Clinical trial NCT03322631
Conditions: Type 2 Diabetes Mellitus
Sponsor: Eli Lilly and Company
Start date: 2017-11-15; Completion date: 2018-11-28
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purposes of this study are to determine:

* The safety of tirzepatide and any side effects that might be associated with it.
* How much tirzepatide gets into the bloodstream and how long it takes the body to remove it.
* How tirzepatide affects the levels of blood sugar.

This study includes eight weekly doses of tirzepatide or placebo given as subcutaneous (SC) injections just under the skin. The study will last about 16 weeks (total), including screening and follow-up. This study is for research purposes only and is not intended to treat any medical conditions.

Detailed description:

Arms: arm 1: Participants received escalating doses of 2.5 milligrams (mg), 5 mg, 10 mg and 15 mg of tirzepatide administered into the subcutaneous (SC) tissue of the abdominal wall. arm 2: Participants received placebo administered into the SC tissue of the abdominal wall.
Interventions: intervention 1: Tirzepatide intervention 2: Placebo
Intervention descriptions: intervention 1: Administered SC. intervention 2: Administered SC.

Protocol documents:
Prot_000.pdf: 
Protocol I8F-JE-GPGC (a)
A Multiple-Ascending Dose Study in Japanese Patients with Type 2 Diabetes Mellitus to Investigate 
the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of LY3298176
NCT03322631
Approval Date: 15-Oct-2018


I8F-JE-GPGC(a)Clinical Pharmacology Protocol
Page 1
LY3298176
Protocol I8F-JE-GPGC
A Multiple-Ascending Dose Study in JapanesePatients 
with Type 2 Diabetes Mellitusto Investigate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of 
LY3298176
Confidential Information
The information contained in this protocol 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.  
Approval Date: 15-Oct-2018 GMT
LY3298176
Eli Lilly Japan K.K.
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly:
24 August 2017
Amendment (a) Electronically Signed and Approved by Lilly
on approval date provided below.
PPD


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
Page 2
LY3298176
Table of Contents
A Multiple-Ascending Dose Study in Japanese Patients with 
Type 2 Diabetes Mellitus to Investigate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of 
LY3298176
Section
Page
Protocol I8F-JE-GPGC A Multiple-Ascending Dose Study in Japanese 
Patients with Type 2 Diabetes Mellitus to Investigate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of 
LY3298176.........................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................19
3.1.
Study Rationale............................................................................................................19
3.2.
Background..................................................................................................................19
3.3.
Benefit/Risk Assessment..............................................................................................21
4.
Objectives and Endpoints..................................................................................................22
5.
Study Design.....................................................................................................................23
5.1.
Overall Design .............................................................................................................23
5.2.
Number of Participants.................................................................................................25
5.3.
End of Study Definition ...............................................................................................25
5.4.
Scientific Rationale for Study Design...........................................................................25
5.5.
Justification for Dose ...................................................................................................25
6.
Study Population...............................................................................................................27
6.1.
Inclusion Criteria..........................................................................................................27
6.2.
Exclusion Criteria ........................................................................................................28
6.3.
Lifestyle and/or Dietary Requirements .........................................................................31
6.3.1.
Meals and Dietary Restrictions.............................................................................31
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................31
6.3.3.
Activity................................................................................................................31
6.4.
Screen Failures.............................................................................................................31
7.
Treatment..........................................................................................................................32
7.1.
Treatment Administered...............................................................................................32
7.1.1.
Packaging and Labeling .......................................................................................32
7.2.
Method of Treatment Assignment ................................................................................33


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
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LY3298176
7.2.1.
Selection and Timing of Doses.............................................................................33
7.3.
Blinding .......................................................................................................................33
7.4.
Dose Modification........................................................................................................34
7.4.1.
Dose Escalation....................................................................................................34
7.5.
Preparation/Handling/Storage/Accountability...............................................................35
7.6.
Treatment Compliance .................................................................................................35
7.7.
Concomitant Therapy...................................................................................................35
7.8.
Treatment after the End of the Study............................................................................36
8.
Discontinuation Criteria ....................................................................................................37
8.1.
Discontinuation from Study Treatment.........................................................................37
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................37
8.2.
Discontinuation from the Study....................................................................................37
8.3.
Patients Lost to Follow-up............................................................................................38
9.
Study Assessments and Procedures ...................................................................................39
9.1.
Efficacy Assessments...................................................................................................39
9.2.
Adverse Events ............................................................................................................39
9.2.1.
Serious Adverse Events........................................................................................40
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................40
9.2.2.
Complaint Handling.............................................................................................41
9.3.
Treatment of Overdose.................................................................................................41
9.4.
Safety...........................................................................................................................41
9.4.1.
Laboratory Tests ..................................................................................................41
9.4.2.
Vital Signs ...........................................................................................................41
9.4.2.1.
Body Weight ..................................................................................................41
9.4.3.
Electrocardiograms ..............................................................................................42
9.4.4.
Safety Monitoring ................................................................................................43
9.4.4.1.
Hepatic Safety................................................................................................43
9.4.4.2.
Pancreatic Safety............................................................................................44
9.4.4.3.
Hypersensitivity Reactions .............................................................................44
9.4.4.3.1.
Injection-Site Reactions ............................................................................44
9.4.4.4.
Glucose Monitoring........................................................................................44
9.4.4.4.1.
Hyperglycemia and Hypoglycemia Reporting...........................................45
9.4.4.5.
Nausea and Vomiting .....................................................................................47
9.5.
Pharmacokinetics .........................................................................................................47
9.5.1.
Bioanalysis...........................................................................................................47
9.6.
Pharmacodynamics ......................................................................................................47
9.6.1.
Glucose Samples..................................................................................................48
9.6.1.1.
Oral Glucose Tolerance Test...........................................................................48


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
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LY3298176
9.6.1.2.
7-Point Glucose Monitoring............................................................................48
9.6.2.
Exploratory Sample Assessments and Storage......................................................48
9.6.3.
Meal Intake and Appetite .....................................................................................49
9.6.4.
Immunogenicity Assessments ..............................................................................49
9.7.
Genetics .......................................................................................................................50
9.8.
Biomarkers...................................................................................................................51
9.9.
Health Economics ........................................................................................................51
10.
Statistical Considerations and Data Analysis.....................................................................52
10.1. Sample Size Determination ..........................................................................................52
10.2. Populations for Analyses..............................................................................................52
10.2.1.
Study Participant Disposition ...............................................................................52
10.2.2.
Study Participant Characteristics ..........................................................................52
10.3. Statistical Analyses ......................................................................................................52
10.3.1.
Safety Analyses....................................................................................................53
10.3.1.1.
Clinical Evaluation of Safety..........................................................................53
10.3.1.2.
Statistical Evaluation of Safety.......................................................................53
10.3.2.
Pharmacokinetic Analyses....................................................................................53
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................53
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................54
10.3.3.
Pharmacodynamic Analyses.................................................................................54
10.3.3.1.
Pharmacodynamic Parameter Estimation ........................................................54
10.3.3.2.
Pharmacodynamic Statistical Inference...........................................................54
10.3.4.
Pharmacokinetic/Pharmacodynamic Analyses......................................................55
10.3.5.
Evaluation of Immunogenicity .............................................................................55
10.3.6.
Data Review During the Study.............................................................................55
10.3.7.
Interim Analyses..................................................................................................55
11.
References ........................................................................................................................56


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
Page 5
LY3298176
List of Tables
Table
Page
Table GPGC.1.
Objectives and Endpoints .......................................................................22
Table GPGC.2.
Treatments Administered........................................................................32
Table GPGC.3.
Amendment Summary for Protocol I8F-JE-GPGC Amendment(a) .........77


