20
24
26
(30)
Study Day/(Dose 
number)
0/(1)
7/(2)
14/(3)
28/(5)
56/(9) 84/(13)
112/(17) 140/(21) 168/(25) 182/(27)
Visit Window (days)
±7
±3 
±3
±3
±3
±3
±3
±3
±3
±3
PK Specific Visita
X
X
X
X
Administrative
Informed consent
X
Diabetes/medical
history/therapy
X
Inclusion/Exclusion
X
X
Preexisting conditions
X
X
Randomization
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
X
X
BG meter/supplies, if 
needed
X
X
X
X
X
X
X
X
BG meter, instructions
X
X
Diet, exercise, BG 
counseling
X
Study diary, dispense
X
X
X
X
X
X
X
X
X
X
X
Review patient diaries 
for BG values, AEs, 
hypoglycemic or 
hyperglycemic events
X
X
X
X
X
X
X
X
X
X
X
X
X
Subcutaneous injection 
training
X
X


I8F-MC-GPGB(a) Clinical Protocol
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LY3298176
Study Phase
Screen Lead -
in
Randomize
Treatment Phase
Follow
up
Early 
Term
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
801
Week of Treatment 
3
2
0
1
1
2
2
4
4
8
12
12 
16
20
24
26
(30)
Study day/(Dose 
number)
0/(1)
7/(2)
14/(3)
28/(5)
56/(9) 84/(13)
112/(17) 140/(21) 168/(25) 182/(27)
Visit Window (days)
±7
±3 
±3
±3
±3
±3
±3
±3
±3
±3
PK Specific Visita
X
X
X
X
Study drug and injection 
supplies, dispense
X
X
X
X
X
X
X
X
X
X
Health habits (alcohol 
use yes/no, tobacco use 
current/past)
X
Patient returns unused 
study drug supplies
X
X
X
X
X
X
X
X
Study drug, assess 
compliance
X
X
X
X
X
X
X
X
Patient Demographics
Age
X
Gender
X
Race/Ethnicity
X
Clinical Variables
Physical examination
X
X
X
Symptom-driven 
physical exam
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
X
Vital signs (BP and PR)
X
X
X
X
X
X
X
X
X
X
X
X
Antidiabetic medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X


I8F-MC-GPGB(a) Clinical Protocol
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LY3298176
Study Phase
Screen Lead -
in
Randomize
Treatment Phase
Follow
up
Early 
Term
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
801
Week of Treatment 
3
2
0
1
1
2 
2
4
4
8
12
12 
16
20
24
26
(30)
Study day/(Dose 
number)
0/(1)
7/(2)
14/(3)
28/(5)
56/(9) 84/(13)
112/(17) 140/(21) 168/(25) 182/(27)
Visit Window (days)
±7
±3 
±3
±3
±3
±3
±3
±3
±3
±3
PK Specific Visita
X
X
X
X
Other
ECGsb
X
X
Xc
Xc
Xc
Xc
X
X
Evaluation of Injection 
Site Reactions
X
X
X
X
X
X
X
X
X
X
X
APPADL and IW-SP 
questionnaires
X
X
X
X
Diagnostics (Safety)
Screening Laboratory 
Testsd
X
Pregnancy teste
X
X
Estradiol, FSH, LHf
X
Chemistry panel
X
X
X
X
X
X
X
Lipase and amylase
X
X
X
X
X
X
X
X
X
X
X
X
X
Lipid panel
X
X
X
X
X
X
eGFR
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
Urine albumin, 
creatinine, UACR
X
X
X
X
X


I8F-MC-GPGB(a) Clinical Protocol
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LY3298176
Study Phase
Screen
Lead -
in
Randomize
Treatment Phase
Follow
up
Early 
Term
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
801
Week of Treatment 
3
2
0
1
1
2
2
4
4
8
12
12 
16
20
24
26
(30)
Study day/(Dose 
number)
0/(1) 7/(2)
14/(3)
28/(5)
56/(9) 84/(13)
112/(17) 140/(21) 168/(25) 182/(27)
Visit Window (days)
±7
±3 
±3
±3
±3
±3
±3
±3
±3
±3
PK Specific Visita
X
X
X
X
Diagnostics (Efficacy)
Calcitonin
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting glucose
X
X
X
X
X
X
X
X
Fasting insulin and 
c-peptide
X
X
X
X
X
Fasting glucagon
X
X
X
X
X
Total and active 
GLP-1/GIP
X
X
X
X
X
X
Remind Patients about 
7-point SMBG
X
X
X
X
X
7-point SMBG
Xg
X
X
X
X
Osteopontin, FGF-21
(active), Adiponectin, 
-hydroxy butyrate, 
glycerol, free fatty acids,
MCP-1, CTX-1, P1NP, 
osteocalcin
X
X
X
X


I8F-MC-GPGB(a) Clinical Protocol
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LY3298176
Study Phase
Screen
Lead -
in
Randomize
Treatment Phase
Follow
up
Early 
Term
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
801
Week of Treatment 
3
2
0
1
1
2
2
4
4
8
12
12 
16
20
24
26
(30)
Study day/(Dose 
number)
0/(1) 7/(2)
14/(3)
28/(5)
56/(9) 84/(13)
112/(17) 140/(21) 168/(25) 182/(27)
Visit Window (days)
±7
±3 
±3
±3
±3
±3
±3
±3
±3
±3
PK Specific Visita
X
X
X
X
Pharmacogenetic stored 
samples
X
Nonpharmacogenetic 
stored samples
X
X
X
X
X
Immunogenicity testing
X
X
X
X
X
X
X
X
PK sample for 
Immunogenicityh
Xh
Xh
Xh
Pharmacokinetics (see 
PK schedule)a
Xa*
Xa
Xa
Xa
Xa*
Xa*
Xac
Xa*
Xa
Abbreviations:  AE = adverse event; APPADL = Ability to Perform Physical Activities of Daily Living; BG = blood glucose; BP = blood pressure; d = day; 
eGFR = estimated glomerular filtration rate; ECG = electrocardiogram; FGF-21 = fibroblast growth factor-21; FSH = follicle-stimulating hormone; 
GLP-1 = glucagon-like peptide-1; GIP = glucose-dependent insulinotropic peptide; HbA1c = hemoglobin A1c; IWRS = Interactive Web Response System; 
IW-SP = Impact of Weight on Self-Perception; LH = luteinizing hormone; PK = pharmacokinetics; PR = pulse rate; SMBG = self-monitoring of blood 
glucose; UACR = urine albumin-to-creatinine ratio.
*
Indicates PK samples to be collected predose.
a
See Pharmacokinetics Schedule of Events, Appendix 6.
b
ECGs should be collected centrally at Visits 3, 10, 11, 12, 16, and 801, and locally at screening and early termination.
c
ECG should be collected immediately prior to PK sample collection.
d
Screening laboratory tests include serum hepatitis B surface Ag, hepatitis C antibody (Ab), and human immunodeficiency virus Ab tests for all patients.
e
Serum pregnancy test will be performed by central laboratory at Visit 1 for women of childbearing potential.  For the remainder of the study, a urine 
pregnancy test may be performed at the investigator’s discretion if pregnancy is suspected during the study (local laboratory).
f
Collect serum estradiol, FSH, and LH in women whose menopausal status needs to be determined.
g
Two baseline collections during the lead-in period.
h
PK samples specifically for immunogenicity.


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3.
Introduction
3.1.
Study Rationale
Study I8F-MC-GPGB is a 26-week Phase 2 study designed to examine the safety, efficacy, and 
pharmacokinetics (PK)/pharmacodynamics (PD) of 4 dose levels of once weekly (QW) 
subcutaneously administered LY3298176 compared with QW subcutaneously administered 
dulaglutide 1.5 mg and QW placebo in patients with type 2 diabetes mellitus (T2DM) who have 
inadequate glycemic control with diet and exercise with or without a stable dose of metformin.  
The primary objective will be the effect on hemoglobin A1c (HbA1c).  These data will support 
dose selection for Phase 3.
3.2.
Background
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
CCI


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LY3298176
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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3.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, serious adverse events (SAEs), 
and reasonably anticipated AEs of LY3298176 may be found in the Investigator’s Brochure (IB). 
Information on AEs expected to be related to the investigational product may be found in 
Section 7 (Development Core Safety Information) of the IB.  Information on SAEs that are 
expected in the study population independent of drug exposure will be assessed by the sponsor in
aggregate, periodically during the course of the study, and may be found in Section 6 (Effects in 
Humans) of the IB.
More detailed information about the known and expected benefits and risks of dulaglutide may 
be found in the USPI or SmPC (TrulicityUSPI, 2015; TrulicitySmPC, 2016).


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4.
Objectives and Endpoints
Table GPGB.1shows the objectives and endpoints of the study.
Table GPGB.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
The primary objective of this study is to demonstrate a 
dose–response relationship of QW SC injections of 
LY3298176 on HbA1c change from baseline relative to 
placebo, in patients with T2DM inadequately controlled 
with diet and exercise alone or treated with a stable dose 
of metformin.
The change in HbA1c from baseline to 26 weeks
Secondary
To determine the effect of LY3298176 versus 
dulaglutide (and to compare the effect of each versus 
placebo) on:

The mean body weight change from baseline to 12 
and 26 weeks

The percentage of patients with 5% or greater body 
weight loss at 26 weeks

The change in mean body weight from baseline to 
12 and 26 weeks

The percentage of patients with 5% or greater body 
weight loss from baseline to 26 weeks

The change from baseline of HbA1c at 12 weeks

The change in HbA1c from baseline to 12 weeks

The percentage of patients with 10% or greater 
body weight loss at 26 weeks

The percentage of patients reaching the HbA1c 
target of 6.5% and of 7.0%.

The percentage of patients with10% or greater body 
weight loss from baseline to 26 weeks

The percentage of patients reaching the HbA1c 
target of 6.5% and of 7.0%

The change from baseline of fasting blood glucose
(FBG) at 12 and 26 weeks

The change from baseline to 26 weeks in high-
density lipoprotein cholesterol (HDL-C), total 
cholesterol, triglycerides, and low-density 
lipoprotein cholesterol (LDL-C)

The change in FBG from baseline to 12 and 
26 weeks

The change in lipid laboratory data from baseline to 
26 weeks

The waist circumference

Change from baseline to 12 and 26 weeks
Safety and tolerability, including GI tolerability, 
incidence and rate of hypoglycemia, hypersensitivity 
reactions, and pancreatic safety

AE reports and evaluation of laboratory data
To evaluate the development of treatment-emergent anti-
drug antibodies to LY3298176

Number of patients testing positive for 
anti-LY3298176 antibodies
To assess the PK and PD of LY3298176 and potential 
patient factors that may influence its PK and PD

PK and PD
To assess the relationship between LY3298176 dose 
and/or exposure and key efficacy and safety measures, 
where applicable
Dose-exposure–response analyses


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Tertiary/Exploratory
Evaluate the effect of LY3298176 compared with 
placebo and dulaglutide on:

Change from baseline of 7-point self-monitoring of 
blood glucose (SMBG) profiles at 4, 12, 26, and 
30 weeks

Biomarkers 

The change in SMBG profile from baseline to 4, 12, 
26, and 30 weeks

The change from baseline to 12 and 26 weeks

Patient-reported outcomes (PRO) 

The change from baseline to 12 and 26 weeks

Pharmacogenetic objectives are
a.
To evaluate genetic variants in genes 
in the glucagon signaling pathway and 
GIP/GLP-1-associated genes for 
association with efficacy responses to 
LY3298176 such as change from 
baseline in HbA1c, fasting glucose, 
body weight, and body mass index 
(BMI).
b.
To evaluate the association of genetic 
variants in the glucagon signaling 
pathway and GIP/GLP-1-associated 
genes with other PD and clinical 
endpoints of interest (including 
circulating glucagon levels, BP, serum 
amylase and lipase, GI tolerance, lipid 
metabolism, bone metabolism, etc.).
c.
To investigate the genetic variants 
associated with dulaglutide treatment 
response (identified from dulaglutide 
clinical trials) on the efficacy and 
safety endpoints in response to 
LY3298176.


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5.
Study Design
5.1.
Overall Design
Study GPGB is a multicenter, randomized, double-blind, parallel, placebo-controlled trial with 
3 study periods in patients who have type 2 diabetes.
Figure GPGB.1 illustrates the study design, including recommended dose titration scheme (see 
Section 7.1 for details on dose titration).
Illustration of study design for Protocol I8F-MC-GPGB
Week
Visit
-3
-2
0
1
2
3
4
5
6
23
24
25
26
19
20
21
22
15
16
17
18
11
12
13 14
7
8
9
10
30
26 Weeks
LY Placebo + Dulaglutide 1.5 mg
LY 15 mg + Dulaglutide Placebo
LY 10 mg + Dulaglutide Placebo
LY 5 mg + Dulaglutide Placebo
LY 1 mg + Dulaglutide Placebo
LY Placebo + Dulaglutide Placebo
1
2
3
4
6
8
15
29
14
13
11
10
801
27
28
16
PK Visit
5
7
9
12
Lead-in
Screening
Follow Up
26 Week Treatment Period
4 Weeks
5, 5 mg
5, 5, 10, 10, 10, 10 mg
1 Week
2 Weeks
Study Period 1
Study Period 2
Study Period 3
Randomization
End of Treatment
Figure GPGB.1.
Illustration of study design for Clinical Protocol I8F-MC-GPGB.
All LY3298176 dose levels above 5 mg will be reached through dose titration (see Section 7.1).
Study procedures and timing for the lead-in, blinded treatment, and follow-up phases are 
outlined in Section 2.  Eligibility for this study will be determined at a screening visit (Visit 1).  
Screening procedures will be performed on approximately Day 21 according to the Schedule of 
Activities.  Patients will receive training on the routine blood glucose monitoring and paper diary 
completion required during the study.  Patients should follow the investigator’s instructions 
related to frequency of SMBG but should test their glucose a minimum of 3 times per week and 


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as specified for determination of 7-point glucose profiles (see Section 9.1.2.1).  Eligible patients 
will return to the site for some baseline procedures during the lead-in phase (Visit 2) and again 
for randomization to treatment and to receive their first dose of study drug at Visit 3.
After randomization and the first dose (Visit 3), patients will return to the site for PK collection 
just prior to the second dose (Visit 4).  Patients will also have a predose PK collection prior to 
Week 8 (Visit 10), Week 12 dose (Visit 11), and Week 26 (Visit 16) dose.  There will be 
postdose PK collections after the second dose (PK-specific Visit 5), third dose (PK-specific 
Visit 7), fifth dose (PK-specific Visit 9, and 12-week dose (PK-specific Visit 12) (see Appendix 
6, Pharmacokinetics Schedule of Events).
A safety follow-up visit will occur approximately 4 weeks following the last dose of the study 
drug.  Patients randomized to LY3298176 who develop treatment-emergent anti-LY3298176 
antibodies will be monitored after the last visit (see Section 9.8.1).
Throughout the study, patients treated with metformin will remain on the same dose they were 
receiving at Visit 1 unless changes need to be made for safety reasons.  All patients will be 
encouraged to maintain their prestudy diet and exercise levels through the course of the study.
In the treatment phase, a double-dummy dose administration scheme will be employed to ensure 
patients and investigators (as well as sponsor study team and monitors) remain blind to the 
LY3298176, dulaglutide 1.5 mg, and placebo treatment assignments within each treatment group.  
At each dosing occasion, the study drug will be administered as 1 to 3 SC injections of 
LY3298176 or matched placebo and 1 SC injection of dulaglutide 1.5 mg or its placebo.  
Therefore, each patient will self-administer 2 to 4 injections per week.
5.2.
Number of Participants
Approximately 540 participants will be screened to achieve 300 randomized and 270 evaluable 
participants for an estimated total of 45 evaluable participants per treatment group.
5.3.
End of Study Definition
End of the trial 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 GPGB is a Phase 2 study designed to examine the efficacy and safety of QW LY3298176 
compared with dulaglutide 1.5 mg and placebo in patients with T2DM who have inadequate 
glycemic control with diet and exercise alone or on a stable dose of metformin.
Inclusion of an active comparator (dulaglutide 1.5 mg) in Study GPGB will allow for a direct 
comparison of the safety and efficacy of QW LY3298176 to an injectable GLP-1 RA (as well as 
to placebo) over a 6-month time period.  In addition, effects of the medication on other 
parameters such as circulating biomarkers, other measures of glycemic control, lipids, and 
various safety-related assessments will also be determined.  The planned duration of 6 months 
will allow for a more optimal comparison of the body weight effects of the 2 drugs, as the 


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LY3298176
putative mechanism of action of LY3298176 suggests that treatment with LY3298176 will result 
in continued weight loss over a 6-month period.  The data from this trial will form the primary 
basis to assess dose/exposure–response of LY3298176 efficacy for selection of doses to be 
included in Phase 3 testing.  In addition, safety and tolerability over a wide dose range of 
LY3298176 versus placebo and dulaglutide 1.5 mg will be assessed to enable robust benefit–risk 
characterizations in T2DM.
The placebo arm was included in order to determine whether any efficacy or safety effects of 
LY3298176 that are different in magnitude from those of dulaglutide 1.5 mg are in fact 
equivalent to or are also different from no treatment (i.e., placebo).
The current study will enroll patients with inadequate glycemic control based on HbA1c values 
ranging from 7.0% to 10.5%, inclusive.  Similar ranges of screening HbA1c have been used in 
numerous studies of T2DM treatments.
Patients treated with diet and exercise alone, or in combination with stable metformin 
monotherapy (1000 mg/day), will be enrolled.  Patients on a second oral antihyperglycemic 
medication (OAM) may be also be eligible if the second OAM was discontinued 3 months or 
more prior to Visit 1 (refer to Section 6.2, Exclusion Criterion 23).  Stable metformin treatment 
for at least 3 months is required to minimize glucose variability prior to study entry.
5.5.
Justification for Dose
LY3298176 doses of 1 mg, 5 mg, 10 mg (titrated), and 15 mg (titrated), administered 
subcutaneously QW, were selected based on the following:

Safety and tolerability of LY3298176 in healthy subjects and T2DM patients in the 
Phase 1 study GPGA through doses of 10 mg.

The margin of safety for the 15-mg maximum dose in this study has an exposure multiple 
of approximately 1 to the no-observed-adverse-effect level in rats and monkeys in the 
6-month toxicology studies.

The 1 mg was selected using PK/PD modeling and is predicted to achieve LY3298176 
concentration levels that will demonstrate HbA1c lowering compared with placebo.

The selected dose levels and dose range support a robust dose-exposure–response 
analysis of multiple safety and efficacy measures to support selection of dose(s) of 
LY3298176 with optimal benefit/risk ratio for further clinical development.


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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 T2DM for at least 6 months before screening based on the disease 
diagnostic criteria (Appendix 5, World Health Organization [WHO] 
Classification for Diabetes).
[2]
Have an HbA1c value at screening of 7.0% and 10.5% and treated with diet 
and exercise alone or a stable dose of metformin (either immediate release or 
extended release, 1000 mg/day and not more than the locally approved dose)
for at least 3 months prior to screening/Visit 1.  Note:  patients from some 
countries may be required to be on metformin in order to enroll in the 
protocol.
Patient Characteristics
[3]
Male or female patients 18 to 75 years of age, inclusive
[3a] Male patients:
Male patients should be willing to use reliable contraceptive methods 
throughout the study and for at least 3 months after last injection (see 
Appendix 7).
[3b] Female patients:
Female patients not of childbearing potential due to surgical sterilization 
(hysterectomy or 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).


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Female patients of child-bearing potential (not surgically sterilized and between 
menarche and 1-year postmenopausal) must:

test negative for pregnancy at Visit 1 based on a serum pregnancy 
test
AND

if sexually active, agree to use two forms of effective contraception, 
where at least one form is highly effective for the duration of the trial 
and for 30 days thereafter (see Appendix 7).

not be breastfeeding.
[4]
Have a BMI between 23 and 50 kg/m2 (inclusive) at screening.
Informed Consent
[5]
In the investigator’s opinion, are well motivated, capable, and willing to:

perform SMBG

prepare (with assistance if necessary) study medication

self-inject (with assistance if necessary) up to 4 injections each week

complete study diary(ies), as required for this protocol

are receptive to continuing their prestudy diet, activity levels, and 
follow simple dietary advice as appropriate
[6]
Be willing to maintain metformin dose during the trial, if taking a stable 
dose of metformin at study entry.  Patients experiencing hypoglycemia 
during the study may have their metformin dose reduced.
[7]
Are reliable and willing to make themselves available for the duration of the 
study, and who will comply with the required study and dosing visits and 
abide by the Clinical Research Site policy and procedure and study 
restrictions.
[8]
Are able and willing to give signed informed consent and have given written 
informed consent to participate in this study in accordance with local 
regulations and the ethical review board (ERB) governing their site.
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening:
Medical Conditions
[9]
Have type 1 diabetes mellitus.
[10] Have uncontrolled diabetes defined as more than 2 episodes of ketoacidosis or 
hyperosmolar state requiring hospitalization in the 6 months prior to Visit 1.


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[11] Have had more than 1 episode of severe hypoglycemia, as defined by the 
occurrence of neuroglycopenic symptoms requiring the assistance of another 
person for recovery, within 6 months prior to Visit 1, or has a history of 
hypoglycemia unawareness or poor recognition of hypoglycemic symptoms.  
Any patient that the investigator feels will not be able to communicate an 
understanding of hypoglycemic symptoms and the appropriate treatment of 
hypoglycemia should also be excluded.
[12] Have a history of acute or chronic pancreatitis or elevation in serum 
lipase/amylase (greater than 2 times the upper limit of normal [ULN]) or 
fasting serum triglyceride level of >500 mg/dL at screening.
[13] Have a diagnosis of gastroparesis or history of bariatric surgery or a clinically 
significant gastric emptying abnormality, in the opinion of the investigator.
[14] Have active proliferative diabetic retinopathy.
[15] Have known liver disease, obvious clinical signs or symptoms of liver disease, 
acute or chronic hepatitis, or alanine aminotransferase (ALT) levels 
>2.5 times the ULN at Visit 1, as determined by the central laboratory at 
screening.
[16] Have a known self or family history (first-degree relative) of multiple 
endocrine neoplasia type 2A or type 2B, thyroid C-cell hyperplasia, or 
medullary thyroid carcinoma.
[17] Evidence of hypothyroidism or hyperthyroidism based on clinical evaluation 
and/or an abnormal thyroid-stimulating hormone that, in the opinion of the 
investigator, would pose a risk to patient safety.  Subjects on a stable dose of 
thyroid replacement therapy for at least the prior 3 months who are clinically 
euthyroid and who are anticipated to remain on this dose throughout the trial 
period may be eligible if they meet the other criteria.
[18] Have a screening calcitonin 20 pg/mL as determined by the central 
laboratory at Visit 1.
[19] Have had any of the following within the last 6 months prior to screening:
myocardial infarction (MI), unstable angina, coronary artery bypass graft, 
percutaneous coronary intervention (diagnostic angiograms are permitted), 
transient ischemic attack (TIA), cerebrovascular accident or decompensated 
congestive heart failure, or currently have New York Health Association Class 
III or IV heart failure.  
[20] Have an electrocardiogram (ECG) considered by the investigator indicative of 
active cardiac disease or with abnormalities that may interfere with the 
interpretation of changes in ECG intervals at screening.  A QTc (Fridericia)
interval greater than 450 ms in men and greater than 470 ms in women is 
specifically excluded.
[21] Known significant autonomic neuropathy as evidenced by urinary retention,
resting tachycardia, orthostatic hypotension, or diabetic diarrhea.


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[22] Have a personal or family history of long QT syndrome, family history of 
sudden death in a first-degree relative (parents, sibling, or children) before the 
age of 40 years, or a personal history of unexplained syncope within the last 
year.  Use of prescription or over-the-counter medications known to 
significantly prolong the QT or QTc interval at screening.
[23] Have poorly controlled hypertension (i.e., mean seated systolic BP
160 mm Hg or mean seated diastolic BP 95 mm Hg) at screening, or a 
change in antihypertensive medications within 30 days of screening, renal 
artery stenosis, or evidence of labile BP including symptomatic postural 
hypotension.
[24] Random triglycerides >500 mg/dL (5.7 mmol/L).  If the patient is on 
lipid-lowering therapies, doses must be stable for 30 days prior to screening.
[25] Have an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2, as 
determined by the central laboratory at Visit 1, or a level of eGFR that would 
contraindicate the use of metformin per the label in the respective country.  
Patients on metformin must meet local label requirements.
[26] Have a history of atopy (severe or multiple allergic manifestations) or 
clinically significant multiple or severe drug allergies, or intolerance to topical 
corticosteroids, or severe post-treatment hypersensitivity reactions (including, 
but not limited to, erythema multiforme major, linear immunoglobulin A 
dermatosis, toxic epidermal necrolysis, anaphylaxis, angioedema, or 
exfoliative dermatitis).
[27] Have an active or untreated malignancy or have been 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 prior to screening.
[28] Have evidence of human immunodeficiency virus (HIV) and/or positive HIV 
antibodies historically or at screening.
[29] Evidence of hepatitis B and/or positive hepatitis B surface antigen or evidence 
of hepatitis C.
[30] Have a history of a transplanted organ (corneal transplants [keratoplasty] 
allowed).
[31] Have evidence of a significant active, uncontrolled medical condition or a 
history of any medical problem capable of constituting a risk when taking the 
study medication or interfering with the interpretation of data, as judged by 
the screening investigator at screening.
[32] Have had a significant change in weight, defined as a gain or loss of at least 
4 kg (9 lb) in the 3 months prior to screening.


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[33] Have had a blood donation of 450 mL or more in the prior 3 months of 
screening or any blood donation within the prior month, or a blood 
transfusion or severe blood loss within the prior 3 months, or have known 
hemoglobinopathy, hemolytic anemia, sickle cell anemia, or have a 
hemoglobin value <11 g/dL (males) or <10 g/dL (females), or any other 
condition known to interfere with HbA1c methodology.
[34] Have any other condition (including known drug or alcohol abuse or 
psychiatric disorder) that, in the opinion of the investigator, may preclude the 
patient from following and completing the protocol.
Prior/Concomitant Therapy
[35] With the exception of stable doses of metformin, patients on another OAM 
(including, but not limited to, sulfonylureas, DPP-4i, sodium–glucose 
cotransport 2 inhibitors, alpha-glucosidase inhibitors, meglitinides) in addition 
to metformin therapy may be randomized if the additional OAM treatment 
was discontinued at least 3 months prior to screening.
[36] Have used insulin for diabetic control within the prior year.  However, short-
term use of insulin for acute conditions is allowed (14 days) in certain 
situations, such as during a hospitalization or perioperatively (see 
Section 7.7).
[37] Have had any exposure to dulaglutide, other GLP-1 analogs, or other related 
compounds within the prior 3 months or any history ever of allergies to these 
medications.  Patients who previously took GLP-1 analogs or related 
compounds and who discontinued those medications >3 months prior to 
Visit 1 for intolerability or lack of efficacy should not be randomized.
[38] Have been treated or plan to be treated with drugs that promote weight loss 
(e.g., 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 [e.g., allī]) within 3 months prior to Visit 1.
[39] Are receiving chronic (>2 weeks) systemic glucocorticoid therapy (excluding 
topical, intraocular, intranasal, intra-articular, or inhaled preparations) or have 
received such therapy within 4 weeks immediately prior to screening.
[40] Are currently taking a central nervous system stimulant (e.g., Ritalin-SR) 
with the exception of caffeinated beverages at screening.
[41] Within 30 days of the initial dose of study drug, have received treatment with 
a drug that has not received regulatory approval for any indication.  If the 
previous study drug has a long half-life, 3 months or 5 half-lives (whichever is 
longer) should have passed.


