Clinical trial NCT03311724
Conditions: Type 2 Diabetes
Sponsor: Eli Lilly and Company
Start date: 2017-10-19; Completion date: 2018-04-24
Enrollment: 111 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Detailed description:

Arms: arm 1: Participants received Tirzepatide by subcutaneous (SC) injection in three dose escalations starting with 4 milligrams (mg) for four weeks followed by 8mg for four weeks followed by 12mg for four weeks. arm 2: Participants received Tirzepatide by SC injection in four dose escalations starting with 2.5mg for two weeks followed by 5mg for two weeks followed by 10mg for four weeks followed by 15mg for four weeks. arm 3: Participants received Tirzepatide by SC injection in three dose escalations starting with 2.5mg for four weeks followed by 7.5mg for four weeks followed by 15mg for four weeks. arm 4: Placebo administered by SC injection.
Interventions: intervention 1: Tirzepatide intervention 2: Placebo
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
I8F-MC-GPGF Clinical Protocol 
A Phase 2, Double-Blind, Placebo-Controlled, 3-Month Trial of LY3298176 versus Placebo in 
Patients with Type 2 Diabetes Mellitus. 
NCT03311724 
Approval Date: 02-Aug-2017 


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LY3298176
Protocol I8F-MC-GPGF
A Phase 2, Double-Blind, Placebo-Controlled, 3-Month Trial 
of LY3298176 versus Placebo 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-arm, placebo-controlled, Phase 2, multicenter 
study in patients with type 2 diabetes mellitus.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 02-Aug-2017 GMT


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Table of Contents
Section
Page
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..............................................................................................17
4.
Objectives and Endpoints..................................................................................................18
5.
Study Design.....................................................................................................................19
5.1.
Overall Design .............................................................................................................19
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 ........................................................................................................26
6.3.
Lifestyle Restrictions....................................................................................................30
6.4.
Screen Failures.............................................................................................................30
7.
Treatments........................................................................................................................31
7.1.
Treatments Administered .............................................................................................31
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......................................................................33
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
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


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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....................................................................................40
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..........................................43
9.2.1.2.
Adverse Events of Special Interest..................................................................44
9.2.1.2.1.
Nausea, Vomiting, and Diarrhea ...............................................................44
9.2.1.2.2.
Injection Site Reactions ............................................................................44
9.2.1.2.3.
Hypersensitivity Reactions........................................................................44
9.2.1.2.4.
Hypoglycemia...........................................................................................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 ..................................46
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 ...........................................................................................................48
9.4.3.
Laboratory Tests ..................................................................................................49
9.4.4.
Safety Monitoring ................................................................................................49
9.5.
Pharmacokinetics .........................................................................................................49
9.6.
Pharmacodynamics ......................................................................................................50
9.7.
Pharmacogenomics ......................................................................................................50
9.8.
Biomarkers...................................................................................................................50
9.9.
Health Economics ........................................................................................................50
9.10. Samples for Immunogenicity Research.........................................................................50
10.
Statistical Considerations ..................................................................................................52
10.1. Sample Size Determination ..........................................................................................52
10.2. Populations for Analyses..............................................................................................52


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10.3. Statistical Analyses ......................................................................................................52
10.3.1.
General Statistical Considerations ........................................................................52
10.3.2.
Treatment Group Comparability...........................................................................53
10.3.2.1.
Patient Disposition..........................................................................................53
10.3.2.2.
Patient Characteristics ....................................................................................53
10.3.2.3.
Concomitant Therapy .....................................................................................53
10.3.2.4.
Treatment Compliance....................................................................................53
10.3.3.
Efficacy Analyses ................................................................................................54
10.3.3.1.
Primary Analyses ...........................................................................................54
10.3.3.2.
Secondary Analyses........................................................................................54
10.3.3.2.1.
Analyses on Secondary Efficacy Endpoints...............................................54
10.3.3.3.
Exploratory Analyses .....................................................................................55
10.3.4.
Safety Analyses....................................................................................................55
10.3.4.1.
Clinical Evaluation of Safety..........................................................................55
10.3.4.2.
Adverse Events...............................................................................................56
10.3.4.3.
Vital Signs......................................................................................................56
10.3.4.4.
Laboratory Measures ......................................................................................56
10.3.4.5.
Evaluation of Immunogenicity........................................................................56
10.3.4.6.
Adverse Events of Special Interest..................................................................57
10.3.4.7.
Hypoglycemic Episodes .................................................................................57
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................57
10.3.6.
Other Analyses.....................................................................................................58
10.3.6.1.
Subgroup Analyses.........................................................................................58
10.3.6.2.
Interim Analyses.............................................................................................58
11.
References ........................................................................................................................59
12.
Appendices .......................................................................................................................61


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List of Tables
Table
Page
Table GPGF.1.
Schedule of Activities....................................................................................12
Table GPGF.2.
Objectives and Endpoints...............................................................................18
Table GPGF.3.
Study Treatments and Dose Titration.............................................................32
Table GPGF.4.
Dose–Response Assumption Used in Sample Size Determination..................52
Table GPGF.5.
Definitions of Populations to Be Analyzed in Study GPGF............................52


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List of Figures
Figure
Page
Figure GPGF.1. Illustration of study design for clinical protocol I8F-MC-GPGF.....................19


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List of Appendices
Appendix
Page
Abbreviations and Definitions........................................................................62
Appendix 1.
Clinical Laboratory Tests...............................................................................66
Appendix 2.
Study Governance Considerations..................................................................68
Appendix 3.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................72
Appendix 4.
Criteria for Diagnosing Type 2 Diabetes Mellitus (American Diabetes 
Appendix 5.
Association 2017)..........................................................................................73
Contraceptive Methods..................................................................................74
Appendix 6.
World Health Organization Standardized Protocols for the 
Appendix 7.
Measurement of Height and Weight...............................................................76


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1. Synopsis 
Title of Study:   
A Phase 2, Double-Blind, Placebo-Controlled, 3-Month Trial of LY3298176 versus Placebo in 
Patients with Type 2 Diabetes Mellitus 
Rationale:   
Study I8F-MC-GPGF is a 3-month Phase 2 study designed to examine the efficacy and 
tolerability of subcutaneously administered once-weekly (QW) LY3298176 compared with 
placebo in patients with type 2 diabetes mellitus (T2DM) who have inadequate glycemic control 
with diet and exercise alone or with a stable dose of metformin.  This study will use 3 different 
titration schemes of LY3298176 to reach the highest planned dose.  The primary endpoint will be 
the change from baseline in hemoglobin A1c (HbA1c) at the end of study drug treatment.  
Efficacy and tolerability data from this study and from the large Phase 2 study I8F-MC-GPGB 
(GPGB) will be used to set doses and titration scheme for the Phase 3 studies. 
Objectives/Endpoints:   
Objectives 
Endpoints 
Primary 
 To demonstrate that at least 1 LY3298176 titration 
scheme is superior to placebo in hemoglobin A1c 
(HbA1c) reduction at 3 months in patients with type 2 
diabetes mellitus (T2DM) inadequately controlled 
with diet and exercise alone or treated with a stable 
dose of metformin 
 
 Change in HbA1c from baseline 
Secondary 
Efficacy 
 To compare each titration scheme to placebo at 
3 months for secondary efficacy parameters 
 
 
 Proportion of patients achieving HbA1c target of 
<7.0%  
 The change in fasting blood glucose (FBG; central 
laboratory) from baseline  
 The change in body weight from baseline  
 The change in waist circumference from baseline 
Safety 
 To compare each titration scheme to placebo for 
selected safety parameters at 3 months 
 
 Treatment-emergent adverse events (TEAEs) and 
serious adverse events (SAEs) 
 Incidence of nausea, vomiting, and diarrhea 
 Discontinuation of study drug due to adverse events 
(AEs) 
 Incidence and rate of hypoglycemia (severe, total, 
documented symptomatic, and nocturnal) 
 Incidence of anti-LY3298176 antibodies 
Pharmacokinetics  
 To evaluate the pharmacokinetics (PK) of LY3298176 
 
 PK trough samples 
 
 


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LY3298176
Summary of Study Design:
LY3298176 is being investigated for its potential use in the treatment of T2DM.  LY3298176 is 
a long-acting, dual incretin receptor co-agonist that binds to both the glucose-dependent 
insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor.  
Study GPGF is a Phase 2, multicenter, randomized, double-blind, parallel-arm, placebo-
controlled titration study designed to evaluate efficacy, tolerability, and safety of LY3298176 in 
patients with T2DM with inadequate glycemic control on diet and exercise alone or on a stable 
dose of metformin monotherapy.  
Treatment Arms and Duration:
Study GBGF includes 4 treatment arms: 3 titration arms of LY3298176 and matching placebo.
Patients will be randomized in a 1:1:1:1 ratio to 1 of the 3 LY3298176 titration groups or 
placebo. Study participants will be treated for 3 months after randomization in a double-blind 
manner, followed by a 4-week safety evaluation. 
Number of Patients:
A total of approximately 92 patients (23 patients per titration group or placebo) will be 
randomized, and approximately 80 are expected to complete the treatment period.  
Statistical Analysis:
Efficacy:  The primary analysis for the endpoint of the primary objective, change from baseline 
in HbA1c at 3 months, will be mixed model for repeated measures (MMRM) analysis. It will be 
performed on the modified intent-to-treat (mITT) analysis data set.  This model will include
baseline body mass index (BMI; <30, 30), metformin use, treatment, visit, and treatment-by-
visit as fixed effects, and baselineHbA1c value as a covariate.  
Additional covariates may be added and will be detailed in the statistical analysis plan (SAP).
The mean weight change from baseline at 3 months will be analyzed using similar MMRM
models as the primary analysis with treatment, visit, treatment-by-visit, metformin use, baseline 
HbA1C category (<8.5%, ≥8.5%) as fixed effects, and baseline body weight as covariate.  The 
change from baseline of fasting blood glucose (FBG) and waist circumference will be analyzed 
using a similar MMRM-based model.  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).
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. 
Pharmacokinetics (PK)/Pharmacodynamics (PD):  Trough PK samples collected over the course 
of this study will be used to assess that LY3298176 exposures in the study are consistent with
known LY3298176 PK. Additionally, PK/PD data from this study may be used as a validation 
dataset to enable evaluation of PK/PD models developed from the core Phase 2 study GPGB


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LY3298176
data. These analyses may be conducted using nonlinear mixed-effects modeling implemented
with the NONMEM software. If positive antibody titers to LY3298176 are observed, the 
relationship between antibody titer and LY3298176 PK or any relevant PD parameters will be 
evaluated.


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2. Schedule of Activities


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LY3298176 
Table GPGF.1. 
Schedule of Activities 
Study Phase 
Screen Lead-In Randomize
Treatment 
Follow-Up
Early Term. 
Visit 
1 
2 
3 
4 
5 
6 
7Ta 
8 
9Ta 
10b 
801d  
ET 
Week of Treatment 
2 
1 
0 
1 
2 
4 
4 
8 
8 
12 
(15) 
 
Study Day/(dose number) 
 
 
0/(1) 
7/(2) 
14/(3) 
28/(5) 
31-34 
56/(9) 
59-62 
84 
105 
 
Visit Window (days) 
 
+7 
0 
0 
±2 
±3 
 
±3 
 
±3 
±3 
 
Administrative 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Diabetes medical history/therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 X 
 
 
 
 
 
 
 
 
 
Preexisting conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
IWRS 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
BG meter/supplies, if needed 
 
X 
 
 
 
 
 
 
 
 
 
 
BG meter, instructions 
 
X 
 
 
 
 
 
 
 
 
 
 
Diet, exercise, BG counseling 
 
X 
 
 
 
 
 
 
 
 
 
 
Study diary, dispense 
 
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 
Subcutaneous injection training 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
Study drug and injection supplies, 
dispense 
 
 
X 
X 
X 
X 
 
X 
 
 
 
 
Health habits (alcohol use, 
tobacco use current/past) 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient returns study drug vials 
 
 
 
  
  
X 
 
X 
 
X 
 
 
Study drug, assess compliance 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
 
Patient Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
Age 
X 
 
 
 
 
 
 
 
 
 
 
 
Gender 
X 
 
 
 
 
 
 
 
 
 
 
 
Race/ethnicity 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Phase 
Screen Lead-In Randomize
Treatment 
Follow-Up
Early Term. 
Visit 
1 
2 
3 
4 
5 
6 
7Ta 
8 
9Ta 
10b 
801d 
ET 
Week of Treatment 
2 
1 
0 
1 
2 
4 
4 
8 
8 
12 
(15) 
 