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
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LY3298176
List of Figures
Figure
Page
Figure GPGC 5.1.
Illustration of study design for Protocol I8F-JE-GPGC. ..........................23


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
Page 7
LY3298176
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................58
Appendix 2.
Clinical Laboratory Tests........................................................................62
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................64
Appendix 4.
Clinically Significant Adverse Effects ....................................................67
Appendix 5.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............69
Appendix 6.
Pancreatic Monitoring ............................................................................70
Appendix 7.
Blood Sampling Summary......................................................................73
Appendix 8.
Protocol I8F-JE-GPGC Blinding/Unblinding Plan..................................74


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
Page 8
LY3298176
1. Protocol Synopsis
Title of Study:
A Multiple-Ascending Dose Study in Japanese Patients with Type 2 Diabetes Mellitus to Investigate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of LY3298176.
Rationale:  
LY3298176 is a dual agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors
being developed as a weekly treatment for type 2 diabetes mellitus (T2DM).  This study of LY3298176, 
I8F-JE-GPGC (GPGC), will investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics 
(PD) of LY3298176 administered once weekly for 8 weeks as subcutaneous (SC) injections to Japanese patients 
with T2DM.
Objectives/Endpoints:  
Primary Objective
Endpoints
To investigate the safety and tolerability of 
LY3298176 following multiple SC doses administered 
to Japanese patients with T2DM
Adverse events
Secondary Objectives
Endpoints
To characterize the PK of LY3298176 following 
multiple SC doses in Japanese patients with T2DM
AUC and Cmax of LY3298176
To investigate the PD effect of LY3298176 following 
multiple SC doses administered to Japanese patients 
with T2DM
Fasting plasma glucose
Abbreviations:  AUC = area under the concentration-time curve; Cmax = maximum drug concentration; 
PD = pharmacodynamic; PK = pharmacokinetics; SC = subcutaneous; T2DM = type 2 diabetes mellitus.
Summary of Study Design:  
Study GPGC is a Phase 1, multiple-site, patient- and investigator-blind, placebo-controlled, randomized, parallel 
dose–group, 8-week, multiple-ascending dose (MAD) study in Japanese patients with T2DM.
Treatment Arms and Planned Duration for an Individual Patient:  
This study consists of 3 cohorts.  Approximately 49 Japanese patients with T2DM will be randomized to 4 treatment 
groups, including 3 dose levels of LY3298176 and placebo.  Patients will be administered 8 weekly SC doses of 
LY3298176 or placebo in a ratio of 12 LY3298176:3 placebo for Cohorts 1 and 3, and 16 LY3298176:3 placebo for 
Cohort 2.  Patients in Cohort 1 will receive either LY3298176 with titration regimen starting from 2.5 mg for Days 1 
and 8 followed by 5 mg for Days 15 and 22, and 10 mg for Days 29, 36, 43, and 50, or corresponding volume-
matched placebo.  Patients in Cohort 2 will be dosed after evaluation of safety data at the 10 mg-dose level in 
Cohort 1.  The safety data up to Day 36 from at least 8 patients will be reviewed. Patients in Cohort 3 will be dosed
after evaluation of safety data of the initial staggered group of Cohort 2. Patients in Cohort 2 will receive either 
LY3298176 with titration regimen starting from 5 mg for Days 1 and 8 followed by 10 mg for Days 15, 22, 29, and 


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
Page 9
LY3298176
36, and 15 mg for Days 43 and 50, or corresponding volume-matched placebo.  Patients in Cohort 3 will receive 
either 5 mg LY3298176 or placebo for 8 weeks.
Number of Patients:  
Approximately 49 Japanese patients with T2DM may be enrolled so that approximately 32 patients complete the 
study, in compliance with the defined dosing regimen.  
Statistical Analysis:
Pharmacokinetic (PK) and PD analyses will be conducted on data from all patients who receive at least 1 dose of the 
investigational medicinal product (IMP) and have evaluable PK and PD data.  Safety analyses will be conducted for 
all enrolled patients, whether or not they completed all protocol requirements.  
Safety:  All IMP and protocol procedure–related adverse events (AEs) will be listed, and if the frequency of events 
allows, safety data will be summarized using descriptive methodology.  Safety parameters that will be assessed 
include safety laboratory parameters, vital signs, electrocardiogram parameters, injection-site reactions, and 
hypoglycemia.
Pharmacokinetics:  PK parameter estimates for LY3298176 will be calculated by standard noncompartmental 
methods of analysis.  The primary parameters for analysis will be maximum drug concentration (Cmax), area under 
the concentration-time curve (AUC), and time to Cmax (Tmax) of LY3298176.  Other noncompartmental parameters, 
such as half-life, apparent clearance, and apparent volume of distribution, may be reported.
PK dose proportionality may be assessed in an exploratory manner in model-based analysis.
The parameter Tmax of LY3298176 will be analyzed using a nonparametric method.
PK parameters will be summarized using descriptive statistics.
Pharmacodynamics:  The ability of LY3298176 to reduce fasting or dynamic glucose and the effects on insulin will 
be assessed.  Such effects will be explored for different treatment regimens of LY3298176.
The AUC(0-2hr) for glucose and insulin during an oral glucose tolerance test will be calculated using the trapezoidal 
rule.
Absolute values, as well as change from baseline in each parameter, will be analyzed using mixed-effects models to 
evaluate treatment effects as well as treatment comparisons.  The model will include treatment as fixed effects and 
the patient as a random effect.  For repeated measured parameters, day and treatment-by-day interaction terms will 
be included in the model. Baseline (Day -1) values, as well as other influencing variables, may be used as 
covariates.  The main comparisons will be between each LY3298176-treated group and placebo group.  
Pharmacokinetics/Pharmacodynamics:  PK/PD modeling may be used to characterize the exposure-response 
relationships between LY3298176 concentrations and various PD endpoints, provided data are sufficient.
Immunogenicity:  The frequency of antibody formation to LY3298176 may be determined.  If any cross-reactive or 
neutralization assays are performed, the frequency of these antibodies will be determined.  
The relationship between the presence of antibodies, antibody titers, and clinical parameters (eg, AEs) may be 
assessed. Likewise, the relationship between antibody titers, PK parameters, and PD response to LY3298176 may 
be assessed.


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
Page 10
LY3298176
2. Schedule of Activities


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
Page 11
LY3298176
Study Schedule Protocol I8F-JE-GPGC Cohorts 1, 2, and 3 except for Treatment Period
Procedure
Screeninga
Prestudyb
Treatment Period
Follow-Up
ADA Follow-Upc
Days
≤28 days
Before Day −1
64 ±2
85 ±2
ET2d
Every 3 months
Outpatient visits to CRU
X
X
X
X
X
Informed consent
X
Distribution of glucose meters, test strips, and 
diaries/SMPG training
Xe
X
7-point SMPG
Xf
Medical history
X
Physical examination
X
Medical assessment
X
X
X
X
AEs/concomitant medications
X
X
X
X
X
Chest x-rayg
X
Height and weight
X
Body temperature
X
Vital signs (BP/PR)h,i
X
X
X
X
12-Lead ECGi,j
X
X
X
X
PK samplingk,l
X
X
X
X
Clinical safety lab (hematology, chemistry, 
urinalysis)m,n
X
X
X
X
Clinical safety lab (serology)n
X
Pregnancy test (serum, urine)n,o,p
X
Follicle-stimulating hormonen,o
X
Urine drug and alcohol screenn,p
X
Hemoglobin A1cl,m
X
Fasting glucose, insulin, glucagonl,m
X
X
X
Immunogenicityl
X
X
X