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[42] Have an average weekly alcohol intake that exceeds 21 units per week (males) 
and 14 units per week (females) [1 unit = 12 oz or 360 mL of beer; 5 oz or 
150 mL of wine; 1.5 oz or 45 mL of distilled spirits].
[43] Evidence of regular use of known drugs of abuse in the opinion of the 
investigator.
Prior/Concurrent Clinical Trial Experience
[44] Have previously completed or withdrawn from this study or any other study 
investigating LY3298176.
[45] Previous exposure or known allergies to LY3298176.
[46] Are currently enrolled in any other clinical trial involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study.
Other Exclusions
[47] 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.
[48] Are Eli Lilly and Company employees or are employees of any third party 
involved in study who require exclusion of their employees.
[49] Are, in the opinion of the investigator or sponsor, unsuitable for inclusion in 
the study.
6.3.
Lifestyle Restrictions
Study participants should be instructed not to donate blood or blood products during the study or 
for 8 weeks following the study.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failures) may be 
rescreened only once at the discretion of the investigator.  Before rescreening is performed, the 
patient must sign a new informed consent form (ICF) and receive a new identification number.  
If, in the opinion of the investigator, an ineligible lab test result is the result of an error or 
extenuating circumstance, then that parameter can be retested once (if feasible within the time 
constraints of the screening period) without the patient having to be rescreened.  However, 
screen failures for HbA1c may not be retested or rescreened.


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7.
Treatments
7.1.
Treatments Administered
This study will evaluate 4 parallel dose groups of LY3298176 at SC dose levels of 1 mg, 5 mg,
10 mg, and 15 mg QW for up to 26 weeks and the results will be compared with those for 
dulaglutide 1.5 mg and placebo.  The study design is composed of 6 parallel treatment groups 
(approximately 45 patients per group).  One treatment group will receive LY3298176 placebo 
and placebo for dulaglutide.  One treatment group will receive active dulaglutide 1.5 mg and 
LY3298176 placebo. In the 4 remaining treatment groups, patients randomized to the 1-mg and 
5-mg doses of LY3298176 will receive 1 injection of active LY3298176 and 1 injection of 
dulaglutide placebo. Patients randomized to the 10-mg dose of LY3298176 will receive 
2 injections of active LY3298176 and 1 injection of dulaglutide placebo after the titration period, 
and patients randomized to the 15-mg dose of LY3298176 will receive 3 injections of active 
LY3298176 and 1 injection of dulaglutide placebo after the titration period (Table GPGB.2).  All 
SC dose administrations of LY3298176 and dulaglutide should be in different quadrants of the 
abdomen.
This study involves dose titration in 5-mg increments for doses above 5 mg (Table GPGB.3).  
Although the investigator and patients will know dose group assignment (LY3298176 1 mg, 
5 mg, 10 mg, or 15 mg) due to the study drug dose volume and titration scheme, they will not 
know whether they are actually receiving placebo, LY3298176, or dulaglutide.  Thus, patients 
may be titrating placebo.  In the description of the titration below, please note patients may 
receive LY3298176 or a complementary dose volume of placebo.
Patients assigned to the 1-mg and 5-mg treatment groups will receive that dose level throughout 
the study and will not have dose titration.  All patients in the 10-mg and 15-mg groups will 
receive 5 mg as the first and second doses (Visits 3 and 4).  Patients assigned to the 10-mg and 
15-mg groups will receive 10 mg as the third dose (Visit 6), and the patients assigned 10 mg will 
continue that dose for the duration of the study.  The patients assigned to the 15-mg dose will 
continue to receive 10 mg through dose 6 and will begin 15 mg as dose 7 and will continue that 
dose for the duration of the study.  Patients in every dose group except the 1-mg and 5-mg 
groups who have reached their target dose and have received the target dose for 2 weeks but still 
are unable to tolerate that dose level (have vomiting or moderate to severe nausea), may have the 
dose reduced by 5 mg (10-mg patients would receive 5 mg and 15-mg patients would receive 
10 mg) and may remain on the reduced dose for the remainder of the study.  The dose the patient 
administers each week should be recorded on the case report form (CRF) during titration and 
throughout the study.


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Table GPGB.2.
Investigational Product Administration and Treatment Regimens
Total Number of Injections
Randomization
LY3298176
PBO LY3298176
Dulaglutide 1.5 mg SDP
PBO Dulaglutide 
SDP
LY 1 mg
1
0
0
1
LY 5 mg
1
0
0
1
LY 10 mg
2
0
0
1
LY 15 mg
3
0
0
1
Dulaglutide 1.5 mg
0
Up to 3
1
0
PBO
0
Up to 3
0
1
Abbreviations:  LY = LY3298176; PBO= placebo; SDP = single-dose pen.
Table GPGB.3.
Recommended Dose Titration Schedulea
Study Phase
Randomization
Treatment Phase
Visit
3
4
6
N/S
8
N/S
N/S
N/S
10–16
Day
0
7
14
21
28
35
42
49
56–182
Week of Treatmentb
0
1
2
3
4
5
6
7
8–26
Dose Number
1
2
3
4
5
6
7
8
9–27
LY 1-mg Group
1
1
1
1
1
1
1
1
1
LY 5-mg Group
5
5
5
5
5
5
5
5
5
LY 10-mg Group
5
5
10
10
10
10
10
10
10
LY 15-mg Group
5
5
10
10
10
10
15
15
15
Abbreviations:  LY = LY3298176; N/S = none scheduled.
a
This is the recommended titration time course.  The dose utilized should be captured on the study drug CRF.
b
There are no scheduled visits for Weeks 3, 5, 6,and 7 dosing.  The investigator should give the patient the 
expected titration dose for Week 3 at the Week 2 visit (Visit 6) and for Weeks 5- 7 at the Week 4 visit (Visit 8).  
However, for any titration week, the investigator may have the patient come to the site for an unscheduled visit to 
dilute the vials and self-administer the study drug under study site supervision.  If a patient does not tolerate a 
target dose level for 2 weeks due to vomiting or moderate to severe nausea and the investigator believes that the 
patient will not tolerate the dose with further exposure, the investigator may decrease the dose by 5 mg and the 
patient should remain at that dose level for the duration of the study (see Section 7.4 for additional discussion on 
dose modification).


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Patients will be required to dilute study drug vials and administer injections of the study drug by 
syringe and to administer 1 single-dose pen (SDP) injection of dulaglutide or matching placebo 
themselves. Patients should inject study drug and SDP injections on the same date and at 
approximately the same time.  The study site will send vials, diluent, syringes, needles, and SDPs
home with patients.  Patients will be diluting the vials and self-injecting at home during weeks 
without a clinical site visit and instructions will be provided.  For all clinical site visits other than 
PK-specific visits, the patient should dilute the vials and administer the study drug (including 
dulaglutide SDP or matching placebo) at the clinical research site under the supervision of study 
personnel in order to reinforce patient understanding and confidence.  The investigator or site 
staff may assist patients with vial reconstitution and study drug injection any other time they 
deem necessary.
Patients taking background metformin (either immediate release or extended release) are 
strongly encouraged to remain on the same type of metformin during the trial, if possible.  
Changing formulations or manufacturers of metformin during the study participation should be 
minimized.  If a dose change (i.e., conversion of extended release to immediate release or vice 
versa) is required, the investigator should determine the most appropriate clinically equivalent 
metformin dose.  The metformin dose should be at least 1000 mg/day and not more than the 
highest dose allowed per local label.
The patient receiving metformin should continue the baseline dose of metformin, unless the 
patient experiences documented hypoglycemia, in which case the dose may be reduced.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational agents to the patient or the 
patient’s legal representative

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

at the end of the study returning all unused medication to Lilly, or its designee,
unless the sponsor and sites have agreed that all unused medication is to be 
destroyed by the site, as allowed by local law.
Patients will be instructed to contact the investigator as soon as possible if he/she has a complaint 
or problem with the study drug or drug delivery system so that the situation can be assessed.
7.1.1. Packaging and Labeling
Clinical trial materials will be labeled according to the country’s regulatory requirements.  
LY3298176, dulaglutide 1.5 mg, and their matched placebos will be supplied by Lilly.  
 
 
 
 
 
 Patients will inject the dose volume appropriate for their 
CCI


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treatment group, including placebo patients within a group.  Dulaglutide or matching placebo 
will be provided as SDPs.  LY3298176 vials and dulaglutide 1.5 mg SDPs must always be stored 
in a secure location with access limited to designated study staff members.
Instructions for the reconstitution of study drug will be provided separately to each patient and 
the investigator.  
 
 The reconstituted LY3298176 or placebo solution 
should be used immediately after reconstitution.
Study drug (including dulaglutide 1.5 mg) must be stored in a refrigerator at 2C to 8C (36F 
to 46F).  Temperature logs must be maintained to verify correct storage conditions at the 
investigator site, throughout the study. Patients should be instructed to store the study drug in 
their refrigerator but are not required to maintain temperature logs.
Dulaglutide 1.5 mg or its placebo should be injected in a different quadrant of the abdomen from 
the concomitant LY3298176 or LY3298176 placebo injections.
7.1.2. Medical Devices
The manufactured medical devices provided for patient use in the study are dulaglutide and 
matching placebo SDPs, glucose meters, and lancet devices.
7.2.
Method of Treatment Assignment
A unique 4-digit patient number will be assigned to each patient when the patient signs the ICF.
Patients will be assigned to dulaglutide 1.5 mg, placebo, or 1 of 4 LY3298176 dose levels.  
Patients who meet all criteria for enrollment will be randomized at Visit 3 and assigned to their 
respective treatment arms via IWRS using the following stratification variables:  baseline HbA1c 
(<8.5%, 8.5%), metformin use (Yes, No), and BMI (<30, 30).  There will be equal 
randomization to the treatment arms (1:1:1:1:1:1).  However, LY3298176 placebo patients will 
be randomized such that a portion will be randomized to each cohort in order to receive the same 
dose volume as that cohort in order to maintain the study blind.  For the active dulaglutide 
1.5 mg group, LY3298176 placebo patients should also be distributed through the treatment 
groups in order to maintain the blind.
The randomization scheme will be performed using IWRS that will ensure balance between 
treatment arms.
7.2.1. Selection and Timing of Doses
Assignment to 1 of the 4 LY3298176 doses, dulaglutide 1.5 mg, or placebo will occur at 
randomization.  There are no restrictions on the time of day each weekly dose is given, but it is 
advisable to administer SC injections on the same day and same time each week. The actual date 
and time of all dose administrations will be recorded in the subject’s CRF. If a dose of study 
drug, including dulaglutide or its placebo, is missed, the patient should take it as soon as possible 
unless it is within 72 hours of the next dose, in which case that dose should be skipped and the 
next dose taken at the appropriate time.
CCI


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7.2.2.
Specific Restrictions/Requirements
Prior to beginning the study, patients will complete informed consent and baseline tests.
Throughout the study, patients may undergo medical assessments and review of compliance with 
restrictions before continuing in the study.
Patients will report to the clinical research site for safety assessments and will remain in the 
clinic until all procedures for that visit are complete and the investigator has deemed it safe to 
release the patient from the clinic.  There will be no inpatient stays.  In addition, patients will 
report to the clinical research site for PK-specific visits (Visits 5, 7, 9, and 12).
Meals/Diet – Patients shall fast for at least 8 hours overnight prior to each outpatient visit where 
fasting samples are drawn or weight measurements taken.
Alcohol – Alcohol will not be permitted 8 hours prior to the dosing day, until the patient has 
been discharged from the clinical research site.
Exercise – Patients will be advised to maintain their regular levels of physical activity/exercise 
during the study.  When certain study procedures are in progress at the site, patients may be 
required to remain recumbent or sitting.
Blood donation – Study participants should be instructed not to donate blood or blood products 
during the study or for 8 weeks following the study.
Contraception – Male patients or their female partners of child-bearing potential must use 
reliable contraception during intercourse throughout the treatment period and for 3 months after 
the last dose of study drug (as the risk of LY3298176 to the unborn fetus is unknown).  Female 
patients of childbearing potential, if sexually active, should use two forms of effective 
contraception, where at least one form is highly effective for the duration of the trial and for
30 days thereafter. Please see Appendix 7 for further details regarding contraception.
7.3.
Blinding
This is a double-blind study.  Although the patient and the investigator will know which dose 
group (1 mg, 5 mg, 10 mg, or 15 mg LY3298176) the patient is assigned to, they will not know 
whether the patient is receiving LY3298176, dulaglutide 1.5 mg, or placebo.
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomization table and treatment assignments before the study is complete.
Emergency codes, generated by a computer drug-labeling system, will be available to the 
investigator.  These codes, which reveal the patient’s treatment group when opened, may be 
opened during the study ONLY if the patient’s well-being requires knowledge of the patient’s 
treatment assignment.
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 
may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment.  All calls resulting in an unblinding event are recorded and reported by the IWRS.


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If an investigator, site personnel performing assessments, or patient is unblinded, the patient
must be discontinued from the study.  In cases where there are ethical reasons to have the patient
remain in the study, the investigator must obtain specific approval from a Lilly clinical research 
physician (CRP) for the patient to continue in the study.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted.  Patient safety must always be the first 
consideration in making such a decision.  If the investigator decides that unblinding is warranted, 
the investigator should make every effort to contact the Lilly CRP prior to unblinding a patient’s 
treatment assignment unless this could delay emergency treatment of the patient.  If a patient’s 
treatment assignment is unblinded, Lilly must be notified immediately.
Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dosage Modification
Adjustment in study drug dose level will be allowed for patients assigned to the LY3298176 
10-mg and 15-mg groups.  If a patient in a LY3298176 treatment group of 10 mg or 15 mg does 
not tolerate the target titrated dose for 2 weeks once the assigned dose is reached, in other words 
if the patient is still vomiting or has moderate to severe nausea and the investigator does not 
believe that the patient will tolerate the dose with further exposure, then the investigator may 
drop the dose back to the next lower dose.  Thus, if a patient has reached the target dose of 
10 mg and has vomiting or moderate to severe nausea for 2 weeks, then the patient’s dose level 
may be dropped back to 5 mg and the patient may remain on 5 mg for the duration of the study.  
Similarly, the 15-mg dose would be dropped to 10 mg.  The actual dose received should be 
recorded on the CRF each week.  Dosing of concomitant metformin is discussed in Section 7.7.
7.5.
Preparation/Handling/Storage/Accountability
The study site must store the study drug in a locked and secure environment. The study drug 
must be refrigerated (not frozen) at 2C to 8C. Dry ice should not be used for cooling. Patients 
will be provided with double-blinded vials containing lyophilized LY3298176 or LY3298176 
placebo and Sterile Water for Injection (along with syringes) and SDPs containing dulaglutide or 
dulaglutide placebo, at clinic visits according to the Study Schedule. The patients will also 
receive insulated bags with cooling gel packs for use in transporting the study drug from the site 
to the home. Study drug in each participating country will be labeled according to the country’s 
regulatory requirements.
Commercial metformin may be made available during the treatment period to patients who 
entered the trial on this agent. Appropriate use and storage information will be available by 
referring to the package insert.
7.6.
Treatment Compliance
During the study, patients will be asked to return their unused study drug materials and 
completed diaries to the site so that their compliance may be assessed.


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Patients who are significantly noncompliant will be permanently discontinued from study
medication.  A patient will be considered significantly noncompliant if he/she intentionally 
misses 4 or more doses of study medication.  Similarly, a patient will be considered significantly 
noncompliant if he/she is judged by the investigator to have intentionally or repeatedly taken 
more than the prescribed amount of medication.
7.7.
Concomitant Therapy
Treatment with drugs that are excluded in the entry criteria (Section 6) is not permitted.
The only concomitant antihyperglycemic medication permitted during this study is metformin, 
unless glycemic criteria for rescue therapy are met (see Section 7.8.1).  Metformin treatment 
must be stable for at least 3 months prior to screening at a daily dose of 1000 mg/day.  Patients
who enter the study on diet and exercise alone will not be allowed to initiate metformin therapy 
after study entry unless criteria for rescue therapy are met.
Patients who are being treated with metformin upon entering this study should remain on the 
same (or equivalent if switching to sustained release) metformin dose throughout the course of 
the study unless a change in dose is required to protect patient safety.
If a patient switches from the immediate-release formulation of metformin to the 
sustained-release formulation, the change will be on a milligram-per-milligram basis.
In certain situations (such as during a hospitalization or perioperatively), it may be necessary for 
a patient to be treated with insulin(s).  Treatment with insulin will be allowed for up to 
14 consecutive days prior to or during the trial.  If a patient requires treatment with insulin for 
more than 14 consecutive days, that patient will be considered a “rescue” patient and may remain 
in the study but will not receive additional study drug.
Doses of antihypertensive and lipid-lowering therapies must be stable for 30 days prior to 
screening.  Doses of antihypertensive and lipid-lowering agents should not be changed during 
this study unless necessary to protect patient safety on an emergency basis (e.g., hypertensive 
crisis).
Doses of other prescription medications (e.g., thyroxine, estrogen or progesterone replacement, 
or selective estrogen receptor modulators) for treatment of concurrent medical conditions should 
remain constant during the study whenever possible.
If the need for additional concomitant medication arises, the patient may be continued in the 
study on study medication if, in the investigator’s opinion, the addition of the new medication 
does not pose a safety risk. If an additional concomitant medication is started, the sponsor 
should be informed as soon as possible. Nausea and/or vomiting during this study may be 
treated with antiemetics that do not increase QTc (e.g., cyclizine or meclizine) but should not be 
used prophylactically.  Nonsteroidal anti-inflammatory medications (including ibuprofen, 
aspirin), acetaminophen, cough suppressants, antihistamines, vitamin/mineral supplements, 
antibiotics, and topical ointments may be used on an as-needed basis without notifying the 
sponsor and are not restricted by the stable dosing requirements listed above. Any additional 


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medication used during the course of the study (including those not requiring sponsor 
notifications) must be documented on the appropriate electronic case report form (eCRF).
Specifically excluded concomitant medications include the following:

Chronic use of drugs that directly reduce GI motility including but not limited to 
anticholinergics, antiemetics, and opiates (e.g., metoclopramide, phenergan, dicyclomine, 
and morphine)

Chronic use of medications that directly promote motility (e.g., bethanechol and 
cisapride)

Prescription or over-the-counter medications to promote weight loss

Systemic glucocorticoid therapy of greater than 14 consecutive days’ duration (with the 
exception of topical, intranasal, intraocular, intra-articular, and inhaled preparations)

Central nervous system stimulants (e.g., Ritalin-SR)

Any drug, other than those provided in this study, that has not received regulatory 
approval.
7.8.
Treatment after the End of the Study
7.8.1. Special Treatment Considerations (Rescue Therapy)
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 26-week treatment period.  
An additional therapeutic intervention should be considered in patients who meet the following 
criteria:

The patients are fully compliant with assigned therapeutic regimen.
AND

In the absence of any acute condition that raises blood glucose either of the following 
occurs:
o
During the first 6 weeks post-randomization: An average fasting glucose 
level above 270 mg/dL (15.0 mmol/L) occurs over at least a 2-week period 
(at least 4 values/week must be available).
OR
o
Any time after the first 6 weeks to 26 weeks post-randomization: An 
average fasting glucose level above 240 mg/dL (13.3 mmol/L) occurs over 
at least a 2-week period (at least 4 values/week must be available).
If these conditions are met, then patients may begin treatment with another antihyperglycemic 
agent as determined by their physician.  If treatment with another antihyperglycemic agent is 
instituted, then study drug should be permanently discontinued.  Patients may remain in the study 
for safety follow-up, but the date at which they begin rescue therapy will be the last date for 
collection of efficacy measures.


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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
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:

Abnormal liver tests or when a patient meets one of the following conditions:
o
ALT or aspartate aminotransferase (AST) >8ULN
o
ALT or AST >5ULN for more than 2 weeks
o
ALT or AST >3ULN and total bilirubin level >2ULN or prothrombin time 
>1.5ULN
o
ALT or AST >3ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
o
Alkaline phosphatase (ALP) >3ULN
o
ALP >2.5ULN and total bilirubin >2x ULN
o
ALP >2.5ULN with the appearance of fatigue, nausea, vomiting, right quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%)

Investigator Decision
o
the investigator decides that the patient should be discontinued from the study 
medication

Any medication for weight loss is given for more than 1 week

Adverse Event

When any one of the following events occur, Lilly or its designee is to be alerted 
immediately:
o
Pancreatitis or pancreatic cancer (refer to Section 9.2.1.2.5 for details)
o
Estimated glomerular filtration <30 mL/min
o
Any severe injection site reaction or 2 or more moderate injection site reactions 
occurring a week or more apart
o
Any significant study drug-related hypersensitivity reaction
o
Any nonfatal major cardiovascular (CV) events (refer to Section 9.2.1.2.6 for 
details)
o
Any other treatment-emergent adverse event (TEAE), SAE, or clinically
significant laboratory value for which the investigator believes that permanent 
study drug discontinuation is the appropriate measure to be taken.

If the patient, for any reason (including protocol-mandated institution of rescue therapy; 
see Section 7.8.1), requires treatment for greater than 1 week with another therapeutic 
agent that has been demonstrated to be effective for treatment of diabetes.  Also, a change 
in dose of metformin is not allowed (except for incidences of hypoglycemia; see 
Section 7.1).  However, a change to an equivalent dose strength from immediate-release 
to extended-release (or vice versa) formulation is allowed.


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
If the patient intentionally misses 4 or more doses (consecutive or not) of study 
medication or intentionally or repeatedly takes more than the prescribed dose of study 
medication (see Section 9.3).

If the patient develops any exclusion criteria, such as pregnancy or nursing.
If study drug is permanently discontinued, the patient should remain in the study if possible.
8.1.2. Temporary Discontinuation from Study Treatment
After randomization, the investigator may temporarily discontinue study drug, for example, due 
to an AE (e.g., nausea and vomiting), a clinically significant laboratory value, or a natural 
disaster.  If study drug discontinuation is due to an AE, the event is to be followed and 
documented.  Every effort should be made by the investigator to maintain patients in the study 
and to restart study drug promptly after any temporary discontinuation, as soon as it is safe to do 
so.  The dates of study drug discontinuation and restart will be documented.  Patient 
noncompliance should not be recorded as temporary discontinuation of study drug on the eCRF.  
In the event that the patient requires the discontinuation of the study drug, he/she may continue 
participation in the study, attend all visits, and undergo all protocol procedures, and patient data 
from the time of discontinuation of study drug will not be included in the primary analyses.
After study drug discontinuation, patients may commence any standard diabetes therapy in line 
with local or regional standards of care, and as considered appropriate by the investigator.
8.1.3. Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly. If the sponsor or investigator identifies a 
patient who did not meet enrollment criteria and was inadvertently enrolled, notified discussion 
must occur between the sponsor CRP/ clinical research scientist (CRS) and the investigator to 
determine if the patient may continue in the study.  If both agree that it is medically appropriate
to continue, the investigator must obtain documented approval from the sponsor CRP/CRS to 
allow the inadvertently enrolled patient to continue in the study with or without treatment with 
the investigational product.
8.2.
Discontinuation from the Study
Some possible reasons that may lead to permanent discontinuation include the following:

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study

Sponsor decision
o
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).


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
Investigator decision
o
The investigator decides that the patient should be discontinued from the study

Subject decision
o
The patient requests to be withdrawn from the study.
Patients who discontinue the study early will have end-of-study procedures performed as shown 
in the Schedule of Activities (Section 2).
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.
Site personnel, or an independent third party, will attempt to collect the vital status of the patient 
within legal and ethical boundaries for all patients randomized, including those who did not get 
investigational product.  Public sources may be searched for vital status information.  If vital 
status is determined, this will be documented and the patient will not be considered lost to 
follow-up.
Lilly personnel will not be involved in any attempts to collect vital status information.


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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1. Primary Efficacy Assessments
The primary efficacy measure is HbA1c, as determined by the central laboratory.  Blood samples 
for HbA1c measurements will be collected at specific clinic visits as summarized in Section 2.
9.1.2. Secondary Efficacy Assessments
The following secondary efficacy measures will be collected at the times shown in Section 2.

Body weight: Patients will be weighed on an electronic scale in a light hospital gown at 
approximately the same time in the morning after an overnight fast and evacuation of any 
bowel and bladder contents (See Appendix 8).  The scale’s performance will be 
monitored at least monthly using standard weights, and records of these assessments will 
be kept in the study binder.

HbA1c

FBG

Serum lipids, circulating biomarkers (including fasting insulin, glucagon, lipids, free fatty 
acids, glycerol, -hydroxy butyrate, fibroblast growth factor-21 [FGF-21], and 
adiponectin).

Waist circumference:  Waist circumference should be measured at the midpoint between 
the lower margin of the least palpable rib and the top of the iliac crest.  The patient
should stand with feet close together, arms at the side and body weight evenly distributed, 
and should wear little clothing. The patient should be relaxed, and the measurements 
should be taken at the end of a normal expiration.  The measurement should be repeated.  
If the difference between the 2 measurements exceeds 1 cm, the 2 measurements should 
be repeated.
9.1.2.1.
Exploratory Efficacy Assessments

Seven-point SMBG profiles consisting of measurements obtained before each meal, 
approximately 2 hours after each meal, and at bedtime on a day during the week before 
the scheduled clinic visit.  Patients will record their SMBG levels in their diaries, 
according to instructions.  The complete 7-point profile must be collected on a single day.  


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If a patient does not complete the entire profile on a single day, all 7 points must be 
collected on a subsequent day.
9.1.3. Appropriateness of Assessments
All efficacy measures are widely used and generally recognized as reliable, accurate, and 
relevant with respect to the management of T2DM.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish drug effect.
After the ICF is signed, study site personnel will record via CRF the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs. Investigators should record their assessment of the 
potential relatedness of each AE to protocol procedure or investigational product via CRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a cause-and-effect relationship between the 
investigational product, study device, and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
In addition to records of observations made at specific times, unexpected signs and symptoms 
and concomitant medications will be recorded in the clinical trial records throughout the study.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.


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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 CRF, clarifying if possible the circumstances leading 
to any dosage modifications or discontinuations of treatment.
If the AE or SAE is believed to have been caused by a device issue, in addition to recording the 
relatedness in the CRF, a product complaint must also be reported.
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 (i.e., immediate risk of dying)

Persistent or significant disability/incapacity

Congenital anomaly/birth defect

Considered significant by the investigator for any other reason:  important 
medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious, based upon appropriate medical 
judgment.

When a condition related to the investigational device necessitates medical or 
surgical intervention to preclude either permanent impairment of a body function 
or permanent damage to a body structure, the serious outcome of “required 
intervention” will be assigned.
Although all AEs occurring after signing the ICF are recorded in the CRF, SAE reporting 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, it needs to be 
reported ONLY 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 by official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.
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 summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.


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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 guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs. Lilly has procedures that will be followed for the recording 
and expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidances.
9.2.1.2.
Adverse Events of Special Interest
The following Adverse Events of Special Interest (AESIs) of varying clinical significance will be 
used to determine the tolerability of LY3298176 over the range of doses selected for this clinical 
trial.  All AESIs should be captured and reported to Lilly on the AE eCRF or on a specific eCRF, 
if applicable (see below).  Any AESI that meets the definition of an SAE (see Section 9.2.1) 
must be reported as an SAE.
When any one of the following events occur, Lilly or its designee must be alerted immediately, 
whether it is assessed as an SAE or not:

Confirmed pancreatitis or pancreatic cancer

Any severe injection site reaction or 2 or more moderate injection site reactions 
occurring a week or more apart

Any study drug-related hypersensitivity reaction

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.
9.2.1.2.1. Injection Site Reactions
All injection site reactions and information regarding their time of day, time relative to injection, 
size, amount of erythema, induration, and pruritus, as well as severity, will be recorded on 
specific CRFs.  In addition, if the reaction is clinically significant, the site should attempt to 
contact the sponsor for potential follow-up procedures.  Injection site reactions do not need to be 
recorded as AEs as well unless they meet SAE criteria.
9.2.1.2.2. Hypersensitivity Reactions
All hypersensitivity reactions will be reported by the investigator as either AEs or, if any serious 
criterion is met, as SAEs.  Study drug should be temporarily discontinued for any individual 
suspected of having a severe or serious allergic/hypersensitivity reaction to study drug.  Study 
drug may be restarted if, in the opinion of the investigator, the event was not related to study 
drug and when/if it is safe to do so.  If study drug is permanently discontinued, the patient should 
remain in the study.
9.2.1.2.3. Hypoglycemia
Hypoglycemia episodes will be recorded on a specific eCRF. Information regarding severity, 
time of day, and investigator’s opinion of relatedness to study drug and procedure will be 


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recorded.  Hypoglycemia episodes should not be recorded as AEs unless the event meets serious 
criteria.  Hypoglycemia will be classified as follows (American Diabetes Association 2005):

Documented Symptomatic Hypoglycemia:  Any time a patient feels that he/she is 
experiencing symptoms and/or signs associated with hypoglycemia and has a plasma 
glucose level of 3.9 mmol/L (70 mg/dL)

Asymptomatic Hypoglycemia:  An event not accompanied by typical symptoms of 
hypoglycemia, but with 3.9 mmol/L (70 mg/dL) plasma glucose.