Study Day/(dose number) 
 
 
0/(1) 
7/(2) 
14/(3) 
28/(5) 
31-34 
56/(9) 
59-62 
84 
105 
 
Visit Window (days) 
 
+7 
0 
0 
±2 
±3 
 
±3 
 
±3 
±3 
 
Clinical Variables 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationc 
X 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Waist circumference 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Vital signs (BP and PR) 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Antidiabetic medication 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
ECGe 
Xe 
 
X 
 
 
X 
 
X 
 
X 
X 
Xe 
Evaluation of injection site 
reactions 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Collect AEs 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Diagnostics (Safety) 
 
 
 
 
 
 
 
 
 
 
 
 
Screening laboratory testsf 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testg 
X 
 
Xg 
 
 
 
 
 
 
 
 
 
FSHh 
X 
 
 
 
 
 
 
 
 
 
 
 
Chemistry panel 
X 
 
X 
 
 
 
 
 
 
X 
X 
X 
Lipid panel 
X 
 
X 
 
 
 
 
 
 
X 
X 
X 
Lipase and amylase 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
eGFR 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
X 
 
 
 
 
 
 
X 
X 
X 
Urinalysis 
X 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
 


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LY3298176 
Study Phase 
Screen Lead-In Randomize
Treatment 
Follow-Up
Early Term. 
Visit 
1 
2 
3 
4 
5 
6 
7Ta 
8 
9Ta 
10b 
801d 
ET 
Week of Treatment 
2 
1 
0 
1 
2 
4 
4 
8 
8 
12 
(15) 
 
Study Day/(dose number) 
 
 
0/(1) 
7/(2) 
14/(3)
28/(5)
31-34 
56/(9) 
59-62
84 
105 
 
Visit Window (days) 
 
+7 
0 
0 
±2 
±3 
 
±3 
 
±3 
±3 
 
Diagnostics (Efficacy) 
 
 
 
 
 
 
 
 
 
 
 
 
Calcitonin 
X 
 
 
 
 
 
 
 
 
X 
 
X 
HbA1c 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Fasting glucose 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Total and active GLP-1/GIP 
 
 
X 
 
 
X 
 
X 
 
X 
X 
 
7-point SMBG 
 
 
Xi 
 
 
 
 
 
 
Xj 
 
 
PKk 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
Immunogenicity 
 
 
X 
 
 
X 
 
X 
 
X 
Xl 
X 
Nonpharmacogenetic stored 
samples 
 
 
X 
 
 
 
 
 
 
X 
 
 
Abbreviations:  AE = adverse event; BG = blood glucose; BP = blood pressure; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; ET = 
Early Termination; FSH = follicle-stimulating hormone; GLP-1 = glucagon-like peptide-1; GIP = glucose-dependent insulinotropic peptide; HbA1c = 
hemoglobin A1c; IWRS = interactive web response system; LH = luteinizing hormone; PK = pharmacokinetics; PR = pulse rate; SMBG = self-monitoring of 
blood glucose; T = telephone visit; TE = treatment emergent; Term. = termination.   
a Telephone visits occur during the week following a dose escalation and should be done 3 to 6 days after a site visit for dose escalation and administration.  At 
telephone visits, the sites should call the patient, ask how the patient is, and ask whether the patient would like to come to the site for assistance with the next 
study drug dilution and administration.  Sites should also remind patients to write down any AEs in their diaries at the telephone visits (as well as at all site 
visits). 
b Visit should occur approximately 1 week after the last dose (Dose 12). 
c Additional physical examinations may be performed throughout the study if determined necessary due to patient symptoms. 
d Visit should occur 4 weeks after the last dose of study drug or 3 weeks after Visit 10. 
e ECGs should be collected prior to all blood draws and study drug administrations.  Local ECGs will be collected for screening (Visit 1) and Early 
Termination.  Centralized ECGs, collected in supine position and in triplicate, should be collected for all other designated visits. 
f Screening laboratory tests include serum hepatitis B surface Ag, hepatitis C antibody (Ab), and human immunodeficiency virus (HIV) Ab tests for all patients 
(see Appendix 2). 
g Serum pregnancy test will be performed by central laboratory at Visit 1 for women of child-bearing 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).  A urine pregnancy test (local) 
should be given to all women of child-bearing potential at Visit 3 prior to administration of first dose of study drug to confirm lack of pregnancy. 
h Collect serum FSH in women whose menopausal status needs to be determined. 


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LY3298176
i
The patients should collect the SMBG during the lead-in period between Visits 2 and 3 and return the results within their diaries at Visit 3.
j
The patients should collect the SMBG during the week after Dose 12 and return the results within their diaries at Visit 10.
k PK samples are to be collected pre-dose.
l
Patients who have clinically significant TE-ADA should 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 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.


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3. Introduction  
3.1. Study Rationale 
Study I8F-MC-GPGF (GPGF) is a 3-month Phase 2 study designed to examine the efficacy, 
safety, and tolerability of subcutaneously administered once-weekly (QW) LY3298176 
administered in 3 different titration schemes compared with placebo in patients with type 2 
diabetes mellitus (T2DM) who have inadequate glycemic control with diet and exercise alone or 
with a stable dose of metformin monotherapy.  The primary endpoint will be the change in 
hemoglobin A1c (HbA1c) at the end of study drug treatment.  These data will support selection 
of doses and a titration scheme to attain the highest dose for Phase 3 trials.   
3.2. Background 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
CCI


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LY3298176
 
 
 
 
 
 
 
 
 
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.
CCI


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LY3298176
4.
Objectives and Endpoints
Table GPGF.2 shows the objectives and endpoints of the study.
Table GPGF.2.
Objectives and Endpoints
Objectives
Endpoints
Primary
To demonstrate that at least 1 LY3298176 titration 
scheme is superior to placebo in HbA1c reduction at 
3 months in patients with T2DM inadequately 
controlled with diet and exercise alone or treated with 
a stable dose of metformin
Change in HbA1c from baseline
Secondary
Efficacy
To compare each titration scheme to placebo at 
3 months for secondary efficacy parameters
Proportion of patients achieving HbA1c target of 
<7.0% 
The change in FBG (central laboratory) from baseline 
The change in body weight from baseline 
The change in waist circumference from baseline
Safety
To compare each titration scheme to placebo for 
selected safety parameters at 3 months
TEAEs and SAEs
Incidence of nausea, vomiting, and diarrhea
Discontinuation of study drug due to AEs
Incidence and rate of hypoglycemia (severe, total, 
documented symptomatic, and nocturnal)
Incidence of anti-LY3298176 antibodies
Pharmacokinetics 
To evaluate the PK of LY3298176
PK trough samples
Exploratory
To compare each titration scheme to placebo at 
3 months for effect on SMBG profile.
SMBG values at baseline and end of treatment.
Abbreviations:  AE = adverse event; FBG = fasting blood glucose; HbA1c = hemoglobin A1c; PK = 
pharmacokinetics; SAE = serious adverse event; SMBG = self-monitoring of blood glucose; T2DM = type 2 
diabetes mellitus; TEAE = treatment-emergent adverse event.  


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5. Study Design
5.1.
Overall Design
Study GPGF is a randomized, multicenter, placebo-controlled, double-blind, parallel arm, Phase 
2 titration study in T2DM patients who have inadequate glycemic control with diet and exercise 
with or without a stable dose of metformin monotherapy. The study is designed to measure the 
change in HbA1c at the end of study treatment compared with placebo.  These data will support 
dose selection and the optimal titration scheme that minimizes GI-related AEs for Phase 3 trials.
The study will consist of 3 treatment periods: approximately 1-week lead-in period, followed by 
a 3-month treatment period, and a 4-week safety follow-up period (see Figure GPGF.1).  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 and placebo
treatment assignments within each titration group.
Placebo
Group 1
2.5mg
2.5mg
5mg
5mg
10mg
10mg
10mg
10mg
15mg
15mg
15mg
15mg
Group 2
2.5mg
2.5mg
2.5mg
2.5mg
7.5mg
7.5mg
7.5mg
7.5mg
15mg
15mg
15mg
15mg
Group 3
4mg
4mg
4mg
4mg
8mg
8mg
8mg
8mg
12mg
12mg
12mg
12mg
Dose Number:
1
2
3
4
5
6
7
8
9
10
11
12
12 Weeks Treatment
Screening
Lead in
Follow up
Early Termination
1 week
1 week
4 weeks
Visit        1        2                3                4 
5       
6   (7T)
8  (9T)
10a
801b
ET
T = Telephone Visit;   Visit 801 =  End of Study Visit;   ET = Early Termination Visit
a =  Visit 10 occurs 1 week after the last dose (Dose 12) of study drug.
b =   Visit 801 (follow up visit) occurs 4 weeks after Dose 12 or 3 weeks after Visit 10.
Figure GPGF.1.
Illustration of study design for clinical protocol I8F-MC-GPGF.


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Study Period I (Screening and Lead-In):
Screening (Visit 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.
The purpose of screening procedures at Visit 1 is to establish initial eligibility (see Section 6) and 
to obtain blood samples for laboratory assessments needed to confirm eligibility.  Patients who 
meet all applicable inclusion criteria and none of the applicable exclusion criteria at Visit 1 will 
continue on to Visit 2.
Lead-In (Visit 2 to Visit 3)
During the lead-in period, eligible patients should continue their prestudy therapy, metformin 
(same formulation and dose), in order to allow reliable assessment of HbA1c at baseline 
(Visit 3).  During the lead-in period, patients will be trained on disease monitoring and disease 
management procedures, glucometer use, study diaries, and study procedures.  Patients will 
receive training on routine blood glucose monitoring and paper diary completion required during 
the study.  Patients should follow the investigator’s instructions related to frequency of blood 
glucose testing but should test their glucose a minimum of 3 times per week.  Patients will also 
be required to conduct a 7-point self-monitoring glucose test (SMBG) prior to randomization 
(Visit 3) and return the results in their diary at Visit 3 (see Section 9.1.2.1). Patients will also
receive education on how to dilute study drug in the vials, perform SC injections, appropriate 
injection site locations, injection technique, and the signs and symptoms of local adverse 
reactions including injection site reactions.  Patients will receive instructions on timing of doses
(Table GPGF.3 and Section 7.1), and will be instructed to record the date and time of all 
injections administered throughout the study in their study diaries.  Study site staff will observe 
each patient diluting the study drug vials and self-injecting for training purposes at all site visits 
beginning with Visit 3.  
Visit-specific subject diaries will be dispensed at Visit 2 and at each visit thereafter, until the last 
study visit (see Schedule of Activities, (Section 2).  Patients should be instructed to record all 
AEs in their diaries.
Study Period II (Treatment Period):
Randomization (Visit 3)
At Visit 3, patients will undergo study procedures that are required prior to randomization.
Patients who continue to be eligible will then be randomized in a 1:1:1:1 ratio to 1 of the titration 
schemes (Group 1, Group 2, or Group 3) or placebo.  Placebo patients will be distributed within 
each titration group in order to maintain treatment blinding.  After randomization, the patient will 
dilute the study drug vial and inject the first dose of study drug while at the study site.  Although 
patients will be diluting study drug and injecting themselves at home between study site visits, 
they will be required to dilute the vials and inject themselves under the supervision of site 


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personnel at every scheduled site visit.  However, unscheduled visits to help patients with 
diluting study drug in the vials and self-injecting are permitted whenever the patient needs or 
wants additional support.
Following randomization, patients will participate in a 3-month treatment period that consists of 
dose titrations to reach and maintain the highest scheduled dose level of LY3298176. 
Treatment Phase (Visit 3 to Visit 10)
During the treatment phase, the dose of LY3298176 will be escalated within each titration group 
according to 1 of 3 dose titration schedules as outlined in Figure GPGF.1.  
At each dosing time point, the study drug will be self-administered as 1 to 3 SC injections of 
LY3298176 or matched placebo (number of injections will be determined by where the patient is 
in the dose titration scheme) (see Section 7.1).  
The last treatment visit, Visit 10, will occur approximately 1 week after the last dose of study 
drug for collection of efficacy and safety parameters.
In addition to the clinic visits, 2 telephone visits will be scheduled during this period and will 
occur 3 to 6 days after a site visit for dose escalation and will be scheduled to occur prior to the 
next dose administration.  At the telephone visit, the site is to check on the patient and ask if the 
patient needs to come to the site for an unscheduled visit for help with diluting and self-injecting
the study drug.  Patients are also to be reminded to write down any AEs in their study diaries.  At 
each of the scheduled site visits, procedures will include assessments of study drug compliance, 
hypoglycemic events, concomitant medications, and AEs.  
General Considerations
At each visit, patients should be reminded to write down any AEs in their study diaries, including 
any events associated with self-injecting study drug when at the study site visit. 
Patients will undergo or perform study procedures listed in the Schedule of Activities 
(Section 2).  
Patients taking a stable dose of metformin at study entry will continue to use concomitant 
metformin throughout the treatment period.  Discontinuation or changes to dose are generally not 
permitted, except in the situations of patient safety (for further details, see Section 7.1).
Patients will be instructed to perform fasting blood glucose (FBG) measurements and to record 
all results in diaries; these results will be used for glucose management only.  
Patients who develop severe, persistent hyperglycemia based on prespecified thresholds (see 
Section 9.2.1.2.4) will receive a new glucose-lowering intervention (or rescue therapy) based on 
clinical judgment of the investigator, and the patient will discontinue study drug.  Patients who 
need rescue therapy for this reason will be asked to remain in the trial until they complete all 
study visits for collection of safety information.  Patients who discontinue study drug due to AEs 
will also be asked to continue in the trial for collection of safety information.  Patients who are 
unable or unwilling to continue in the study because of an AE or any other reason will perform 