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
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LY3298176
Study Schedule Protocol I8F-JE-GPGC Cohort 1 for Treatment Period
Procedure
Treatment Period (Cohort 1)
Days
−1
1
2
3
4
8
15
16
17
18
22
±1
29
30
31
32
36
±1
43
±1
50
51
52
57
ET1d
Inpatient stay at CRUq
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Outpatient visits to CRU
X
X
X
X
X
X
Remind Patients about 
7-point SMPG
X
X
X
X
7-point SMPG
X
X
X
X
Randomization
X
IMP administrationr
X
X
X
up-
titra
tion
X
X
up-
titra
tion
X
X
X
Medical assessments
Pre
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs/concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weightt
Pre
Pre
Pre
Pre
Pre
Pre
Pre
Pre
X
X
Body temperature
X
Pre
X
Vital signs (BP/PR)h,i
X
Pre, 1, 
4, 8, 12
24
48
72
Pre
Pre
24
48
72
Pre
Pre
24
48
72
Pre
Pre
Pre
168
X
12-Lead ECGi,j
Pre, 8
24
48
72
Pre
Pre
Pre
Pre
Pre
Pre
Pre, 
8
24
168
X
PK samplingk,l
Pre, 8
24
48
72
Pre
Pre
Pre
Pre
Pre
Pre
Pre, 
8
24
48
168
X
Clinical safety lab
(hematology, chemistry, 
urinalysis)m,n
X
24
48
Pre
Pre
24
48
Pre
Pre
24
48
Pre
Pre
Pre
24
48
168
X
OGTTl,u
X
X
Hemoglobin A1cl,m
Pre
Pre
168
X
Fasting glucose, insulin, 
glucagonl,m
Pre
24
Pre
Pre
24
Pre
Pre
24
Pre
Pre
Pre
24v
168
X
Meal intake and 
appetitew
L/D
L/D
L/D
Lipid panell,m,x
Pre
Pre
24
X


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
Page 13
LY3298176
Study Schedule Protocol I8F-JE-GPGC Cohort 1 for Treatment Period
Procedure
Treatment Period (Cohort 1)
Days
−1
1
2
3
4
8
15
16
17
18
22
±1
29
30
31
32
36
±1
43
±1
50
51
52
57
ET1d
Exploratory storage
samplesl,m,y
Pre
Pre
24
X
Pharmacogenetic
samplel
Pre
Nonpharmacogenetic 
sample (storage)l,m
Pre
Pre
Pre
Pre
Pre
168
X
Immunogenicityl
Pre
Pre
168
X


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
Page 14
LY3298176
Study Schedule Protocol I8F-JE-GPGC Cohort 2 for Treatment Period
Procedure
Treatment Period (Cohort 2)
Days
−1
1
2
3
4
8
15
16
17
18
22
±1
29
±1
36
±1
43
44
45
46
50
51
52
57
ET1d
Inpatient stay at CRUq
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Outpatient visits to CRU
X
X
X
X
X
X
X
X
Remind Patients about 
7-point SMPG
X
X
X
X
7-point SMPG
X
X
X
X
Randomization
X
IMP administrationr
X
X
X
up-
titra
tion
X
X
X
X
up-
titra
tion
X
Medical assessments
Pre
X
X
X
Pre
Pre
X
X
X
Pre
Pre
Pre
Pre
X
X
X
Pre
X
X
X
X
AEs/concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weightt
Pre
Pre
Pre
Pre
Pre
Pre
Pre
Pre
X
X
Body temperature
X
Pre
X
Vital signs (BP/PR)h,i
X
Pre, 1, 
4, 8, 12
24
48 72
Pre
Pre
24
48
72
Pre
Pre
Pre
Pre
24
48
72
Pre
168
X
12-Lead ECGi,j
Pre, 8
24
48 72
Pre
Pre
Pre
Pre
Pre
Pre
Pre, 
8
24
168
X
PK samplingk,l
Pre, 8
24
48 72
Pre
Pre
Pre
Pre
Pre
Pre
Pre, 
8
24
48 168
X
Clinical safety lab
(hematology, chemistry, 
urinalysis)m,n
X
24
48
Pre
Pre
24
48
Pre
Pre
Pre
Pre
24
48
Pre
24
48 168
X
OGTTl,u
X
X
Hemoglobin A1cl,m
Pre
Pre
168
X
Fasting glucose, insulin, 
glucagonl,m
Pre
24
Pre
Pre
24
Pre
Pre
Pre
Pre
24
Pre
24v
168
X
Meal intake and 
appetitew
L/D
L/D
L/D
Lipid panell,m,x
Pre
Pre
24
X


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
Page 15
LY3298176
Study Schedule Protocol I8F-JE-GPGC Cohort 2 for Treatment Period
Procedure
Treatment Period (Cohort 2)
Days
−1
1
2
3
4
8
15
16
17
18
22
±1
29
±1
36
±1
43
44
45
46
50
51
52
57
ET1d
Exploratory storage
samplesl,m,y
Pre
Pre
24
X
Pharmacogenetics
samplel
Pre
Nonpharmacogenetic 
sample (storage)l,m
Pre
Pre
Pre
Pre
Pre
168
X
Immunogenicityl
Pre
Pre
168
X


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
Page 16
LY3298176
Study Schedule Protocol I8F-JE-GPGC Cohort 3 for Treatment Period
Procedure
Treatment Period (Cohort 3)
Days
−1
1
2
3
4
8
15
±1
22
±1
29
±1
36
±1
43
±1
50
51
52
57
ET1d
Inpatient stay at CRUq
X
X
X
X
X
X
X
X
Outpatient visits to CRU
X
X
X
X
X
X
X
X
Remind Patients about 7-point SMPG
X
X
X
X
7-point SMPG
X
X
X
X
Randomization
X
IMP administrationr
X
X
X
X
X
X
X
X
Medical assessments
Pre
X
X
X
Pre
Pre
Pre
Pre
Pre
Pre
Pre
X
X
X
X
AEs/concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weightt
Pre
Pre
Pre
Pre
Pre
Pre
Pre
Pre
X
X
Body temperature
X
Pre
X
Vital signs (BP/PR)h,i
X
Pre, 1, 
4, 8, 12
24
48
72
Pre
Pre
Pre
Pre
Pre
Pre
Pre
168
X
12-Lead ECGi,j
Pre, 8
24
48
72
Pre
Pre
Pre
Pre
Pre
Pre
Pre, 
8
24
168
X
PK samplingk,l
Pre, 8
24
48
72
Pre
Pre
Pre
Pre
Pre
Pre
Pre, 
8
24
48
168
X
Clinical safety lab (hematology, chemistry, 
urinalysis)m,n
X
24
48
Pre
Pre
Pre
Pre
Pre
Pre
Pre
24
48
168
X
OGTTl,u
X
X
Hemoglobin A1cl,m
Pre
Pre
168
X
Fasting glucose, insulin, glucagonl,m
Pre
24
Pre
Pre
Pre
Pre
Pre
Pre
Pre
24v
168
X
Meal intake and appetitew
L/D
L/D
L/D
Lipid panell,m,x
Pre
Pre
24
X
Exploratory storage samplesl,m,y
Pre
Pre
24
X
Pharmacogenetics samplel
Pre
Nonpharmacogenetic sample (storage)l,m
Pre
Pre
Pre
Pre
Pre
168
X
Immunogenicityl
Pre
Pre
168
X