Severe Hypoglycemia:  An episode requiring the assistance of another person to actively 
administer carbohydrate, glucagon, or other resuscitative actions.  These episodes may be 
associated with sufficient neuroglycopenia to induce seizure or coma.  Plasma glucose 
measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration.

Nocturnal Hypoglycemia:  Any hypoglycemic event that occurs between bedtime and 
waking

Probable Symptomatic Hypoglycemia:  An event during which symptoms of 
hypoglycemia are not accompanied by a plasma glucose determination (but that was 
presumably caused by a plasma glucose concentration 3.9 mmol/L [70 mg/dL]).
9.2.1.2.4. Nausea, Vomiting, and Diarrhea
Nausea, vomiting, and diarrhea events will be recorded on a specific eCRF.  They should not be 
recorded as AEs unless the event meets an SAE criterion.  For each event, assessment of severity, 
duration, and Investigator’s opinion of relatedness to study drug and protocol procedure will be 
captured.
9.2.1.2.5. Acute Pancreatitis
Acute pancreatitis is defined as an AE of interest for this study. Acute pancreatitis is an acute 
inflammatory process of the pancreas that may also involve peripancreatic tissues and/or remote 
organ systems(Banks et al. 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 
et al. 2006; Koizumi et al. 2006]; the pain is often associated with nausea and 
vomiting);

serum amylase (total and/or pancreatic) and/or lipase 3ULN;

characteristic findings of acute pancreatitis on computed tomography (CT) 
scan or magnetic resonance imaging (MRI).
If acute pancreatitis is suspected, appropriate laboratory tests (including levels of pancreatic 
amylase and lipase) should be obtained via the central laboratory (and locally, if needed). 
Imaging studies, such as abdominal CT scan with or without contrast, MRI, or gallbladder 
ultrasound, should be performed.  If laboratory values and/or abdominal imaging support the 
diagnosis of acute pancreatitis, the patient must discontinue therapy with investigational product,


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but will continue in the study on another glucose-lowering regimen (see Section 7.8.1 for details 
on rescue intervention).  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 case of 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.
In addition to the diagnostic assessment in patients who develop symptoms of acute pancreatitis, 
each patient will have measurements of pancreatic amylase and lipase at screening, baseline, and 
at each non-PK-specific visit to assess any potential effects of LY3298176 on the exocrine 
pancreas (refer to Section 2, Schedule of Activities).  Further diagnostic assessment per Lilly 
algorithm for assessment of asymptomatic pancreatic hyperenzymemia will be required 
whenever lipase and/or pancreatic amylase are 3ULN at any time during the study.  If this 
situation occurs at Visit 801 (Week 30), the patient will be required to undergo this additional 
workup, and the data will be collected in the clinical trial database.
All suspected cases of acute or chronic pancreatitis, as well as cases of confirmed lipase or 
pancreatic amylase values 3ULN, will be adjudicated by an independent committee of expert 
physicians. 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, those with severe or 
serious abdominal pain, and those that undergo additional assessments due to confirmed 
hyperenzymemia will be entered into a specifically designed eCRF page by study site or Lilly 
staff. The adjudication committee representative will enter the results of adjudication in a 
corresponding eCRF page.
9.2.1.2.6. Major Adverse Cardiovascular Events
Deaths (CV and non-CV), nonfatal MIs, supraventricular arrhythmias, and nonfatal strokes that 
occur during the treatment period or follow-up period will be adjudicated by an independent 
adjudication committee in compliance with a study-specific adjudication charter.  Investigative 
sites will also be asked to submit any cases of TIA or hospitalization for unstable angina for 
adjudication as well to ensure that all true stroke and MI events are captured.  Hospitalizations 
for heart failure and coronary interventions (such as coronary artery bypass graft or percutaneous 
coronary intervention) will also be submitted for adjudication.
Cardiovascular event definitions will be based on the Standardized Definitions for 
Cardiovascular and Stroke Endpoint Events in Clinical Trials (Hicks et al. 2015) and the 
ESC/ACCF/AHA/WHF Expert Consensus Document Third Universal Definition of Myocardial 
Infarction (Thygesen et al. 2012).  An adjudication committee will enter the results of 
adjudication in the corresponding eCRF page.


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9.2.1.2.7. Thyroid C-Cell Hyperplasia and C-Cell Neoplasms
Individuals with personal or family history of certain thyroid or nonthyroid endocrine 
abnormalities or certain preexisting laboratory and genetic characteristics will be excluded from 
the study (see Section 6.2).  The assessment of thyroid safety during the trial will include 
reporting of thyroid TEAEs and measurements of calcitonin according to Section 2 at screening, 
baseline, and Visits 11 and 16 (Months 3 and 6) or ET visit.  The purpose of calcitonin 
measurements is to assess the potential of LY3298176 to affect thyroid C-cell function, which 
includes development of C-cell hyperplasia and neoplasms.
Patients who develop serum calcitonin increases 50% of the mean of the baseline and screening 
values AND an absolute value 20 pg/mL and <35 pg/mL at Visits 11 and 16 (Months 3 and 6) 
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% of the mean of the baseline and screening 
values AND an absolute value 35 pg/mL at Visits 9 and 12 (Months 3 and 6) will be 
recommended to immediately undergo additional endocrine assessments and longer term 
follow-up by an endocrinologist.
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. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he/she has a complaint 
or problem with the investigational product or drug delivery system so that the situation can be 
assessed.
9.3.
Treatment of Overdose
For patients with suspected or confirmed overdose with LY3298176 or dulaglutide, there is no 
specific antidote.  The patient should be watched for GI symptoms and hypoglycemia.  
Treatment is supportive, depending on the patient’s symptoms.
Refer to the IB for LY3298176 and to the Product Label for dulaglutide.
9.4.
Safety
9.4.1. Electrocardiograms
For each patient, 12-lead ECGs should be collected according to Section 2. Patients must be 
supine for approximately 5 to 10 minutes before ECG collection and remain supine, but awake, 
during ECG collection.


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Electrocardiograms should be recorded in triplicate according to study-specific recommendations 
included in the Manual of Operations for the study, using standardized equipment provided by 
the sponsor.
Consecutive replicate ECGs will be obtained at approximately 1-minute intervals.  
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs than expected at a particular time point is allowed when needed to 
ensure high-quality records.
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, to determine whether the subject meets entry criteria and 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.  The investigator (or qualified designee) is responsible for determining if any change 
in patient management is needed, and must document his/her review of the ECG printed at the 
time of evaluation.
After enrollment, if a clinically significant increase in the QT/QTc interval from baseline or 
other clinically significant quantitative or qualitative change from baseline is identified, the 
patient will be assessed by the investigator for symptoms (e.g., palpitations, near syncope, and 
syncope) and to determine whether the patient can continue in the study.  The investigator or 
qualified designee is responsible for determining if any change in patient management is needed 
and must document his/her review of the ECG printed at the time of evaluation from at least 1 of 
the replicate ECGs from each time point.
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 (e.g., 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).
In addition, for each patient, a single ECG will be recorded at screening and if the patient 
discontinues from the study prematurely (Section 2) for immediate patient management. These 
ECGs will be stored at the investigation site.
Any treatment-emergent clinically significant ECG finding resulting in a diagnosis should be 
reported as an AE in the eCRF.


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9.4.2. Vital Signs
Sitting BP and PR will be measured using standardized equipment provided by the sponsor 
according to Section 2. Vital sign measurements should be taken before obtaining an ECG 
tracing and before collection of blood samples for laboratory testing, at visits where required (see
Section 2). The participant should be required to sit quietly for 5 minutes before vital sign 
measurements are taken. An appropriately sized cuff (cuff bladder encircling at least 80% of the 
arm) should be used to ensure the accuracy of BP measurements.  The arm used for the BP 
measurement should be supported at heart level. At Visit 1 (screening), to determine which arm 
should be used to collect BP and PR throughout the study, BP and PR will be measured once in 
each arm, and the arm that had the higher systolic BP should be used to collect all 
3 measurements of both BP and PR at all study visits.  For each parameter (PR, systolic BP, and 
diastolic BP), 3 measurements will be taken using the same arm; the recordings should be taken 
at least 1 minute apart, and each measurement of sitting PR and BP will be recorded in the eCRF.  
Any AE related to changes in BP and PR should be reported.
9.4.3. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to
Section 2.
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.
9.4.4. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.  In addition, the study team will review safety reports in a blinded fashion according to 
the schedule provided in the Trial-Level Safety Review plan.  Lilly will also review SAEs within 
time frames mandated by company procedures.  The Lilly CRP/CRS will, as appropriate, consult 
with the functionally independent Global Patient Safety therapeutic area physician or clinical 
scientist.
In addition, specific safety measures are included in the protocol to ensure appropriate 
monitoring of pancreatic, thyroid, and liver safety.  Laboratory findings that trigger pancreatic 
and thyroid safety monitoring per Lilly standards are provided in Sections 9.2.1.2.5 and
9.2.1.2.7, respectively.  Details of liver safety monitoring are provided in Section 8.1.1.  If a 
study patient experiences elevated ALT 3ULN or elevated total bilirubin 2ULN, clinical 
and laboratory monitoring should be initiated by the investigator.  Details for hepatic monitoring 
depend upon the severity and persistence of observed laboratory test abnormalities.  To ensure 
patient safety and comply with regulatory guidance, the investigator is to consult with the Lilly 
CRP/CRS regarding collection of specific recommended clinical information and follow-up 
laboratory tests (see Appendix 4).


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9.5.
Pharmacokinetics
Blood samples for PK analyses will be collected from all randomized patients in accordance with 
Section 2 and Appendix 6 and at early termination.  However, only samples from patients 
assigned to treatment with LY3298176 will be analyzed for drug concentration.

Predose PK samples will be collected only at Weeks 1, 8, 12, and 26.

Following dose at Weeks 1, 2, 4, and 12, a postdose PK sample will be collected.  
Patients may have their PK sample collected any time within the pre-specified collection 
window at their convenience.
o
At Weeks 1 and 2 all patients will have a PK sample collected within a time 
window of 1 to 48 hours (within 2 days of dose).
o
At Week 4 all patients will have a PK sample collected within a time window of  
48 to 72 hours (2 to 3 days postdose).
o
At Week 12 all patients will have a PK sample collected within a time window of 
96 to 168 hours (i.e., any time between 4 days after study drug administration up 
to just prior to the next dose of study drug administration).  

The patient will be required to come to the site for additional PK-specific visits 
dependent on the time window of PK sampling.
Date and time of each sample and the most recent LY3298176 dose prior to PK blood draw must 
be recorded.
Drug concentration information that would unblind the study will not be reported to study sites 
or blinded personnel while the study is blinded.
Bioanalytical samples collected to measure study drug concentration will be retained for a 
maximum of 1 year following the last patient visit for the study.
9.6.
Pharmacodynamics
Samples to evaluate the PD properties of LY3298176 are included in the efficacy measures and 
not applicable here.
9.7.
Pharmacogenetics
9.7.1. Whole Blood Samples for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analyses as specified in 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
dulaglutide, and to investigate genetic variants thought to play a role in T2DM and related 
complications.  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.


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Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and/or ERBs/investigational review boards impose 
shorter time limits, at a facility selected by Lilly or its designee. 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 
becomes commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome-wide association studies, and candidate gene studies.  Regardless of 
technology utilized, genotyping data generated will be used only for the specific research scope 
described in this section.
9.8.
Biomarkers
Collection of samples for other biomarker research is part of this study.  Blood samples will be 
collected as specified in Section 2.
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of patient response (including safety), and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurements of biomolecules, including DNA, RNA, proteins, lipids, 
and other cellular elements.
Serum and plasma ethylenediaminetetraacetic acid (EDTA) and P800 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 diabetes, mechanism of action of LY3298176, and/or 
research method or in validating diagnostic tools or assay(s) related to diabetes.
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and ERBs impose shorter time limits, at a facility selected 
by Lilly.  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 becomes commercially available.
9.8.1. Samples for Immunogenicity Research
Samples from patients in each treatment arm will be tested for the development of 
treatment-emergent LY3298176 antidrug antibodies (ADA), defined as 4-fold increase in titer 
from baseline.  A blood sample will be collected at specific study visits according to the 
Schedule of Activities (Section 2).
Treatment-emergent positive LY3298176 ADA samples will be evaluated for their ability to 
neutralize the activity of assigned treatment (LY3298176-neutralizing antibodies).  Positive


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LY3298176 ADA samples may also be tested for cross-reactivity with native GLP-1 and GIP, 
and if positive, then for neutralizing antibodies against native GLP-1 and GIP.
All patients will have an ADA sample measured at the follow-up visit (Visit 801) approximately
1 month after the last dose of LY3298176.  A risk-based approach will be used to monitor 
patients who develop treatment-emergent antidrug antibodies (TE-ADA) (defined as >4-fold titer 
increase over baseline) after treatment with LY3298176.  Clinically significant TE-ADA will be 
defined as any TE-ADA at the follow-up visit (Visit 801) with:

A high (1280) or increasing titer

An association of TE-ADA with a moderate to severe injection site reaction or 
infusion-related reaction

Cross-reactive and neutralizing binding of an ADA with endogenous GLP-1 or GIP.
Patients who have clinically significant TE-ADA will be followed with ADA testing every 
3 months for approximately 1 year or until the ADA titers have returned to baseline ADA titer 
(defined as ADA titer within 2-fold of baseline).
Patients followed for at least 1 year since last dose who have not returned to baseline, as defined 
above, will be assessed for safety concerns and, if no clinical sequelae is recognized by the 
clinical team, no further follow-up will be required.
Patients who have clinical sequelae that are considered potentially related to the presence of 
TE-ADA may also be asked to return for additional follow-up testing.
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if regulations and ERBs impose shorter time limits, at a facility selected by 
Lilly.  The duration allows the sponsor to respond to future regulatory requests related to 
LY3298176.
9.9.
Health Economics
Health-related quality of life will be assessed using the Ability to Perform Physical Activities of 
Daily Living (APPADL) and Impact of Weight on Self-Perception (IW-SP) questionnaires, 
which are self-rated questionnaires that provide standardized measures of patients’ perceived 
current health status.  Patients will complete the questionnaires at the specific clinic visits 
summarized in Section 2.  At these visits, the questionnaires should be completed before any 
other study procedures (if the patient is not adversely affected by their fasted state) or completed 
after the patient has sufficiently recovered from the preceding visit procedures.

The APPADL questionnaire has demonstrated test–retest reliability, validity, and 
responsiveness to weight loss in individuals with T2DM, thereby making it useful in 
evaluating weight loss interventions (Hayes et al. 2011, 2012).  The APPADL 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.  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 summing the scores of the 
7 items.  A transformed overall score is obtained by linearly transforming the raw overall 


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score to a 0 to 100 scale.  Higher raw overall scores and lower transformed overall scores 
indicate better ability to perform activities of daily living.

The IW-SP questionnaire contains 3 items that assess how often the patient’s 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).  Items are scored on a 
5-point numeric rating scale where 5 = never and 1 = always.  A raw overall score is 
calculated by summing the scores of the 3 items.  A transformed total score is obtained 
by linearly transforming the raw total score to a 0 to 100 scale.  Higher raw overall score 
and lower transformed overall score indicate better self-perception.


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10. Statistical Considerations
10.1. Sample Size Determination
Approximately 300 patients will be randomized to placebo, dulaglutide, or 1 of 4 LY3298176
treatment arms assuming a 10% dropout rate resulting in approximately 45 completers per arm.
The Bayesian approach using a dose–response model with respect to an HbA1c change from 
baseline to 26 weeks will provide approximately 98% probability to show with 90% confidence 
that at least 1 LY3298176 dose has superior glycemic control over placebo with a superiority 
bound of 0.8%.  The sample size also provides more than 95% probability to show with 80% 
confidence that at least 1 LY3298176 dose has noninferior glycemic control compared with 
dulaglutide from baseline to 26 weeks with a 0.3% noninferiority bound. This assumes a change 
from baseline glycemic effect profile shown in Table GPGB.4, and a standard deviation (SD) of 
1.0%.
In addition, this sample size also provides approximately 89% probability to show with 60% 
confidence that at least 1 LY3298176 dose has superior weight loss compared with dulaglutide 
from baseline to 26 weeks with a superiority bound of 2 kg.  This assumes a change from 
baseline weight loss profile shown in Table GPGB.4, and a SD of 6 kg.
Table GPGB.4.
Dose–Response Assumption Used in Sample Size Determination
Placebo
LY 1 mg
LY 5 mg
LY 10 mg
LY 15 mg
Dulaglutide
CFBL HbA1c (%)
0%
0.74%
1.17%
1.29%
1.44%
1.28%
CFBL body weight (kg)
0
2.0
3.0
5.0
6.0
2.5
Abbreviations: CFBL = change from baseline; kg = kilogram; LY = LY3298176.
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined in Table GPGB.5.
Table GPGB.5.
Definitions of Populations to Be Analyzed in Study GPGB
Population
Description
Enrolled
All participants who sign informed consent.
ITT (intention-to-treat)
All randomized patients.
mITT (modified ITT)
All randomized patients with at least 1 post-baseline measurement according to the 
treatment the patients were assigned.
PP (per protocol)
All randomized patients who were compliant with study drug and completed the 
protocol.
Safety
All randomized participants who take at least 1 dose of study treatment.  Participants will 
be included in the treatment group to which they were randomized.  In the event of a 
treatment error, participants will be analyzed according to the treatment they actually 
received.


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10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.  Any change to 
the statistical methods described in the protocol will require an amendment only if it changes a 
principal feature of the protocol.  Any other change to the statistical analyses and the justification 
for the change will be described in the statistical analysis plan (SAP) and/or clinical study report.  
Additional exploratory analyses of the data may be performed as deemed appropriate.  Analyses 
will be fully detailed in the SAP.
The intention-to-treat (ITT) population is defined as all randomized patients.  Statistical analyses 
(including the primary analysis) will be conducted on the modified ITT (mITT) population.  The 
mITT population is defined as all randomized patients with at least 1 post-baseline measurement 
according to the treatment the patients were assigned.  The per-protocol (PP) population is 
defined as all randomized patients who were compliant with study drug and completed the 
protocol and is a subset of the mITT population.  The safety population is defined as all 
randomized patients who have received at least 1 dose of study drug.  Safety analyses will be 
performed on the safety population.
Some efficacy measures will also be analyzed on the PP dataset.  The PP analysis will include 
patients who meet the following additional criteria:

Have been appropriately randomized

Have not discontinued from the study for any of the early discontinuation criteria

Have not missed 4 or more doses during the treatment period

Have not been rescued or taken a concomitant antihyperglycemic medication besides 
metformin for more than 7 cumulative days during the treatment period
Patients who have had rescue therapy will be included in the mITT population, but not the PP 
population. The efficacy measures will be censored at the time of rescue for analyses using 
mITT population.
No adjustments for multiplicity will be performed.
All tests of treatment effects will be conducted at a one-sided alpha level of 0.1 and/or one-sided 
90% confidence interval, unless otherwise stated.
The baseline value used for the analyses will be the last scheduled baseline value obtained for 
each patient prior to randomization.
The primary analysis of the primary endpoint and possibly other Bayesian analyses may be 
computed using Fixed and Adaptive Clinical Trial Simulator software.  Remaining summaries 
and analyses will be performed using the SAS System.


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10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
All patients who discontinue the study will be identified, and the extent of their participation in 
the study will be reported.  If known, a reason for their discontinuation will be given.  The 
primary reasons for discontinuation will be listed and will be summarized by treatment.  The 
percentage of patients discontinuing from each treatment will be compared using the Fisher’s 
exact test.
10.3.2.2. Patient Characteristics
Demographic and baseline characteristics will be summarized by treatment group.  Categorical 
variables will be summarized by frequencies and percentages.  For categorical variables, 
comparisons between treatment groups will be assessed using a Pearson Chi-Square test.  
Continuous variables will be summarized by means and SDs.  For continuous variables, 
comparisons between the treatment groups will be performed using a 1-way analysis of variance 
with treatment as the fixed effect.
10.3.2.3. Concomitant Therapy
Listings and summary of concomitant therapies will be provided by treatment group.
10.3.2.4. Treatment Compliance
Treatment compliance will be listed using all randomized patients and summarized using the 
mITT population.  For a given patient, overall compliance for treatment period is defined as not 
missing 2 or more consecutive doses of the assigned treatment or missing 4 or more at any point 
in the study.  Patients who miss 4 or more doses at any point during the study will be considered 
significantly noncompliant and will be permanently discontinued from study medication.  These 
patients will not be included in the PP analysis.
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary efficacy outcome is HbA1c changes from baseline to the 26-week endpoints.
The primary analyses will be performed on the mITT analysis set using a Bayesian dose–
response model.  The model will include LY3298176 doses and placebo.
The Hierarchical Logistic Model will be used as the dose–response model for HbA1c change 
from baseline to the 26-week endpoint.  Priors for modeled dose–response will follow a normal 
distribution.  Priors for variance will follow inverse gamma distributions.  The placebo group 
will be modeled with the LY3298176 doses, whereas dulaglutide will be modeled separately.  
Details of these prior distributions will be provided in the SAP.
The primary analysis will consist of this dose–response model and examining the probability 
each LY3298176 dose has demonstrated superiority relative to placebo using a superiority 
margin of 0.8%.  Analyses will also consist of the 90% one-sided credible interval for the 
difference in mean response for each LY3298176 dose versus placebo at 26 weeks.  No 
adjustment for multiplicity will be performed.  Probabilities based on posterior distributions of 


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each dose group’s mean response exceeding the placebo group’s mean response by clinical 
thresholds of interest (e.g., by 0.6%) will also be provided.
The longitudinal model will be the linear regression longitudinal model.  The observed 26-week 
endpoint will be modeled using a linear regression model from previous time points.  Priors for 
terms in the mean dose–response function will follow a normal distribution.  Priors for variance 
will follow an inverse gamma distribution.  All the doses will be modeled separately using this 
longitudinal model.  Details of these prior distributions will be provided in the SAP.
Descriptive statistics by treatment for HbA1c and HbA1c change from baseline at the 26-week 
endpoint will be presented using all observed data with no imputations and no elimination of 
patients with protocol violations.  The descriptive statistics will be presented by visit and will 
include sample size, mean, SD, median, minimum, and maximum.
10.3.3.2. Supporting Analyses of Primary Outcome
Supportive analyses of the primary efficacy outcome for the mITT dataset will be MMRM using 
restricted maximum likelihood with metformin use (yes/no), treatment, visit, and treatment-by-
visit interaction as fixed effects, HbA1c baseline as a covariate, and patient as a random effect.  
The dependent variable will be the post-baseline change from baseline values.  The unstructured 
covariance matrix will be selected initially.  If the unstructured covariance structure leads to 
nonconvergence, Akaike’s information criterion will be used to select the best covariance 
structure.  The treatment p-value will be used as evidence of difference between active drug and 
placebo, whereas the comparison of least-square (LS) means versus placebo (unadjusted for 
multiple comparisons) will provide magnitude and significance of this difference.
A further robustness check will be made using the PP dataset and applying the same MMRM 
procedure as described in the above paragraph.  Any differences in conclusions will be further 
investigated by examining differences in the mITT and the PP datasets.
The MMRM analysis will be examined for robustness by checking for treatment-by-strata and 
treatment-by-baseline HbA1c interactions in the MMRM model using the mITT dataset.  If any 
of these checks give positive indications, supportive analyses accounting for the identified issues 
will be compared along with the primary analysis.
An analysis of covariance (ANCOVA) model will be used for the primary efficacy outcome for 
the mITT dataset with fixed effects of metformin use, treatment, and baseline HbA1c as 
covariates.  Missing endpoints will be imputed using last observation carried forward (LOCF).  
For this model, the endpoint is defined as latest HbA1c measurement obtained for a patient in the 
time interval between randomization and 26 weeks after randomization.
10.3.3.3. Secondary Analyses
10.3.3.3.1.Secondary Analysis on Primary Efficacy Endpoint
The secondary analysis of the primary endpoint will consist of the dose–response model, which 
will also be used to examine the probability that any LY3298176 dose has exhibited 
noninferiority in comparison to the dulaglutide dose using a noninferiority margin of 0.3%.  This 
analysis will be used for internal business decisions.


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10.3.3.3.2.Analyses on Secondary Efficacy Endpoints
In addition to the primary efficacy analysis of HbA1c, the following secondary efficacy 
outcomes will be analyzed on the mITT population:

Body weight change from baseline to 12 and 26 weeks

Percentage of patient with 5% or greater body weight loss at 26 weeks

Change from baseline of HbA1c at 12 weeks

Percentage of patients with 10% or greater body weight loss at 26 weeks

Percentage of patients reaching the HbA1c target of 6.5% and of 7.0%

Change from baseline of FBG at 12 and 26 weeks

Change from baseline of waist circumference at 12 and 26 weeks
The mean weight change at 12 and 26 weeks as well as the 12-week HbA1c endpoint will be 
analyzed using a similar dose–response model as the primary endpoint.  HbA1c will continue to 
be analyzed using a superiority bound of 0.8% to placebo as well as a noninferiority bound of 
0.3% relative to dulaglutide.  The weight change from baseline at both 12 and 26 weeks will use 
a superiority bound of 2.0 kg.  In addition, supportive analyses of the mean weight change for the 
mITT dataset will be the MMRM similar to that of the primary efficacy outcome.
The percentage of patients with 5% (and with 10%) body weight loss, the percentage of 
patients reaching the HbA1c target of 6.5% (and of 7.0%) at 26 weeks, and the proportion of 
patients requiring rescue therapy will be analyzed using a logistic regression analysis with fixed 
effects of treatment and stratification factors, and baseline as a covariate.
The change from baseline of FBG and waist circumference profiles will be calculated using a 
similar MMRM-based model to the one used for the primary analysis.  The corresponding 
baseline will be used in the model instead of the baseline HbA1c levels.  The MMRM model will 
also include a term for the HbA1c stratification group.
Patients who initiated rescue therapy will be analyzed.  The proportion of such patients in each 
group will be analyzed using a logistic regression analysis with fixed effects of treatment and 
strata.  Time to start of rescue therapy will also be analyzed between the groups using a log-rank 
test.
In addition to change from baseline in weight and waist circumference, change from baseline in 
BMI will be listed and summarized.
Descriptive statistics for each outcome will be presented by treatment group.  For continuous 
variables, the descriptive statistics will include sample size, LS means, LS means standard error, 
mean, SD, median, minimum, and maximum.  For categorical variables, the descriptive statistics 
will include sample size, frequency, and percentage.