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an early termination (ET) visit as their final study visit.  If the patient is discontinuing during an 
unscheduled visit, that visit should be performed as the ET visit.  If the patient is discontinuing 
during a scheduled visit, that visit should be considered the ET visit.  At this visit, patients will 
perform procedures listed in the Schedule of Activities (Section 2).
Study Period III (Safety Follow-Up, Visit 801):
All randomized patients who complete the treatment period will complete the safety follow-up 
approximately 4 weeks after their last visit on treatment.  
Patients randomized to LY3298176 who have treatment-emergent anti-LY3298176 antibodies or 
antibodies to native GIP or GLP-1 at the last visit may be monitored after the last visit (see 
Section 9.9).
5.2.
Number of Participants
Approximately 150 participants will be screened to achieve 92 randomized and 80 evaluable 
participants for an estimated total of 20 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 visit shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
Study GPGF is a 3-month Phase 2 study designed to evaluate the efficacy, safety, and tolerability 
of 3 different titration schemes of LY3298176 compared with placebo in patients with T2DM
inadequately controlled with diet and exercise with or without stable metformin monotherapy.
The titration algorithms to be used in Study GPGF have been chosen based on tolerability data 
from the Phase 1 study GPGA, and the highest dose and dose titration scheme being evaluated in 
the Phase 2 study GPGB.  Study GPGF is designed to explore titration schemes different from 
those in Study GPGB.  In Study GPGB, the 15 mg dose is attained using a dose titration of 5 mg 
for the first 2 weeks, followed by 10 mg for 4 weeks, before reaching 15 mg at Week 7.  This 
approach for titrating a drug with GLP-1 RA activity is expected to allow patients to reach the 
15 mg dose with minimal GI-related AEs.  However, there may be other titration schemes that 
that are superior for minimizing the GI-related AEs that were observed in the Phase 1 study 
GPGA at the 15 mg dose.  It is possible that giving patients a very low first dose of 2.5 mg may 
improve tolerability of higher doses; thus, a 2.5 mg dose will be utilized in Study GPGF.  Study 
GPGF also contains 1 titration scheme with the highest LY3298176 dose level of 12 mg.  The 
12 mg dose was chosen in order to compare the tolerability and efficacy of 12 mg with 15 mg.  
The 12 mg dose may provide efficacy similar to that of the 15 mg dose but with superior 
tolerability, and this titration scheme provides additional data for dose and dose titration 
decisions for Phase 3.  Efficacy, safety, and tolerability data from both Study GPGB and Study 
GPGF will be used to set doses and the titration scheme for the Phase 3 development program.


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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 also be eligible if the second OAM was discontinued 3 months prior to 
Visit 1 (refer to Section 6.2, Exclusion Criterion 35).  Stable metformin treatment for at least 
3 months is required to minimize glucose variability prior to study entry.
5.5.
Justification for Dose
The highest dose to be evaluated in Study GPGF is 15 mg, which is the highest dose being 
evaluated in the Phase 2 study GPGB.  Depending on the safety, tolerability, and efficacy data in 
Study GPGB, the LY3298176 15 mg dose may be the high dose tested in the Phase 3 program.  
The 15 mg dose was considered safe in the Phase 1 study GPGA although not well tolerated.  
Based on experience with other GLP-1 RAs, higher doses may be attained through dose titration 
to minimize GI-related AEs. The 3 titration schemes to reach either LY3298176 12 mg or 15 mg 
were selected based on the following:

Phase 1 tolerability data in T2DM patients utilizing the dose titration scheme of QW 
LY3298176 doses of 5 mg for the first 2 weeks, 10 mg for the third week, and 15 mg the 
fourth week showed that this titration scheme to reach 15 mg was too rapid and resulted 
in more incidents of vomiting following the 15 mg dose than had been observed with 
other titration schemes with lower LY3298176 doses.  Thus, a more gradual titration may 
be needed to reach 15 mg.

The current titration scheme for Study GPGB is LY3298176 5 mg for the first 2 weeks, 
followed by 10 mg for 4 weeks before reaching the first 15 mg dose at Week 7, and 
continuing on 15 mg for the duration of the study.  This titration scheme is expected to be 
tolerated; however, other titration schemes may have improved tolerability or patient and 
physician convenience.  This will be explored in different titration schemes in Study 
GPGF.

It is possible that a slightly lower dose (>10 mg but <15 mg) would have improved 
tolerability with comparable efficacy compared with 15 mg.  Therefore, LY3298176 
12 mg was chosen as the high dose for 1 titration scheme.  


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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).
[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.  
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 6).
[3b] Female patients:
Women not of child-bearing potential may participate and include those 
who are:

infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, 
or tubal ligation), congenital anomaly such as mullerian agenesis; or

postmenopausal – defined as 
o
A woman at least 50 years of age with an intact uterus, not on hormone 
therapy, who has had either cessation of menses for at least 1 year; or
o
at least 6 months of spontaneous amenorrhea with a follicle-stimulating 
hormone (FSH) >40 mIU/mL; or
o
A woman 55 or older not on hormone therapy, who has had at least 
6 months of spontaneous amenorrhea; or
o
A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy.
Women of child-bearing potential (not surgically sterilized and between 
menarche and 1-year postmenopausal) may participate.  In order to 
participate, they must:


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
Women of child-bearing potential who are abstinent (if this is complete 
abstinence, as their preferred and usual lifestyle) or in a same sex 
relationship (as part of their preferred and usual lifestyle) must agree to 
either remain abstinent or stay in a same sex relationship without sexual 
relationships with males.

Otherwise, women of child-bearing potential participating must agree to use 
1 highly effective method (<1% failure rate) of contraception, or a 
combination of 2 effective methods of contraception for the entirety of the 
study:
o
Women of child-bearing potential must test negative for pregnancy prior 
to initiation of treatment as indicated by a negative serum pregnancy test 
at the screening visit and followed by a negative urine pregnancy test 
within 24 hours prior to exposure. (Any pregnancy testing subsequent to 
this initial test should be based on compound specific concerns and is 
not mandated by this guidance.)
o
Either 1 highly effective method of contraception (such as combination 
oral contraceptives, implanted contraceptives, or intrauterine device) or 
a combination of 2 effective methods of contraception (such as male or 
female condoms with spermicide, diaphragms with spermicide, or 
cervical sponges) will be used. The subject may choose to use a double 
barrier method of contraception. Barrier protection methods without 
concomitant use of a spermicide are not a reliable or acceptable method. 
Thus, each barrier method must include use of a spermicide. It should 
be noted that the use of male and female condoms as a double barrier 
method is not considered acceptable due to the high failure rate when 
these methods are combined.

Not be breastfeeding.
[4]
Have a body mass index (BMI) between 23 and 45 kg/m2 (inclusive) at 
screening.
Informed Consent
[5]
In the investigator’s opinion, are well motivated, capable, and willing to:

prepare (with assistance if necessary) study medication

self-inject (with assistance if necessary) up to 3 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

perform SMBG using the provided glucose meter.
[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.


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[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 or latent autoimmune diabetes in adults.
[10] Have uncontrolled diabetes defined as an episode of ketoacidosis or 
hyperosmolar state requiring hospitalization.
[11] Have had an 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 have 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 [>2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
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.


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[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) with abnormalities that may interfere with 
the interpretation of changes in ECG intervals at screening in the opinion of 
the investigator.  A QTc (Fridericia) interval >450 ms in men and >470 ms in 
women is specifically excluded.
[21] Known significant autonomic neuropathy as evidenced by urinary retention,
resting tachycardia, orthostatic hypotension, or diabetic diarrhea.
[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 (OTC) medications known to 
significantly prolong the QT or QTc interval at screening is prohibited.
[23] Have poorly controlled hypertension (ie, mean seated systolic blood pressure 
[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 fasting 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 <5 years
prior to screening.


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[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 active 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 
5% body weight in the 3 months prior to screening.
[33] Have had a blood donation of 450 mL 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, dipeptidyl peptidase-4 inhibitor 
[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 GLP-1 analogs or other related compounds within 
the prior 12 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 for intolerability or lack of efficacy should not 
be randomized.


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[38] Have been treated or plan to be treated with drugs that promote weight loss 
(eg, 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 OTC medications [eg, 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 (eg, 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.
[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.


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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 60 days 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
In this study, patients will receive treatment with 1 of 3 LY3298176 titration schemes for 
3 months to assess the reduction in HbA1c compared with placebo.  The titration doses of 
LY3298176 will range from 2.5 mg through 15 mg to reach either 12 mg or 15 mg as the highest 
titrated maintained dose.  Study drug will be supplied as lyophilized drug in a vial and each vial 
will contain 5 mg.  There will be matching placebo vials.  Patients will receive 1 to 3 injections 
of study drug per week depending on which dose the patient is scheduled to receive in the
titration schedule.  At the highest dose attained, 12 mg or 15 mg, patients will receive 
3 injections per week (to be taken at the same time).  Each SC dose administration of study drug 
should be in different quadrants of the abdomen. If the recommendation following the first 
interim analysis of Study GPGB is to lower the highest dose of 15 mg to 12.5 mg, then the 
highest dose administered for Groups 1 and 2 of this study, GPGF, will also be lowered to 
12.5 mg from 15 mg.  The high dose for Group 3, 12 mg, will be unchanged.  If this change 
occurs, it will be prior to the first patient visit for Study GPGF.  Furthermore, patient user 
materials will be modified to indicate that the highest titrated LY3298176 dose for Groups 1 and 
2 will be 12.5 mg.
This study will involve dose titration in 2.5 mg, 4 mg, 5 mg, or 7.5 mg dose increments 
(Table GPGF.3).  Although the investigators and patients will know which titration group the 
patients are assigned, they will not know whether they are receiving LY3298176 or a 
complementary volume of placebo.
Patients will be required to dilute study drug in the vials and administer injections of the study 
drug or matching placebo at approximately the same time each week. The study site will send 
vials, diluent (Sterile Water for Injection), and syringes with needles home with patients.  For all 
clinical site visits, the patient should dilute the vials and administer the study drug at the clinical 
research site under the supervision of study personnel in order to reinforce patient understanding 
and confidence.  Patients will be diluting study drug in the vials and self-injecting at home 
during weeks without a clinical site visit and instructions will be provided.  The investigator or 
site staff may assist patients with vial reconstitution and study drug injection any time they deem 
necessary.


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Table GPGF.3.
Study Treatments and Dose Titration
Study Phase
Random-
ization
Treatment Phase
Visit
3
4
5
N/S
6
N/S
N/S
N/S
8
N/S
N/S
N/S
Week
0
1
2
3
4
5
6
7
8
9
10
11
Dose number
1
2
3
4
5
6
7
8
9
10
11
12
Titration schemes  (dose in mg)
Group 1 
2.5
2.5
5
5
10
10
10
10
15
15
15
15
Group 2 
2.5
2.5
2.5
2.5
7.5
7.5
7.5
7.5
15
15
15
15
Group 3 
4
4
4
4
8
8
8
8
12
12
12
12
Abbreviation:  N/S= none scheduled.
Note:  For each of the groups, visits are scheduled to occur on the day of the next scheduled titrated dose.  For non-
scheduled visits, it is expected that the patient will dilute study drug and self-inject at home.  However, the 
investigator may have the patient come to the site for an unscheduled visit to dilute the vials and self-inject at any 
time the investigator feels that the patient would benefit from added instruction and supervision.  Visit 10 (not 
shown) will occur 1 week after the last dose of study drug (Dose 12).
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 (ie, 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 so that the situation can be assessed.
7.1.1. Packaging and Labeling
Clinical trial materials will be labeled according to the regulatory requirements.  LY3298176 and 
the matched placebos will be supplied by Lilly.  
 