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LY3298176
Study Schedule Protocol I8F-JE-GPGC
Abbreviations:  ADA = antidrug antibody; AE = adverse event; BP = blood pressure; CRU = clinical research unit; D = dinner; DPP = dipeptidyl peptidase; 
ECG = electrocardiogram; ET = early termination; IMP = investigational medicinal product; L = lunch; lab = laboratory tests; OGTT = oral glucose tolerance 
test; PK = pharmacokinetic; PR = pulse rate; SMPG = self-monitored plasma glucose.
Note:  numbers are in hours in relation to dosing; Pre = predose.
a
Screening shall be completed up to 28 days before treatment assignment.  Patients treated with metformin or DPP-IV inhibitors (except for omarigliptin, 
trelagliptin, and linagliptin) will be required to withdraw their treatment and have at least a-28-day washout period before dosing with IMP.
b
Patients who passed screening tests will visit the CRU to receive glucose meters, test strips, and diaries for 7-point SMPG before Day −1.
c
Only for the patients who have clinically significant treatment-emergent antidrug antibodies.  Refer to Section 9.6.4 for details.
d
The patient who discontinues from the study between Day 1 to Day 57 inclusive will complete ET1 procedures as soon as possible.  And then, the patient will 
be asked to complete ET2 procedures after a washout period of at least 28 days from the last IMP administration.  The patient who discontinues from the 
study after the completion of Day 57 will complete ET2 procedures after a washout period of at least 28 days from the last IMP administration.
e
Patients who were taking metformin or DPP-IV inhibitors (except for omarigliptin, trelagliptin, and linagliptin) at screening will be required to monitor their 
plasma glucose levels during the 28-day washout period.
f
Patients will conduct the 7-point SMPG from the distribution of glucose meters until the day before Day −1.
g
Patients who have completed chest x-ray within the past 12 months and whose x-ray and/or report are available for review are exempt from the chest 
x-ray examination.
h
Refer to Section 9.4.2 for instructions on vital signs.  
i
Vital signs and ECGs should be scheduled before, but as close as possible to the PK sample times.  Scheduled meals should occur after ECG/vital signs 
measurement.
j
Refer to Section 9.4.3 for instructions on ECGs.  Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but 
awake during ECG collection.  A single local safety ECG will be measured at screening and Day 85 (follow-up) or ET visit.  The Day 1 predose ECG will be 
taken in triplicate every 15 minutes for 1 hour (–60, –45, –30, and –15 min) to establish a baseline.  At the other visits, ECGs will be collected in triplicate at 
the specified time points. ECGs must be recorded before collecting any blood for safety or PK samples and as close as possible to the time of the blood draw.
k
PK sampling for LY3298176 on Day 1 at predose, 8 and 24 (Day 2), 48 (Day 3), 72 (Day 4), and 168 (Day 8) hours after the first dose (168-hour sample to be 
collected before the second dose of LY3298176).  Additional PK samples to be collected at predose on Days 15, 22, 29, 36, and 43, and on Day 50 at predose, 
8 and 24 (Day 51), 48 (Day 52), and 168 (Day 57) hours after the last dose, and at the follow-up visits on Day 64 and Day 85.  A maximum of 3 samples may 
be collected at additional time points during the study if warranted and agreed upon by both the investigator and sponsor.
l
These tests will be performed or stored at the central laboratory or Lilly-designated laboratory.
m Patients will be required to fast for at least 8 hours before each blood sample is drawn.
n
These tests will be performed at the local laboratory.
o
These tests will be performed per investigator’s discretion.
p
Procedures may be repeated throughout the study as deemed necessary by the investigator.
q
Patients may be required to remain at the CRU longer than the planned discharging day at the investigator’s discretion to assure patients’ safety or to provide 
additional safety monitoring.
r
IMP will be administered after an overnight fast of at least 8 hours.  IMP must be administered at least 6 days after the previous dose.


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LY3298176
s
Assessments of injection-site reactions will be included in the medical assessments.
t
Weight will be measured in a consistent way per Section 9.4.2.1, always predose.
u
OGTT (serum glucose and insulin) sampling schedule:  Pre-glucose dose (75 g) and 0.5, 1, 1.5, and 2 hours post glucose dose.  Patients should consume the 
glucose load within 5 minutes after an overnight fast of at least 10 hours.
v
Only insulin and glucagon will be measured at 24 hours postdose on Day 51.  All other time points include fasting glucose.  
w Meal intake and subjective rating of appetite sensation will be evaluated before and 4 to 5 hours after standardized lunch and dinner meals on Days –1, 2,
and 51.  The standardized lunch and dinner meals will be provided at least 4 hours after the previous meal or the ingestion of glucose in the OGTT.  
x
Lipid panel includes high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, and triglycerides.  Triglyceride and total 
cholesterol concentrations in the safety panel will not be required on the days that the lipid panel is performed.
y
Exploratory storage samples may be assayed for biomarkers like adiponectin, cortisol, and bone biomarkers. Refer to Section 9.6.2 for details.


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LY3298176
3. Introduction
3.1.
Study Rationale
LY3298176 is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and 
glucagon-like peptide-1 (GLP-1) receptors being developed for the treatment of type 2 diabetes 
mellitus (T2DM).  This study of LY3298176, I8F-JE-GPGC (GPGC), will investigate the safety, 
tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of LY3298176 administered
once weekly for 8 weeks as subcutaneous (SC) injections to Japanese patients with T2DM.
3.2.
Background
In normal physiology, the incretins GLP-1 and GIP are secreted from enteroendocrine cells in 
the gut after a meal to enhance the physiological responses to food intake, including sensation of 
satiety, insulin secretion, and nutrient disposal.  It is now well known that patients with T2DM
have impaired incretin responses (Nauck et al. 2004), and pharmacologic interventions providing 
either GLP-1 receptor agonistic peptides or dipeptidyl peptidase (DPP)-IV inhibitors (which 
delay degradation of endogenous GIP and GLP-1) are successfully used in the treatment of 
T2DM (Drucker and Nauck 2006; Amori et al. 2007; Baynes 2010).  
Although GLP-1 is regarded as the incretin of therapeutic utility, published data demonstrate that 
overexpression of GIP may lead to improved body weight and glycemic control, and the 
combination of GLP-1 and GIP may result in improved glycemic efficacy and weight 
management compared with GLP-1 agonists alone in patients with T2DM (Kim et al. 2012; 
Finan et al. 2013).
LY3298176 is a long-acting, dual-incretin mimetic (dual agonist) based on a GIP peptide 
sequence that has been modified so that it binds to both GIP and GLP-1 receptors with similar 
affinity and shows selectivity over glucagon receptors. LY3298176 is conjugated to a fatty acid 
chain, which is expected to provide prolonged half-life and PD time action compared with native 
incretins because of its albumin-binding properties and allows for once-weekly SC dosing.  By 
combining the 2 incretin pharmacology profiles, improved glycemic control may be expected on 
the basis of potential additive or synergistic effects on glycemic and weight benefits (Irwin et al. 
2009).
LY3298176 is being investigated and intended for the treatment of T2DM as an adjunct to diet, 
exercise, and/or oral medications.
The safety, tolerability, and PK/PD of LY3298176 are being evaluated in an ongoing Phase 1 
clinical pharmacology trial, Study I8F-MC-GPGA (GPGA).  In Part A (single-ascending dose 
[SAD] portion) of Study GPGA, more than 50 healthy subjects received study drug with doses of 
LY3298176 ranging from 0.25 mg to 8 mg.  Single doses of study drug were generally well
tolerated.  Gastrointestinal (GI) events (for example, loss of appetite, bloating, nausea, vomiting) 
were the most commonly reported adverse events (AEs).  At the 8-mg dose level, the majority of 
subjects experienced drug-related GI events.  Two of the subjects who received 8 mg reported 
AEs of nausea and vomiting that required treatment with antiemetics and intravenous fluids.  
Further dose escalation was therefore stopped.  Following a single SC injection in healthy 