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10.3.4. Safety Analyses
10.3.4.1. Clinical Evaluation of Safety
The safety population will be used for safety analyses.  Both the overall and the pairwise 
comparisons of each LY3298176 dose versus placebo and dulaglutide will be reported for these 
safety analyses.
Safety measures will include vital signs, body weight, TEAEs (including SAEs and AEs of 
special interest), laboratory measures (including anti-LY3298176 antibodies), and ECGs.  
Summary statistics will be presented by treatment for the safety measures.
The summary statistics for continuous variables will be sample size, mean, SD, median, 
minimum, and maximum.
The summary statistics for categorical variables will be sample size, frequency, and percentage.
Exposure to each therapy during the treatment period of the study will be calculated for each 
patient and summarized by treatment group.
In addition, the following safety outcomes will be analyzed on the mITT population:

Change from baseline to 26 weeks in HDL-C, total cholesterol, triglycerides, and LDL-C

Change from baseline to 12 and 26 weeks in fasting FGF-21, adiponectin, -hydroxy 
butyrate, glucagon, and insulin levels

Percentage of patients requiring rescue therapy
The change from baseline of HDL-C, total cholesterol, triglycerides, LDL-C, fasting FGF-21, 
adiponectin, -hydroxy butyrate, glucagon, and insulin levels will be calculated using a similar 
MMRM-based model to the one used for the primary analysis.  The corresponding baseline will 
be used in the model instead of the baseline HbA1c levels.  The MMRM model will also include 
a term for the HbA1c stratification group.
Additional analysis, such as concentration–safety lab plots, may be performed if warranted upon 
review of the data.
10.3.4.2. Adverse Events
Adverse events will be listed by patient, actual term, preferred term, severity, and relationship to 
the treatment.  AEs will be summarized as TEAEs (defined as events that are newly reported 
after randomization or reported to worsen in severity from baseline).  The incidence of patients 
with at least 1 TEAE and the incidence of TEAEs by preferred term and system organ class will 
be presented by treatment group.  The frequency and percentage of TEAEs will be presented.  
The incidence of patients with at least 1 TEAE assessed as possibly related to the investigational 
drug will be summarized by treatment group, in addition to the incidence of these possibly 
related TEAEs by preferred term.  In addition, a summary of TEAEs by severity will be 
presented descriptively by treatment group.
Reported and adjudicated CV, pancreatic, and thyroid-related AEs will be listed by patient, and 
if there are a sufficient number of cases they may be summarized by treatment group.


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All SAEs will be listed by patient.  If a sufficient number of SAEs are reported, incidence 
summaries similar to incidence of TEAEs will be included.
Discontinuations due to TEAEs will be listed by patient and summarized by treatment group.
In addition, exposure–response analyses of TEAEs may be performed if necessary.
10.3.4.3. Vital Signs
All vital signs will be listed using all randomized patients.
Descriptive statistics for the actual measurements and changes from baseline for systolic and 
diastolic BP and PR will be presented by treatment arm and visit.  Corresponding figures may be 
presented.
Vital signs will be analyzed using a similar MMRM-based model as for the secondary analysis 
on the primary endpoint.
In addition, exposure–response analysis of vital signs may be performed if deemed necessary.
10.3.4.4. Laboratory Measures
Summary statistics will be provided for laboratory measures, by visit.
A listing of laboratory measurements for individual patients will be presented by visit.  An
additional listing will be presented for all laboratory measurements that are outside the normal 
range.
Descriptive statistics for the laboratory analyses will be presented by treatment group and visit, 
including safety off-treatment visits.
Laboratory analyses with categorical responses will be summarized by visit and treatment group 
using frequency and percentage.
Shift tables will be evaluated at endpoint (LOCF); the maximum/minimum post-baseline 
observation (as applicable for a lab) will be compared to the baseline observation by examining 
the proportion of patients whose test values are within and outside the reference ranges.
10.3.4.5. Evaluation of Immunogenicity
The frequency of antibody formation to LY3298176 will be determined.  If a neutralization assay 
is performed, the frequency of neutralizing antibodies will be determined.  If there are a 
sufficient number of patients with positive antibodies to LY3298176, the change of antibodies 
(negative to positive) will be summarized using shift tables.
The relationship between the presence of antibodies, antibody titers, and clinical parameters 
(e.g., AEs, efficacy measures) may be assessed.  Likewise, the relationship between antibody 
titers, the PK parameters, and PD response to LY3298176 may be assessed.
10.3.4.6. Electrocardiograms
A listing of the individual and averaged ECG measurements, by patient, will be produced.  This 
will include the time elapsed between the onset of ventricular depolarization and the end of 
ventricular repolarization (QT) corrected values described below.


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Descriptive statistics for the absolute measurements, outliers, and changes from baseline for 
selected ECG parameters will be presented by treatment arm.  These include the ECG heart rate, 
and the following intervals: QT and QT corrected for heart rate using Fridericia’s formula 
(QTcF).
In addition, LY3298176 concentration–response analysis of QTcF results will be performed as 
well as a categorical analyses of absolute and change from baseline QTc intervals.  Any 
additional ECG analyses will be detailed in the SAP.
10.3.4.7. Adverse Events of Special Interest
Hypoglycemia, hypersensitivity reactions, injection site reactions, acute pancreatitis, major 
adverse CV events, and selected GI events such as nausea, vomiting, and diarrhea are defined as 
AESIs.
Descriptive statistics for the AESIs will be presented by treatment group and visit.  Continuous 
responses will be summarized using sample size, mean, SD, median, minimum, and maximum, 
whereas categorical responses will be summarized using frequencies and percentages.
Continuous elements of AESIs, such as the durations of hypoglycemia and injection site 
reactions, will be analyzed using a similar MMRM-based model as for the secondary analysis on 
the primary endpoint.
Statistical analyses on categorical AESIs will be analyzed using a logistic regression analysis 
with fixed effects of treatment, metformin use, and HbA1c strata.  Additional analyses will be 
run if necessary.
10.3.4.8. Hypoglycemic Episodes
Hypoglycemic episodes will be defined as follows:  documented symptomatic hypoglycemia, 
asymptomatic hypoglycemia, probable symptomatic hypoglycemia, relative hypoglycemia, 
nocturnal hypoglycemia, and severe hypoglycemia.  Total or overall hypoglycemia is defined as 
any event meeting the criteria for documented symptomatic hypoglycemia, asymptomatic 
hypoglycemia, or probable symptomatic hypoglycemia.
The total hypoglycemia monthly rate per patient will be summarized where 1 month is defined as 
a 30-day period.  This will be calculated by dividing the total number of hypoglycemic events by 
the total number of days between visits and multiplying by 30 days.  This rate will also be 
calculated per patient for nocturnal hypoglycemia episodes, and summarized by treatment.
The incidence and rate of total hypoglycemic episodes and nocturnal hypoglycemic episodes will 
be presented for each visit (incidence between visits) and overall.  Nocturnal hypoglycemia 
episodes are episodes that occur between bedtime and waking. The incidence of hypoglycemic 
episodes during a time period on treatment is defined as patients with at least 1 hypoglycemic 
episode occurring within that period of time.  Statistical analyses will be performed for overall 
total hypoglycemia using a logistic regression analysis with fixed effects of treatment, metformin 
use, and HbA1c strata.


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Listings of hypoglycemic episodes and severe hypoglycemic episodes will be presented by visit 
for each patient.  If a sufficient number of severe hypoglycemic episodes are reported, then 
incidence summaries similar to incidence of hypoglycemic episodes will be included.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
LY3298176 concentration data will be analyzed using a population PK approach via nonlinear 
mixed-effects modeling with the NONMEM software. The relationships between LY3298176 
dose and/or concentration and efficacy, tolerability, and safety endpoints will be characterized.
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 antidrug 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. Other Analyses
10.3.6.1. Health Outcome/Quality of Life Analyses
Each instrument is transformed to a single score on a scale from 0 to 100.  Patient-reported 
outcomes endpoint change from baseline at Weeks 12 and 26 will be analyzed using ANCOVA 
with treatment, country, metformin use (Yes/No), gender, and baseline HbA1c as independent 
variables.  Missing observations will be imputed with LOCF.  Any additional analysis on 
patient-reported outcomes will be detailed in the SAP.
10.3.6.2. Subgroup Analyses
Subgroup analyses of important factors, including age, race, ethnicity, gender, duration of 
diabetes, baseline HbA1c (<8.5%, 8.5%), metformin use (Yes/No) at baseline, BMI, and other 
factors to be specified in the SAP are planned for the key outcomes of HbA1c.
These will be conducted using the ANCOVA model with strata, treatment, factor, 
treatment-by-factor interaction as fixed effects, and baseline as covariate.
Other exploratory subgroup analyses may be performed as deemed appropriate.
10.3.6.3. Exploratory Analyses
The change from baseline of 7-point SMBG profiles will be calculated using a similar 
MMRM-based model to the one used for the primary analysis.  The corresponding baseline will 
be used in the model instead of the baseline HbA1c levels.  The MMRM model will also include 
a term for the HbA1c stratification group.
Statistical analyses on categorical exploratory objectives like the effect of intrinsic factors, such 
as baseline levels of endogenous FGF-21, GLP-1, or GIP, on the pharmacologic effects of 
LY3298176 will be done using a logistic regression analysis with fixed effects of treatment, 
metformin use, and HbA1c strata.
Genetic markers will be evaluated for their contribution to the variability of LY3298176
pharmacology and will also be included as covariates in PK/PD model-based analyses if 
applicable.


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LY3298176 concentration–response analyses of exploratory biomarkers may be performed.
Exploratory analysis on efficacy endpoints such as HbA1c and body weight may be performed 
on dataset that includes data from patients who received rescue therapy.
Other exploratory subgroup analyses may be performed as deemed appropriate.
10.3.7. Interim Analyses
There may be up to 3 interim analyses for this study.  This study will not be stopped for either 
positive efficacy or futility at any interim analysis.  No change in study design will occur based 
on these interim analyses.
The first interim analysis may occur to support evaluation of the titration scheme.  The second 
interim analysis may occur to support Phase 3 dose selection.  The third interim analysis may 
occur when all patients have completed the treatment part of the study (prior to completion of the 
follow-up phase for all patients) and will include all safety, efficacy, and PK data available 
through the 26-week treatment for all patients to confirm Phase 3 doses.
It is not considered a protocol deviation if one or more interim analysis is not performed.  
Detailed information on the interim analyses will be specified in an Assessment Committee 
charter or SAP.


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11. References
American Diabetes Association, Workgroup on Hypoglycemia Defining and reporting 
hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on 
Hypoglycemia. Diabetes Care. 2005; 28(5):1245–1249.
Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 
2007;132(6):2131–2157.
Banks PA, Freeman ML, Practice Parameters Committee of the American College of 
Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol.
2006;101(10):2379–2400.
Dungan KM, Povedano ST, Forst T, Gonzalez JG, Atisso C, Sealls W, JL Fahrbach. Once 
weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 
diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 2014; 
384(9951):1349–1357.
Giorgino F, Benroubi M, Sun JH, Zimmermann AG, Pechtner V. Efficacy and safety of once 
weekly dulaglutide versus insulin glargine in patients with type 2 diabetes on metformin and 
glimepiride (AWARD-2). Diabetes Care. 2015;38(12):2241–2249.
Hayes RP, DeLozier AM. Reliability, validity, and responsiveness of the Impact of Weight on 
Self-Perceptions Questionnaire (IW-SP) in individuals with type 2 diabetes and obesity. 
Diabetes Technol Ther. 2015;17(3):210–214.
Hayes RP, Nelson DR, Meldahl ML, Curtis BH. Ability to perform daily physical activities in 
individuals with type 2 diabetes and moderate obesity: a preliminary validation of the Impact 
of Weight on Activities of Daily Living Questionnaire. Diabetes Technol Ther. 
2011;13(7):705–712.
Hayes RP, Schultz EM, Naegeli AN, Curtis BH. Test-retest, responsiveness, and minimal 
important change of the ability to perform physical activities of daily living questionnaire in 
individuals with type 2 diabetes and obesity. Diabetes Technol Ther. 2012;14(12):1118–1125.
Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A, Fonarow GC, Jacobs JP, 
Jaff MR, Lichtman JH, Limacher MC, Mahaffey KW, Mehran R, Nissen SE, Smith EE, 
Targum SL, American College of Cardiology and American Heart Association. 2014 
ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical 
Trials: A Report of the American College of Cardiology/American Heart Association Task 
Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints 
Data Standards). Circulation. 2015;132(4):302–361.
Jendle J, Grunberger G, Blevins T, Giorgino F, Hietpas RT, Botros FT. Efficacy and safety of 
dulaglutide in the treatment of type 2 diabetes: a comprehensive review of the dulaglutide 
clinical data focusing on the AWARD phase 3 clinical trial program. Diabetes Metab Res Rev. 
2016;32(8):776–790.
Koizumi M, Takada T, Kawarada Y, Hirata K, Mayumi T, Yoshida M, Sekimoto M, Hirota M, 
Kimura Y, Takeda K, Isaji S, Otsuki M, Matsuno S. JPN Guidelines for the management of 
acute pancreatitis: diagnostic criteria for acute pancreatitis. J Hepatobiliary Pancreat Surg. 
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Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, Zdravkovic M, During M, 
Matthews DR, for the and for the LEAD-2 Study Group. Efficacy and safety comparison of 
liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the 
LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009;32(1):84–90.
Nauck MA, Petrie JR, Sesti G, Mannucci E, Courreges JP, Lindegaard ML, Jensen CB, Atkin 
SL, Study 1821 Investigators. A phase 2, randomized, dose-finding study of the novel once 
weekly human GLP-1 analog, semaglutide, compared with placebo and open-label liraglutide 
in patients with type 2 diabetes. Diabetes Care. 2016;39(2):231–241.
Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Joint 
ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction, 
Katus HA, Lindahl B, Morrow DA, Clemmensen PM, Johanson P, Hod H, Underwood R, Bax 
JJ, Bonow RO, Pinto F, Gibbons RJ, Fox KA, Atar D, Newby LK, Galvani M, Hamm CW, 
Uretsky BF, Steg PG, Wijns W, Bassand JP, Menasche P, Ravkilde J, Ohman EM, Antman 
EM, Wallentin LC, Armstrong PW, Simoons ML, Januzzi JL, Nieminen MS, Gheorghiade M, 
Filippatos G, Luepker RV, Fortmann SP, Rosamond WD, Levy D, Wood D, Smith SC, Hu D, 
Lopez-Sendon JL, Robertson RM, Weaver D, Tendera M, Bove AA, Parkhomenko AN, 
Vasilieva EJ, Mendis S. Third universal definition of myocardial infarction. Circulation. 
2012;126(16):2020–2035.
Trulicity[Summary of Product Characteristics].  Retrieved December 9, 2016, from 
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_Product_Information/human/002825/WC500179470.pdf; 2016.
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http://pi.lilly.com/us/trulicity-uspi.pdf; 20 March 2015.


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Abbreviations and Definitions
Appendix 1.
Term
Definition
ADA
antidrug 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.
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APPADL
Ability to Perform Physical Activities of Daily Living
AST
aspartate aminotransferase
Blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received.
BMI
body mass index
BP
blood pressure
CIOMS
Council for International Organizations of Medical Sciences
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.
CRF
case report form
CRP
Clinical Research Physician: Individual responsible for the medical conduct of the 
study.  Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician, or other medical officer.
CRS
clinical research scientist
CT
computed tomography


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CTX-1
carboxy-terminal telopeptide of type I collagen
CV
cardiovascular
Documented 
symptomatic 
hypoglycemia
Defined as any time a patient feels that he/she is experiencing symptoms and/or signs 
associated with hypoglycemia, and has a plasma glucose level of 3.9 mmol/L 
(70 mg/dL)
DPP-4i
Dipeptidyl peptidase 4 inhibitor (an OAM)
ECG
electrocardiogram
eCRF
electronic case report form
EDTA
ethylenediaminetetraacetic acid
Enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
eGFR
estimated glomerular filtration rate
Enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
FBG
fasting blood glucose
FGF-21
fibroblast growth factor-21
GCP
Good Clinical Practice
GI
Gastrointestinal
GIP
glucose-dependent insulinotropic peptide
GLP-1
glucagon-like peptide-1
GLP-1 RA
glucagon-like peptide-1 receptor agonist
HbA1c
hemoglobin A1c
HDL-C
high-density lipoprotein cholesterol
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
Interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.


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Investigational 
product
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.
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 (i.e., 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
LDL-C
low-density lipoprotein cholesterol
LOCF
last observation carried forward
LS
least squares
MAD
multiple ascending dose
MI
myocardial infarction
mITT
modified intent-to-treat
MMRM
mixed model for repeated measures
MRI
magnetic resonance imaging
OAM
oral antihyperglycemic medication
P1NP
procollagen type 1 N-terminal propeptide
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PP
Per protocol dataset:  The set of data generated by the subset of patients who 
sufficiently complied with the protocol to ensure that these data would be likely to 
exhibit the effects of treatment, according to the underlying scientific model.
PRO
patient-reported outcomes
QTc
corrected QT interval
QW
once weekly
SAD
single ascending dose
SAE
serious adverse event


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SAP
statistical analysis plan
SC
subcutaneous
Screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.
SD
standard deviation
SDP
single-dose pen
SMBG
self-monitoring of blood glucose
SmPC
Summary of Product Characteristics
SUSAR
suspected unexpected serious adverse reactions
T2DM
type 2 diabetes mellitus
TE-ADA
treatment-emergent antidrug antibodies
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, which and does not necessarily have to have a causal 
relationship with this treatment.
TIA
transient ischemic attack
ULN
upper limit of normal (reference range)
USPI
United States Package Insert
WHO
World Health Organization


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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
Mean cell volume 
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
ALP
Neutrophils, segmented
ALT
Lymphocytes
AST
Monocytes
BUN
Eosinophils
Creatinine
Basophils
Uric acid
Platelets
Calcium
Total Protein
Hemoglobin A1c
Lipase
Amylase
Urinalysis:
eGFRb
pH
Glucose, fasting or random
Protein
Albumin
Glucose
Calcitonin
Blood
Hormones (females):
Urine leukocyte esterase
Pregnancy Test, serum and/or urinec
Urine albumin, creatinine, UACR
Serum estradiold
Serum FSHd
Lipid Panel (Fasting)
Serum LHd
Total Cholesterol
Triglycerides
Serologye
HDL-C
Hepatitis B Surface Ag
LDL-C (calculated)
Hepatitis C Ab
HIV Ab
Immunogenicity
Nonpharmacogenetic Stored Samples
Anti-LY3298176 Antibodies
EDTA plasma
Anti-LY3298176 antibody neutralization assay
Serum
P800 plasma
Pharmacogenetics Sample
Pharmacokinetic Samples
Biomarkers
Fasting insulin, C-peptide, glucagon
-hydroxy butyrate
Adiponectin (Total and HMW)
Optional urine drug screen (local, at the 
discretion of the investigator)
FGF-21 (active), GIP and GLP-1 (total and 
active), osteopontin, free fatty acids, glycerol, 
MCP-1, CTX-1, P1NP, osteocalcin


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Abbreviations:  Ab = antidrug antibody; Ag = antigen; ALP = alkaline phosphatase; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CTX-1 = carboxy-terminal 
telopeptide of type I collagen; EDTA = ethylenediaminetetraacetic acid; eGFR = estimated glomerular filtration 
rate; FGF-21 = fibroblast growth factor-21; FSH = follicle-stimulating hormone; GIP = glucose-dependent 
insulinotropic peptide; GLP-1 = glucagon-like peptide-1; HDL-C = high-density lipoprotein cholesterol; 
HIV = human immunodeficiency virus; LDL-C = low-density lipoprotein cholesterol; P1NP = procollagen type 1 
N-terminal propeptide; RBC = red blood cells; UACR = urine albumin-to-creatinine ratio; WBC = white blood 
cells.
a
All tests will be performed by a Lilly-designated central laboratory, unless otherwise noted.
b
Estimated glomerular filtration rate will be calculated by the central laboratory at all visits and included in lab 
result reports.
c
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.
d
Performed at screening by central laboratory to establish menopausal status.
e
Performed at screening only.


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Study Governance Considerations
Appendix 3.


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Appendix 3.1. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for ensuring:

that the patient understands the potential risks and benefits of participating in the 
study

that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the 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/her participation in the trial.
Appendix 3.1.2.
Ethical Review
The investigator or an appropriate local representative must give assurance that the 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 GCP.
The study site’s ERB(s) should be provided with the following:

the current IB and dulaglutide Package Insert or dulaglutide SmPC, and updates 
during the course of the study

ICF

relevant curricula vitae
Appendix 3.1.3.
Regulatory Considerations
This study will be conducted in accordance with:
1. consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of
Medical Sciences (CIOMS) International Ethical Guidelines
2. applicable ICH GCP Guidelines
3. applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party.


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Appendix 3.1.4.
Investigator Information
Physicians with a specialty in diabetes/endocrinology, internal medicine, or family medicine will 
participate as investigators in this clinical trial.
Appendix 3.1.5.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his/her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.6.
Final Report Signature
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his/her knowledge, the report accurately describes the conduct and results of 
the study.
The investigator with the most enrolled patients will serve as the CSR coordinating investigator.  
If this investigator is unable to fulfill this function, another investigator will be chosen by Lilly to 
serve as the CSR coordinating investigator.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his/her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instructions on the protocol, the completion of the CRFs, and 
study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by
mail, telephone, and/or fax

review and evaluate CRF data and use standard computer edits to detect errors in 
data collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.


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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
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Case report form data will be encoded and stored in InForm.  Data managed by a central vendor, 
such as laboratory test data or ECG data, will be stored electronically in the central vendor’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse.
Any data for which paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect 
patient-reported outcome (PRO) measures (e.g., a rating scale), a daily dosing schedule, or an 
event diary.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, 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 judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.


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Hepatic Monitoring Tests for 
Appendix 4.
Treatment-Emergent Abnormality
The following hepatic monitoring tests should be considered for patients with 
treatment-emergent hepatic abnormalities in Lilly or its designee-sponsored clinical trials to 
ensure patient safety and comply with regulatory guidance.
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required during follow-up with patients in consultation with the Lilly, or its designee, CRP.
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
ALP isoenzymes
ALT
Antinuclear antibodya
AST
Anti-F actin antibodya
GGT
Anti-smooth muscle antibodya
CPK
Abbreviations:  ALP = alkaline phosphatase; 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 Classification 
Appendix 5.
for Diabetes
Type 1 Diabetes Mellitus:  Type 1 diabetes mellitus 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 Mellitus:  Type 2 diabetes mellitus, 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 (e.g., severe 
infection or mesenteric artery thrombosis) due to 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.
References:
Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its 
complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a 
WHO consultation. Diabetic Med. 1998;15(7):539–553.
Bennett P. Classification and diagnosis of diabetes mellitus and impaired glucose tolerance. In: 
Pickup J, William G, editors. Textbook of diabetes. Vol. 1. Oxford: Blackwell Scientific 
Publications; 1991:p 37–44.
Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. 
Diabetes Care. 1999;22(suppl 1):S5–S19.


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Pharmacokinetics Schedule of Events
Appendix 6.
Study Phase
Screen Lead-
in
Randomize
Treatment Phase
Follow
-up
Early 
Term
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
801
Month of 
treatment
0
0
0
0
0
0
1
1
2
3
3
4
5
6
6
(7)
Week of treatment 
3
2
0
1
1
2
2
4
4
8
12
12
16
20
24
26
(30)
Study day/(Dose 
number)
±7d
0/(1)
7/(2)
14/(3)
28/(5)
56/(9)
84/(13)
112/(17
)
140/(21) 168/(25) 182/(27)
PK-specific visit
X
X
X
X
PK blood draw 
X*
X
X
X
X*
X*
X
X*
X
[I] Predose PK samples will be collected at Visit 4 (Week 1), Visit 10 (Week 8), Visit 11 (Week 12), and Visit 16 (Week 26).  X* = Predose sample.
[II] Postdose PK samples will be collected per the assigned schedule after dosing at Visit 5 (Week 1), Visit 7 (Week 2), Visit 9 (Week 4), and Visit 12 (Week 12),
and at early termination from all patients.  An early termination PK sample may be taken at any time during the visit.
1. At Visit 5 (Week 1), 1 predose PK sample should be collected prior to administering study drug from all patients. Later in the week (Visit 5), an additional 
PK sample should be taken within 1 to 48 hours (i.e., within 2 days of administrating study drug).
2. At Visit 7 (Week 2), 1 PK sample should be collected after administration of the study drug within 1 to 48 hours (i.e., within 2 days of administrating study 
drug).
3. At Visit 9 (Week 4), 1 PK sample should be collected after administration of the study drug within 48 to 72 hours (i.e., 2 to 3 days after the administration of 
study drug).
4. At Visit 12 (Week 12), 1 predose PK sample should be collected prior to administering the study drug from all patients.  Later in the week (Visit 12), an 
additional PK sample should be taken within 96 to 168 hours (i.e., any time between 4 days after study drug administration up to just prior to the next dose of 
study drug administration).


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Contraceptive Methods
Appendix 7.
Male patients with female partners of childbearing potential will be required to use a condom in 
conjunction with a spermicidal gel, foam, cream, or suppository.  In addition, the female partner, 
as well as female patients of child-bearing potential will be requested to use an additional 
effective form of contraception, which can be any of the following:

female condom with spermicide

diaphragm with spermicide

cervical sponge

cervical cap with spermicide

combined oral contraceptive pill and mini-pill

NuvaRing

implantable contraceptives

injectable contraceptives (such as Depo-Provera)

intrauterine device (such as Mirenaand ParaGard)

true abstinence, when in line with the preferred and usual lifestyle of the patient
Men who have had a vasectomy with appropriate postvasectomy documentation of the absence 
of sperm in the ejaculate are not required to use contraception.  In addition, Inclusion 
Criterion 3b provides a specific definition of women not of childbearing potential; these subjects 
will not be required to use contraception.  Male patients with a female partner meeting the 
definition of a woman not of childbearing potential will not be required to use contraception.


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World Health Organization Standardized 
Appendix 8.
Protocols for the Measurement of Height and Weight
The following information has been adapted from standardized physical measurement protocols 
for the World Health Organization’s STEPwise approach to Surveillance (STEPS) (WHO 2008)
(Available at: http://www.who.int/chp/steps/Part3_Section3.pdf. Accessed August 16, 2016).
Measuring Height
Step 1 Ask the patient to remove their footwear and any headgear (light headgear worn for 
religious reasons can remain, but this should be worn by the patient at every clinic visit when 
their weight is measured).
Step 2 Ask the patient to stand on the calibrated height measuring board (stadiometer) or against 
a wall with their feet together and their knees straight with their heels against the back board or 
the stadiometer or the wall.
Step 3 Ask the patient to look straight ahead without tilting their head up.
Step 4 Ask the patient to breathe in and stand tall. If using a stadiometer or fixed measuring 
device, move the device’s measurement arm gently down onto the top of the patient’s head. 
Record the patient’s height in centimeters (cm).
Measuring Weight
Body weight measurements should be done in a consistent manner using a calibrated scale 
(mechanical or digital scales are acceptable). All weights for a given patient should be measured 
using the same scale, whenever possible, after the patient has emptied their bladder. Patients 
should be lightly clothed but not wearing shoes while their weight is measured.
Step 1 Ask the patient to remove their footwear and any headgear (light headgear worn for 
religious reasons can remain, but this should be worn by the patient at every clinic visit when 
their weight is measured).
Step 2 Make sure the scale is placed on a firm, flat, even surface (not on carpet or on a sloping 
surface or a rough uneven surface).
Step 3 Ask the patient to step onto the scale with one foot on each side of the scale.
Step 4 Ask the patient to stand still with their arms by their sides and then record their weight in 
kilograms (kg).


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Protocol Amendment I8F-MC-GPGB(a)
Appendix 9.
Summary: A Phase 2 Study of Once-Weekly LY3298176
Compared with Placebo and Dulaglutide in Patients with 
Type 2 Diabetes Mellitus
Overview
Protocol I8F-MC-GPGB A Phase 2 Study of Once-Weekly LY3298176 Compared with Placebo 
and Dulaglutide in Patients with Type 2 Diabetes Mellitus has been amended.  The new protocol 
is indicated by amendment (a) and will be used to conduct the study in place of any preceding 
version of the protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table:


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Amendment Summary for Protocol I8F-MC-GPGB Amendment (a)
Section # and Name
Description of Change
Brief Rationale
Section 2 Schedule of Activities
Visit 13 Study Day/(Dose number) changed from 
98/(15) to 112/(17)
Math error
Section 6.3 Lifestyle Restrictions
30 days changed to 8 weeks
Typographical error.  Changing to 8 weeks is 
consistent with Section 7.2.2. Specific 
Restrictions/Requirements
Section 7.6 Treatment Compliance
Added “intentionally” to the following sentence: A 
patient will be considered significantly 
noncompliant if he/she intentionally misses 4 or 
more doses of study medication.  
Added to clarify from Section 8.1.2.
Section 8.1.1 Permanent Discontinuation from 
Study Treatment
Added “significant” to the following bullet:

Any significant study drug-related 
hypersensitivity reaction
Added “intentionally” to the following sentence:

If the patient intentionally misses 4 or 
more doses (consecutive or not) of study 
medication or intentionally or repeatedly 
takes more than the prescribed dose of 
study medication (see Section 9.3).
Added to clarify and align with Section 9.2.1.2.2
Added to clarify from Section 8.1.2
Section 8.1.2 Temporary Discontinuation from 
Study Treatment
Added “a natural disaster” to the following 
sentence: After randomization, the investigator 
may temporarily discontinue study drug, for 
example, due to an AE (eg, nausea and vomiting), a 
clinically significant laboratory value, or a natural 
disaster.  
Added because we had patients miss doses and 
visits due to hurricanes Irma and Maria, both of 
which have shut sites, resulted in loss of study drug 
due to lack of power/refrigeration, and made it a 
logistical challenge for patients to attend site visits 
or take study drug.  Since this is not a patient 
compliance issue, we want to keep patients in the 
study.