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 Patients will 
inject the dose volume appropriate for their treatment group, including placebo patients within a 
group.  LY3298176 vials 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 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.  Sterile water vials may be stored at room temperature.
7.1.2. Medical Devices
The manufactured medical devices provided for patient use in the study are 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 placebo or 1 of 3 LY3298176 titration groups.  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 approximately an equal 
randomization to the treatment arms (1:1:1:1).  
The randomization algorithm will be performed using IWRS that will ensure balance between 
treatment arms.
7.2.1. Selection and Timing of Doses
Assignment to 1 of 3 LY3298176 titration groups or placebo will occur at randomization.  There 
are no restrictions on the time of day each QW dose is given, but it is advisable to administer SC 
injections on the same day and same time each week. Patients should be instructed to record the 
actual date and time of all dose administrations in the diary provided.  The actual date and time 
of all dose administrations will be recorded in the subject’s case report form (CRF). If a dose of 
study drug, including placebo, is missed, the patient should take it as soon as possible and 
contact the study site for further instructions on timing of the next scheduled dose.
7.2.2.
Specific Restrictions/Requirements
Prior to beginning the study, patients will complete informed consent and baseline tests.
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Throughout the study, patients may undergo medical assessments and compliance reviewed 
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.  
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 child-bearing potential, if sexually active, should use 2 forms of effective 
contraception, where at least 1 form is highly effective for the duration of the trial and for
30 days thereafter. Please see Appendix 6 for further details regarding contraception.
7.3.
Blinding
This is a double-blind study.  Although the patient and the investigator will know which dose 
titration group (Group 1, Group 2, or Group 3) the patient is assigned to, they will not know 
whether the patient is receiving LY3298176 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.
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


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remain in the study, the investigator must obtain specific approval from a Lilly clinical research 
physician (CRP)/clinical research scientist (CRS) for the patient to continue in the study.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event.  Patient 
safety must always be the first consideration in making such a determination.  If a patient’s 
treatment assignment is unblinded, Lilly must be notified immediately.  If the investigator 
decides that unblinding is warranted, it is the responsibility of the investigator to promptly 
document the decision and rationale and notify Lilly as soon as possible.  
Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dosage Modification
Generally, no adjustment in study drug doses (LY3298176 or placebo) will be allowed.
However, if a patient is unable to tolerate a titrated dose for 2 weeks due to vomiting or moderate 
to severe nausea, the site should call the study CRS/CRP to discuss whether the patient should 
have the dose lowered to the previous dose level.  Dosing of required concomitant metformin is 
discussed in Section 7.7.
The highest dose of Groups 1 and 2, LY3298176 15 mg, may be reduced to 12.5 mg prior to first 
patient visit of this study, GPGF, if the first interim analysis of the large Phase 2 study GPGB 
indicates that the 15 mg dose is not well tolerated.  In that case, sites will be informed at the 
start-up meeting and in training materials.  Patients will be provided dosing instructions for the 
12.5 mg dose rather than the 15 mg dose.
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 placebo and 
Sterile Water for Injection (along with syringes), at clinic visits according to the Schedule of 
Activities (Section 2). 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 study drug vials 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 misses 2 doses of 
study medication.  Similarly, a patient will be considered significantly noncompliant if he/she is 


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judged by the investigator to have intentionally or repeatedly taken more or less than the 
prescribed amount of medication.
7.7.
Concomitant Therapy
Treatment with drugs that are excluded in the entry criteria (Section 6.2) 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 
>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 (eg, hypertensive 
crisis).
Doses of other prescription medications (eg, 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 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 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:


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
Chronic use of drugs that directly reduce GI motility including but not limited to 
anticholinergics, antiemetics, and opiates (eg, metoclopramide, phenergan, dicyclomine, 
and morphine)

Chronic use of medications that directly promote motility (eg, bethanechol and cisapride)

Prescription or OTC medications to promote weight loss

Systemic glucocorticoid therapy of >14 consecutive days’ duration (with the exception of 
topical, intranasal, intraocular, intra-articular, and inhaled preparations)

Central nervous system stimulants (eg, 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 12-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 
>270 mg/dL (15.0 mmol/L) occurs over at least a 2-week period (at least 
3 values/week must be available).
OR
o
Any time after the first 6 weeks post-randomization:  An average fasting glucose 
level >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 due to a hepatic event or liver test abnormality.  Patients who are 
discontinued from investigational product due to a hepatic event or liver test abnormality 
should have additional hepatic safety data collected via case report form (eCRF).
Discontinuation of the investigational product for abnormal liver tests should be
considered by the investigator when a patient meets one of the following conditions after 
consultation with the Lilly designated medical monitor:  
o
Abnormal liver tests or when a patient meets one of the following conditions:

ALT or aspartate aminotransferase (AST) >8ULN

ALT or AST >5ULN for >2 weeks

ALT or AST >3ULN and total bilirubin level >2ULN or prothrombin 
time >1.5ULN

ALT or AST >3ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)

Alkaline phosphatase (ALP) >3ULN

ALP >2.5ULN and total bilirubin >2x ULN

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 >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
eGFR <30 mL/min/1.73 m2
o
Any severe injection site reaction or ≥2 moderate injection site reactions 
occurring a week or more apart
o
Any study drug-related hypersensitivity reaction
o
Any nonfatal major CV events (refer to Section 9.2.1.2.6 for details)
o
Any other treatment-emergent adverse event (TEAE), serious adverse event 
(SAE), or clinically significant laboratory value for which the investigator 
believes that permanent study drug discontinuation is the appropriate measure to 
be taken.


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
If the patient, for any reason (including protocol-mandated institution of rescue therapy; 
see Section 7.8.1), requires treatment for >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.

If the patient misses 2 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.
Patients discontinuing from the investigational product prematurely for any reason should 
complete adverse event and other follow-up procedures per Section 2 (Schedule of Activities), 
Section 9.2 (Adverse Events), and Section 9.4 (Safety) of this protocol.
8.1.2. Temporary Discontinuation from Study Treatment
After randomization, the investigator may temporarily discontinue study drug, for example, due 
to an AE (eg, nausea and vomiting), or a clinically significant laboratory value.  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 ≥2 doses of study 
medication (consecutive or not) are missed for any reason, then the patient should be 
permanently discontinued from study medication.
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
If the sponsor or investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the patient to continue on 
study treatment.  If the investigator and the sponsor CRP/CRS agree it is medically appropriate 
to continue, the investigator must obtain documented approval from the sponsor CRP/CRS to 
allow the inadvertently enrolled patient to continue in the study with or without treatment with 
investigational product. Safety follow up is as outlined in Section 2 (Schedule of Activities), 
Section 9.2 (Adverse Events), and Section 9.4 (Safety) of the protocol.


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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).

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 discontinuing from the study prematurely for any reason should complete adverse event 
and other safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), 
and Section 9.4 (Safety) of this protocol.
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  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 clinical 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.

HbA1c target of <7.0% 

Body weight: Patients will be weighed on an electronic (digital) 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 7).  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.

FBG 

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 a hospital gown. 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 blood glucose measurements should be obtained 
before each meal, approximately 2 hours after each meal, and at bedtime on a day during the 
week before the relevant 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.  If a patient does not complete the entire profile on a single day, all 7 points must be 
collected on a subsequent day.


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9.1.3. Appropriateness of Assessments
All 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 eCRF the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs. Investigators should record their assessment of the 
potential relatedness of each AE to protocol procedure or investigational product via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a cause-and-effect relationship between the 
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.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF, clarifying if possible the circumstances leading 
to any dosage modifications or discontinuations of treatment.


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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 (ie, 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 be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes 
listed in the definition above.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.

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.
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  The SAE reporting to the sponsor begins after the patient has signed the ICF and has 
received investigational product.  However, if an SAE occurs after signing the ICF, but prior to 
receiving investigational product, the SAE should be reported to the sponsor as per SAE 
reporting requirements and timelines (see Section 9.2) if it is considered reasonably possibly 
related to study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed 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 eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  


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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 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. 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.
9.2.1.2.2. Injection Site Reactions
All injection site reactions, including reports of pain and burning, 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 eCRFs.  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 unless they meet SAE criteria.
9.2.1.2.3. 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.


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9.2.1.2.4. 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 
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]).
9.2.1.2.5. 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,
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.


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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 
during the study, including follow up, 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 15), 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.
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


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and Visit 10 (end of treatment) 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 screening values AND 
an absolute value 20 pg/mL and <35 pg/mL at Visit 10 (end of treatment) or at ET 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.
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, there is no specific 
antidote.  The patient should be watched for GI symptoms and hypoglycemia.  Treatment is 
supportive, depending on the patient’s symptoms.
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.
Electrocardiograms should be recorded in triplicate 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 


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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 (eg, 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 (eg, demographics and study details) and then store the 
ECGs in a database.  At a future time, the stored ECG data may be overread by a cardiologist at 
the central ECG laboratory for further evaluation of machine-read measurements or to meet 
regulatory requirements.
The machine-read ECG intervals and heart rate may be used for data analysis and report-writing 
purposes, unless a cardiologist overreading of the ECGs is conducted prior to completion of the 
final study report (in which case, the overread data would be used).
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.
9.4.2. Vital Signs
Sitting BP and PR will be measured using standardized equipment provided by the sponsor.
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 


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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 the 
Schedule of Activities (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).
9.5.
Pharmacokinetics
Blood samples for PK analyses will be collected from all randomized patients in accordance with 
the Schedule of Activities (Section 2) and at ET.  However, only samples from patients assigned 
to treatment with LY3298176 will be analyzed for drug concentration.
Date and time of each sample and the most recent LY3298176 dose prior to PK blood draw must 
be recorded.  Scheduled PK samples must be collected prior to dose administration at scheduled 
visits.
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.


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9.6.
Pharmacodynamics
Samples to evaluate the PD properties of LY3298176 are included in the secondary efficacy 
measures and not applicable here.
9.7.
Pharmacogenomics
Not applicable.
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) 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.
9.9.
Health Economics
Not applicable.
9.10. Samples for Immunogenicity Research
Samples from all patients will be tested for antidrug antibodies (ADA) against LY3298176.  A 
blood sample will be collected at specific study visits according to the Schedule of Activities
(Section 2).  All samples for immunogenicity should be taken predose when applicable.  To 
interpret the results of immunogenicity, a PK sample should be collected at the same time point 
as an the immunogenicity sample.  In the event of drug hypersensitivity reactions (immediate or 
nonimmediate), additional samples will be collected as close to the onset of the event as possible, 
at the resolution of the event, and 30 days following the event.  Instructions for the collection and 
handling of blood samples will be provided by the sponsor.  The actual date and 24-hour clock 
time of each sampling will be recorded.


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Immunogenicity will be assessed using a validated ligand-binding assay designed to detect and 
titer ADA in the presence of LY3298176 at a laboratory approved by the sponsor. Confirmed 
positive samples for LY3298176 ADA will be titrated and then evaluated for cross-reactive 
binding to native GIP and GLP-1 using a validated ligand-binding assay. They may also be 
tested for their ability to neutralize the activity of assigned treatment (LY3298176-neutralizing 
antibodies) in separate cell-based neutralizing assays over-expressing the GIP and GLP-1 
receptors.  Antidrug antibody samples that test positive for neutralizing activity against 
LY3298176 and/or for cross-reactive binding to native GIP and GLP-1 may then be further
tested for neutralizing activity against native GLP-1 and GIP using cell-based neutralizing 
assays.  
All patients will have an ADA sample measured at ET or 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 have clinically significant treatment-emergent antidrug antibodies (TE-
ADA) at the last visit.  Treatment-emergent ADA are defined as those with a titer 2‑fold 
(1 dilution) greater than the minimum required dilution if no ADA were detected at baseline or 
those with a 4-fold (2 dilutions) increase in titer compared to baseline if ADA were detected at 
baseline. Clinically significant TE-ADA will be defined as any TE-ADA at the follow-up visit 
(Visit 801) with:

A high titer (1280) or an increasing titer from last measured value

An association of TE-ADA with a moderate to severe injection site reaction or 
infusion-related reaction

Cross-reactive and/or neutralizing binding of an ADA with endogenous GLP-1 or GIP.
Patients who have clinically significant TE-ADA should 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).  A PK sample may be collected at the follow-up 
immunogenicity assessment(s) if warranted and agreed upon between both the investigator and 
sponsor.
Every attempt should be made to contact patients for the follow-up immunogenicity assessment; 
however, if patients are unwilling or unable to return for the visit, this is not considered a 
protocol violation.
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.  Any samples remaining after 15 years will be destroyed.