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subjects, the maximum drug concentration (Cmax) increased with increasing dose and occurred 
between 8 and 96 hours (time to Cmax [tmax]).  The mean half-life (t1/2) ranged from 109 to 
123 hours (~5 days).  In Part B (the multiple-ascending dose [MAD] portion) of Study GPGA, 
more than 30 healthy subjects have been dosed in cohorts of 4 weekly SC fixed doses of 0.5 mg, 
1.5 mg, and 4.5 mg and an additional titration regimen cohort of 5 mg for 2 doses (Weeks 1 
and 2), 8 mg (Week 3), and 10 mg (Week 4).  Similar to Part A, the most commonly reported 
AEs have been GI events, including loss of appetite, nausea, bloating, heartburn, and vomiting.  
A majority of the AEs have been reported after the first week of dosing, with fewer AEs being 
reported after the third and fourth doses.  The 8-mg dose was better tolerated in this titration 
approach compared with the single 8-mg dose evaluated in Part A.  The limits of tolerability 
were not reached in the multiple-dose escalation in healthy subjects.  Following multiple SC 
injections in healthy subjects, the Cmax increased with increasing dose and occurred between 
8 and 72 hours (tmax).
As of 30 June 2017, Part C of Study GPGA was currently ongoing; however, dosing had been 
completed. The first cohort of patients with T2DM received a fixed dose of 5 mg for 4 weeks. 
Gastrointestinal events were the most commonly reported AEs in these patients. LY3298176 
appears to be better tolerated by patients with T2DM who received 5-mg doses compared to 
healthy subjects who received 4.5 mg in Part B of the study.
The second cohort of patients with T2DM received LY3298176 in a dose-titration scheme (5 mg 
LY3298176 for Weeks 1 and 2, and 10 mg for Weeks 3 and 4).  Preliminary data have shown 
that more GI-related AEs occurred after the first 5- and 10-mg doses; however, patients with 
T2DM reported fewer and less severe GI-related AEs compared with those reported by the 
healthy subjects who received the weekly dose-titration schedule of 5 mg, 5 mg, 8 mg, and 
10 mg.  
The third cohort of patients with T2DM received LY3298176 via titration once weekly for 
4 weeks, SC doses of 5 mg, 5 mg, 10 mg, and 15 mg. In this cohort, 15 patients with T2DM 
received the first dose of 5 mg, with 13 patients completing all 4-dose levels. Most of the AEs 
were mild and moderate, and 10 of 13 AEs were GI related, with symptoms of nausea and 
vomiting being the most frequently reported symptoms. Two patients discontinued the study. 
One patient was discontinued after the first dose of 5 mg because of increases in amylase and 
lipase without any clinical symptoms. This patient had a history of fatty liver, and an abdominal 
computed tomography showed fatty liver and no sign of pancreatitis. This patient also had 
increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The second 
patient was discontinued after receiving doses of 5 mg, 5 mg, and 10 mg because of an AE of 
colicky diarrhea. Diarrhea started after the second dose of 5 mg and lasted approximately 
12 days. This patient required treatment with loperamide and hydration. The patient was early 
terminated (did not receive the last dose of 15 mg) because of prolonged diarrhea and resulting 
dehydration.
The last cohort of 12 patients with T2DM received 0.5 mg weekly for 4 weeks; all patients
completed dosing. Four of 12 patients experienced AEs considered to be related to the study 
drug. Most common AEs were GI in nature with one subject reporting more AEs than the 


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LY3298176
others:  3 episodes of vomiting (one requiring treatment with Zofran), nausea, decreased appetite,
and diarrhea; all these AEs occurred after the first dose. Two patients reported AEs related to 
pancreatic enzymes and 1 patient reported decreased appetite. At this time these events have 
been resolved.
These data in both healthy subjects and patients with T2DM support using dose titration to 
increase tolerability of higher doses of LY3298176.
Preliminary data have shown that there has been no apparent concentration-dependent increase in 
systolic or diastolic blood pressure (BP) after single or multiple doses; however, there was an 
increase in heart rate in the MAD portion of the study.
LY3298176 PK was studied across a range of doses administered as single doses or multiple 
doses (4 doses) via a once-weekly dosing regimen.  Based on preliminary data, LY3298176 PK 
appeared linear and dose proportional during the dose range studied.  Peak concentrations were 
observed at 1 to 2 days postdose, and the half-life was approximately 5 days.
In conclusion, based on preliminary data, PK profile of LY3298176 supports once-weekly SC 
dosing, and there were no safety concerns to preclude further clinical development.
3.3.
Benefit/Risk Assessment
There is no anticipated therapeutic benefit for the patients.
To minimize the risk of hyperglycemia due to the washout of prestudy oral antidiabetic 
medication, patients will monitor their fasting glucose by SMPG, and the episodes of 
hyperglycemia will be reported and managed by the investigator or designated physician 
(Section 9.4.4.4.1).
Because LY3298176 is a long-acting, GIP and GLP-1 receptor dual agonist, the potential risks 
associated with LY3298176 may be similar to the risks associated with currently available long-
acting GLP-1 receptor agonists.  The known risks associated with increased GLP-1 receptor 
activity include but are not limited to: GI-related adverse reactions (particularly nausea, 
vomiting, and diarrhea), pancreatitis, cardiovascular risk (increased heart rate), hypoglycemia, 
systemic allergic reaction, injection-site reactions, antibody formation, and medullary thyroid 
carcinoma.  
More information about the known risks, serious AEs (SAEs), and reasonably anticipated AEs of 
LY3298176 can be found in the Investigator’s Brochure (IB).  
More information about the known risks for the once-weekly GLP-1 receptor agonists can be 
found in the Bydureon® ([exenatide extended-release] for injectable suspension) package insert 
(AstraZeneca 2015, Japan) Trulicity® (dulaglutide injection, solution) package insert (Eli Lilly 
2017, Japan).


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LY3298176
4. Objectives and Endpoints
Table GPGC.1 shows the objectives and endpoints of the study.
Table GPGC.1.
Objectives and Endpoints
Primary Objective
Endpoints
To investigate the safety and tolerability of LY3298176 
after multiple SC doses administered to Japanese
patients with T2DM
Adverse events
Secondary Objectives
Endpoints
To characterize the PK of LY3298176 after multiple SC 
doses in Japanese patients with T2DM
AUC and Cmax of LY3298176
To investigate the PD effect of LY3298176 after 
multiple SC doses administered to Japanese patients 
with T2DM
Fasting plasma glucose levels
Exploratory Objectives
Endpoints
To investigate the exploratory PD effects of LY3298176 
after multiple SC doses administered to Japanese 
patients with T2DM
Body weight, OGTT (serum glucose and insulin), 
7p-SMPG, hemoglobin A1C, lipids, glucagon, 
subjective appetite sensation
To evaluate the formation of ADAs to LY3298176 after
multiple SC doses administered to Japanese patients 
with T2DM
Presence of ADAs to LY3298176
Abbreviations:  ADA = antidrug antibody; AUC = area under the concentration-time curve; Cmax = maximum drug 
concentration; OGTT = oral glucose tolerance test; PD = pharmacodynamic; PK = pharmacokinetics; 
SC = subcutaneous; 7p-SMPG = 7-point self-monitored plasma glucose; T2DM = type 2 diabetes mellitus.