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Amendment Summary for Protocol I8F-MC-GPGB Amendment (a)
Section # and Name
Description of Change
Brief Rationale
Section 8.1.2 Temporary Discontinuation from 
Study Treatment
Sentence deleted: If 4 or more doses of study 
medication (consecutive or not) are missed for any 
reason, then the patient should be permanently 
discontinued from study medication.
This sentence has been removed because we are 
allowing patients to miss 4 or more doses when the 
reason has been beyond their control, such as the 
length of time it has taken for follow up for 
abnormal laboratory results and due to natural 
disasters (hurricanes).  Of note, because of 
hurricanes Irma and Maria we have had sites 
without power and issues of patient logistics that 
have necessitated patients missing doses fully 
beyond their control.  We want to keep those 
patients in the study.
Appendix 6 Pharmacokinetics Schedule of Events
Visit 13 Study Day/(Dose number) changed from 
98/(15) to 112/(17)
Math error


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.


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2.
Schedule of Activities
Study Phase
Screen Lead -
in
Randomize
Treatment Phase
Follow
up
Early 
Term
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
801
Week of Treatment
3
2
0
1
1
2
2
4
4
8
12
12
16
20
24
26
(30)
Study Day/(Dose 
number)
0/(1)
7/(2)
14/(3)
28/(5)
56/(9) 84/(13)
98112/(
1517)
140/(21) 168/(25) 182/(27)
Visit Window (days)
±7
±3 
±3
±3
±3
±3
±3
±3
±3
±3
PK Specific Visita
X
X
X
X


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6.3
Lifestyle Restrictions
Study participants should be instructed not to donate blood or blood products during the study or 
for 30 days 8 weeks following the study.
7.6
Treatment Compliance
During the study, patients will be asked to return their unused study drug materials and 
completed diaries to the site so that their compliance may be assessed.
Patients who are significantly noncompliant will be permanently discontinued from study
medication.  A patient will be considered significantly noncompliant if he/she intentionally
misses 4 or more doses of study medication.  Similarly, a patient will be considered significantly 
noncompliant if he/she is judged by the investigator to have intentionally or repeatedly taken 
more than the prescribed amount of medication.
8.1.1
Permanent Discontinuation from Study Treatment
o
Any significant study drug-related hypersensitivity reaction

If the patient intentionally misses 4 or more doses (consecutive or not) of study 
medication or intentionally or repeatedly takes more than the prescribed dose of study 
medication (see Section 9.3).
8.1.2
Temporary Discontinuation from Study Treatment
After randomization, the investigator may temporarily discontinue study drug, for example, due 
to an AE (e.g., nausea and vomiting), or a clinically significant laboratory value, or a natural 
disaster.  If study drug discontinuation is due to an AE, the event is to be followed and 
documented.  Every effort should be made by the investigator to maintain patients in the study 
and to restart study drug promptly after any temporary discontinuation, as soon as it is safe to do 
so.  The dates of study drug discontinuation and restart will be documented.  Patient 
noncompliance should not be recorded as temporary discontinuation of study drug on the eCRF.  
If 4 or more doses of study medication (consecutive or not) are missed for any reason, then the 
patient should be permanently discontinued from study medication.


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Appendix 6
Pharmacokinetics Schedule of Events
Study Phase
Screen Lead-
in
Randomize
Treatment Phase
Follow
-up
Early 
Term
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
801
Month of 
treatment
0
0
0
0
0
0
1
1
2
3
3
4
5
6
6
(7)
Week of treatment 
3
2
0
1
1
2
2
4
4
8
12
12
16
20
24
26
(30)
Study day/(Dose 
number)
±7d
0/(1)
7/(2)
14/(3)
28/(5)
56/(9)
84/(13)
98112/(
1517)
140/(21) 168/(25) 182/(27)
PK-specific visit
X
X
X
X
PK blood draw 
X*
X
X
X
X*
X*
X
X*
X


Leo Document ID = 86d2f081-d91d-40be-af2b-9a2f91db9fa2
Approver: 
Approval Date & Time: 28-Nov-2017 15:25:37 GMT
Signature meaning: Approved
PPD

SAP_001.pdf: 
 
Statistical Analysis Plan I8F-MC-GPGB (3) 
 
I8F-MC-GPGB: A Phase 2 Study of Once-Weekly LY3298176 Compared with Placebo and 
Dulaglutide in Patients with Type 2 Diabetes Mellitus 
NCT03131687 
Approval Date: 26-Mar-2018 


I8F-MC-GPGB Statistical Analysis Plan Version 3
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1.
Statistical Analysis Plan:  
I8F-MC-GPGB:  A Phase 2 Study of Once-Weekly 
LY3298176 Compared with Placebo and Dulaglutide in 
Patients with Type 2 Diabetes
Confidential Information
The information contained in this Statistical Analysis Plan (SAP) is confidential and the 
information contained within it may not be reproduced or otherwise disseminated without 
the approval of Eli Lilly and Company or its subsidiaries.  This document and its associated 
attachments or appendices are subject to United States Freedom of Information Act 
Exemption 4.
LY3298176 Type 2 Diabetes Mellitus
This is a randomized, double blinded, parallel, placebo- and active comparator-controlled 
Phase 2 multicenter, multi-country study in patients with type 2 diabetes mellitus.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I8F-MC-GPGB
Phase 2
Statistical Analysis Plan Version 1 electronically signed and approved by Lilly:  27 July 
2017
Statistical Analysis Plan Version 2 electronically signed and approved by Lilly
on date provided below.
Approval Date: 26-Mar-2018 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   I8F-MC-GPGB:  A Phase 2 Study of 
Once-Weekly LY3298176 Compared with Placebo and Dulaglutide 
in Patients with Type 2 Diabetes .........................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................8
4.
Study Objectives.................................................................................................................9
4.1.
Primary Objectives.........................................................................................................9
4.2.
Secondary Objectives.....................................................................................................9
4.3.
Exploratory Objectives...................................................................................................9
4.4.
Pharmacogenomics Objectives.......................................................................................9
5.
Study Design.....................................................................................................................11
5.1.
Study Design and Treatment ........................................................................................11
5.2.
Treatment Assignment .................................................................................................12
5.3.
Determination of Sample Size ......................................................................................12
6.
A Priori Statistical Methods ..............................................................................................14
6.1.
General Considerations ................................................................................................14
6.1.1.
Analysis of Repeated Measures............................................................................14
6.1.2.
Analysis of Covariance Model for Change from Baseline 
Endpoints.............................................................................................................15
6.2.
Patient Disposition .......................................................................................................15
6.3.
Analysis Populations....................................................................................................16
6.4.
Patient Characteristics and Medical History .................................................................16
6.5.
Treatment Compliance .................................................................................................16
6.6.
Exposure of Study Treatment .......................................................................................17
6.7.
Concomitant Drugs ......................................................................................................17
6.8.
Protocol Deviations......................................................................................................18
6.9.
Efficacy Analyses ........................................................................................................18
6.9.1.
Primary Outcome and Methodology.....................................................................18
6.9.1.1.
Primary Analyses ...........................................................................................18
6.9.1.2.
Secondary Analysis of the Primary Efficacy Outcome ....................................21
6.9.1.3.
Supporting Analyses of Primary Outcome ......................................................21
6.9.2.
Efficacy - Secondary Outcomes ...........................................................................22
6.9.2.1.
Dose Response Analyses on HbA1c and  Body Weight ..................................22
6.9.2.2.
Continuous Variable Analyses........................................................................22
6.9.2.3.
Analyses Based on Multiple Imputations ........................................................23


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6.9.2.4.
Analyses on Variables with Percent of Patients Reaching 
a Target ..........................................................................................................23
6.10. Safety Analyses............................................................................................................23
6.10.1.
Vital Signs ...........................................................................................................24
6.10.2.
HDL-C, Total Cholesterol, Triglycerides, and LDL-C..........................................25
6.10.3.
Adverse Events ....................................................................................................25
6.10.3.1.
All Treatment-Emergent Adverse Events........................................................25
6.10.3.2.
Related Adverse Events..................................................................................26
6.10.3.3.
Serious Adverse Events ..................................................................................26
6.10.3.4.
Adverse Events Leading to Discontinuation....................................................26
6.10.3.5.
Most Common Adverse Events.......................................................................26
6.10.3.6.
Deaths ............................................................................................................26
6.10.4.
Adverse Events of Special Interest .......................................................................27
6.10.4.1.
Hypersensitivity Reactions .............................................................................27
6.10.4.2.
Injection Site Reactions ..................................................................................27
6.10.4.3.
Nausea, Vomiting, and Diarrhea .....................................................................28
6.10.4.4.
Hypoglycemic Episodes and Total Hypoglycemia ..........................................28
6.10.4.5.
Pancreatitis.....................................................................................................29
6.10.4.6.
C-cell Hyperplasia and C-cell Neoplasms .......................................................30
6.10.5.
Laboratory Measurements....................................................................................30
6.10.6.
Electrocardiograms ..............................................................................................31
6.10.7.
Renal Safety.........................................................................................................31
6.11. Exploratory Analyses ...................................................................................................32
6.11.1.
7-Point SMBG .....................................................................................................32
6.11.2.
Health Outcome/Quality of Life Measures ...........................................................33
6.11.2.1.
Ability to Perform Physical Activities of Daily Living....................................33
6.11.2.2.
Impact of Weight on Self-Perception..............................................................33
6.11.2.3.
Missing Data Imputation for Ability to Perform Physical 
Activities of Daily Living and Impact of Weight on Self-
Perception ......................................................................................................34
6.11.3.
Pharmacodynamic or Biomarker Analyses ...........................................................34
6.11.4.
Evaluation of Immunogenicity .............................................................................34
6.11.4.1.
Definitions of Sample ADA Status .................................................................34
6.11.4.2.
Definitions of Immunogenicity Assessment Periods .......................................36
6.11.4.3.
Definitions of Patient ADA Status ..................................................................36
6.11.4.4.
Analyses to be Performed ...............................................................................37
6.12. Pharmacokinetic and Pharmacodynamic Analyses........................................................38
6.13. Subgroup Analyses.......................................................................................................39
6.14. Interim Analyses ..........................................................................................................40


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6.14.1.
Overview .............................................................................................................40
6.14.2.
Description of Analyses .......................................................................................41
6.15. Clinical Trial Registry Analyses...................................................................................41
7.
Unblinding Plan................................................................................................................42
7.1.
Operational Procedures ................................................................................................42
7.2.
Site-Level Unblinding ..................................................................................................43
7.3.
Trial-Level Safety Reviews ..........................................................................................44
7.4.
Assessment Committee Reports ...................................................................................44
7.4.1.
Interim Reports ....................................................................................................44
7.4.1.1.
First Interim....................................................................................................45
7.4.1.2.
Second Interim ...............................................................................................45
7.4.1.3.
Reports Delivery.............................................................................................45
7.4.2.
Primary Lock (Third Interim)...............................................................................46
7.5.
End of Study Unblinding..............................................................................................46
8.
References ........................................................................................................................47
9.
Appendices .......................................................................................................................48


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Table of Contents
Table
Page
Table 5.1.      Dose-Response Assumption Used in Sample Size 
Determination......................................................................................................13
Table 6.1.     Analysis Populations.............................................................................................16
Table 6.2.     Dose Strength Parameters and Corresponding Dose Strengths...............................20
Table 6.3.     Summary of Analyses for Primary Outcome .........................................................22
Table 6.4.     Vital Sign Summary Categories ............................................................................24
Table 6.5.     Electrocardiogram Abnormal Categories...............................................................31
Table 6.6      Sample Anti-Drug Antibodies (ADA) Assay Results ............................................36
Table 6.7.    Sample Clinical Anti-Drug Antibodies (ADA) Interpretation 
Results..................................................................................................................36
Table 6.8.     Adverse Events for Analysis with Immunogenicity Results...................................37
Table 7.1.    Study I8F-MC-GPGB Group Name and Membership ............................................43


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Table of Contents
Figure
Page
Figure 5.1.     Study design for I8F-MC-GPGB. ........................................................................11


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Table of Contents
Appendix
Page
Appendix 1.     Protocol GPGB Study Schedule (Schedule of Events) .......................................49
Appendix 2.     Protocol GPGB Illustration of PK Sampling Schedule.......................................55
Appendix 3.     Important Protocol Deviations...........................................................................57


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3.
Revision History
The Statistical Analysis Plan (SAP) Version 1 was approved prior to first production data 
transfer.  
The second version is approved before the first interim analysis.  The following changes are 
made for the second version:
1. The second interim analysis time is changed from 100% patients finishing 16 weeks of 
treatment to 90% patients finishing 12 weeks of treatment.
2. A titrated dose integrated two-component prediction (ITP) model is added for the dose 
response analyses.
The third version is approved before the primary database lock.  The following changes are made 
for the third version:
1. Clarify analyses datasets.  Analysis dataset for modified intent-to-treat (mITT)
population, excluding data after study drug discontinuation or rescue drug initiation, is 
added for the efficacy analyses to better reflect the study treatment effect. 
2. Add a missing data imputation analysis for HbA1c and body weight.
3. Delete country from the statistical analyses that was accidently included as a strata factor.
Delete visit window.


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4.
Study Objectives
4.1.
Primary Objectives
The primary objective of this study is to demonstrate a dose-response relationship of once-
weekly subcutaneous (SC) injections of LY3298176 on hemoglobin A1c (HbA1c) change from 
baseline relative to placebo, in patients with type 2 diabetes mellitus (T2DM) inadequately 
controlled with diet and exercise alone or treated with a stable dose of metformin.
4.2.
Secondary Objectives
To determine the effect of LY3298176 versus dulaglutide and placebo on:

mean body weight change from baseline to 12 and 26 weeks

change from baseline of HbA1c at 12 weeks

percentage of patients with ≥5% body weight loss at 26 weeks

percentage of patients with ≥10% body weight loss at 26 weeks

percentage of patients reaching the HbA1c target of ≤6.5% and of ≤7.0%

change from baseline of fasting plasma glucose (FPG) at 12 and 26 weeks

change from baseline to 26 weeks in high-density lipoprotein cholesterol (HDL-C), total 
cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C)

waist circumference

safety and tolerability, including gastrointestinal (GI) tolerability, incidence and rate of 
hypoglycemia, hypersensitivity reactions and pancreatic safety.  
In addition, it is intended to assess

the development of treatment-emergent anti-drug antibodies (TE ADA) to LY3298176

the pharmacokinetics (PK) of LY3298176 and potential patient factors that may influence 
its PK and pharmacodynamics (PD).

the relationship between LY3298176 dose and/or exposure and key efficacy, and safety 
measures, where applicable.
4.3.
Exploratory Objectives
Evaluate the effect of LY3298176 compared with placebo and dulaglutide on: 

Change from baseline of 7-point self-monitoring of blood glucose (SMBG) profiles at 4, 
12, 26, and 30 weeks

Biomarkers

Evaluate patient-reported outcomes (PROs) questionnaires:  the Ability to Perform 
Physical Activities of Daily Living Questionnaire (APPADL), and the Impact of Weight 
on Self-Perception (IW-SP).
4.4.
Pharmacogenomics Objectives

To evaluate genetic variants in genes in the glucagon signaling pathway and 
glucose-dependent insulinotropic peptide/glucagon-like peptide-1 (GIP/GLP-1)


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associated genes for association with efficacy responses to LY3298176 such as change 
from baseline in HbA1c, fasting glucose, body weight, and body mass index (BMI).

To evaluate the association of genetic variants in the glucagon signaling pathway and 
GIP/GLP-1 associated genes with other PD and clinical endpoints of interest (including 
circulating glucagon levels, blood pressure (BP), serum amylase and lipase, GI tolerance, 
lipid metabolism, bone metabolism, etc).

To investigate the genetic variants associated with dulaglutide treatment response 
(identified from dulaglutide clinical trials) on the efficacy and safety endpoints in 
response to LY3298176.


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5.
Study Design
5.1.
Study Design and Treatment
Study I8F-MC-GPGB (GPGB) is a randomized, double-blind, parallel, placebo- and active 
comparator-controlled, Phase 2 multicenter, multi-country study designed to examine the 
efficacy and safety of once-weekly LY3298176 compared to dulaglutide and placebo in patients 
with T2DM.  
The design for Study GPGB is illustrated in Figure 5.1.
Illustration of study design for Protocol I8F-MC-GPGB
Week
Visit
-3
-2
0
1
2
3
4
5
6
23
24
25
26
19
20
21
22
15
16
17
18
11
12
13
14
7
8
9
10
30
26 Weeks
LY Placebo + Dulaglutide 1.5 mg
LY 15 mg + Dulaglutide Placebo
LY 10 mg + Dulaglutide Placebo
LY 5 mg + Dulaglutide Placebo
LY 1 mg + Dulaglutide Placebo
LY Placebo + Dulaglutide Placebo
1
2
3
4
6
8
15
29
14
13
11
10
801
27
28
16
PK Visit
5
7
9
12
Lead-in
Screening
Follow Up
26 Week Treatment Period
4 Weeks
5, 5 mg
5, 5, 10, 10, 10, 10 mg
1 Week
2 Weeks
Study Period 1
Study Period 2
Study Period 3
Randomization
End of Treatment
Abbreviations:  LY = study drug LY3298176; PK = pharmacokinetics.
Figure 5.1.
Study design for I8F-MC-GPGB.
Study procedures and timing for the lead-in, blinded treatment, and follow-up phases are 
outlined in the schedule of events (appendix 1).  Eligibility for this study will be determined at a 
screening visit (Visit 1).  Screening procedures will be performed on approximately Day 21 
according to the Schedule of Activities.  Patients will receive training on the routine BG
monitoring and paper diary completion required during the study.  Patients should follow the 
investigator’s instructions related to frequency of SMBG but should test their glucose a 


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minimum of 3 times per week and as specified for determination of 7-point glucose profiles.  
Eligible patients will return to the site for some baseline procedures during the lead-in phase and 
again for randomization to treatment and to receive their first dose of study drug at Visit 3.
After randomization and the first dose (Visit 3), patients will return to the site for PK collection 
just prior to the second dose (Visit 4).  Patients will also have a predose PK collection prior to 
Week 8 (Visit 10), Week 12 dose (Visit 11), and Week 26 (Visit 16) dose.  There will be 
postdose PK collections after the second dose (PK-specific Visit 5), third dose (PK-specific 
Visit 7), fifth dose (PK-specific Visit 9, and 12-week dose (PK-specific Visit 12).  A safety 
follow-up visit will occur approximately 4 weeks following the last dose of the study drug.  
Patients randomized to LY3298176 who develop treatment-emergent anti-LY3298176 antibodies 
will be monitored after the last visit.
Throughout the study, patients treated with metformin will remain on the same dose they were 
receiving at Visit 1 unless changes need to be made for safety reasons.  All patients will be 
encouraged to maintain their prestudy diet and exercise levels through the course of the study.
In the treatment phase, a double-dummy dose administration scheme will be employed to ensure 
patients and investigators (as well as sponsor study team and monitors) remain blind to the 
LY3298176, dulaglutide 1.5 mg, and placebo treatment assignments within each treatment 
group.  At each dosing occasion, the study drug will be administered as 1 to 3 SC injections of 
LY3298176 or matched placebo and 1 SC injection of dulaglutide 1.5 mg or its placebo.  
Therefore, each patient will self-administer 2 to 4 injections per week.
5.2.
Treatment Assignment
A unique 4-digit patient number will be assigned to each patient when the patient signs the 
informed consent form (ICF).
Patients will be assigned to dulaglutide 1.5 mg, placebo, or 1 of 4 LY3298176 dose levels.  
Patients who meet all criteria for enrollment will be randomized at Visit 3 and assigned to their 
respective treatment arms via interactive web response system (IWRS) using the following 
stratification variables:  baseline HbA1c (<8.5%, 8.5%), metformin use (Yes, No), and BMI 
(<30, 30).  There will be equal randomization to the treatment arms (1:1:1:1:1:1).  However, 
LY3298176 placebo patients will be randomized such that a portion will be randomized to each 
cohort in order to receive the same dose volume as that cohort in order to maintain the study 
blind.  For the active dulaglutide 1.5 mg group, LY3298176 placebo patients will be distributed 
through the treatment groups in order to maintain the blind.
The randomization scheme will be performed using IWRS that will ensure balance between 
treatment arms.
5.3.
Determination of Sample Size
Approximately 300 patients will be randomized to placebo, dulaglutide, or 1 of the 4 LY3298176
treatment arms assuming a 10% dropout rate resulting in approximately 45 completers per arm.


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The Bayesian approach using a dose-response model with respect to an HbA1c change from 
baseline to 26 weeks will provide approximately 98% probability to show with 90% confidence 
that at least 1 LY3298176 dose has superior glycemic control over placebo with a superiority 
bound of -0.8%.  The sample size also provides >95% probability to show with 80% confidence 
that at least 1 LY3298176 dose has non-inferior glycemic control compared with dulaglutide 
from baseline to 26 weeks with a 0.3% non-inferiority bound.  This assumes a profile for the
change in HbA1c from baseline to 26 weeks shown in Table 5.1, and a standard deviation (SD) 
of 1.0%.
In addition, this sample size also provides approximately 89% probability to show with 60% 
confidence that at least 1 LY3298176 dose has superior weight loss compared with dulaglutide 
from baseline to 26 weeks with a superiority bound of -2 kg.  This assumes a profile for the
change in body weight from baseline to 26 weeks shown in Table 5.1, and an SD of 6 kg.
Table 5.1.
Dose-Response Assumption Used in Sample Size Determination
Placebo
LY 1
LY 5
LY 10
LY 15
Dulaglutide
CFBL HbA1c (%)
0%
-0.74%
-1.17%
-1.29%
-1.44%
-1.28%
CFBL Body Weight (kg)
0
-2.0
-3.0
-5.0
-6.0
-2.5
Abbreviations:  CFBL = change from baseline; HbA1c = hemoglobin A1c; LY = study drug LY3298176.  


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6.
A Priori Statistical Methods
6.1.
General Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.  Any change to 
the statistical methods described in the protocol will require an amendment only if it changes a 
principal feature of the protocol.  Any other change to the statistical analyses and the justification 
for the change will be documented in the clinical study report.  Additional exploratory analyses 
of data may be conducted as deemed appropriate without further changes made to the protocol or 
SAP even after the database lock (DBL).  
Tests of treatment effects will be conducted at a one-sided alpha level of 0.1 and/or one-sided 
90% credible interval (CI) for the Bayesian dose response analysis, and at a two-sided alpha 
level of 0.05 for other analyses, unless otherwise stated. No adjustments for multiplicity will be 
performed.  
The baseline visit will be Visit 3.  The baseline values used for the analyses will be the last 
scheduled baseline value obtained for each patient prior to first dosing. For all variables, if 
baseline data are not available or if they are missing, then the last non-missing measurement 
taken prior to first treatment will be used for the baseline measurement.  
All efficacy and safety data will be summarized by each treatment group at each scheduled visit
unless otherwise indicated. A scheduled visit is based on the actual visit number reported by the
site.  Imputed data may be applied in model-based data analysis, but will not be used in data 
listing.
6.1.1. Analysis of Repeated Measures
The mixed model for repeated measures (MMRM) using restricted maximum likelihood 
(REML) will be used to fit change from baseline values at all scheduled visits.  The model will 
include the treatment group, strata (that is, baseline HbA1c category, baseline BMI category, and 
metformin use [yes, no]), visit, and treatment-by-visit interaction as fixed effects, baseline value 
of the dependent variable as a covariate, and patient as a random effect.  If the analysis is on the 
primary endpoint, baseline HbA1c category will not be included in the model in addition to the 
continuous covariate of baseline HbA1c.  To model the covariance structure within patients, the 
unstructured covariance matrix will be selected initially.  If the unstructured covariance structure 
leads to nonconvergence, the following covariance structures will be tested in order:

toeplitz with heterogeneity

autoregressive with heterogeneity

compound symmetry with heterogeneous variances

toeplitz

autoregressive

compound symmetry without heterogeneous variances

compound symmetry
The first covariance structure that converges will be used.


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Kenward-Roger method will be used to estimate the denominator degrees of freedom and the 
restricted maximum likelihood approach will be used to determine the model estimates.
The MMRM model will present least squares (LS) mean estimates for each scheduled week by 
treatment group and 2-sided 95% CIs for mean changes from baseline within and (when 
warranted) between treatments.  T-statistics corresponding to the Type III sums of squares for 
the differences in the LS means will be used to obtain p-values for treatment group comparisons.
6.1.2. Analysis of Covariance Model for Change from Baseline 
Endpoints
The analysis of covariance (ANCOVA) models of change from baseline to Week 26 efficacy 
endpoints will include treatment group, strata (that is, baseline HbA1c category, baseline BMI 
category, and metformin use [yes, no]) as fixed effects and baseline measurement as a covariate.  
If the analysis is for the primary endpoint, baseline HbA1c category will not be included in the 
model in addition to the continuous covariate of baseline HbA1c.
The ANCOVA will present LS mean estimates and 2-sided 95% CIs for mean changes from 
baseline within and (when warranted) between treatments.  T-statistics corresponding to the 
Type III sums of squares for the differences in the LS means will be used to obtain p-values for 
treatment group comparisons.
6.2.
Patient Disposition
The primary reasons for discontinuation by treatment will be listed and summarized.  Using the 
Fisher’s exact test, the percentage of patients discontinuing from each treatment will be 
compared.
Patient statuses at the end of the 26-week treatment period displaying the numbers of patients
will be summarized:

entered

screen failed, along with the primary reason for screen failure

randomized

randomized and not treated

permanently discontinued from treatment

discontinued from study, along with the primary reason for study discontinuation

completed 26 weeks blinded treatment

completed study.
The summary of status at the end of the 26-week treatment period will count patients by 
randomized treatment group and overall, except that “Entered” and “Screen failures” only apply 
to the overall entered population.  Entered is defined as signing an ICF.  The percentage of 
patients discontinuing from each treatment using the Fisher’s exact test will be provided.


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6.3.
Analysis Populations
Five patient populations for the analyses with detailed information are defined in Table 6.1. 
Unless otherwise specified, listings will include all randomized patients.  
Table 6.1.
Analysis Populations
Population
Definition
All Entered 
All patients who signed informed consent forms (ICFs)
Intend-to-Treat (ITT)
All patients who were randomized to a treatment arm
Safety Population
All patients who took at least 1 dose of double-blind treatment.  The taking of at least 
1 dose will be established using the “Study Treatment” electronic case report form (eCRF)
pages.  In all safety analyses, patients  by the actual treatment group will be presented.
Modified Intent-to-
Treat (mITT)
All randomized patients who have taken at least 1 dose of the study medication and have 
at least 1 post baseline measurement.  Analyses, by planned treatment group, using the 
mITT population will be presented.
Per-Protocol (PP)
All patients in mITT who complete the study and also meet the following criteria:
Have been appropriately randomized
Have not discontinued from the study for any of the early discontinuation criteria
Have not missed 4 or more doses during the treatment period
Have not been rescued or taken a concomitant antihyperglycemic medication besides 
metformin for >7 cumulative days during the treatment period
No important protocol deviations.  The deviations to be used for excluding patients 
from the PP population will be specified prior to study unblinding.
6.4.
Patient Characteristics and Medical History
Demographic and baseline characteristics, by treatment and overall, will be summarized using 
the mITT population and PP population.  Categorical variables will be summarized using 
frequencies and percentages, and compared between treatments using a Pearson Chi-Square test.  
Continuous variables will be summarized using means and SDs, and compared between 
treatments using a 1-way analysis of variance.
Demographic and baseline diabetes characteristics in listings for each patient randomized will be 
provided.
The numbers and percent of patients with general medical history findings will be provided using 
the randomized (that is, ITT) population.  A listing by patient will be provided .
6.5.
Treatment Compliance
Treatment compliance will be listed using all randomized patients and summarized using the 
mITT population.  For a given patient, overall compliance for treatment period is defined as not 
missing 2 or more consecutive doses of the assigned treatment or missing 4 or more doses at any 
point through the entire study.  Patients who miss 4 or more doses at any point during the study 
will be considered significantly noncompliant, will not be included in the PP analysis.
Safety population during the 26-week treatment period by treatment group will be used to 
summarize the number and percent of patients compliant at 26-week.