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10.
Statistical Considerations
10.1. Sample Size Determination
Approximately 92 patients will be randomized to placebo or 1 of 3 LY3298176 titrations arms 
assuming a 13% dropout rate resulting in approximately 20 completers per arm.
Assuming a standard deviation of 1.1, 20 patients per arm will provide at least 90% power to 
detect a statistically significant difference between LY treatments to placebo with a dose 
response assumption as shown in Table GPGF.4.
Table GPGF.4.
Dose–Response Assumption Used in Sample Size Determination
Placebo
LY 12 mg
LY 15 mg-1
LY 15 mg-2
CFBL HbA1c (%)
-0.2%
1.4%
1.5%
1.5%
Abbreviations: CFBL = change from baseline; LY = LY3298176.
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined in Table GPGF.5.
Table GPGF.5.
Definitions of Populations to Be Analyzed in Study GPGF
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 postbaseline 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.
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
(CSR).  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 postbaseline 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 


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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 2 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.
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.
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 


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missing 2 doses of the assigned treatment at any point in the study.  Patients who miss 2 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 outcome is the difference in HbA1c change from baseline between treatment groups 
based on the mITT population at the planned end of the treatment period of 3 months.  The 
primary analysis model will be a mixed model for repeated measures (MMRM) for HbA1c 
change from baseline to 3 months in the mITT population with treatment, visit, treatment-by-
visit,  baseline BMI category, and metformin use (yes, no) as fixed effects, and baseline HbA1c 
as a covariate. The dependent variable will be the postbaseline change from baseline values.  An 
unstructured covariance structure will be used to model the within-patient errors. If this model 
fails to converge, the following covariance structures will be tested in order:

toeplitz with heterogeneity

autoregressive with heterogeneity, by visit

compound symmetry with heterogeneous variances by visit 

toeplitz

autoregressive

compound symmetry without heterogeneous variances, by visit

compound symmetry.
The first covariance structure that converges will be used.
The treatment p-value will be used as evidence of difference between active drug and placebo, 
while the comparison of least-squares (LS) means versus placebo (unadjusted for multiple 
comparisons) will provide magnitude and significance of this difference. The primary analysis 
model, MMRM, will be repeated using the PP population.  If the conclusion differs from that of 
the mITT population, the data and analyses will be further investigated.  
Descriptive statistics by treatment for HbA1c and HbA1c change from baseline at the 12-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. Secondary Analyses
10.3.3.2.1.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 3 months

Percentage of patients reaching the HbA1c target of 7.0%

Change from baseline of FBG at 3 months


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
Change from baseline of waist circumference at 3 months.
The secondary continuous efficacy measures (change from baseline in body weight, waist 
circumference, and FBG) will also be analyzed using the MMRM models described above (with 
censoring data collected after initiation of rescue intervention).  The MMRM model will include 
the model terms given for the previously described primary analysis model except the baseline of 
the corresponding variable replacing the baseline of HbA1c, and with the addition of the HbA1c 
strata (<8.5% or ≥8.5%). Baseline BMI category will be dropped from the analysis models for 
body weight change from baseline.
The percentage of patients reaching the HbA1c target of 7.0% at 3 months will be analyzed 
using a logistic regression analysis with fixed effects of treatment and stratification factors, and 
baseline as a covariate.
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.
10.3.3.3. Exploratory Analyses
The change from baseline of 7-point SMBG profiles will be analyzed using analysis of 
covariance model (ANCOVA) with treatment, baseline strata (metformin category, BMI 
category, and HbA1C category) as fixed effects, and the corresponding baseline as covariate.  
10.3.4. Safety Analyses
10.3.4.1. Clinical Evaluation of Safety
The safety population will be used for safety analyses.  
Safety measures will include vital signs, body weight, TEAEs (including SAEs and AESIs), and 
laboratory measures (including anti-LY3298176 antibodies).  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, percent of patients requiring rescue therapy will be summarized.
Additional analysis, such as concentration–safety lab plots, may be performed if warranted upon 
review of the data.


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10.3.4.2. Adverse Events
Adverse events will be listed by patient, actual term, preferred term, severity, and relationship to 
the treatment.  Adverse events 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 thyroid and adjudicated CV and pancreatic-related AEs will be listed by patient, and if 
there are a sufficient number of cases, they may be summarized by treatment group.
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.
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 primary analysis.
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 (last observation carried forward [LOCF]); the 
maximum/minimum postbaseline 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 (including titers) to LY3298176 will be determined.  If a
cross-reactivity or neutralization assay is performed, the frequency of antibodies will be 


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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 (eg, 
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. 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.
Summaries and analyses for incidence, time to onset, duration, and severity of GI events (nausea, 
vomiting, and diarrhea) will be provided for each treatment group during the 12-week treatment 
period and by visit. The planned reports will be detailed in the statistical analysis plan.
Additional analyses will be performed if necessary.
10.3.4.7. Hypoglycemic Episodes
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.
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.  
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 trough PK samples collected over the course of this study will be used to assess that 
exposures in the study are consistent with known LY3298176 PK. 


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Additionally, PK/PD data from this study may be used as a validation dataset to enable 
evaluation of PK/PD models built based on data from the core Phase 2 study GPGB.  These 
analyses may be conducted using nonlinear mixed-effects modeling implemented with the 
NONMEM software.
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. 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.
10.3.6.2. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly medical director, or designee, will be consulted to determine 
whether it is necessary to amend the protocol.


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11.
References
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, Fahrbach JL. 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.
Herbst R, Bolton W, Shariff A, Green JB. Cardiovascular Outcome Trial Update in Diabetes: 
New Evidence, Remaining Questions. Current Diabetes Reports. 2017; 17:67.
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; 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. JPN guidelines for the management 
of acute pancreatitis: diagnostic criteria for acute pancreatitis. J Hepatobiliary Pancreat Surg. 
2006;13(1):25–32.
Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, Zdravkovic M, During M, 
Matthews DR; 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.


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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.


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12.
Appendices


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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
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.
BG
blood glucose
BMI
body mass index
BP
blood pressure
CFBL
change from baseline
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, CRS, global safety 
physician, or other medical officer.
CRS
clinical research scientist


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CT
computed tomography
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
ET
early termination
ET
early termination
FBG
fasting blood glucose
FSH
follicle-stimulating hormone
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
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation


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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 (ie, 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
LH
luteinizing hormone
LOCF
last observation carried forward
LS
least squares
MI
myocardial infarction
mITT
modified intent-to-treat
MMRM
mixed model for repeated measures
OAM
oral antihyperglycemic medication
OTC
over-the-counter
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.
PR
pulse rate
QTc
corrected QT interval
QW
once weekly
SAE
serious adverse event
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.


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SD
standard deviation
SMBG
self-monitoring of blood glucose
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)


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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
Serum FSHd
Lipid Panel (Fasting)
Total Cholesterol
Triglycerides
Serologye
HDL-C
Hepatitis B Surface Ag
LDL-C (calculated)
Hepatitis C Ab
HIV Ab
Immunogenicity:
Anti-LY3298176 antibodies
GIP and GLP-1 (total and active)
Anti-LY3298176 antibody neutralization assay
Optional urine drug screen (local, at the 
discretion of the investigator)
Nonpharmacogenetic Stored Samples
EDTA plasma
Serum
Abbreviations:  Ab = antidrug antibody; Ag = antigen; ALP = alkaline phosphatase; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; EDTA = 
ethylenediaminetetraacetic acid; eGFR = estimated glomerular filtration rate; FSH = follicle-stimulating 
hormone; GIP = glucose-dependent insulinotropic peptide; GLP-1 = glucagon-like peptide-1; HIV = human 
immunodeficiency virus; LH = luteinizing hormone; 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.


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b eGFR 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 child-bearing 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.  Of note, women of child-bearing potential must have a local (urine) pregnancy 
test prior to the first dose of study drug (Visit 3) to confirm lack of pregnancy.
d Performed at screening by central laboratory to establish menopausal status. Women who meet the criteria for 
postmenopausal status in Section 6.1 by age and/or cessation of menses do not need to have postmenopausal 
status confirmed with hormone tests. 
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 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 (eg, 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 Lilly or its designee.
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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Criteria for Diagnosing Type 2 Diabetes 
Appendix 5.
Mellitus (American Diabetes Association 2017)
Criteria for Diabetes Diagnosis:  4 Options

Fasting blood glucose (FBG) ≥126 mg/dL (7.0 mmol/L)
Fasting is defined as no caloric intake for at least 8 hours.*

2-hr plasma glucose (PG) ≥200 mg/dL (11.1 mmol/L) during oral glucose tolerance test 
(OGTT)
The test should be performed as described by the World Health Organization (WHO), 
using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in 
water.*

A1c ≥6.5% (48 mmol/mol)
The test should be performed in a laboratory using a method that is National 
Glycohemoglobin Standardization Program (NGSP)-certified and standardized to the 
Diabetes Control and Complications Trial (DCCT) assay.*

In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random 
PG ≥200 mg/dL (11.1 mmol/L).
* In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing.
Reference:
American Diabetes Association. Classification and diagnosis of diabetes. Diabetes Care.
2017;40(Suppl. 1):S11–S24.


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Contraceptive Methods
Appendix 6.
Men
Male patients with female partners of child-bearing potential will be required to use a condom in 
conjunction with a spermicidal gel, foam, cream, or suppository.  In addition, the female partner, 
will be requested to use an additional effective form of contraception, which can be any of the 
following:

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 (Section 6.1) provides a specific definition of women not of child-bearing potential; 
these subjects will not be required to use contraception.  Male patients with a female partner 
meeting the definition of a woman not of child-bearing potential will not be required to use 
contraception.
Women of Child Bearing Potential
Women of child-bearing potential will be required to use contraception, which can be any of the 
following:

Abstinence: If this is complete abstinence, as their preferred and usual lifestyle or in a same 
sex relationship (as part of their preferred and usual lifestyle) must agree to either remain 
abstinent or stay in a same sex relationship without sexual relationships with males.

Birth Control:  Use of 1 highly effective method (<1% failure rate) of contraception, or a 
combination of 2 effective methods of contraception for the entirety of the study:
o
Either 1 highly effective method of contraception (such as combination oral 
contraceptives, implanted contraceptives, or intrauterine device) 
o
A combination of 2 effective methods of contraception (such as male or female condoms 
with spermicide, diaphragms with spermicide, or cervical sponges) will be used. The 
subject may choose to use a double barrier method of contraception. Barrier protection 
methods without concomitant use of a spermicide are not a reliable or acceptable method. 
Thus, each barrier method must include use of a spermicide. 


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It should be noted that the use of male and female condoms as a double barrier method is not
considered acceptable due to the high failure rate when these methods are combined.


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World Health Organization Standardized 
Appendix 7.
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 2017).
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 
(digital). All weights for a given patient should be measured using the same scale, whenever 
possible, after the patient has emptied their bladder. Patients should wear a light hospital gown 
while their weight is measured.
Step 1. Ask the patient to remove their outer clothing and footwear (underwear may remain on), 
and change into a light hospital gown.
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).
Reference:
[WHO] World Health Organization. STEPwise approach to Surveillance (STEPS). Updated 
2017.Available at: http://www.who.int/chp/steps/Part3_Section3.pdf. Accessed 31 July 2017.


Leo Document ID = 784a9ec8-125f-47cb-8aea-83d160dd2ea3
Approver: 
Approval Date & Time: 01-Aug-2017 18:36:27 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 02-Aug-2017 18:23:57 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
 
I8F-MC-GPGF Statistical Analysis Plan Version 2 
 
 
A Phase 2 Study of Once-Weekly LY3298176 Compared with Placebo in Patients with Type 2 
Diabetes. 
 