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LY3298176
5. Study Design
5.1.
Overall Design
Study GPGC is a Phase 1, multiple-site, patient- and investigator-blind, placebo-controlled, 
randomized, parallel dose–group, 8-week MAD study in Japanese patients with T2DM.
Study governance considerations are described in detail in Appendix 3.
Figure GPGC 5.1 illustrates the study design.
Abbreviations:  LY = LY3298176; PL = placebo; FU = follow-up.
Figure GPGC 5.1.
Illustration of study design for Protocol I8F-JE-GPGC.
This study consists of 3 cohorts.  Patients will be randomized to 4 treatment groups, including 
3 dose levels of LY3298176 and placebo as shown in Figure GPGC 5.1. Patients will be 
administered 8 weekly SC doses of LY3298176 or placebo.  Study procedures and timing for 
prestudy, treatment, and follow-up phases are outlined in Section 2.  
Screening to Prestudy
Patient eligibility for this study will be determined at a screening visit.  Eligible patients will visit 
the clinical research unit (CRU) before Day -1 to receive training on the 7-point self-monitored 
plasma glucose (SMPG), glucose meters, test strips, and diaries.  Patients will conduct the 
7-point SMPG until the day before Day -1.  In addition, patients treated with metformin or 
DPP-IV inhibitors (except for omarigliptin, trelagliptin, and linagliptin) will be required to 
withdraw their treatment and have at least a 28-day washout period before dosing with 
investigational medicinal product (IMP).  These patients will be required to monitor their plasma 
glucose (PG) levels during the washout period.


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LY3298176
Treatment Period
Patients will be admitted to the CRU on Day -1.  If the investigator decides not to administer the 
first dose to a patient on a particular day based on the results of medical assessments, vital signs, 
or electrocardiograms (ECGs), the patient may be rescheduled to participate in the study, and any 
procedures performed up to that point may be repeated.
Patients will be given SC doses of LY3298176 (or placebo) on Days 1, 8, 15, 22, 29, 36, 43, and 
50 after an overnight fast (at least 8 hours).  Even if there are visit allowances of ±1 day, the 
interval of each IMP administration must be at least 6 days.  
Patients in Cohort 1 will receive either LY3298176 with titration regimen starting from 2.5 mg 
for Days 1 and 8 followed by 5 mg for Days 15 and 22, and 10 mg for Days 29, 36, 43, and 50, 
or corresponding volume-matched placebo.  Patients in Cohort 2 will receive either LY3298176 
with titration regimen starting from 5 mg for Days 1 and 8 followed by 10 mg for Days 15, 22, 
29, and 36, and 15 mg for Days 43 and 50, or corresponding volume-matched placebo. Patients 
in Cohort 3 will receive either 5 mg LY3298176 or placebo for 8 weeks (Section 5.5). The 
planned highest dose or dosing regimen of Cohort 2 may be changed for the reason of tolerability 
(Section 7.4).
If the investigator decides not to up-titrate the dose level of IMP for individual patients in the 
titration regimen in Cohorts 1 or 2 for the reason of safety and/or tolerability, patients may keep 
current dose level to the planned last dose at Day 50 and will no longer be allowed up-titration 
during the treatment period.  Down-titration is not allowed during the treatment period for any
patients in Cohorts 1, 2, or 3.
Safety, as assessed by AEs, vital signs, 12-lead ECGs, concomitant medications, safety 
laboratory measurements, and medical assessments from at least 8 patients (to include at least 5 
on LY3298176) up to Day 36 predose procedure of Cohort 1, will be reviewed by the sponsor 
and investigator before dose-escalation decision to Cohort 2 (Section 7.4.1).
Dosing will be staggered in Cohorts 1 and 2 so that an initial group of up to 6 patients receiving 
LY3298176 and 2 patients receiving placebo will be dosed.  On Days 4 and 32 of Cohort 1 and 
on Days 4, 18, and 46 of Cohort 2, the investigator and Lilly clinical pharmacologist, clinical 
research physician (CRP), or clinical research scientist (CRS) will review available safety data 
from these patients, and if no relevant safety signals are noted, the remaining patients will be 
dosed.  Patients in Cohort 3 will be dosed after evaluation of safety data of the initial staggered 
group of Cohort 2.  
PK sampling and safety assessments, including AEs, concomitant medications, medical 
assessments, clinical laboratory tests, vital signs, and ECGs, will be performed according to the 
Schedule of Activities (Section 2).
The investigator or qualified designee will review all available inpatient safety data before 
discharging patients from the CRU on the morning of each planned discharging day provided 
they are deemed medically fit by the investigator.  Patients may be required to remain at the 
CRU longer than the planned discharging day at the investigator’s discretion to assure patients’


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LY3298176
safety or to provide additional safety monitoring.  Patients will be discharged after the review of 
all final safety assessments from the last follow-up visit is completed by the investigator.
Follow-Up Period
Safety follow-up visits will occur approximately 2 and 5 weeks after the last dose of IMP.  
Patients who have treatment-emergent LY3298176 antidrug antibodies (ADAs) at the planned 
follow-up visit (Day 85) or early termination visit may be monitored until return to baseline (see 
Section 9.6.4).
5.2.
Number of Participants
Approximately 49 Japanese patients with T2DM may be enrolled so that approximately 
32 patients complete the study, in compliance with the defined dosing regimen.  For purposes of 
this study, a patient completes the study when all scheduled procedures are completed in 
compliance with the defined dosing regimen, shown in the Schedule of Activities (Section 2) 
have been finished.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) or the date of the last ADA follow-up visit for the last patient, if 
applicable.
5.4.
Scientific Rationale for Study Design
Study GPGC is a Phase 1 study to investigate safety, tolerability, PK, and PD of LY3298176 
subcutaneously administered once weekly to Japanese patients with T2DM. On the basis of the 
preliminary results of Study GPGA, patients with T2DM were selected over healthy subjects in 
this study to more accurately evaluate GI tolerability and the effects of glycemic control. The 
planned treatment duration of 8 weeks may allow patients to reach the planned 10-mg and 15-mg 
dose levels in Cohorts 1 and 2, respectively, by using an up-titration regimen from 2.5 mg and 
5 mg, respectively, to reduce GI-related AEs. The staggered dosing design is used to minimize 
the safety risk because this is the first study to dose LY3298176 in Japanese subjects/patients.
The study is intended to evaluate whether doses used in this study are safe and tolerated in 
Japanese patients with T2DM. The data from this trial will support identification of an 
appropriate dose range for subsequent clinical studies in Japan.
5.5.
Justification for Dose
The doses of LY3298176 in this study are selected to provide a full evaluation of the safety,
tolerability, PK, and PD of LY3298176 in Japanese patients with T2DM to support dose 
selection in future clinical trials in patients with T2DM in Japan. The dose of LY3298176 for 
Cohort 1 is titrated from 2.5 mg to 10 mg—2.5 mg for Days 1 and 8; followed by 5 mg for Days 
15 and 22; and then 10 mg for Days 29, 36, 43, and 50.  The dose of LY3298176 for Cohort 2 is 
titrated from 5 mg to 15 mg—5 mg for Days 1 and 8; followed by 10 mg for Days 15, 22, 29,
and 36; and then 15 mg for Days 43 and 50.  The dose of LY3298176 for Cohort 3 is a fixed 


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LY3298176
5-mg weekly dose for 8 weeks. The anticipated dose-limiting safety and tolerability of 
LY3298176 are GI-related AEs, such as nausea and vomiting (Section 3.2), which have been 
consistently demonstrated with the GLP-1 drug class.
The planned dose levels of LY3298176 were selected on the basis of the following:

Safety and tolerability of LY3298176 in healthy subjects and patients with T2DM in the 
Phase 1 Study GPGA through doses of up to 15 mg (Section 3.2). In Study GPGA, using a 
rapid titration scheme of 5 mg, 5 mg, 10 mg, and 15 mg, the dose of 15 mg was considered 
safe but not well tolerated. It is expected that a more gradual titration method is needed to 
reach 15 mg with better tolerability; hence, this study will explore getting to the highest dose 
of 15 mg via a longer titration during 8 weeks.