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6.6.
Exposure of Study Treatment
For the safety population, exposure for each patient during the treatment period of the study, will 
be calculated  and will be summarized by treatment group.  
The extent of exposure to study medication (LY3298176, placebo, or dulaglutide) during the 
26-week treatment period is defined as:
Date of last dose of study medication +7 days - date of first dose of study medication.
The extent of exposure to study medication will be summarized at 26 weeks using the safety 
population and categorized by the actual treatment group.  The number and percent of patients 
with an extent of exposure within pre-specified day ranges for the 26-week treatment period will 
be summarized by treatment group.
The mean, SD, median, minimum, and maximum days of exposure will also be presented.
In addition, the exposure in terms of total patient-years will be calculated by treatment group,
using the sum of the exposure to study medication of all patients (in years) in a treatment group.
A patient listing of study medication taken will also be generated.
6.7.
Concomitant Drugs
Listings and summary of concomitant therapies by treatment group will be provided.
Previous and concomitant medications will be summarized using the randomized (that is, ITT) 
population by drug class with generic drug name and planned treatment group, as defined by the 
World Health Organization (WHO) drug dictionary most current at the time of DBL.  A 
summary will be produced for all concomitant medications during the:

26-week treatment period 

follow up period
All previous and concomitant medication use will be listed.
Previous medication is defined as medication with a recorded stop date before the date of the 
first dose of study treatment.
Concomitant medication during the 26-week treatment period is defined as medication with 
either a recorded medication start date falling:  

within the 26-week treatment period, or

prior to the first day of study medication but continuing or stopping after at least 1 day on 
study medication.
This means that concomitant medications for the 26-week treatment period will be any 
medication taken for at least 1 day during the 26-week treatment period.
Similarly, concomitant medications for the follow-up period will be any medication taken for at 
least 1 day during the follow-up period.


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Anti-hyperglycemic medication taken for any reason as well as taken as rescue for severe, 
persistent hyperglycemia will be summarized and listed.  Metformin dose at baseline will be 
summarized, as will proportion of patients who adjusted their metformin dose during the trial.
6.8.
Protocol Deviations
Important protocol deviations will be listed for all randomized patients and summarized by 
treatment group.  A list of important protocol deviation criteria for patients from the trial issues 
management plan is given in Appendix 3.  Patients who deviate from the protocol in ways that 
would possibly affect efficacy results are going to be excluded from the per protocol analyses.  
That information can be found in Appendix 3.  Patients meeting criteria for important protocol 
deviations will be identified either by statistical programming or based off of study monitoring
that maintained by the study clinical trial manager (CTM).  The final list of important protocol 
deviations will be reviewed and documented in the Important Protocol Deviations document by 
the study team prior to the primary outcome DBL.  
6.9.
Efficacy Analyses
The primary efficacy analysis, which is the Bayesian dose-response analysis on the change in 
HbA1c, will be performed on mITT population without rescue (i.e., data after use of rescue 
medication will not be included). Unless specified, all other efficacy analyses will be performed 
on mITT population on treatment without rescue (i.e., data after rescue medication or data after 
study treatment discontinuation will not be included). Some key efficacy measures, such as 
HbA1C and body weight, will also be analyzed on mITT population with all available data and 
on a PP dataset.
With the exception of the dose-response analyses on the HbA1c and body weight endpoints, all 
statistical models will include all treatment groups, including LY3298176, placebo, and 
dulaglutide.
6.9.1. Primary Outcome and Methodology
The primary efficacy outcome is HbA1c change from baseline to the 26-week endpoint.  
6.9.1.1.
Primary Analyses
The primary objective is to examine the probability each LY3298176 dose has demonstrated 
superiority relative to placebo using a superiority margin of 0.8%.  Analyses will also consist of 
the 90% one-sided credible interval for the difference in mean response for each LY3298176 
dose versus placebo at 26 weeks.  
The primary analyses will be performed on the mITT without rescue analysis set using a 
Bayesian dose-response model and will include data from the blinded 26-week treatment period.  
The model will include LY3298176 doses, dulaglutide, and placebo.
The Hierarchical Logistic Model will be used to model the dose response in HbA1c change from 
baseline to the 26-week endpoint, .  .  The placebo group (d=0) will be modeled with the 
LY3298176 doses (d=1,…,D-1) using the Hierarchical Logistic model.  Dulaglutide(d=D) is 
modeled independently.  Each dose arm follows a prior structure as specified below:


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ەۖ۔
ۖۓߠௗ்~ܽଵ൅
ܽଶݔௗ்
ݔௗ்൅ܽଷ
൅߫ௗ்,         ݀ൌ0, … , ܦെ1 
ݕ்|ܽଵ, ܽଶ, ܽଷ, ߫ௗ், ݔௗ்~ܰሺߠௗ், ߪଶሻ,
ߠௗ்∼ܰሺߤௗ், ߥௗ்
ଶሻൌܰ൫0, 30 ൯,         ݀ൌܦ
 
where  
ە
ۖۖۖ
۔
ۖۖۖ
ۓ߫ௗ்~ܰሺ0, ߙସ
ଶሻ,   ∑߫ௗ்ൌ0
ߙସ
ଶ~ܫܩ൬Λ௡
2 , Λఓ
ଶΛ௡
2
ቇ ,
ܽ௜~ܰ൫Λ௜, ߣ௜൯, for ݅ൌ1,2
ܽ௜~ܰା൫Λ௜, ߣ௜൯, for ݅ൌ3
ߪଶ~ܫܩቆߪ௡
2 , ߪఓ
ଶߪ௡
2 ቇ,
 
and  Λଵൌ0, Λଶൌ0, Λଷൌ20, Λఓൌ3, Λ௡ൌ1, ߪఓൌ3.3, ߪ௡ൌ1, and ߣ௜ൌ30,  where ݅ൌ
1,2,3.  T denotes the final time point at 26 weeks.  The parameters ܽଵ, ܽଶ,  and ܽଷ represent, 
respectively, the basal effect when the dose level is zero, the maximum effect that can be 
achieved by any dose level, and the dose level that produces half of the maximum improvement 
(ED50).  So ܽଶെܽଵ gives the maximum improvement attributable to the drug.  The parameter 
߫ௗ் is equivalent to a dose-specific random effect term but the sum of ߫ௗ is constrained at zero to 
make sure it is identifiable from the error term, ߪଶ. 
For placebo (d=0) and LY3298176 (d = 1,…,D-1), each successive ߠௗ் is modeled using all 
other estimated dose level means.   
Additional definitions are as follows: 
 d is the dose arm index, with d = 0,…,D (d=0 as placebo, and d=D as dulaglutide) 
 D is the number of non-placebo dose arms, including dulaglutide.  D is also the dose arm 
index for dulaglutide. 
 xୢ୘ is the dose strength, with d = 0, 1, …, D-1 in ascending order.  Dulaglutide is not 
included in the Hierarchical Logistic model, and therefore does not require a dose 
strength. 
 Λ୧ and λ୧ are, respectively, the prior means and variances of a୧, i ൌ1,2,3. 
 θୢ୘ is the modeled dose arm effect at dose d at the final time point T of the 26-week  of 
the study. 
 E ቀ
ଵ
ୟరమቁൌ
ଵ
ஃಔ  and Λ୬ represents the weight of the prior information carried in Λஜ. 
 E ቀ
ଵ
஢మቁൌ
ଵ
஢ಔమ  and σ୬ represents the weight of prior information carried in σஜ
ଶ. 
The dose strength, ݔௗ், used in the model will reflect the actual selected doses for the study.  The 
planned values for ݔௗ் are shown in Table 6.2.  Dulaglutide is modeled separately.  The 
magnitude of the parameters ݔௗ் impact the estimation in the dose-response model.   


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Table 6.2. 
Dose Strength Parameters and Corresponding Dose Strengths 
Dose Strength Parameter 
Dose Strength (mg) 
ݔ଴ 
0* 
ݔଵ 
1 
ݔଶ 
5 
ݔଷ 
10 
ݔସ 
15 
ݔହ 
NA 
Abbreviation:  NA = not applicable. 
* Different FACTS files are used when comparing to placebo and dulaglutide.  When comparing to dulaglutide, 
ݔ଴ൌ1 because of limitations in FACTS. 
 
Any missing responses for the primary outcome will be imputed using the longitudinal integrated 
two-component prediction (ITP) model.  This is a slight deviation from the protocol, which is 
specified to use the Simple Linear Regression (SLR) model.  The model is as follows: 
)
1
1
(
)
(
)
,
(
)
1
1
(
)
(
26
26














d
d
d
d
k
t
k
djt
dj
k
t
k
djt
dj
d
djt
e
e
S
t
d
f
e
e
S
Y



 
Where Ydjt represents the response for dose d, subject j at time t.  where time is t = 1, 2, …, 9 (1, 
2, 4, 8, 12, 16, 20, 24, 26 weeks), T is the 26 week time point, patient is i = 1, …, ܰௗ, where ܰௗ 
is the number of patients for dose d, and d = 0, …, D.  f(d,t) represents the mean response.  
The prior distributions for time t and d = 0, …, D dose levels are as follows: 
ە
ۖ
ۖ
ۖ
۔
ۖ
ۖ
ۖ
ۓ߱ௗ∼ܰ൫߱ఓ, ߱ఙ
ଶ൯ൌܰሺ0,3ଶሻ,
ܵௗ௝∼ܰሺ0, ߬ଶሻ,
ߝௗ௝௧∼ܰሺ0, ߣଶሻ,
ߣଶ∼ܫܩቆߣ௡
2 , ߣఓ
ଶߣ௡
2 ቇ,
߬ଶ∼ܫܩቆ߬௡
2 , ߬ఓ
ଶ߬௡
2 ቇ,
݇∼ܰሺμ௞, ߪ௞
ଶሻ,
 
where ߣఓൌ1 and ߣ௡ൌ1,  ߬ఓൌ1 and ߬௡ൌ1  and ܫܩሺݔ|ߙ, ߚሻ is an inverse gamma distribution 
ఉഀ௘షഁೣ
⁄
௫ഀశభ୻ሺఈሻ  , μ௞=-0.1, and ߪ௞=1. 
Since there are two treatment arms have titration doses, we will implement a titration ITP model 
for those two arms if data permits. Specifically, the mean response will be modeled as 
݂ࢊ,࢚೎ሺݐሻൌ݂ሺݐ; ݀ଵሻ൅෍
൫݂ሺݐെݐ௖௜; ݀௜ାଵሻെ݂ሺݐെݐ௖௜; ݀௜ሻ൯ܫሺݐ൐ݐ௖௜ሻ
௠ିଵ
௜ୀଵ
,                     
where ࢊൌሺ݀ଵ, ݀ଶ, … , ݀௠ሻ are the doses a subject takes, and ࢚௖ൌሺݐ௖ଵ, ݐ௖ଶ, … , ݐ௖,௠ିଵሻ are the 
times of the dose change. 


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The longitudinal ITP and Hierarchical Logistic dose-response models will be analyzed using 
Markov Chain Monte Carlo (MCMC).  To obtain final results, at least 60 000 total MCMC 
iterations will be run, with at least 10 000 initial MCMC iterations being discarded as burn-in 
and at least 50 000 iterations used in calculations.  Each iteration of the MCMC chain progresses 
as follows:  Missing observations for the 26-week time point T are imputed for each subject  at 
each dose level “d” using the longitudinal ITP model.  These data are then used in the 
Hierarchical Logistic dose-response model to update ߠௗ்.  Therefore, at each MCMC iteration, 
parameters from both the ITP model as well as the Hierarchical Logistic model will be updated.  
The 2 models are linked together through the missing data by imputing the missing response at 
the 26-week endpoint.  If there was no missing data, the longitudinal model would not affect the 
fit of the Hierarchical Logistic model. 
Primary analysis will consist of the posterior mean and 90% one-sided credible interval for the 
difference in mean response for each LY3298176 dose versus placebo (posterior mean and 90% 
credible intervals for ߠௗ்െߠ଴் for d = 1, ..., D-1 at the 26-week T time point).  The primary 
objective will be met if at least 1 of the 90% credible intervals excludes -0.8% HbA1c at 
26 weeks in favor of LY3298176.  No adjustment for multiplicity will be performed. 
Probabilities based on posterior distributions of each dose group’s mean response exceeding the 
placebo group’s mean response by clinical thresholds of interest (by -0.3%, -0.6%, and -1.2%) 
will be provided. 
6.9.1.2. Secondary Analysis of the Primary Efficacy Outcome 
This secondary analysis is to evaluate the non-inferiority of LY3298176 to dulaglutide for the 
change in HbA1c from baseline to 26 weeks, using the primary analysis model. This secondary 
objective will be met if the upper limit for the 90% credible interval for the difference between 
LY3298176 and dulaglutide less than 0.3% (non-inferiority margin) for at least one LY3298176 
dose arm. 
6.9.1.3. Supporting Analyses of Primary Outcome 
The following supportive analyses will be performed for the primary outcome: 
 An analysis using the same statistical model as the primary analysis will also be 
performed using mITT population on treatment without rescue dataset. 
 The change in HbA1c from baseline will be analyzed using MMRM with restricted 
maximum likelihood estimation described in section 6.1.1.  Comparisons between each 
LY3298176 dose arm with dulaglutide and placebo will be made. This analysis will be 
performed on three analyses sets: mITT population on treatment without rescue data, 
mITT population with all data, and PP dataset.  
 An ANCOVA model will be used on the last observation carried forward (LOCF) 
endpoint of HbA1c as described in section 6.1.2. using MITT on treatment without 
rescue, and mITT population.    
Table 6.3 describes the analyses to meet the primary objective, all performed on the HbA1c 
change from baseline values, including the above sensitivity analyses.  
 


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Table 6.3. 
Summary of Analyses for Primary Outcome 
Analysis Type 
LOCF or Observed Values
Analysis Set
Hierarchical Logistica  
Observed 
mITT without 
rescue 
Hierarchical Logistic 
 
Observed 
mITT on treatment  
without rescue 
MMRM  
Observed 
mITT 
MMRM  
Observed 
PP 
MMRM 
Observed 
mITT on treatment 
without rescue 
MMRM, subgroup analyses
Observed 
mITT on treatment 
without rescue
ANCOVA 
LOCF
 mITT on treatment 
without rescue, 
mITT 
Abbreviations:  ANCOVA = analysis of covariance; HbA1c = hemoglobin A1c; LOCF = last observation carried 
forward; mITT = modified intent-to-treat; MMRM = mixed model repeated measures; PP = per protocol. 
a primary analysis 
6.9.2. Efficacy - Secondary Outcomes 
6.9.2.1. Dose Response Analyses on HbA1c and  Body Weight  
Change from baseline in  HbA1c at 12 weeks will be accessed using a superiority margin of -
0.8% to placebo as well as a non-inferiority margin of 0.3% to dulaglutide, based on the primary 
analysis model.   
The body weight change from baseline at both 12 and 26 weeks will compare to a superiority 
margin of -2 kg to placebo.  Similar Bayesian dose-response analysis as for HbA1c will also be 
performed for the change in body weight, except with an exponential dose-response model: 
 
ߠௗ்~ܽ൅ܾ∗݀ఊ൅߫ௗ்,         ݀ൌ0, … , ܦെ1 
ݕ்~ܰሺߠௗ், ߪଶሻ,
 
γ is a sigmoidicity parameter indicating shape or steepness of dose response.  The priors for each 
parameters are:  α~N(0, 50), b~N(1, 10), γ~N(1, 5).  Other dose-response models may be explored 
if the exponential dose-response model does not fit the data well. The analysis will be performed 
in two datasets: mITT without rescue, and mITT on treatment without rescue. 
6.9.2.2. Continuous Variable Analyses 
The MMRM model described in Section 6.1.1 will be performed on the following variables to 
obtain inference for the corresponding secondary objectives: 
 Body weight change from baseline  
 Change from baseline of HbA1c 


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 Change from baseline of FBG  
 Change from baseline of waist circumference 
BMI (kg/m2) will be calculated at each visit at which weight is measured, using height as 
measured during screening.  Change from baseline in BMI will be listed and summarized. 
6.9.2.3. Analyses Based on Multiple Imputations 
The MMRM model produces consistent estimator for missing at random (MAR). To understand 
the key efficacy results with potential missing not at random (MNAR), analyses will be further 
explored using selected pattern mixture models for missing data  in the mITT population for the 
change in HbA1c and change in body weight. In this case, the missing data will be imputed using 
the non-missing data in the placebo arm through a multiple imputation procedure. The imputed 
26-week HbA1c or body weight response for the missing data along with the non-missing 26-
week data will be employed using an ANCOVA model or MMRM model.  The parameter 
estimates and inferences will be calculated by method of Little and Rubin (1987).  
6.9.2.4. Analyses on Variables with Percent of Patients Reaching a Target 
The proportion of patients who have ≥5% and ≥10% body weight loss will be analyzed using a 
longitudinal logistic regression model with treatment, strata (baseline HbA1c category,  and 
baseline BMI category) and metformin use (yes, no), visit, and treatment-by-visit interaction as 
fixed effects, and baseline body weight as a covariate.   
The proportion of patients who have achieved an HbA1c level of <=7% and <=6.5% at 26 weeks 
will be analyzed by a logistic regression with factors  treatment, baseline BMI category, and 
metformin use (yes, no) will be fixed effects and continuous baseline HbA1c level will be a 
covariate. Other HbA1C categories may be added. 
6.10. Safety Analyses 
Safety analyses will be performed on the safety population and classified by the actual treatment 
group unless specified.  Safety descriptive statistic summaries may also include all LY3298176 
doses combined if appropriate.  Unless specified otherwise, safety listings will display 
values/events during all study periods; key adverse events (AEs) summaries will be presented 
separately for the treatment period and for the treatment period and follow-up period combined if 
applicable.  Any events/values reported after start of rescue therapy but before the start of the 
follow-up period will be included in safety analyses for the treatment period. 
Safety measures will include extent of exposure, vital signs, physical characteristics, treatment-
emergent adverse events (TEAEs; including serious adverse events [SAEs]), adverse events of 
special interest (AESIs; that is, injection site reactions, hypersensitivity reactions, hypoglycemia 
episodes, GI events - nausea, vomiting, and diarrhea-, acute pancreatitis, and major adverse 
cardiovascular [CV] events), laboratory measures (including hematology, chemistry, urinalysis, 
and samples collected for testing for anti-LY3298176 and antibodies), and electrocardiograms 
(ECGs).  In addition, the change from baseline to 26 weeks in HDL-C, total cholesterol, 
triglycerides, and LDL-C will be analyzed on the mITT population.   


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The summary statistics for continuous variables will be sample size, mean, SD, median, 
minimum, and maximum.  If applicable (for example, in the case of MMRM analyses) these 
descriptive statistics may also include LS means, LS means standard error (SE), and 95% CI for 
each treatment group as well as for LY3298176 difference from placebo.   
The summary statistics for categorical variables will be sample size, frequency, and percentage.   
Additional analyses, such as concentration-safety lab plots, may be performed if warranted upon 
review of the data. 
6.10.1. Vital Signs 
Vital sign measurements (that is, systolic blood pressure [SBP] and diastolic blood pressure 
[DBP; mmHg] and pulse rate [PR; beats/minute]) will be collected according to the Study 
Schedule of Events (Appendix 1).  The average 3 measurements for BP and PR is going to be 
calculated and analyzed; however, values obtained from fewer than 3 measurements will also be 
included in summaries and analyses.   
Descriptive statistics will be provided by treatment arm for change from baseline at each visit for 
SBP, DBP, PR.  Figures will display LS mean values for change from baseline at each visit for 
the LY3298176 groups versus placebo and dulaglutide.   
The change from baseline for the above measures will be analyzed using an MMRM-based 
model as described in Section 6.1.1. on two analysis sets: mITT and mITT population on 
treatment without rescue. 
The frequency and percentage of patients showing vital sign results in each of the categories 
specified in Table 6.4 will also be summarized by treatment and visit.   
Table 6.4. 
Vital Sign Summary Categories 
Vital Sign Measure 
Unit 
Low 
High 
Systolic Blood Pressure 
mmHg 
≤90 and decrease ≥20 
≥160 and increase ≥20 
Diastolic Blood Pressure 
mmHg 
≤50 and decrease ≥10 
≥100 and increase ≥10 
Pulse Rate 
bpm 
<50 and decrease ≥15 
>100 and increase ≥15 
 
A Bayesian analysis for pulse rate will be performed to assess the probability of the posterior 
distribution of the change in HR from baseline of 26 weeks for each LY3298176 treatment dose 
arm compared to placebo  
Pr(ΔLY - ΔPlacebo ≤10 bpm|Data) 
The mixed effect linear model will be used to fit the response for treatment i, subject j and time 
k:  
ܻ௜௝௞ൌߤ௜௞൅ݏ௜௝൅݁௜௝௞, 


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where ߤ௜௞ is the mean response for treatment i at time point k, and ݏ௜௝~ܰሺ0, ߪ௦
ଶሻ and 
݁௜௝~݊ሺ0, ߪଶሻ are independent.  The analysis will be performed on mITT population on treatment 
without rescue medication. 
All vital signs and physical characteristics measurements will be listed, for all randomized 
patients.   
6.10.2. HDL-C, Total Cholesterol, Triglycerides, and LDL-C 
Change from baseline in HDL-C, total cholesterol, triglycerides, and LDL-C will be analyzed 
using the MMRM model described in Section 6.1.1.   
6.10.3. Adverse Events 
No statistical tests will be performed to compare AE rates between treatment groups.   
Treatment-emergent AEs, defined as events that are newly reported after randomization or 
reported to worsen in severity from baseline, will be determined based on occurrence on or after 
the date of first dose of investigational product.  Since the eCRF does not collect dosing time, it 
is acknowledged that there is a possibility that a small number of TEAEs could actually have 
onset prior to the time of first dose.   
Adverse events will be summarized as TEAEs.  Summaries of TEAEs will be presented for the 
combined treatment and follow-up periods, and the treatment period only.   
Adverse event summary tables will include a “Total LY3298176” column for all LY3298176 
treatment groups combined if appropriate.   
In summaries by System Organ Class (SOC) or Preferred Term (PT), SOC will be displayed in 
alphabetical order and PT will be displayed by decreasing frequency of the “Total LY3298176” 
patient incidence within each SOC.  In summaries by PT, PT will be displayed by decreasing 
frequency of the “Total LY3298176” patient incidence.  Ordering by frequency should be based 
on percentages and not on frequency counts.   
All AEs (not only TEAEs) will be presented in listings by patient, actual term, PT, severity and 
relationship to treatment (yes, no).  Listings will also include treatment group, start date and stop 
date (or ongoing), assessment of seriousness, relationship to nonstudy drug treatment (study 
disease, study procedure, none), relationship to study device (yes, no), action taken with study 
medication and outcome of AE.   
Listings will report data as recorded (for example unknown severity or relationship and partial or 
unknown dates).  Where necessary, such as for determination of TEAEs, partial or unknown 
dates will be imputed. 
6.10.3.1. All Treatment-Emergent Adverse Events 
The incidence of patients with at least 1 TEAE and the incidence of TEAEs will be summarized, 
showing frequency and percentage of patients, by SOC, PT, and treatment group.  The total 
number of TEAEs and the number of TEAEs for each SOC and PT will also be reported for each 


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treatment group. Chi-square test will be performed for overall comparison between treatments if 
deemed appropriate.
The patient incidence of TEAEs will also be summarized by SOC, PT, maximum severity, and 
treatment group.  
6.10.3.2. Related Adverse Events
The incidence of patients with at least 1 TEAE assessed as related (including possibly related or 
unknown) and the patient incidence of related TEAEs will be summarized by SOC, PT, and 
treatment group.  In addition, the total number of related TEAEs and the number of related 
TEAEs for each SOC and PT will be reported for each treatment group.
6.10.3.3. Serious Adverse Events
A listing of all SAEs by patient will be produced.  If a sufficient number of SAEs are reported
(that is, >1 SAE overall per treatment group or >3 SAEs in any 1 treatment group) summary 
tables will be produced showing the incidence of patients with at least 1 SAE and the patient 
incidence of SAEs by SOC, PT, and treatment group.  In addition, if a sufficient number of SAEs 
are reported, the total number of SAEs and the number of SAEs for each SOC and PT will be 
reported for each treatment group.
6.10.3.4. Adverse Events Leading to Discontinuation
Treatment-emergent AEs reported with an action taken of “drug withdrawn” will be 
summarized, using patient incidence, by SOC, PT, and treatment group.  In addition, a listing of 
AEs leading to discontinuation of study treatment (that is, with action taken as “drug 
withdrawn”) will be presented.  
Treatment-emergent AEs reported as reason for study discontinuation (that is, discontinuation of 
study procedures as well as study treatment) will be summarized, using patient incidence, by 
SOC, PT, and treatment group.  In addition, a listing of AEs leading to discontinuation of study 
will be presented.  
6.10.3.5. Most Common Adverse Events
The most common TEAEs, determined as TEAEs occurring in ≥5% in any LY3298176 arm, will 
be summarized by SOC, PT, and treatment group.  This summary will also include the number of 
such events by SOC, PT, and treatment group.  
6.10.3.6. Deaths
All deaths recorded on the status page, the AE page, or the SAE page (with a death date, cause of 
death, outcome or SAE categorization present) of the CRFs will be considered a death for 
summary purposes.  All deaths (CV or non-CV) that occur during the treatment period or follow-
up period will be adjudicated by an independent central adjudication committee in compliance 
with a study-specific adjudication charter.  Results of the adjudication will be entered in the 
death adjudication eCRF page.  
A listing of adjudicated results will include the adjudicator assessment of death type, whether or 
not the adjudicator’s assessment of the event date agrees with the investigator’s assessment of 


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the event date, and the date of the event, showing the adjudicator’s assessment in the case of 
non-agreement. If adjudicated results show >1 death per treatment group or >3 deaths within 
any 1 treatment group, a summary table will present patient incidence of deaths by SOC, PT, and 
treatment group.  
6.10.4. Adverse Events of Special Interest
Adverse events of special interest to be identified and described during this study are injection 
site reactions, hypersensitivity reactions, hypoglycemia, acute pancreatitis, major adverse CV 
events, and selected GI events (nausea, vomiting, and diarrhea).  
Descriptive statistics for AESIs will be presented by treatment group and visit.  Continuous 
responses will be summarized using sample size, mean, SD, median, minimum and maximum, 
while categorical responses will be summarized using sample size, frequency and percentage.  
If data warrant, continuous elements of AESIs (such as the duration of hypoglycemaic events)
will be analyzed using an MMRM-based model described in Section 6.1.1.  
In addition, for AESIs with information collected on the AE eCRF page (that is, hypersensitivity 
reactions, acute pancreatitis, and major adverse CV events) summary tables will be presented
only if >3% of patients has the AESI.  The incidence of patients with at least 1 AESI and the 
patient incidence of AESIs will be summarized, showing frequency and percentage of patients, 
by SOC (if applicable), PT, and treatment group.  The total number of AESIs and the number of 
AESIs for each SOC (if applicable) and PT will also be reported for each treatment group.  
Listings by patient will be provided for AESIs.  Listings will also present adjudication 
information by patient for adjudicated events.
6.10.4.1. Hypersensitivity Reactions
A listing of potential hypersensitivity reactions will be provided.  For the purpose of this listing, 
any event satisfying any one of the Anaphylaxis reaction SMQ, Hypersensitivity SMQ, or 
Angioedema SMQ will be included.  Summary tables will be presented only if the number or 
nature of the events warrants such a comparison.  
6.10.4.2. Injection Site Reactions
Injection site reactions are collected in a questionnaire.  The following items or other available 
categories may be collected and summarized for each injection site reaction:

pain 

itching 

rash 

reaction timing

swelling

redness

erythema

bruising

hematoma.