NCT03311724 
 
Approval Date: 01-May-2018 
 
 


I8F-MC-GPGF Statistical Analysis Plan Version 2
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1.
Statistical Analysis Plan: 
I8F-MC-GPGF:  A Phase 2 Study of Once-Weekly 
LY3298176 Compared with Placebo 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-GPGF
Phase 2
Statistical Analysis Plan Version 1 was approved on 02-Jan-2018 GMT
Statistical Analysis Plan Version 2 is electronically signed and approved by Lilly
on date provided below.
Approval Date: 01-May-2018 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:  I8F-MC-GPGF:  A Phase 2 Study of Once-
Weekly LY3298176 Compared with Placebo in Patients with Type 2 
Diabetes..............................................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................7
4.
Study Objectives.................................................................................................................8
4.1.
Primary Objectives.........................................................................................................8
4.2.
Secondary Objectives.....................................................................................................8
4.3.
Exploratory Objectives...................................................................................................8
5.
Study Design.......................................................................................................................9
5.1.
Study Design and Treatment ..........................................................................................9
5.2.
Treatment Assignment ...................................................................................................9
5.3.
Determination of Sample Size ......................................................................................10
6.
A Priori Statistical Methods ..............................................................................................11
6.1.
General Considerations ................................................................................................11
6.1.1.
Analysis of Repeated Measures............................................................................11
6.1.2.
Analysis of Covariance Model for Change from Baseline 
Endpoints.............................................................................................................12
6.2.
Patient Disposition .......................................................................................................12
6.3.
Analysis Populations and Datasets ...............................................................................13
6.4.
Patient Characteristics and Medical History .................................................................13
6.5.
Treatment Compliance .................................................................................................14
6.6.
Exposure of Study Treatment .......................................................................................14
6.7.
Concomitant Drugs ......................................................................................................14
6.8.
Protocol Deviations......................................................................................................15
6.9.
Efficacy Analyses ........................................................................................................15
6.9.1.
Primary Outcome and Methodology.....................................................................15
6.9.1.1.
Supporting Analyses of Primary Outcome ......................................................16
6.9.2.
Efficacy - Secondary Outcomes ...........................................................................16
6.9.2.1.
Continuous Variable Analyses........................................................................16
6.9.2.2.
Analyses on Variables with Percent of Patients Reaching 
a Target ..........................................................................................................17
6.9.2.3.
Exploratory Analyses .....................................................................................17
6.10. Safety Analyses............................................................................................................17
6.10.1.
Vital Signs ...........................................................................................................18


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6.10.2.
High-Density Lipoprotein Cholesterol, Total Cholesterol, 
Triglycerides, and Low-Density Lipoprotein Cholesterol .....................................18
6.10.3.
Adverse Events ....................................................................................................18
6.10.3.1.
All Treatment-Emergent Adverse Events........................................................19
6.10.3.2.
Related Adverse Events..................................................................................19
6.10.3.3.
Serious Adverse Events ..................................................................................19
6.10.3.4.
Adverse Events Leading to Discontinuation....................................................20
6.10.3.5.
Most Common Adverse Events.......................................................................20
6.10.3.6.
Deaths ............................................................................................................20
6.10.4.
Adverse Events of Special Interest .......................................................................20
6.10.4.1.
Hypersensitivity Reactions .............................................................................21
6.10.4.2.
Injection Site Reactions ..................................................................................21
6.10.4.3.
Nausea, Vomiting, and Diarrhea .....................................................................21
6.10.4.4.
Hypoglycemic Episodes and Total Hypoglycemia ..........................................22
6.10.4.5.
Pancreatitis.....................................................................................................23
6.10.4.6.
C-cell Hyperplasia and C-cell Neoplasms .......................................................23
6.10.5.
Laboratory Measurements....................................................................................24
6.10.6.
Electrocardiograms ..............................................................................................24
6.11. Exploratory Analyses ...................................................................................................25
6.11.1.
7-Point SMBG .....................................................................................................25
6.11.2.
Evaluation of Immunogenicity .............................................................................26
6.11.2.1.
Definitions of Sample Anti-drug Antibody Status...........................................26
6.11.2.2.
Definitions of Immunogenicity Assessment Periods .......................................27
6.11.2.3.
Definitions of Patient ADA Status ..................................................................27
6.11.2.4.
Analyses to be Performed ...............................................................................28
6.12. Pharmacokinetic and Pharmacodynamic Analyses........................................................29
6.13. Subgroup Analyses.......................................................................................................29
6.14. Interim Analyses ..........................................................................................................29
6.15. Clinical Trial Registry Analyses...................................................................................29
7.
Unblinding Plan................................................................................................................31
7.1.
Operational Procedures ................................................................................................31
7.2.
Site-Level Unblinding ..................................................................................................32
7.3.
Trial-Level Safety Reviews ..........................................................................................32
7.4.
End of Study Unblinding..............................................................................................32
8.
References ........................................................................................................................33
9.
Appendices .......................................................................................................................34


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Table of Contents
Table
Page
Table 5.1.
Dose-Response Assumption Used in Sample Size Determination.........................10
Table 6.1.
Analysis Populations............................................................................................13
Table 6.2.
Analyses Datasets ................................................................................................13
Table 6.3.
Summary of Analyses for Primary Endpoint ........................................................16
Table 6.4.
Vital Sign Summary Categories ...........................................................................18
Table 6.5.
Electrocardiogram Abnormal Categories..............................................................25
Table 6.6.
Sample Anti-Drug Antibodies (ADA) Assay Results............................................26
Table 6.7.
Sample Clinical Anti-Drug Antibodies (ADA) Interpretation Results...................27
Table 6.8.
Adverse Events for Analysis with Immunogenicity Results..................................28


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Table of Contents
Figure
Page
Figure 5.1.
Study design for I8F-MC-GPGF. ...........................................................................9


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Table of Contents
Appendix
Page
Appendix 1.
Schedule of Events .........................................................................................35
Appendix 2.
Important Protocol Deviations ........................................................................40


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3.
Revision History
The Statistical Analysis Plan (SAP) Version 1 is approved prior to first production data transfer.
The SAP Version 2 was approved prior to the primary database lock and contains the following 
changes:

Changed the modified intent-to-treat (mITT) population to not require 1 postbaseline 
measurement so it is the same as the safety population

Analysis datasets were altered to only include full analysis set (FAS) and efficacy 
analysis set (EAS)

Removed the per-protocol (PP) population and all associated analyses

Removed description of calculation of type 2 diabetes mellitus (T2DM) duration as it is 
in data standard

Changed thresholds of glycated hemoglobin (HbA1c) targets for categorical analyses

Corrected classification categories for calcitonin

Removed all subgroup analyses unless needed post-hoc


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4.
Study Objectives
4.1.
Primary Objectives
The primary objective of this study is to demonstrate that at least one LY3298176 titration 
scheme is superior to placebo in HbA1c reduction at 3 months in patients with T2DM 
inadequately controlled with diet and exercise alone, or treated with a stable dose of metformin.
4.2.
Secondary Objectives
The secondary objectives are to compare each titration scheme to placebo at 3 months for the 
following secondary efficacy parameters:

proportion of patients achieving HbA1c target of <7.0% 

the change in fasting blood glucose (FBG) (central laboratory) from baseline 

the change in body weight from baseline 

the change in waist circumference from baseline

incidence of treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs)

incidence of nausea, vomiting, and diarrhea

discontinuation of study drug due to adverse events (AEs)

incidence and rate of hypoglycemia (severe, total, documented symptomatic, and 
nocturnal)

incidence of anti-LY3298176 antibodies
4.3.
Exploratory Objectives

To compare each titration scheme to placebo at 3 months for effect on self-monitoring 
blood glucose (SMBG) profile.


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5.
Study Design
5.1.
Study Design and Treatment
Study I8F-MC-GPGF (GPGF) is a randomized, double-blind, parallel, placebo-controlled, 
Phase 2, multicenter, study designed to examine the efficacy and safety of once-weekly 
LY3298176, compared with placebo in patients with T2DM.  
The design for Study GPGF is illustrated in Figure 5.1.
Placebo
Group 1
2.5mg
2.5mg
5mg
5mg
10mg
10mg
10mg
10mg
15mg
15mg
15mg
15mg
Group 2
2.5mg
2.5mg
2.5mg
2.5mg
7.5mg
7.5mg
7.5mg
7.5mg
15mg
15mg
15mg
15mg
Group 3
4mg
4mg
4mg
4mg
8mg
8mg
8mg
8mg
12mg
12mg
12mg
12mg
Dose Number:
1
2
3
4
5
6
7
8
9
10
11
12
12 Weeks Treatment
Screening
Lead in
Follow up
Early Termination
1 week
1 week
4 weeks
Visit        1        2                3                4 
5       
6   (7T)
8  (9T)
10a
801b
ET
T = Telephone Visit;   Visit 801 =  End of Study Visit;   ET = Early Termination Visit
a =  Visit 10 occurs 1 week after the last dose (Dose 12) of study drug.
b =   Visit 801 (follow up visit) occurs 4 weeks after Dose 12 or 3 weeks after Visit 10.
Figure 5.1.
Study design for I8F-MC-GPGF.
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 
the screening visit (Visit 1).  
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 placebo, or one of three LY3298176 dose groups.  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 body mass index (BMI) (<30, 
30).  There will be equal randomization to the treatment arms (1:1:1:1).  However, placebo 
patients will be randomized such that a portion will be randomized to each cohort to receive the 
same dose volume as that cohort in order to maintain the study blind.  


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The randomization scheme will be performed using IWRS to ensure balance between treatment 
arms.
5.3.
Determination of Sample Size
Approximately 92 patients will be randomized to placebo or to one of three LY3298176
titrations arms, assuming a 13% dropout rate, resulting in approximately 20 completers per arm.
Assuming a standard deviation of 1.1, 20 patients per arm will provide at least 90% power to 
detect a statistically significant difference between LY3298176 titration schemes to placebo with 
a dose response assumption as shown in Table 5.1.
Table 5.1.
Dose-Response Assumption Used in Sample Size Determination
Placebo
LY 12 mg
LY 15 mg-1
LY 15 mg-2
CFBL HbA1c (%)
-0.2%
1.4%
1.5%
1.5%
Abbreviations: CFBL = change from baseline; HbA1c = glycated hemoglobin; LY = 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 described in the SAP and/or clinical study report (CSR).  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).  
No adjustments for multiplicity will be performed.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05 and/or 2-sided 
95% confidence interval (CI) unless otherwise stated.  This is different from what is stated in the 
protocol.
The baseline visit will be Visit 3.  For all variables, if baseline data are not available or are 
missing, the last nonmissing measurement taken prior to Visit 3 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. 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


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The first covariance structure that converges will be used.
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 12 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
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.
Patient statuses at the end of the 12-week treatment period will be summarized, displaying the 
numbers of patients:

entered

screen failed, along with the primary reason for screen failure

randomized

randomized and not treated

permanently discontinued from treatment, along with the primary reason for 
treatment discontinuation

discontinued from study, along with the primary reason for study discontinuation

completed 12 weeks blinded treatment

completed study


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The summary of status at the end of the 12-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 informed consent form (ICF).  
The percentage of patients discontinuing from each treatment will be compared using the 
Fisher’s exact test.
6.3.
Analysis Populations and Datasets
Three patient populations are defined for the analyses in this study with detailed information 
listed in Table 6.1. Analyses datasets specifying data exclusion are listed in Table 6.2.
Unless otherwise specified, listings will include FAS for all randomized patients; safety analyses, 
except for hypoglycemia events, will be conducted in the mITT population with the FAS; and
efficacy analyses including primary and key secondary efficacy analyses will be conducted in the 
mITT population with the EAS. 
Table 6.1.
Analysis Populations
Population
Definition
All Entered 
All patients who signed informed consent forms (ICFs)
All randomized (Intent-to-
Treat [ITT])
All patients who were randomized to a treatment arm
Safety Population (Modified 
Intent-to-Treat [mITT])
All randomized patients who have taken at least 1 dose of the study medication.  
This is different from what is stated in the protocol.  Analyses using the mITT 
population will be presented by the planned treatment group.
Table 6.2.
Analyses Datasets
Analysis Dataset Name
Description
Full Analysis Set
All data available
Efficacy Analysis Set
Only include data on study medication without using rescue medication, i.e., 
excluding data after rescue medication initiation or after study treatment 
discontinuation (last dose date +7).
6.4.
Patient Characteristics and Medical History
Demographic and baseline characteristics will be summarized by treatment group and overall 
using the mITT population and the FAS.  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 standard deviations (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.
Demographic and baseline diabetes characteristics will be presented in listings for each patient.