The dose-titration regimen starting at 2.5 mg and 5 mg in Cohorts 1 and 2, respectively, are 
based on tolerability modelling and intended to reduce GI-related AEs.

The 10-mg and 15-mg doses for Cohorts 1 and 2, respectively, will provide information on 
safety, tolerability, PK, and PD around expected maximum tolerated dose levels in the 
up-titration regimen.

The fixed 5-mg dose in Cohort 3 is to compare safety, tolerability, PK, and PD profiles of 
LY3298176 in this study with that of Study GPGA (first cohort of Part C).


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LY3298176
6. Study Population
Eligibility of patients for study enrollment will be based on the results of screening medical 
history, physical examination, medical assessment, vital signs, clinical laboratory tests, and 
ECG.
A chest x-ray will be completed at screening unless one has been obtained within the past 
12 months, and the x-ray and/or report are available for review.  
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days before Day 1.  Patients who are not enrolled within 28 days 
of screening may be subjected to an additional medical assessment and/or clinical measurements 
to confirm their eligibility.
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 for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrollment:
[1]
Japanese males or females between the ages of 20 and 70 years inclusive at 
screening
[1a] male patients:
agree to use an effective method of contraception (barrier contraceptives,
such as latex condoms, or complete abstinence from sexual intercourse with 
women) for the duration of the study and for 3 months after the last dose of 
IMP
[1b] female patients:
women not of childbearing potential because of surgical sterilization 
(hysterectomy or bilateral oophorectomy or tubal ligation) or menopause;
women with an intact uterus are deemed postmenopausal if they are aged 45
years or older
AND
who have not taken hormones or oral contraceptives within the past year and 
have had cessation of menses for at least 1 year
OR
who had at least 6 months of amenorrhea with follicle-stimulating hormone 
levels consistent with a postmenopausal state
[2]
have T2DM diagnosed at least 1 year before enrollment


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LY3298176
[3]
have T2DM controlled with diet and exercise alone or are stable on a single 
oral antidiabetic medication (OAM), metformin or DPP-IV inhibitor only
(other types of OAM [omarigliptin, trelagliptin, and linagliptin] are not 
allowed in this study), for at least 3 months; however, patients must withdraw 
the single OAM for at least 28 days before dosing with IMP
[4]
have a hemoglobin A1c (HbA1c) ≥7.0% and ≤10.0% for patients treated with 
diet and exercise only, and for the patients who have washed out of 
antidiabetic medications, HbA1c ≥6.5% and ≤9.0%, at the screening visit
[5]
have a body weight of at least 54.0 kg inclusive at screening
[6]
have a body mass index of 20.0 kg/m2 to 35.0 kg/m2 inclusive at screening
[7]
have clinical laboratory test results within normal reference range for the 
population or investigative site or results with acceptable deviations that are 
judged to be not clinically significant by the investigator; abnormalities of 
blood glucose, serum lipids, urinary glucose, and urinary protein consistent 
with T2DM are acceptable
[8]
have blood pressure of <160/90 mm Hg and pulse rate of 50 to 100 bpm 
(supine) at screening, or with minor deviations judged to be acceptable by the 
investigator
[9]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[10] are able and willing to give signed informed consent
[11] have venous access sufficient to allow blood sampling as per the protocol
[12] are taking stable doses of over-the-counter or prescription medications (for 
example, antihypertensive agents, aspirin, lipid-lowering agents) for treatment 
of concurrent medical conditions providing the patients have been stable on 
their treatment regimen for at least 4 weeks before dosing with IMP
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[13] are investigative site personnel directly affiliated with this study or their 
immediate families; immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling
[14] are Lilly employees
[15] are currently enrolled in a clinical study involving an IMP or any other type of 
medical research judged not to be scientifically or medically compatible with 
this study


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LY3298176
[16] have participated in a clinical study involving an IMP within the last
4 months; if the previous IMP has a long half-life, 5 half-lives or 4 months 
(whichever is longer) should have passed
[17] have previously completed or withdrawn from this study or any other study 
investigating LY3298176 and have previously received the IMP
[18] have received treatment with a drug that has not received regulatory approval 
for any indication within 30 days of screening
[19] have known allergies to LY3298176, GLP-1 analogues, or related compounds
[20] have had more than one episode of severe hypoglycemia, as defined by the 
American Diabetes Association criteria, within 6 months before entry into the 
study or has a history of hypoglycemia unawareness or poor recognition of 
hypoglycemic symptoms; any patient who cannot communicate an 
understanding of hypoglycemic symptoms and the appropriate treatment of 
hypoglycemia before to the first dose of IMP should also be excluded
[21] have an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 at 
screening
[22] have had a blood transfusion or severe blood loss or have known 
hemoglobinopathy (alpha-thalassemia), hemolytic anemia, sickle cell anemia, 
a hemoglobin value <11.0 g/dL (males) or <10.0 g/dL (females), or any other 
condition known to interfere with HbA1c methodology
[23] have received chronic (lasting >14 consecutive days) systemic glucocorticoid 
therapy (excluding topical, intra-articular, and inhaled preparations) in the 
past year or have received any glucocorticoid therapy within 30 days before 
screening
[24] have a significant history of or current cardiovascular (for example, 
myocardial infarction, congestive heart failure, cerebrovascular accident, 
venous thromboembolism); respiratory; hepatic; renal; GI; endocrine;
hematological (including history of thrombocytopenia); or neurological 
disorders capable of significantly altering the absorption, metabolism, or 
elimination of drugs or of constituting a risk when taking the study medication 
or interfering with the interpretation of data
[25] have a history of heart block or a pulse rate interval >220/msec or any
abnormality in the 12-lead ECG at screening that, in the opinion of the 
investigator, increases the risks associated with participating in the study
[26] intended use of over-the-counter or prescription medications within 14 days 
before planned dosing and for the duration of the study, apart from occasional 
intake of vitamin/mineral supplements, allowable antiemetics, and 
acetaminophen; if this situation arises, inclusion of an otherwise suitable 
patient may be at the discretion of the investigator (refer to Section 7.7)