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Injection site reactions which meet SAE criteria will also be collected as AEs.  If >3% patients 
have such event occur, then these injection site reactions may be summarized by PT using the 
version of Medical Dictionary for Regulatory Activities (MedDRA) current at the time of 
programming.  
6.10.4.3. Nausea, Vomiting, and Diarrhea
Nausea, vomiting, and diarrhea event information will be collected on a designated separate
eCRF page. 
The incidence of nausea, vomiting, and diarrhea will be summarized by the treatment and the 
time interval of interest.  The duration of each event will also be computed in days as event stop 
date minus event start date.  For computation purposes, the end date for ongoing events is the 
date of last study contact.  
The maximum severity and duration from baseline to Week 26 of nausea, vomiting, and diarrhea 
will be summarized by treatments.
Plot with the % number of subjects with the events vs initiation time course by day and week
will also be generated. The y-axis is the % subjects with the specified AE and the x-axis is the 
time in day or week since the first dose.
A listing with GI TEAEs of interest will be provided.
6.10.4.4. Hypoglycemic Episodes and Total Hypoglycemia
Hypoglycemic episodes will be defined as follows:  documented symptomatic hypoglycemia, 
asymptomatic hypoglycemia, probable symptomatic hypoglycemia, nocturnal hypoglycemia, and 
severe hypoglycemia.  Total or overall hypoglycemia is defined as any event meeting the criteria 
for documented symptomatic hypoglycemia, asymptomatic hypoglycemia, or probable 
symptomatic hypoglycemia:  

Documented Symptomatic Hypoglycemia:  Any time a patient feels that he/she is 
experiencing symptoms and/or signs associated with hypoglycemia and has a plasma 
glucose level of ≤3.9 mmol/L (≤70 mg/dL).

Asymptomatic Hypoglycemia: An event not accompanied by typical symptoms of 
hypoglycemia, but with ≤3.9 mmol/L (≤70 mg/dL) plasma glucose.

Severe Hypoglycemia: An episode requiring the assistance of another person to actively 
administer carbohydrate, glucagon, or other resuscitative actions.  These episodes may be 
associated with sufficient neuroglycopenia to induce seizure or coma.  Plasma glucose 
measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration.

Nocturnal Hypoglycemia: Any hypoglycemic event that occurs between bedtime and 
waking.

Probable Symptomatic Hypoglycemia: An event during which symptoms of 
hypoglycemia are not accompanied by a plasma glucose determination (but that was 
presumably caused by a plasma glucose concentration ≤3.9 mmol/L [≤70 mg/dL]).


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
Total or Overall Hypoglycemia: Any event meeting the criteria for documented 
symptomatic hypoglycemia, asymptomatic hypoglycemia, or probable symptomatic 
hypoglycemia.
Information will be collected on the eCRFs to allow for classification of hypoglycemic episodes 
into these categories.  Note that there is possible overlap among the categories meaning that it is 
possible for a single event to have >1 classification.  
A monthly rate of episodes per patient will be computed by visit, with 1 month defined as a 
30-day period.  At each applicable visit, the total number of episodes since the previous visit and 
the number of days since the previous visit will be determined.  The monthly rate of episodes 
will be calculated as the total number of episodes divided by the number of days since the 
previous visit and multiplied by 30 days.  An overall monthly rate will be determined as the total 
number of episodes over all visits divided by the total number of days between all visits and 
multiplied by 30 days.  
The monthly rate of episodes per patient by visit and overall will be computed for episodes of 
total hypoglycemia and episodes of nocturnal hypoglycemia.  These rates will be summarized by 
treatment for each visit and overall.  
The incidence of hypoglycemic episodes during a time period is defined as the number of 
patients experiencing at least 1 hypoglycemic episode within that time period.  The incidences of 
total hypoglycemic, nocturnal hypoglycemic episodes and severe hypoglycemic episodes will be 
determined at each visit (that is, for the time period since the previous visit), and overall (that is,
for the time period from first dose of study treatment to last study visit while on study treatment).  
The incidences for total and nocturnal hypoglycemic episodes will be summarized by treatment 
for each visit and overall using descriptive statistics (that is, sample size, frequency, and 
percentage); if a sufficient number of severe hypoglycemic episodes are reported, then incidence 
of these episodes will also be summarized. 
In addition, statistical analyses will be performed for the overall total hypoglycemia (occurred 
versus did not occur) using a logistic regression analysis with treatment, metformin use (yes, no), 
and HbA1c strata (<8.5%, ≥8.5%) as fixed effects.  
Listings of hypoglycemic episodes of all types will be presented by visit for each patient.  
Hypoglycemic episodes occurring after a patient discontinues treatment will be counted in the 
determinations of rate or incidence of episodes.  
6.10.4.5. Pancreatitis
Summaries of adjudicated and investigator-reported pancreatic events will be provided by each 
randomized treatment.  However, the summary report will only be generated if >3% patients 
have pancreatic event(s).  Determination of investigator-reported events will be through the 
“Acute pancreatitis” Standardized MedDRA Queries (SMQ) and a “Chronic pancreatitis” Lilly 
Search Categories (LSC) of the AE database, while adjudication-confirmed pancreatitis will be 
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The patients developing pancreatitis will be listed separately for the investigator-reported and the 
adjudicated events.
Each pancreatic enzyme at Week 26, and the maximum post-dose value will be summarized by 
each randomized treatment in a shift table using >1x upper limit of normal (ULN), and ≥3x ULN 
separately for the mITT population, mITT population with normal baseline, mITT population 
with baseline value > ULN.
6.10.4.6. C-cell Hyperplasia and C-cell Neoplasms
Listings of AEs of interest using a LSC will be provided by HLTs thyroid neoplasms, thyroid 
neoplasms malignant and thyroid disorders.  The summary report for these AESIs by each 
randomized treatment will be reported if there are >3% patients with these AESIs.
Calcitonin data will be summarized using an MMRM model similar to the supportive analyses.  
Calcitonin values will be listed for those patients with a post-first dose serum calcitonin increase 
from baseline ≥50% and the absolute value ≥20 pg/ml.  These patients will be classified by their 
absolute calcitonin values into the following categories:  ≥20 and <25 pg/ml; ≥35and <50 pg/ml; 
and ≥50 pg/ml.  A shift table using these categories will be generated if the proportion of patients 
with these changes is >3%.
6.10.5. Laboratory Measurements
Laboratory measurements by treatment group at each scheduled time of assessment during the 
treatment and follow-up periods and including any off-treatment safety follow-up visits that 
occur after discontinuation of study treatment, will be summarized using descriptive statistics.  
Descriptive statistics for laboratory analyses with continuous results will include sample size, 
mean, SD, median, minimum, and maximum for both actual values and change from baseline.  
Laboratory analyses with categorical responses by visit and treatment group will be summarized 
using sample size, frequency, and percentage.  
A listing of laboratory measurements for individual patients by visit will be presented.  An 
additional listing for all laboratory measurements that are outside the normal range will be 
presented.  All laboratory measures that meet the criteria for a listing, including unscheduled and 
repeat or multiple measurements will be reported.  
A summary report and analysis for treatment-emergent abnormal laboratory values (outside the
reference ranges as appropriate) for each continuous analyte by treatment will be provided. Shift
tables of the change from baseline value to the maximum/minimum postbaseline value to 
Week 26 for selected analytes using clinically meaningful thresholds will be summarized.  A 
shift table for ALT, AST, total bilirubin, and direct bilirubin will be generated using cutoff 
≤1 ULN, (>1 ULN and <3 ULN), (≥3 ULN and <5 ULN), (≥5 ULN and <8 ULN), ≥8 ULN.
A listing of ALT, AST, and total bilirubin values at all visits for all patients who meet any of the 
following criteria will be presented:  

Alanine aminotransferase (ALT) ≥3 × ULN

Aspartate aminotransferase (AST) ≥3 × ULN


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
Total bilirubin ≥2 × ULN

ALT or AST ≥3 × ULN and total bilirubin ≥2 × ULN.
6.10.6. Electrocardiograms
For ECG parameters that collected in triplicates, the arithmetic mean from the 3 measures for the 
same parameter at the same visit will be calculated and use for all subsequent analyses.  This will 
include ECG heart rate (HR) in bpm, QRS complex (msec), and PR interval (msec), as well as 
the time elapsed between the onset of ventricular depolarization and the end of ventricular 
repolarization (QT) and QT corrected by HR values using Fridericia’s formula (QTcF).  QTcF in 
milliseconds (msec) will be reported.  Descriptive statistics for the absolute values and changes 
from baseline for the ECG parameters (HR, PR interval, QRS, QT, QTcF) will be presented by 
treatment arm.  Additional summary statistics for abnormal values (categorized as Low or High
as shown in Table 6.5) will be provided.  An MMRM-based model similar to the supportive 
analysis of the primary outcome will also be used for the change from baseline in HR, PR, and 
QTcF.
Table 6.5.
Electrocardiogram Abnormal Categories
Measure
Low
High
PR Interval
<120 msec
≥220 msec
QRS Interval
<60 msec
≥120 msec
HR
<50 and decrease of ≥15 bpm
>100 and increase ≥15 bpm
QT
NA
>500 msec
QTcF 
NA
>450, >480, and >500 msec
Abbreviations:  bpm = beats per minute; HR = heart rate; NA = not applicable; QTcF = QT corrected values using 
Fridericia’s formula.
In addition, LY3298176 concentration-response analysis of QTcF and RR results may be 
performed, using figures that display change from baseline in QTcF on the vertical axis versus 
LY3298176 concentration (from PK/PD) on the horizontal axis, time-matched with the QTcF
measurements. The figures will also include a regression line and corresponding regression 
analysis.  
Summaries of categories for absolute observations and change from baseline for QTcF intervals 
will be provided as well, with absolute categories as >450, >480, and >500 msec and change 
from baseline categories as >30 msec and >60 msec.
6.10.7. Renal Safety
To assess renal safety, a summary and analyses use similar MMRM model as the supportive 
analysis for primary parameter will be performed for renal functional laboratory measures:  
estimated glomerular filtration rate (eGFR), creatinine, urine albumin/creatinine ratio (uACR).  
A log transformation for the analysis of uACR may be performed.  
The minimum eGFR value and the maximum creatinine, urine ACR will be used for baseline and 
postbaseline calculation to generate the shift table.  The shift table will use eGFR cutoff (<30, 


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30-<60, 60-<90, and ≥90 mL/min/1.73m2), creatinine (≤1 ULN, >1 and ≤2 ULN, 2 and 
≤4 ULN, and >4 ULN), and UACR (<30, ≥30 and ≤300, and 300 mg/g).  The overall 
randomized treatment comparison will be tested using a likelihood-ratio Chi-square test.  The 
shift table for minimum eGFR for both baseline and post-first dose at Week 26 will be 
summarized.  
To examine AE indicating decrease in renal function, the SMQ for acute renal failure and a LSC 
for chronic renal failure events will be used to search the clinical trial data base for events of 
interest.  A listing will be provided with all detected TEAE from these categories.  
6.11. Exploratory Analyses
Baseline will be the mean value of the 2 measurements prior to treatment for SMBG.  The 
change from baseline of 7-point SMBG profiles, and PROs will be summarized and analyzed.  
Immunogenicity will besummarized and analyzed .
Genetic markers will be evaluated for their contribution to the variability of LY3298176 
pharmacology and will also be included as covariates in PK/PD model-based analyses if 
applicable.
6.11.1. 7-Point SMBG
The 7-point SMBG profile consists of pre-meal and 2-hour postprandial BG measurements for 
morning, midday, and evening meals, as well as a bedtime BG measurement.  Analyses will 
apply to the changes from baseline in the following variables for 7-point glucose profiles:
1. pre-morning meal-fasting BG (mg/dL)
2. morning meal 2-hour (hr) BG (mg/dL)
3. pre-midday meal BG (mg/dL)
4. midday meal 2-hour BG (mg/dL)
5. pre-evening meal BG (mg/dL)
6. evening meal 2-hour BG (mg/dL)
7. bedtime BG (mg/dL)
8. morning meal 2-hour excursion (mg/dL)
9. midday meal 2-hour excursion (mg/dL)
10. evening meal 2-hour excursion (mg/dL)
11. mean of all meals 2-hour excursion (mg/dL)
12. mean of all 7-point BG (mg/dL)
13. mean of all pre-meals BG (mg/dL)
14. mean of all 2-hour postprandial BG (mg/dL).
The morning, midday, and evening meal 2-hour excursions (that is, variable 8 through 
variable 10) will be calculated for each meal as the 2-hour postprandial BG minus the pre-meal 
BG.
The change from baseline of 7-point SMBG profiles will be calculated using a similar 
MMRM-based model described in section 6.1.1.  The corresponding baseline will be used in the 


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model instead of the baseline HbA1c levels.  The MMRM model will include a term for the 
HbA1c stratification group.
6.11.2. Health Outcome/Quality of Life Measures
Health-related quality of life will be assessed using 2 self-rated questionnaires that provide 
standardized measures of patients’ perceived current health status: the Ability to Perform 
Physical Activities of Daily Living (APPADL) and the Impact of Weight on Self-Perception 
(IW-SP) questionnaires.  Patients will complete the questionnaires at specified clinic visits prior 
to any other visit procedures or after the patient has sufficiently recovered from the preceding
visit procedures (for example, in the case of fasting).  
For each questionnaire change from baseline at Week 12 and Week 26 in the transformed overall 
scores will be analyzed using MMRM model as described in section 6.1.1  An analysis for LOCF 
endpoint will also be performed. 
Additional exploratory analyses may also be done to explore relationships in weight loss (such as 
BMI lowered by >5%) with better HbA1c, APPADL, and IW-SP.
6.11.2.1. Ability to Perform Physical Activities of Daily Living 
The APPADL questionnaire is useful in evaluating weight loss interventions in individuals with 
T2DM.  The APPADL 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.  Items are scored on a 5-point numeric rating scale where 5 = “not at all 
difficult” and 1 = “unable to do.”  
A raw total APPADL score is calculated by summing the scores of the 7 items and dividing by 
the number of items (7).  The raw APPADL total score ranges from 1 to 5.  A transformed 
overall score is obtained by linearly transforming the raw overall score to a 0-100 scale, using 
the following transformation formula:  
[(actual raw score – lowest possible raw score) / 
(highest possible raw score –lowest possible raw score)] x 100
For example, using the transformation formula, a raw APPADL total score of “3.0” becomes 
a transformed total score of “50.0” on a scale of 0 to 100:  
[(3.0-1.0)/(5-1)]*100 = 2/4*100 = 50.0
Higher raw APPADL raw total scores and higher transformed APPADL total scores indicate 
better self-reported ability to perform physical activities of daily living.
6.11.2.2. Impact of Weight on Self-Perception
The IW-SP questionnaire contains 3 items that assess how often the patient’s body weight affects 
how happy they are with their appearance and how often they feel self-conscious when out in 
public.  Items are scored on a 5-point numeric rating scale where 5 = “never” and 1 = “always.”  


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A raw total IW-SP score is calculated by summing the scores of the 3 items and dividing by the 
number of items (3).  The raw IW-SP total score ranges from 1 to 5.  To transform the IW-SP 
total score to a scale ranging from 0 to 100, the same transformation formula as for the APPADL 
scores is used.  For example, using the formula, a raw IW-SP total score of “2.0” becomes a 
transformed total score of “25.0” on a scale of 0 to 100:  
[(2.0-1.0)/(5-1)]*100 =1/4*100 = 25.0
Higher raw IW-SP total scores and higher transformed IW-SP total scores indicate better self-
perception.  
6.11.2.3. Missing Data Imputation for Ability to Perform Physical Activities of Daily 
Living and Impact of Weight on Self-Perception
For both the APPADL and the IW-SP questionnaires, the following rule will be applied in the 
case of missing item scores.  If >50% of item scores are available, then missing item scores will 
be imputed using the mean of the available item scores.  For the APPADL, this means there must 
be ≥4 item scores completed and for the IW-SP there must be ≥2 item scores completed.  If the 
data for any respondent does not meet this missing data rule (>50% of item scores completed), 
then the questionnaire total score for that respondent will be considered missing. For analyses, 
missing scores will be imputed using LOCF.
6.11.3. Pharmacodynamic or Biomarker Analyses
Change from baseline to 12 and 26 weeks in fasting fibroblast growth factor-21 (FGF-21), 
adiponectin, -hydroxy butyrate, glucagon, insulin levels, and other biomarkers will be analyzed 
and summarized using the mITT population on treatment without rescue dataset.
The change from baseline of fasting FGF-21, adiponectin, -hydroxy butyrate, glucagon, insulin 
levels, and the bone biomarkers (CTX-1, PINP, Osteocalcin) will be analyzed using a similar 
MMRM-based model as described in section 6.1.1.   A data transformation may be applied if the 
normality assumption is violated.  If data warrant, a subgroup analysis with age >50 years 
women for the bone biomarkers will be performed.
Additional exploratory analyses may be performed if deemed necessary.  
Additional LY3298176 concentration-response analyses of exploratory biomarkers may be 
performed and will be detailed in the PK modeling plan.  
6.11.4. Evaluation of Immunogenicity 
6.11.4.1. Definitions of Sample ADA Status
At a high level, an individual sample is potentially examined multiple times, in a hierarchical 
procedure, to produce a sample anti-drug antibodies (ADA) assay result and potentially multiple 
cross-reactive antibodies assay results and multiple neutralizing antibodies (NAb) assay results.  
The cut points used, the drug tolerance of each assay, and the possible values of titers are 
operating characteristics of the assay.


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It can be the case that the presence of high concentrations of LY will affect immunoassays, and 
conversely high levels of antibodies may affect the measurement of LY concentration.  Thus, an 
LY drug concentration, assessed from a sample drawn at the same time as the ADA sample, 
plays a key role in clinical interpretation of a sample when the laboratory result is Not Detected
(Table 6.6).


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Table 6.6.
Sample Anti-Drug Antibodies (ADA) Assay Results
Sample Laboratory Result
Explanation
Detected 
ADA are detected and confirmed.  
Not Detected 
The raw result as reported from the laboratory indicates not detected.  The clinical 
interpretation of such results depends other factors (see below).
NO TEST, QNS, etc.
Sample exists but was unevaluable by the assay
Table 6.7.
Sample Clinical Anti-Drug Antibodies (ADA) Interpretation Results
Sample Clinical Interpretation
Explanation
ADA Present
ADA assay result is Detected
ADA Not Present
ADA assay result is Not Detected and simultaneous drug concentration is at a 
level that has been demonstrated to not interfere in the ADA detection method 
(ie, drug concentration is below the assay’s drug tolerance level).  
For patients receiving placebo, drug concentration is not assessed and is 
assumed to be below the assay’s drug tolerance level.
If drug concentration was planned but is not available for a treatment-period 
sample, a Not Detected sample will be declared ADA Inconclusive.
ADA Inconclusive
ADA assay result is Not Detected but drug concentration in the sample is at a 
level that can cause interference in the ADA detection method.
ADA Missing
ADA sample not drawn, QNS, not tested, etc., causing there to be no 
laboratory result reported or the result is reported as “no test.”
Parallel terminology applies for each type of cross-reactive and NAb.  Importantly, each of these 
are distinct assays and, in general, have different assay operating characteristics.
6.11.4.2. Definitions of Immunogenicity Assessment Periods
Immunogenicity Baseline Observations:  Baseline period for immunogenicity assessment for 
each patient includes all observations on or prior to first administration of study drug.  In 
instances where multiple baseline observations are collected, to determine patient ADA status 
the last non-missing immunogenicity assessment prior to first administration of study drug is 
used to determine treatment-emergent status (see below).  In this context, ‘missing’ includes 
explicit ‘ADA Missing’ results, as defined in Table 6.7.
Immunogenicity Postbaseline Period Observations:  Postbaseline period observations for each 
patient includes all observations after the first administration of study drug.  
6.11.4.3. Definitions of Patient ADA Status
Patient evaluable for treatment-emergent ADA (TE ADA):  A patient is evaluable for TE ADA if 
the patient has a non-missing baseline ADA result, and at least 1 non-missing postbaseline ADA 
result.
Treatment-emergent ADA positive (TE ADA+) patient:  A patient who is evaluable for TE ADA 
is TE ADA+ if either of the following holds:


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a.
The patient has baseline status of ADA Not Present and at least 1 postbaseline status of 
ADA Present with titer ≥2*MRD, where the MRD is the minimum required dilution of 
the ADA assay.
b. The patient has baseline and postbaseline status of ADA Present, with the postbaseline 
titer being 2 dilutions (4-fold) greater than the baseline titer.  That is, the patient has 
baseline status of ADA Present, with titer 1:B, and at least 1 postbaseline status of ADA 
Present, with titer 1:P, with P/B ≥4.
Treatment-emergent ADA Inconclusive patient:  A patient who is evaluable for TE ADA is TE 
ADA Inconclusive if ≥20% of the patient’s postbaseline samples, drawn pre-dose, are ADA 
Inconclusive and all remaining postbaseline samples are ADA Not Present.
Treatment-emergent ADA negative (TE ADA-) patient:  A patient who is evaluable for TE ADA 
is TE ADA- when the patient is not TE ADA+ and the patient is not TE-ADA Inconclusive.  
6.11.4.4. Analyses to be Performed
The number and proportion of patients who are TE ADA+ will be tabulated by treatment group, 
where proportions are relative to the number of patients who are TE ADA evaluable, as defined 
above.  The tabulation will include the number and proportion of patients with ADA Present at 
baseline, and the number and proportion of TE ADA+ patients exhibiting each type of cross-
reactive antibodies and NAb.  This analysis will be performed for (a) the active treatment period, 
and also for (b) the entire postbaseline period including follow-up.
A listing will be provided of all immunogenicity assessments for those patients who at any time 
had ADA Present.  This includes the LY concentration from a simultaneous PK sample, and the 
clinical interpretation result (ADA Present, ADA Not Present, ADA Inconclusive, Missing). In 
the case of ADA Present, a titer will be included, and TE ADA+ observations will be flagged. 
Also included, for each cross-reactive antibodies and NAb assay that was performed, will be the 
clinical interpretation result.
A summary will be provided of the number and percentage of LY-treated patients experiencing 
specific TEAE (see Table 6.8) by patient TE ADA status (TE ADA+, TE ADA-, TE ADA 
Inconclusive).  The PT will be ordered by decreasing incidence in TE ADA+ status group.  
A listing will be provided of all TEAE alongside ADA data, for any patient who had ADA 
Present at any time (including baseline) or had any specific TEAE (see Table 6.8).  This listing 
includes a time course of ADA (clinical interpretation result plus flags for samples meeting TE 
ADA+ criteria and for samples with cross-reactive antibodies and NAb present) along with the 
TEAE.  
Table 6.8.
Adverse Events for Analysis with Immunogenicity Results
Events satisfying Anaphylaxis standardized MedDRA query (SMQ) (narrow or broad)
Events satisfying Hypersensitivity SMQ (narrow or broad)
Events satisfying Angioedema SMQ (narrow or broad)


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Events mapping to High Level Term (HLT) of Injection site reaction
Events mapping to HLT of Infusion site reaction
The primary efficacy measure of change in HbA1c from baseline to 26 weeks will be examined 
in relation to ADA.  The initial examination will be boxplots of change in HbA1c at 26 weeks 
compared to maximum observed titer (1 category for each titer value) during the active treatment 
period, for patients who were TE ADA+ during that period.  An additional category will be 
provided for patients who were not TE ADA+ during the active treatment period.
Additional immunogenicity analyses as determined later may be presented.  The relationship 
between antibody titers, the PK parameters, and PD response to LY3298176 may also be 
assessed.  
6.12. Pharmacokinetic and Pharmacodynamic Analyses
This section provides a high level description of the population pharmacokinetic/
pharmacodynamic (PK/PD) analysis.  Initially, a PK model will be developed as described in 
subsequent sections.  PK/PD models for HR, BP, body weight, glucose and HbA1c will 
subsequently be developed incorporating the structural model and parameter estimates from the 
developed PK model.  Detailed descriptions are provided in the Population PK/PD Analysis 
Plan.  
Drug concentration data will be combined with dosing information, covariate data (eg, age, sex, 
weight, BMI, ethnic origin, concomitant medications, and baseline of PD variables), and the 
corresponding time-of-event data to produce the NONMEM dataset for population PK/PD 
analysis.  The PD or clinical endpoints that will be analyzed may include weight, fasting glucose, 
HbA1c, DBP and SBP and heart-rate.  If ADA titers are detected from immunogenicity testing, 
then the impact of immunogenicity titers on LY3298176 PK or any relevant PD parameters may 
also be examined.
Univariate and bivariate descriptive statistics, along with plots of independent and dependent 
variables, will be assessed to verify appropriate data distributions and to identify potential data 
errors, missing data, and outliers, as described in detail in the Population PK/PD Analysis Plan.
The population PK and PK/PD dataset will be analyzed using the nonlinear mixed effects 
modeling program NONMEM with PREDPP.  The data will be fit to provide estimates of the 
population PK and/or PD parameters and error terms.  NONMEM uses the extended-least-
squares fitting routine, which continues iteratively until a minimal value of the objective function 
(MOF) is reached.  
Inter-subject variability will be assessed separately on each of the PK or PD parameters using an 
exponential error structure (ie, log-normal distribution of individual parameter values).  Once 
inter-subject variability terms are selected, covariance between the terms may be assessed by 
application of the omega block.  Proportional, additive, and combined proportional and additive 
error structures may be evaluated for the residual error.  The criteria used in selecting the most 


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appropriate base model will be based on overall goodness of fit, MOF, and robustness of 
parameter estimates.  
Once a structural and statistical model has been established, the effect of potential patient factors 
will be assessed.  Potentially significant patient factors (age, weight, gender, and renal function
among others) based on graphical assessment will first be tested individually for their effect on 
each of the relevant PK (eg, Ka, CL, V) or PD (eg, baseline, Emax, EC50) parameters.  For the 
continuous covariates, a variety of linear and nonlinear models will be tested.  
A full model will be developed by testing, in combination, those covariates individually 
identified as significant in the covariate selection step.  Once the full model has been established, 
the process will be reversed.  The significance of potential covariates will be confirmed by 
removing each covariate individually from the full model.  The criterion for retention of a 
covariate in the final model is an increase of 10.828 point drop in MOF (p<0.001) when the 
covariate is omitted from the full model.  In the case of physiologically related and highly 
correlated factors (eg, weight and BMI), only 1 of the alternative factors may be selected for 
inclusion.  
The validity of the final model will be tested by multiple approaches.  This may include but is 
not limited to objective function mapping, leverage analysis, and posterior predictive check.  
6.13. Subgroup Analyses
The primary efficacy endpoint of HbA1c change from baseline at Week 26 will be summarized 
for the subgroups as defined for each of the grouping variables as follows:

age (<65 years, ≥65 years)

race (White, Non-White)

ethnicity (Hispanic/Latino, Not Hispanic/Latino)

gender (Female, Male)

duration (years) of T2DM, from “Date Diagnosed” to informed consent date (< study 
median, ≥ study median)

baseline HbA1c (<8/5%, ≥8.5%)

metformin use at baseline (Yes, No)

baseline BMI (<30 kg/m2, ≥30 kg/m2

country (US/Puerto Rico, Poland, Slovakia, Mexico).  
If the value of a grouping variable cannot be determined for a patient, the patient will be 
excluded from the corresponding subgroup analysis.
The subgroup by treatment interaction will be assessed for the HbA1c endpoint with the 
following parameters in the ANCOVA model: baseline HbA1c (continuous), metformin use 
(yes, no), baseline BMI category, subgroup factor, treatment group, and subgroup-by-treatment 
group interaction.  For subgroup analyses by baseline HbA1c, the HbA1c category (<8.5%, 
≥8.5%) will be used to replace the continuous HbA1c measurement in the model.  For all other 
subgroup variables, the categories as given above will be used to assess the subgroup-by-
treatment interaction.  