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All summaries of continuous characteristics will be based on nonmissing observations.  For 
categorical characteristics, percentages will be calculated out of the total number of patients in 
the data set, overall and by treatment group (that is, each denominator includes the number of 
patients with missing/unknown values for the characteristic).
The numbers and percent of patients with general medical history findings will be provided using 
the randomized (that is, ITT) population using the FAS.  A listing will be provided by patient.
6.5.
Treatment Compliance
Treatment compliance will be listed using all randomized patients and summarized using the 
mITT population using the FAS for the listings and summaries.  For a given patient, overall 
compliance for treatment period is defined as not missing 2 or more doses of the assigned 
treatment in the study.  Patients who miss 2 or more doses at any point during the study will be 
considered significantly noncompliant.
The number and percent of patients compliant during the 12-week treatment period will be 
summarized at Week 12 using the safety population by the actual treatment group.  
6.6.
Exposure of Study Treatment
Exposure to each therapy during the treatment period of the study will be calculated for each 
patient and summarized by treatment group.  
The extent of exposure to study medication (LY3298176, placebo) during the 12-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 12 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 will be presented for the 12-week
treatment period 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 will be provided by treatment group.
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:

12-week treatment period 


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
treatment period + follow-up period
All previous and concomitant medication use will be listed on a single listing.
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 12-week treatment period is defined as medication with 
either a recorded medication start date falling:  

within the 12-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 12-week treatment period will be any 
medication taken for at least 1 day during the 12-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.
Anti-hyperglycemic medication taken for any reason as well as taken as rescue for severe, 
persistent hyperglycemia will be summarized for mITT and will also be 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 2.  Patients meeting criteria for important protocol 
deviations will be identified either by statistical programming or based off study monitoring that 
is 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
All statistical models will include all treatment groups, including LY3298176 and placebo.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05 and/or 2-sided 
95% CI.  No adjustments for multiplicity will be performed.
6.9.1. Primary Outcome and Methodology
The primary outcome is the difference in HbA1c change from baseline between treatment groups 
at the end of the treatment period of 12 weeks.  The primary analysis model will be a MMRM for 
HbA1c change from baseline to 12 weeks described in Section 6.1.1. The treatment p-value will 
be used as evidence of difference between active drug and placebo, whereas the comparison of 
LS means versus placebo (unadjusted for multiple comparisons) will provide magnitude and 
significance of this difference.


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6.9.1.1.
Supporting Analyses of Primary Outcome
An MMRM analysis on the FAS will be performed for the primary parameter.  
An ANCOVA model will be used on the last observation carried forward (LOCF) endpoint of 
HbA1c with fixed effects of metformin use, baseline BMI category, treatment, and baseline 
HbA1c as a covariate.  Within the framework of this ANCOVA model, point estimates and 95% 
CIs for the mean change from baseline within each treatment group as well as for the difference 
in mean change from baseline between each investigative treatment group and placebo will be 
calculated.  This analysis will be performed on FAS in addition to the EAS.
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.  The descriptive statistics 
will also be performed on the HbA1c measurements at each visit.  
Table 6.3.
Summary of Analyses for Primary Endpoint
Analysis Type
LOCF or Observed Values
Analysis Dataseta
MMRM b
Observed 
EAS
MMRM 
Observed 
FAS
ANCOVA
LOCF
EAS
ANCOVA
LOCF
FAS
Abbreviations:  ANCOVA = analysis of covariance; EAS = efficacy analysis set; FAS = full analysis set; 
LOCF = last observation carried forward; MMRM = mixed model repeated measures.
a
Refer to Table 6.2.
b
Primary analysis.
6.9.2. Efficacy - Secondary Outcomes
The following secondary efficacy endpoints are going to be analyzed:

body weight change from baseline to 12 weeks

percentage of patient with ≥5% body weight loss at 12 weeks

percentage of patients reaching the HbA1c target of 7.0%

change from baseline of FBG at 12 weeks

change from baseline of waist circumference at 12 weeks
6.9.2.1.
Continuous Variable Analyses
For each continuous endpoint (body weight, FBG, and waist circumference), the observed 
absolute values and changes from baseline will be summarized using descriptive statistics by 
scheduled visit.  The change from baseline in body weight at 12 weeks, change from baseline in 
FPG at 12 weeks, and change from baseline in waist circumference at 12 weeks will all be 
analyzed using a MMRM-based model described in Section 6.1.1.
Body mass index (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.


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6.9.2.2.
Analyses on Variables with Percent of Patients Reaching a Target
The proportion of patients who have ≥5% body weight loss at 12 weeks will be analyzed using a 
logistic regression model with treatment, strata (baseline HbA1c category, and baseline BMI
category) and metformin use (yes, no), as fixed effects, and baseline body weight as a covariate.  
Descriptive statistics will also be presented, including sample size, frequency, and percent.  
Additional logistic regression analyses will be performed at 12 weeks for the proportion of 
patients who have achieved an HbA1c level of <7% and HbA1C level of ≤6.5%.  Treatment, 
baseline BMI category, and metformin use (yes, no) will be fixed effects and continuous baseline 
HbA1c level will be a covariate.  Descriptive statistics will also be presented, including sample 
size, frequency, and percent.
The proportion of patients who initiated rescue therapy will be summarize by descriptive 
statistics including sample size, frequency, and percent.
6.9.2.3.
Exploratory Analyses
For HbA1C and body weight, a longitudinal dose-response model with titration may be 
performed.  Other exploratory analyses taking account of patients with titration not as planned 
may also be performed.  
6.10. Safety Analyses
Safety analyses will be classified by the actual titration treatment group. 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; AEs 
summaries will be presented for all postbaseline data.  For some key summary tables, data will 
be presented both for the treatment period only and for the treatment period and follow-up period
combined, if applicable.
For each patient, treatment period is defined as the date of first treatment dose to last treatment 
dose date +7 day.
Safety measures will include extent of exposure, vital signs, physical characteristics, TEAEs 
(including SAEs), adverse events of special interest (AESIs; that is, injection site reactions, 
hypersensitivity reactions, hypoglycemia episodes, gastrointestinal [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).  
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 laboratory plots, may be performed, if 
warranted, upon review of the data.


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6.10.1. Vital Signs
Vital sign measurements (that is, systolic blood pressure [SBP] and diastolic blood pressure 
[DBP] in mmHg and pulse rate [PR] in beats/minute]) will be collected according to the Study 
Schedule of Events (Appendix 1). The average 3 measurements for BP and PR will 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.
The above measures will be analyzed using the MMRM-based model described in Section 6.1.1.  
The dependent variable will be the postbaseline change from baseline value for the applicable 
measure.  
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
Abbreviations:  bpm = beats per minute.
All vital signs and physical characteristics measurements will be listed.  
For pulse rate, a longitudinal dose-response model with titration may be performed, if deemed 
necessary.
6.10.2. High-Density Lipoprotein Cholesterol, Total Cholesterol, 
Triglycerides, and Low-Density Lipoprotein Cholesterol
Change from baseline in high-density lipoprotein cholesterol (HDL-C), total cholesterol, 
triglycerides, and low-density lipoprotein cholesterol (LDL-C) will be analyzed using the 
ANCOVA model similar to the model used for the supportive analysis on the primary endpoint.  
The model will include strata (baseline HbA1c category, baseline BMI category, metformin use 
[yes, no]), treatment, as fixed effects, the applicable baseline measurement as a covariate.  The 
dependent variable will be the postbaseline change from baseline value for the applicable 
measure.  
Descriptive summaries will also be presented.
6.10.3. Adverse Events
No statistical tests will be performed to compare AE rates between treatment groups.  


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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.  
Adverse events will be summarized as TEAEs.  Summaries of TEAEs will be presented for the 
combined treatment and follow-up periods.  A few selected tables may be presented for both the 
treatment period only, and the combined treatment and follow-up period.  
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 patient 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 treatment group.  
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 


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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 case report forms (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 electronic case report page (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 
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.  
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 have the AESI.  The incidence of patients with at least 1 AESI and the 


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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 standard Medical Dictionary for 
Regulatory Activity (MedDRA) queries (SMQs), Hypersensitivity SMQs, or Angioedema SMQs
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
Injection site reactions which meet SAE criteria will also be collected as AEs.  If >3% patients 
have such an event occur, then these injection site reactions may be summarized by PT using the 
version of 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. Summaries and analyses for incidence will be provided for each randomized 
treatment group and by visit.  
The prevalence and incidence of nausea, vomiting, and diarrhea will be summarized by the 
treatment and the time interval of interest. In addition, similar tables will also be generated by 
actual dose and time interval. The duration of each event will also be computed in days as event 
stop date minus event start date.  For computation purposes, events that are ongoing will be 
considered censored (that is, ended) at the date of last study contact.  


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The maximum severity and duration from baseline to Week 12 of nausea, vomiting, and diarrhea 
will be summarized by treatments.
Plots with the percentage number of subjects with the events versus initiation time course will 
also be generated. The y-axis is the percentage of subjects with the specified AE and the x-axis 
is the time 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]).

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 


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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. 
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” SMQ and a “Chronic pancreatitis” Lilly Search Categories (LSC) of the AE 
database, while adjudication-confirmed pancreatitis will be found from adjudication CRF.
The patients developing pancreatitis will be listed separately for the investigator-reported and the 
adjudicated events.
Each pancreatic enzyme at Week 12, and the maximum post-dose value will be summarized by 
each randomized treatment in a shift table using >1× the upper limit of normal (ULN), and ≥3×
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 High-Level Terms (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 ANCOVA model similar to the supportive analyses.  


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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 <35 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 will be summarized by treatment group using descriptive statistics 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.  
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 will be summarized by visit and treatment group 
using sample size, frequency, and percentage.  
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.  All laboratory measures that meet the criteria for a listing will be reported, including 
unscheduled and repeat or multiple measurements.  
A summary report and analysis for treatment-emergent abnormal laboratory values (outside the
reference ranges as appropriate) will be provided for each continuous analyte by treatment. Shift
tables of the change from baseline value to the maximum/minimum postbaseline value to 
Week 12 for selected analytes using clinically meaningful thresholds will be summarized.  A 
shift table for alanine aminotransferase (ALT), aspartate aminotransferase (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 will be presented for all patients 
who meet any of the following criteria:  

ALT ≥3 × ULN

AST ≥3 × ULN

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 beats per minutes (bpm), QRS complex (milliseconds [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 heart rate 
(HR) values using Fridericia’s formula (QTcF).  Fridericia’s correct QT formula will be reported 
in (msec).  Descriptive statistics for the absolute values and changes from baseline for the ECG 


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parameters (HR, PR interval, QRS, QT, QTcF) will be presented by treatment arm.  Additional 
summary statistics will be provided for abnormal values (categorized as Low or High as shown 
in Table 6.5).  An MMRM-based model similar to the 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; msec = milliseconds; 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 pharmacokinetics/pharmacodynamics [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.
6.11. Exploratory Analyses
Baseline will be the measurements prior to treatment for SMBG.
Immunogenicity will be analyzed and summarized.
6.11.1. 7-Point SMBG
The 7-point SMBG profile consists of pre-meal and 2-hour postprandial blood glucose (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)


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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 ANCOVA 
model to the one used for the supporting analysis for the primary endpoint described in Section 
6.9.1.1.  The corresponding baseline will be used in the model instead of the baseline HbA1c 
levels.  The ANCOVA model will include a term for the HbA1c stratification group.
6.11.2. Evaluation of Immunogenicity
6.11.2.1. Definitions of Sample Anti-drug Antibody 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.
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).
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
Abbreviations:  QNS = quantity not sufficient.


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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 
(that is, 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.”
Abbreviations:  QNS = quantity not sufficient.
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.
6.11.2.2. 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 nonmissing 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 include all observations after the first administration of study drug.  
6.11.2.3. 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 nonmissing baseline ADA result, and at least 1 nonmissing 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:

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.

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.


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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.  
6.11.2.4. 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 also 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 TEAEs 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)
Events mapping to High-Level Term (HLT) of Injection site reaction
Events mapping to HLT of Infusion site reaction
Abbreviations:  MedDRA = Medical Dictionary for Regulatory Activities.
The primary efficacy measure of change in HbA1c from baseline to 12 weeks may be examined 
in relation to ADA.  The initial examination will be boxplots of change in HbA1c at 12 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.


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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
LY3298176 trough PK samples collected over the course of this study will be used to assess that 
exposures in the study are consistent with known LY3298176 PK. 
Additionally, PK/PD data from this study may be used as a validation dataset to enable 
evaluation of PK/PD models built based on data from the core Phase 2 study, Study I8F-MC-
GPGB (GPGB).  These analyses may be conducted using nonlinear mixed-effects modeling 
implemented with the NONMEM software.
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.
6.13. Subgroup Analyses
No subgroup analyses are planned for this study.  
6.14. Interim Analyses
No interim analyses are planned for this study.
The study team will perform periodic, blinded safety reviews during the study.
A database lock may be performed when all patients have completed the treatment part of the 
study (prior to completion of the follow-up phase for all patients), if deemed necessary.  It will 
include all safety, efficacy, and PK data available through the 12-week treatment.  
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 PT.  