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The adjusted mean changes from baseline, SEs, 95% CIs within each treatment group as well as 
the difference in mean change from baseline and corresponding 95% CIs between each 
investigative treatment group and the placebo for each subgroup will be calculated.  In addition, 
the corresponding subgroup-by-treatment interaction p-value from the model will be calculated.  
The nominal p-values for the subgroup-by-treatment interactions will not be adjusted for 
multiplicity.  
Change from baseline in body weight will also be analyzed for the subgroup of BMI baseline 
category, and HbA1C baseline category.  
6.14. Interim Analyses
6.14.1. Overview
There will be up to 3 interim analyses for this study.  This study will not be stopped for either 
positive efficacy or futility at any interim analysis.  
The first interim analysis will occur after 30% patients finishing 12 weeks of treatment.  It will 
only include key safety data (demographics, discontinuations, exposure, TEAE, AESIs, SAE, 
vital sign, and some lab parameters) review.  The second interim analysis will occur after 
approximately 90% patients finish 12 weeks of treatment. It will include some key efficacy and 
safety parameters to monitor the compound safety and to support preliminary Phase 3 dose 
selection.  These 2 interims will be for internal business decisions.  The third interim analysis 
will occur when all patients have completed the treatment part of the study (prior to completion 
of the follow-up phase for all patients) and will include all safety, efficacy, and PK data available 
through the 26-week treatment for all patients to determine Phase 3 doses.   We will refer this as 
the primary DBL.  
An Assessment Committee (AC) will be formed to review the first and second interim analyses.  
Any change on the study design based on an interim analysis will be determined by the AC.  A
number of pre-identified individuals may gain access to the limited unblinded data, as specified 
in the unblinding plan, prior to the interim or primary outcome DBL in order to initiate 
population PK/PD model development processes for interim and final analyses, as well as plan 
and prepare for Phase 3 studies. Statistical Analysis Center (SAC) will be authorized to evaluate 
unblinded interim analyses and prepare the reports for the AC to review. Information that may 
unblind the study during the analyses will not be reported to study sites or blinded study team 
until the study has been unblinded.  
All study team members will be unblinded after the primary DBL.  
The study team will perform periodic, blinded safety reviews during the study and if safety 
signals or concerns arise from these reviews, the AC may be called upon to review unblinded 
safety data in an unplanned interim analysis.


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6.14.2. Description of Analyses
For the first interim analyses, only some key safety parameters described in the prior section will 
be examined and summarized.  
The second interim analysis will include the MMRM analyses for HbA1c change from baseline, 
and body weight change from baseline.  In addition to the safety parameters summarized for the 
first interim, ECG data will also be analyzed.    
6.15. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  For CTR analyses, an AE will be considered ‘Serious’ whether or not it is 
a TEAE.  An AE will be considered to be in the ‘Other’ category if it is both a TEAE and not 
serious.
Analyses provided for the CTR requirements include the following:

Summary of AEs, provided as a dataset which will be converted to an XML file.  Both 
Serious AEs and ‘Other’ AEs will be summarized by treatment group and by MedDRA 
Preferred Term (PT).  

For each Serious AE and ‘Other’ AE, for each PT and treatment group, the following will 
be provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event PT
o
the number of events experienced.
Consistent with ClinicalTrials.gov (National Institutes of Health [NIH] [WWW]) requirements, a 
threshold (at a maximum of 5%) for frequency of ‘Other’ AEs can be implemented rather than 
presenting all ‘Other’ AEs.  The determination of a threshold will be based on the overall 
number of ‘Other’ AEs.  


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7.
Unblinding Plan
The purpose of the unblinding plan is to detail the procedures that are in place to minimize bias 
while preparing for or conducting any summary or analysis of the data for AC reports, data 
reviews, dose selection (interim efficacy/safety only), and developing/refining exposure 
analyses.  Additionally, this plan identifies personnel who will be unblinded during the study, 
including unblinding for the AC interim analyses in support of the AC meetings.
The access to subject treatment assignments will not be provided to the investigator and site 
personnel until DBL is authorized for the planned final analysis at the completion of the blinded 
study.  
The access to subject treatment assignments will not be provided to the following personnel until 
the primary data lock is authorized for the third interim analysis at the completion of the 
treatment period:

Lilly personnel with direct site contact

Lilly personnel responsible for data entry and data validation

Lilly study team not in the AC and/or SAC.
After DBL, the study team will be unblinded to the study data to prepare for the analyses for 
CSR.  Investigators can be provided treatment assignments for their subjects when unblinding 
has occurred and the information will not impact scientific integrity or introduce bias after final 
DBL.
7.1.
Operational Procedures
The randomization code (treatment assignment) will be stored in the Lilly IWRS and will not be 
accessible to the blinded Lilly study team, except for those pre-specified in the unblinding plan 
to be unblinded, until the final DBL.  Members from the SAC, AC, and the study global patient 
safety (GPS) scientist may be unblinded to data prior to the DBL.  The SAC, composed of Lilly 
or Lilly designated third party organization (TPO) unblinded statistics personnel, PK/PD 
scientists and the PK/PD analysts (for efficacy/safety interim analysis only) will form a separate 
team from the Lilly blinded team.  The SAC will obtain the randomization code from the 
unblinded data movement group in order to generate unblinded tables, figures, and listings 
(TFLs) for the AC.  Membership is listed in Table 7.1 for each of the groups mentioned above.


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Table 7.1.
Study I8F-MC-GPGB Group Name and Membership
Group Name
Group Members
Blinded Lilly study team
Lilly clinical study team personnel who work on the study and have 
direct site contact including the clinical research physician, CTM, data 
sciences and solutions, GPS personnel, and study monitors, etc, and non-
site direct contact regulatory scientist, statistician(s).  However, per Lilly 
procedure, for patient safety, the study GPS scientist will be unblinded to 
SAE patient-level data for patient safety.  
Blinded Lilly statistics group
Lilly statisticians and statistical analyst(s)
SAC (unblinded)
Lilly statisticians and statistical analyst(s) or TPO statistical analysts
Unblinded PK/PD team scientists (part 
of the SAC)
Lilly study team PK/PD scientists and analyst(s), etc.
Assessment Committee
Lilly physicians, statisticians, and GPS personnel 
Unblinded data movement group
Unblinded data movement representative
The program senior management 
Lilly GIP/GLP senior medical director or above 
Abbreviations:  CTM = clinical trial manager; GIP/GLP = glucose-dependent insulinotropic peptide/glucagon-like 
peptide; GPS = global patient safety; PK/PD = pharmacokinetics/ pharmacodynamics; SAC = Statistical Analysis 
Center; SAE = serious adverse event; TPO = third party organization.
More specifically, the data movement group will load CRF data, clinical laboratory results, ECG, 
and IWRS data into the designed blinded and unblinded locations.  The blinded version of the 
data will then be provided to the blinded Lilly study team.  The unblinded data will be provided 
to the SAC.  The data movement group is not blinded, but is not involved in study-level activities
Periodically throughout the trial until the DBL, blinded data will be transferred by data 
movement per the data transfer plan to the blinded Lilly study team members including the 
blinded Lilly statistics group for the purpose of preparing Study Data Tabulation Model (SDTM) 
and Analysis Data Model (ADaM) dataset, AC reports, trial-level safety review (TLSR) reports, 
blinded AC reviews, TFL reviews, and CSR preparation.  To minimize bias during statistical 
planning and data review, these transfers will be provided under the guidelines described in the 
following sections.
By setting up appropriate access privileges, the Lilly system will only allow unblinded personnel 
(unblinded statistician and/or programmers) to access data that contains unblinding information.
7.2.
Site-Level Unblinding
The procedure for site personnel to unblind an individual patient’s treatment assignment for an 
emergency is described in the protocol Section 7.3.  Emergency unblinding for AEs may be 
performed by accessing the IWRS at the site level.  When an IWRS Clinical Trial Study 
Management System (CT-SMS) is used to unblind a patient’s treatment assignment, the 
computer application will maintain the date, reason for unblinding, and the identification of the 
person unblinding the treatment assignment.  All calls resulting in an unblinding event are 
recorded and reported by the IWRS.


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The site monitor is responsible for verifying compliance with the blinding procedures at the 
investigative site and verifying that access to the patients’ treatment assignments remains 
restricted from the investigator and site personnel in direct contact with patients.
The investigator and site personnel are instructed to make every attempt to contact Lilly 
personnel when a patient’s treatment assignment is unblinded at the site.  The affiliate personnel 
document the unblinding records and inform the designated study team member, CTM, who 
documents the overall unblinding records for the entire study.  The documentation is filed in the 
study files.  A final Study Unblinding Summary will be prepared at the end of the study (at the 
study closeout).
7.3.
Trial-Level Safety Reviews
Periodic TLSR summaries and listings will be produced by the blinded Lilly statistics group and 
delivered to the blinded Lilly study teams.  These summaries will be blinded until after the DBL.  
They will contain neither randomization assignments nor postrandomization primary endpoint 
HbA1c, dose information, or PK data with the potential to unblind.  Blinding flags will be 
created in the central laboratory database, based upon the Alert and Blinding Criteria document 
maintained by the Clinical Laboratory Operations (CLO) group.  These flags will blind specific 
report data to the site and investigators.  Data transferred to and exported from the clinical 
laboratory results will not be blinded to the Lilly team or to the data management of TPO
performing the labs.
The complete list of TLSR variables include overall AEs, SAEs, TEAEs, AESIs, laboratory data, 
vital signs, discontinuations, concomitant medications.
7.4.
Assessment Committee Reports
The blinded Lilly study team will remain blinded to randomization assignments and potentially 
unblinding results until after the DBL.
The SAC statistician is responsible for authorizing the access of Lilly personnel to unblinded 
data.  Every attempt should be made to contact the statistician and document the authorization 
before access is given to unblinded data.  A designated IWRS representative, data movement 
team or the replacement or their designee, will provide all data transfers to the Lilly statistics 
group based on the data transfer plan.
The study project statistician will be responsible for keeping a running log of individuals given 
access to any unblinded study data.  This log will include the person’s name, title, date of 
unblinding, level of unblinding (that is, group or patient), and purpose of unblinding.  This 
record will be stored in a secure area and will be stored in eTFM via the study CTM after DBL.
7.4.1. Interim Reports
The first interim will be safety only reviews.  The second interim will include key efficacy and 
safety. Due to data availability, PK/PD analyses will be performed at a later time.


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7.4.1.1.
First Interim
The following personnel will be unblinded to the first interim data, in order to perform the data 
analysis, prepare the AC reports, and review/discuss the results:
The AC (determined in AC Charter)
SAC (Lilly or TPO study personnel) 
Computational Statisticians
Others:  No, but can be added upon AC Chair’s request
7.4.1.2.
Second Interim
For the second interim or PK/PD analyses, the following personnel will be unblinded to the PK-
related data in order to develop the PK/PD modeling and/or TFLs:
The AC (determined in AC Charter)
SAC (Lilly or TPO study personnel) 
Computational Statisticians
Internal Pharmacokinetic Analysis Group (Lilly study personnel, part of the SAC)
Pharmacokineticist and Pharmacokinetics Analysts
7.4.1.3.
Reports Delivery
The following personnel will be unblinded to the efficacy, safety, and PK data, in order to 
perform data analysis, prepare the interim reports, review the results, and discuss business related 
matters:
AC (determined in AC Charter)
SAC (Lilly personnel) or its delegate
Computational Statisticians
Internal Pharmacokinetic Analysis Group (Lilly personnel, part of SAC) or its 
delegate
Pharmacokineticist and Pharmacokinetics Analysts
Others:  Others who don’t have direct site contact may be granted access to the 
results with approval of program team leader.
If PK reports needs more time to be generated, this interim reviews can be proceeded without PK 
data.  A subsequent PK results review can be formed later after the results are available.
In addition, in order to perform the critical business development and the regulatory interactions, 
some personnel need to be unblinded to the related summary (group) level data, and possibly 
limited patient-level data after the interim safety/efficacy analysis.  This unblinding requires 
approval from AC and signature for Confidentiality Responsibilities Agreement.  The SAC 
statistician should be informed by AC Chair for documentation purpose.


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7.4.2. Primary Lock (Third Interim)
The third interim analyses will be performed at week 26, the end of treatment period including 
both safety and efficacy reviews.  The data will be cleaned and locked.  Results will be 
unblinded for the study team. Lilly PK/PD scientists may obtain unblinding information before 
the DBL in order to perform PK/PD model-based analysis if deemed necessary.
7.5.
End of Study Unblinding
After the final DBL, all transfers of SDTM/ADaM files and TFLs to Lilly will be unblinded and 
will contain unblinded results for all laboratory parameters, PK data, and CRF data.
Immunogenicity data may be obtained later after the final DBL in a separate transfer without 
overwriting the already locked database.


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8.
References
Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & Sons. 
1987.
Lilly] Eli Lilly and Company, Cardiovascular Safety Advisory Committee. August 2013. 
Selected reference limits for pulse/heart rate, arterial blood pressure (including orthostasis), 
and electrocardiogram numerical parameters for use in analyses of Phase 2-4 clinical trials. 
Version 1.2.
   [NIH] National Institutes of Health. Available at: https://www.clinicaltrials.gov/. Accessed 
September 28, 2015.


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9.
Appendices


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Appendix 1.
Protocol GPGB Study Schedule
(Schedule of Events)


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Study Phase
Screen Lead -
in
Randomize
Treatment Phase
Follow
up
Early 
Term
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
801
Week of Treatment
3
2
0
1
1
2
2
4
4
8
12
12
16
20
24
26
(30)
Study Day/(Dose 
number)
0/(1)
7/(2)
14/(3)
28/(5)
56/(9) 84/(13)
98/(15) 140/(21) 168/(25) 182/(27)
Visit Window (days)
±7
±3 
±3
±3
±3
±3
±3
±3
±3
±3
PK Specific Visita
X
X
X
X
Administrative
Informed consent
X
Diabetes/medical 
history/therapy
X
Inclusion/Exclusion
X
X
Preexisting conditions
X
X
Randomization
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
X
X
BG meter/supplies, if 
needed
X
X
X
X
X
X
X
X
BG meter, instructions
X
X
Diet, exercise, BG 
counseling
X
Study diary, dispense
X
X
X
X
X
X
X
X
X
X
X
Review patient diaries 
for BG values, AEs, 
hypoglycemic or 
hyperglycemic events
X
X
X
X
X
X
X
X
X
X
X
X
X
Subcutaneous injection 
training
X
X


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Study Phase
Screen Lead -
in
Randomize
Treatment Phase
Follow
up
Early 
Term
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
801
Week of Treatment 
3
2
0
1
1
2
2
4
4
8
12
12 
16
20
24
26
(30)
Study day/(Dose 
number)
0/(1)
7/(2)
14/(3)
28/(5)
56/(9) 84/(13)
98/(15) 140/(21) 168/(25) 182/(27)
Visit Window (days)
±7
±3 
±3
±3
±3
±3
±3
±3
±3
±3
PK Specific Visita
X
X
X
X
Study drug and injection 
supplies, dispense
X
X
X
X
X
X
X
X
X
X
Health habits (alcohol 
use yes/no, tobacco use 
current/past)
X
Patient returns unused 
study drug supplies
X
X
X
X
X
X
X
X
Study drug, assess 
compliance
X
X
X
X
X
X
X
X
Patient Demographics
Age
X
Gender
X
Race/Ethnicity
X
Clinical Variables
Physical examination
X
X
X
Symptom-driven 
physical exam
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
X
Vital signs (BP and PR)
X
X
X
X
X
X
X
X
X
X
X
X
Antidiabetic medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Study Phase
Screen Lead -
in
Randomize
Treatment Phase
Follow
up
Early 
Term
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
801
Week of Treatment 
3
2
0
1
1
2 
2
4
4
8
12
12 
16
20
24
26
(30)
Study day/(Dose 
number)
0/(1)
7/(2)
14/(3)
28/(5)
56/(9) 84/(13)
98/(15) 140/(21) 168/(25) 182/(27)
Visit Window (days)
±7
±3 
±3
±3
±3
±3
±3
±3
±3
±3
PK Specific Visita
X
X
X
X
Other
ECGsb
X
X
Xc
Xc
Xc
Xc
X
X
Evaluation of Injection 
Site Reactions
X
X
X
X
X
X
X
X
X
X
X
APPADL and IW-SP 
questionnaires
X
X
X
X
Diagnostics (Safety)
Screening Laboratory 
Testsd
X
Pregnancy teste
X
X
Estradiol, FSH, LHf
X
Chemistry panel
X
X
X
X
X
X
X
Lipase and amylase
X
X
X
X
X
X
X
X
X
X
X
X
X
Lipid panel
X
X
X
X
X
X
eGFR
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
Urine albumin, 
creatinine, UACR
X
X
X
X
X


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Study Phase
Screen
Lead -
in
Randomize
Treatment Phase
Follow
up
Early 
Term
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
801
Week of Treatment 
3
2
0
1
1
2
2
4
4
8
12
12 
16
20
24
26
(30)
Study day/(Dose 
number)
0/(1) 7/(2)
14/(3)
28/(5)
56/(9) 84/(13)
98/(15) 140/(21) 168/(25) 182/(27)
Visit Window (days)
±7
±3 
±3
±3
±3
±3
±3
±3
±3
±3
PK Specific Visita
X
X
X
X
Diagnostics (Efficacy)
Calcitonin
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting glucose
X
X
X
X
X
X
X
X
Fasting insulin and 
c-peptide
X
X
X
X
X
Fasting glucagon
X
X
X
X
X
Total and active 
GLP-1/GIP
X
X
X
X
X
X
Remind Patients about 
7-point SMBG
X
X
X
X
X
7-point SMBG
Xg
X
X
X
X
Osteopontin, FGF-21 
(active), Adiponectin, 
-hydroxy butyrate, 
glycerol, free fatty acids,
MCP-1, CTX-1, P1NP, 
osteocalcin
X
X
X
X


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Study Phase
Screen
Lead -
in
Randomize
Treatment Phase
Follow
up
Early 
Term
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
801
Week of Treatment 
3
2
0
1
1
2
2
4
4
8
12
12 
16
20
24
26
(30)
Study day/(Dose 
number)
0/(1) 7/(2)
14/(3)
28/(5)
56/(9) 84/(13)
98/(15) 140/(21) 168/(25) 182/(27)
Visit Window (days)
±7
±3 
±3
±3
±3
±3
±3
±3
±3
±3
PK Specific Visita
X
X
X
X
Pharmacogenetic stored 
samples
X
Nonpharmacogenetic 
stored samples
X
X
X
X
X
Immunogenicity testing
X
X
X
X
X
X
X
X
PK sample for 
Immunogenicityh
Xh
Xh
Xh
Pharmacokinetics (see 
PK schedule)a
Xa*
Xa
Xa
Xa
Xa*
Xa*
Xac
Xa*
Xa
Abbreviations:  AE = adverse event; APPADL = Ability to Perform Physical Activities of Daily Living; BG = blood glucose; BP = blood pressure; d = day; 
eGFR = estimated glomerular filtration rate; ECG = electrocardiogram; FGF-21 = fibroblast growth factor-21; FSH = follicle-stimulating hormone; GLP-1 = 
glucagon-like peptide-1; GIP = glucose-dependent insulinotropic peptide; HbA1c = hemoglobin A1c; IWRS = Interactive Web Response System; IW-SP = 
Impact of Weight on Self-Perception; LH = luteinizing hormone; PK = pharmacokinetics; PR = pulse rate; SMBG = self-monitoring of blood glucose; UACR 
= urine albumin-to-creatinine ratio.
*
Indicates PK samples to be collected predose.
a
See Pharmacokinetics Schedule of Events (Appendix 2)
b
ECGs should be collected centrally at Visits 3, 10, 11, 12, 16, and 801, and locally at screening and early termination.
c
ECG should be collected immediately prior to PK sample collection.
d
Screening laboratory tests include serum hepatitis B surface Ag, hepatitis C antibody (Ab), and human immunodeficiency virus Ab tests for all patients.
e
Serum pregnancy test will be performed by central laboratory at Visit 1 for women of childbearing potential.  For the remainder of the study, a urine 
pregnancy test may be performed at the investigator’s discretion if pregnancy is suspected during the study (local laboratory).
f
Collect serum estradiol, FSH, and LH in women whose menopausal status needs to be determined.
g
Two baseline collections during the lead-in period.
h
PK samples specifically for immunogenicity.


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LY3298176
Appendix 2.
Protocol GPGB Illustration of
PK Sampling Schedule


I8F-MC-GPGB Statistical Analysis Plan Version 3
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LY3298176
Study Phase
Screen Lead-
in
Randomize
Treatment Phase
Follow
-up
Early 
Term
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
801
Month of 
treatment
0
0
0
0
0
0
1
1
2
3
3
4
5
6
6
(7)
Week of treatment 
3
2
0
1
1
2
2
4
4
8
12
12
16
20
24
26
(30)
Study day/(Dose 
number)
±7d
0/(1)
7/(2)
14/(3)
28/(5)
56/(9)
84/(13)
98/(15) 140/(21) 168/(25) 182/(27)
PK-specific visit
X
X
X
X
PK blood draw 
X*
X
X
X
X*
X*
X
X*
X
[I] Predose PK samples will be collected at Visit 4 (Week 1), Visit 10 (Week 8), Visit 11 (Week 12), and Visit 16 (Week 26).  X* = Predose sample.
[II] Postdose PK samples will be collected per the assigned schedule after dosing at Visit 5 (Week 1), Visit 7 (Week 2), Visit 9 (Week 4), and Visit 12 
(Week 12), and at early termination from all patients.  An early termination PK sample may be taken at any time during the visit.
1. At Visit 5 (Week 1), 1 predose PK sample should be collected prior to administering study drug from all patients.  Later in the week (Visit 5), an additional 
PK sample should be taken within 1 to 48 hours (i.e., within 2 days of administrating study drug).  
2. At Visit 7 (Week 2), 1 PK sample should be collected after administration of the study drug within 1 to 48 hours (i.e., within 2 days of administrating study 
drug).
3. At Visit 9 (Week 4), 1 PK sample should be collected after administration of the study drug within 48 to 72 hours (i.e., 2 to 3 days after the administration of 
study drug) .
4. At Visit 12 (Week 12), 1 predose PK sample should be collected prior to administering the study drug from all patients.  Later in the week (Visit 12), an 
additional PK sample should be taken within 96 to 168 hours (i.e., any time between 4 days after study drug administration up to just prior to the next dose of 
study drug administration)


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Appendix 3.
Important Protocol Deviations


I8F-MC-GPGB Statistical Analysis Plan Version 3
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LY3298176
Important Protocol Deviation
Source of 
Information 
Function 
Accountable 
for 
Identifying 
Deviation
Programmable/ 
Nonprogrammable
Excluded 
Per 
Protocol 
Set
(Y/N/NA)
Immediate 
Notification 
(Y/N)
Category
Sub-category
Trial-specific Term
1
Investigational 
Product
Other
Not fit for use
Monitoring
Site Monitor
Non programmable
N
Y
2
Eligibility
Inclusion/Exclusion
Non-compliant to 
T2DM criteria.
Mixed (monitoring
and clinical 
database)
Site Monitor
Non programmable
N
Y
3
Eligibility
Inclusion/Exclusion
HbA1c not in 
compliance with the 
entry criteria
Programmable 
(CLUWE, clinical 
database) 
CLO
Programmable
Y
Y
4
Eligibility
Inclusion/Exclusion
Abnormal thyroid-
stimulating hormone 
(TSH) levels.  
Mixed (monitoring 
and clinical 
database)
Site Monitor
Non programmable 
N
Y
5
Eligibility
Inclusion/Exclusion
Not on stable dose of 
cholesterol lowering 
drugs
Monitoring
Site Monitor
Non programmable
N
Y
6
Eligibility
Inclusion/Exclusion
BMI out of range.  
Monitoring
Site Monitor
Non Programmable
Y
Y
7
Safety
Other
Failure to report 
product complaint 
within 24 hours
Monitoring
Site Monitor
Non programmable
N 
Y
8
Safety
Other
Positive urine and/or 
serum pregnancy test.  
Non 
programmable 
(monitoring)
Programmable 
(CLO)
Site Monitor
Non programmable
N
Y
9
Informed 
Consent
Informed Consent 
Not Obtained
NA
Mixed (monitoring 
and clinical 
database)
Site Monitor
Non programmable
Y 
Y
10
Study 
Procedures 
Violation of 
Discontinuation 
Criteria
NA
Mixed (monitoring 
and clinical 
database)
Site Monitor
Non Programmable
N
Y


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Important Protocol Deviation
Source of 
Information 
Function 
Accountable 
for 
Identifying 
Deviation
Programmable/ 
Nonprogrammable
Excluded 
Per 
Protocol 
Set
(Y/N/NA)
Immediate 
Notification 
(Y/N)
Category
Sub-category
Trial-specific Term
11
Study 
Procedures 
Excluded 
Conmeds 
Conmed 
antihyperglycemic 
besides metformin for 
more than 7 
cumulative days
Mixed (monitoring 
and clinical 
database)
Stats/Site 
Monitor
Programmable
Y
Y
12
Study 
Procedures 
Excluded 
Conmeds 
Receive weight loss 
medication for more 
than 7 days during 
treatment phase
Mixed (monitoring 
and clinical 
database) 
Stats/Site 
Monitor
Programmable
Y
Y 
13
Study 
Procedures 
Lab Criteria 
Missing HbA1c at 
baseline or  wk 26  
Mixed (monitoring 
and clinical 
database)
Stats/Site 
Monitor
Programmable
Y
Y
14
Study 
Procedures 
Lab Criteria 
Missing HbA1c at wk 
12   
Mixed (monitoring 
and clinical 
database)
Stats/Site 
Monitor
Programmable
N
Y
15
Study 
Procedures 
Other 
Missing safety data for 
all 3:BP, Pulse, ECG’s
Mixed (monitoring 
and clinical 
database)
Site Monitor
Non programmable
N
Y
16
Study 
Procedures 
Other 
Missing lab of lipase, 
amylase, LFTs or
FBG.
Programmable 
(CLUWE)
CLO
Programmable
N
Y
17
Study 
Procedures
Other
Missing body weight 
or waist 
circumference.
Mixed (monitoring 
and clinical 
database)
Site Monitor
Non programmable
N
N
18
Investigational 
product
Other
IP lost or stolen
Mixed (monitoring 
and clinical 
database)
Site Monitor
Non programmable
N
Y
19
Investigational 
product
Dosing Error
NA
Mixed (monitoring 
and clinical 
database)
Site Monitor
Non programmable
Y
Y
20
Eligibility
Inclusion/ 
Exclusion
Age out of range
InForm
Site Monitor
Programmable
N
Y
21
Investigational 
product
Compliance
Missing greater than
or equal to 4 doses 
Mixed (monitoring 
and clinical 
database)
Site Monitor
Programmable
Y
Y


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Important Protocol Deviation
Source of 
Information 
Function 
Accountable 
for 
Identifying 
Deviation
Programmable/ 
Nonprogrammable
Excluded 
Per 
Protocol 
Set
(Y/N/NA)
Immediate 
Notification 
(Y/N)
Category
Sub-category
Trial-specific Term
22
Investigational 
product
Compliance
Missing greater than 2 
consecutive doses
and total missing less 
than 4 .
Mixed (monitoring 
and clinical 
database)
Site Monitor
Programmable
N
Y
22
Study 
Procedures 
Violation of 
Discontinuation 
Criteria
Patient met criteria for 
permanent 
discontinuation of 
study drug & stayed 
on study drug
Mixed (monitoring 
and clinical 
database)
Site Monitor
Non Programmable
Y
Y


Leo Document ID = 4ee2464c-d838-4f61-9f3c-6dca7394250a
Approver: 
Approval Date & Time: 26-Mar-2018 19:25:45 GMT
Signature meaning: Approved
PPD