For each Serious AE and “Other” AE, for each PT and treatment group, the number 
of each of the following will be provided:
o
participants at risk of an event
o
participants who experienced each event PT
o
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 


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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 CSR reports, data 
reviews, dose selection (interim efficacy/safety only), and developing/refining exposure 
analyses.  
There is no interim analysis planned for this study.  
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.  
Until the data lock is authorized for the final analysis at the completion of the study, access to 
subject treatment assignments will not be provided to the following personnel:

Lilly personnel with direct site contact

Lilly personnel responsible for data entry and data validation

Lilly study team
After DBL, the study team will be unblinded to the study data to prepare for the analyses for the 
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.  
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 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, trial-level safety review (TLSR) reports table, figure, 
listing (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.


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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.
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 DBL.  
They will contain neither randomization assignments nor 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 third party organizations (TPOs) performing the labs. The 
complete list of TLSR variables include overall AEs, SAEs, TEAEs, AESIs, laboratory data, 
vital signs, discontinuations, and concomitant medications.
7.4.
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
[NIH] National Institutes of Health. ClinicalTrials.gov. Available at: 
https://www.clinicaltrials.gov/. Accessed September 28, 2015.


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9.
Appendices


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Appendix 1.
Schedule of Events


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Study Phase
Screen Lead-In Randomize
Treatment
Follow-Up
Early Term.
Visit
1
2
3
4
5
6
7Ta
8
9Ta
10b
801d
ET
Week of Treatment
2
1
0
1
2
4
4
8
8
12
(15)
Study Day/(dose number)
0/(1)
7/(2)
14/(3)
28/(5)
31-34
56/(9)
59-62
84
105
Visit Window (days)
+7
0
0
±2
±3
±3
±3
±3
Administrative
Informed consent
X
Diabetes medical history/therapy
X
Inclusion/exclusion
X
X
X
Preexisting conditions
X
Randomization
X
IWRS
X
X
X
X
X
X
X
X
X
X
BG meter/supplies, if needed
X
BG meter, instructions
X
Diet, exercise, BG counseling
X
Study diary, dispense
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
Subcutaneous injection training
X
X
X
X
X
X
Study drug and injection supplies, 
dispense
X
X
X
X
X
Health habits (alcohol use, 
tobacco use current/past)
X
Patient returns study drug vials
X
X
X
Study drug, assess compliance
X
X
X
X
X
X
Patient Demographics
Age
X
Gender
X
Race/ethnicity
X


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Study Phase
Screen Lead-In Randomize
Treatment
Follow-Up
Early Term.
Visit
1
2
3
4
5
6
7Ta
8
9Ta
10b
801d
ET
Week of Treatment
2
1
0
1
2
4
4
8
8
12
(15)
Study Day/(dose number)
0/(1)
7/(2)
14/(3)
28/(5)
31-34
56/(9)
59-62
84
105
Visit Window (days)
+7
0
0
±2
±3
±3
±3
±3
Clinical Variables
Physical examinationc
X
Height
X
Weight
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
Vital signs (BP and PR)
X
X
X
X
X
X
X
X
X
X
Antidiabetic medication
X
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
Other
ECGe
Xe
X
X
X
X
X
Xe
Evaluation of injection site 
reactions
X
X
X
X
X
X
X
X
Collect AEs
X
X
X
X
X
X
X
X
X
X
Diagnostics (Safety)
Screening laboratory testsf
X
Pregnancy testg
X
Xg
FSHh
X
Chemistry panel
X
X
X
X
X
Lipid panel
X
X
X
X
X
Lipase and amylase
X
X
X
X
X
X
X
eGFR
X
Hematology
X
X
X
X
X
Urinalysis
X
X
X
X
X


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Study Phase
Screen Lead-In Randomize
Treatment
Follow-Up
Early Term.
Visit
1
2
3
4
5
6
7Ta
8
9Ta
10b
801d
ET
Week of Treatment
2
1
0
1
2
4
4
8
8
12
(15)
Study Day/(dose number)
0/(1)
7/(2)
14/(3)
28/(5)
31-34
56/(9)
59-62
84
105
Visit Window (days)
+7
0
0
±2
±3
±3
±3
±3
Diagnostics (Efficacy)
Calcitonin
X
X
X
HbA1c
X
X
X
X
X
X
X
Fasting glucose
X
X
X
X
X
X
X
Total and active GLP-1/GIP
X
X
X
X
X
7-point SMBG
Xi
Xj
PKk
X
X
X
X
X
Immunogenicity
X
X
X
X
Xl
X
Nonpharmacogenetic stored 
samples
X
X
Abbreviations:  AE = adverse event; BG = blood glucose; BP = blood pressure; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; 
ET = Early Termination; FSH = follicle-stimulating hormone; GIP = glucose-dependent insulinotropic peptide; GLP-1 = glucagon-like peptide-1; 
HbA1c = hemoglobin A1c; IWRS = interactive web response system; PK = pharmacokinetics; PR = pulse rate; SMBG = self-monitoring of blood glucose; 
T = telephone visit; TE-ADA = treatment emergent anti-drug antibodies; Term. = termination.  
a
Telephone visits occur during the week following a dose escalation and should be done 3 to 6 days after a site visit for dose escalation and administration.  
At telephone visits, the sites should call the patient, ask how the patient is, and ask whether the patient would like to come to the site for assistance with the 
next study drug dilution and administration.  Sites should also remind patients to write down any AEs in their diaries at the telephone visits (as well as at all 
site visits).
b
Visit should occur approximately 1 week after the last dose (Dose 12).
c
Additional physical examinations may be performed throughout the study if determined necessary due to patient symptoms.
d
Visit should occur 4 weeks after the last dose of study drug or 3 weeks after Visit 10.
e
ECGs should be collected prior to all blood draws and study drug administrations.  Local ECGs will be collected for screening (Visit 1) and Early 
Termination.  Centralized ECGs, collected in supine position and in triplicate, should be collected for all other designated visits.
f
Screening laboratory tests include serum hepatitis B surface antigen (Ag), hepatitis C antibody (Ab), and human immunodeficiency virus (HIV) Ab tests for 
all patients (see Appendix 2).
g
Serum pregnancy test will be performed by central laboratory at Visit 1 for women of child-bearing 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).  A urine pregnancy test (local) 
should be given to all women of child-bearing potential at Visit 3 prior to administration of first dose of study drug to confirm lack of pregnancy.
h
Collect serum FSH in women whose menopausal status needs to be determined.


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i
The patients should collect the SMBG during the lead-in period between Visits 2 and 3 and return the results within their diaries at Visit 3.
j
The patients should collect the SMBG during the week after Dose 12 and return the results within their diaries at Visit 10.
k
PK samples are to be collected pre-dose.
l
Patients who have clinically significant TE-ADA should 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 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.


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Appendix 2.
Important Protocol Deviations


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Important Protocol Deviation
Source of 
Information
Function Accountable 
for Identifying 
Deviation
Programmable/ 
Nonprogrammable
Immediate 
Notification 
(Y/N)
Category
Sub-
category
Trial-specific 
Term
1
Investigational 
Product
Other
Not fit for use
Monitoring
Site Monitor
Nonprogrammable
Y
2
Eligibility
Inclusion/ 
Exclusion
Age out of range
Monitoring
Site Monitor
Nonprogrammable
N
3
Eligibility
Inclusion/
Exclusion
Non-compliant to 
T2DM criteria.
Monitoring
Site Monitor
Nonprogrammable
Y
4
Eligibility
Inclusion/
Exclusion
HbA1c not in 
compliance with 
the entry criteria
CLUWE/CLO
CLO
Programmable
Y
5
Eligibility
Inclusion/
Exclusion
Abnormal 
thyroid-
stimulating 
hormone (TSH) 
levels. 
Monitoring/
CLO
Site Monitor
Monitoring 
(nonprogrammable)/
CLO 
(programmable) 
Y
6
Eligibility
Inclusion/
Exclusion
Not on stable 
dose of 
cholesterol 
lowering drugs.
Monitoring
Site Monitor
Nonprogrammable
Y
7
Eligibility
Inclusion/
Exclusion
BMI out of range. Monitoring
Site Monitor
Nonprogrammable
Y
8
Eligibility
Inclusion/
Exclusion
Non-compliance 
to weight loss 
medication 
criteria.
Monitoring/
CLUWE
Site Monitor/
CLUWE
Monitoring 
(nonprogrammable)/
CLUWE 
(programmable)
N
9
Safety
Other
Failure to report 
product complaint 
within 24 hrs.
Monitoring
Site Monitor
Nonprogrammable
Y
10
Safety
Other
Positive urine 
and/or serum 
pregnancy test. 
Monitoring/
CLO
Site Monitor/
CLO
Monitoring 
(nonprogrammable)/
CLO (programmable)
Y
11
Informed 
Consent
Informed 
Consent Not 
NA
Monitoring/
InForm
Site Monitor
Monitoring 
(nonprogrammable)/
Y


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Important Protocol Deviation
Source of 
Information
Function Accountable 
for Identifying 
Deviation
Programmable/ 
Nonprogrammable
Immediate 
Notification 
(Y/N)
Category
Sub-
category
Trial-specific 
Term
Obtained
InForm 
(programmable)
12
Study 
Procedures 
Violation of 
Discontinua
tion Criteria
NA
Mixed 
(monitoring and  
CLO/CLUWE)
Site Monitor/CLO/
CLUWE
Monitoring 
(nonprogrammable)/
CLO, CLUWE 
(programmable)
Y
13
Study 
Procedures 
Excluded 
Conmeds 
OAMs besides 
met for more than 
7 cumulative 
days.
Monitoring/
InForm/
CLUWE
Stats/Site Monitor
Monitoring 
(nonprogrammable)/
CLUWE, InForm 
(programmable)
N
14
Study 
Procedures 
Excluded 
Conmeds 
Wt. loss meds 
taken 7 days or 
more during tx 
phase
Monitoring/
CLUWE
Stats/Site Monitor
Monitoring 
(nonprogrammable)/
CLUWE 
(programmable)
N
15
Study 
Procedures 
Lab Criteria Missing HbA1c at 
designated visits 
per SoA.  
Monitoring/
CLUWE/
CLO
Stats/Site Monitor/CLO
Monitoring 
(nonprogrammable)/
CLO and CLUWE 
(programmable)
Y
16
Study 
Procedures 
Other 
Missing safety 
data for all 3:BP, 
Pulse, or ECGs.
Monitoring/
InForm
Site Monitor/InForm
Monitoring 
(nonprogrammable)/
InForm 
(programmable)
N
17
Study 
Procedures 
Other 
Missing lab of 
lipase, amylase, 
LFTs, or FBG.
CLUWE
CLO
Programmable
N
18
Study 
Procedures
Other
Missing body wt. 
and/or waist circ. 
per SoA.
Monitoring/
InForm
Site Monitor/InForm
Monitoring 
(nonprogrammable)/I
nForm 
(programmable)
N
19
Investigational 
product
Other
IP lost or stolen
Monitoring
Site Monitor
Nonprogrammable
Y
20
Investigational 
Dosing 
NA
Monitoring/
Site Monitor/InForm
Monitoring 
N


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Important Protocol Deviation
Source of 
Information
Function Accountable 
for Identifying 
Deviation
Programmable/ 
Nonprogrammable
Immediate 
Notification 
(Y/N)
Category
Sub-
category
Trial-specific 
Term
product
Error
InForm
(nonprogrammable)/
InForm 
(programmable)
21
Investigational 
product
Compliance
Missing 2 or 
more doses.
Monitoring/
InForm/ 
CLUWE
Site Monitor/InForm/
CLUWE
Monitoring 
(nonprogrammable)/
InForm and CLUWE 
(programmable)
Y
Abbreviations:  BMI = body mass index; BP = blood pressure; circ. = circumference; CLO = Clinical Laboratory Operations; CLUWE = Clinical Users Working 
Environment; conmeds = concomitant medications; ECGs = electrocardiograms; FBG = fasting blood glucose; HbA1c = glycated hemoglobin; hrs. = hours; 
IP = investigational product; lab = laboratory; LFTs = liver function tests; N = no; NA = not applicable; OAMs = oral antihyperglycemic medications; 
SoA = Schedule of Events; T2DM = type 2 diabetes mellitus; tx = treatment; wt. = weight; Y = yes.