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[27] regularly use known drugs of abuse or show positive findings on drug 
screening
[28] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive HIV antibodies and/or HIV antigen at screening
[29] show evidence of hepatitis B or positive hepatitis B surface antigen and/or 
evidence of hepatitis C or positive hepatitis C antibody at screening
[30] are women who are lactating
[31] have donated 400 mL or more of blood in the last 12 weeks (males) or in the 
last 16 weeks (females), any blood donation (including apheresis) within the 
last 4 weeks, or total volume of blood donation in the past year is 1200 mL 
(males) or 800 mL (females) or more at screening
[32] have an average weekly alcohol intake that exceeds 21 units per week (males) 
or 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) or are unwilling to stop 
alcohol consumption during the 24 hours before and 72 hours postdose, and 
24 hours before each CRU admission and each outpatient visit, and 
throughout the duration of each CRU visit
[33] smoke >10 cigarettes per day or the equivalent or are unable or unwilling to 
refrain from nicotine during CRU admission
[34] have a history or presence of pancreatitis (history of chronic pancreatitis or 
idiopathic acute pancreatitis) or GI disorder (for example, relevant esophageal 
reflux or gall bladder disease) or any GI disease that impacts gastric emptying 
(for example, gastric bypass surgery, pyloric stenosis, with the exception of 
appendectomy) or could be aggravated by GLP-1 analogues or DPP-IV 
inhibitors; patients with dyslipidemia and patients who have had 
cholecystolithiasis (removal of gall stones) and/or cholecystectomy (removal 
of gall bladder) in the past, with no further sequelae, may be included in the 
study at the discretion of the investigator
[35] have a history of atopy or clinically significant multiple or severe drug 
allergies, intolerance to topical corticosteroids, or severe postdose
hypersensitivity reactions (including, but not limited to, erythema multiforme 
major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, or 
exfoliative dermatitis)
[36] have evidence of significant active neuropsychiatric disease as determined by 
the investigator
[37] have a personal or family history of medullary thyroid carcinoma or have 
multiple endocrine neoplasia syndrome type 2
[38] have serum AST or ALT >2× the upper limit of normal (ULN) or total 
bilirubin (TBL) >1.5× ULN (with the exception of Gilbert’s syndrome)
[39] have a history of malignancy within 5 years before screening


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[40] have any skin conditions (including, but not limited to, tattoos or scars) that
may interfere with the interpretation of assessment or administration of IMP
[41] are unsuitable for inclusion in the study in the opinion of the investigator or 
sponsor
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, patients may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
Patients will be required to fast overnight for at least 8 hours before taking an SC dose of 
LY3298176 (or placebo) on Days 1, 8, 15, 22, 29, 36, 43, and 50 and before each blood sample 
is drawn as described in the Schedule of Activities (Section 2).  Water may be consumed freely.  
Standard meals will be provided after approximately 15 minutes from IMP administration in the 
CRU. Standardized lunch and dinner meals will be provided in the CRU to assess meal intake 
and subjective rating of appetite sensation (Section 9.6.3).
When not resident in the CRU, patients should, as much as possible, maintain their routine 
prestudy dietary patterns.
6.3.2. Caffeine, Alcohol, and Tobacco
Caffeine:  Patients should refrain from caffeine-containing food/beverages (for example, cola, 
chocolate drinks, tea, and coffee) during the CRU stay.  Patients will be allowed to maintain their 
regular caffeine consumption outside the CRU throughout the study period.
Alcohol:  No alcohol will be allowed during the 24 hours before and 72 hours postdose, and 
24 hours before each CRU admission and each outpatient visit, and throughout the duration of 
each CRU visit.  Between CRU visits, daily alcohol should not exceed 3 units for males and 2 
units for females (a unit is defined in Exclusion Criterion [32], Section 6.2).  
Tobacco:  No nicotine use will be permitted while at the CRU.  While not resident in the CRU, 
patients may smoke no more than 10 cigarettes or consume the equivalent amount of nicotine per 
day.  
6.3.3. Activity
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 supine, recumbent, or sitting.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  Individuals may be rescreened once.  The interval between rescreenings should be at 
least 2 weeks.  If rescreening is performed, the individual must sign a new informed consent 
form and will be assigned a new identification number.


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7. Treatment
7.1.
Treatment Administered
This study involves a comparison of once-weekly SC dose levels of LY3298176 (2.5 mg to 
10 mg titration regimen for Cohort 1, 5 mg to 15 mg titration regimen for Cohort 2, and 5 mg 
fixed dose for Cohort 3) with corresponding volume-matched placebo. Table GPGC.2 shows the 
treatment regimens.
Each vial of the IMP will contain 5 mg of LY3298176, will be reconstituted in sterile water for 
injection (Japan Pharmacopeia), and will be administered subcutaneously.  Doses will be 
dispensed in accordance with the randomization scheme provided by the sponsor.  Patients
assigned to placebo treatment will receive SC injections of normal saline with the volume 
matching the LY3298176 at each dose level.  Please refer to the IMP Operation/Handling 
Procedure for detailed instructions.
All injections will be administered into the SC tissue of the abdominal wall.  Injection sites will 
be alternated weekly between 4 sites on the abdominal wall (ie, right and left upper quadrants 
and right and left lower quadrants).
Whenever possible, IMP administration should be carried out by the same personnel.  Dosing 
will commence at approximately the same time of day in all dose cohorts.  The actual time of 
dosing will be recorded in the patient’s electronic case report form (eCRF).
Table GPGC.2.
Treatments Administered
Dose level
Number of vial
Volume per 
injection (mL)
Number of 
injection
Total volume of 
injection (mL)
LY 2.5 mg/PL
1
0.5
1
0.5
LY 5 mg/PL
1
1.0
1
1.0
LY 10 mg/PL
2
1.0
2
2.0
LY 15 mg/PL
3
1.0
3
3.0
Abbreviations:  LY = LY3298176; PL= placebo.
The investigator or designee is responsible for:

explaining the correct use of the IMP to the site personnel,

verifying that instructions are followed properly,

maintaining accurate records of IMP dispensing and collection,

returning all unused medication to Lilly or its designee at the end of the study.
7.1.1. Packaging and Labeling
Investigational medicinal products for this study are as follows:

LY3298176 will be provided in a vial, which will be provided in a carton.

Placebo will be provided as sodium chloride (saline) in a vial.


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The IMP will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Randomization tables for allocation of LY3298176 or placebo will be prepared by the statistician 
for the study and provided to the site pharmacists involved in dose preparation.  The allocation 
and dispensing of the IMP will be fully documented and verified by a second person.  Detailed 
records of the amounts of the IMP received, dispensed, and remaining at the end of the study will 
be maintained by the site pharmacist.  
7.2.1. Selection and Timing of Doses
The doses will be administered at approximately the same times on each day.  The actual time of 
all dose administrations will be recorded in the patient’s eCRF.
7.3.
Blinding
The dosing regimen is patient- and investigator-blind.  To preserve the blinding of the study, all 
study site personnel, except pharmacy staff who prepare and dispense study medication, will be 
blinded to treatment allocation.
Blinding will be maintained until the database is locked with data up to Day 85 (blinded period)
as described in the separate Blinding Plan (Appendix 8).
The site pharmacist who prepares and dispenses study medication will receive a randomization 
table with treatment codes to enable preparation of blinded placebo doses.  The pharmacist will 
assign treatment.
Emergency codes will be available to the investigator.  A code, which reveals the treatment 
group for a specific study patient, may be opened during the study only if the patient’s well-
being requires knowledge of the patient’s treatment assignment.
If a patient’s study treatment assignment is unblinded during the blinded period, the patient must 
be discontinued from the study unless the investigator obtains specific approval from a Lilly 
clinical pharmacologist, CRP, or CRS for the study participant to continue in the study.  During 
the study, emergency unblinding should occur only by accessing the study patient’s emergency 
code.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event.  The 
patient’s safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding during the blinded period 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.
For the blinded items in the clinical laboratory tests, please refer to Appendix 2.


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7.4.
Dose Modification
If the investigator decides not to up-titrate the dose level of IMP at Days 15, 29, or 43 in the 
titration regimen for individual patients in Cohorts 1 or 2 for the reason of safety and/or 
tolerability, patients may keep current dose level to the planned last dose at Day 50 and will no 
longer be allowed up-titration during the treatment period.  Down-titration is not allowed during 
the treatment period for any patients in Cohorts 1, 2, or 3.
The planned highest dose of Cohort 2, 15 mg LY3298176, may be reduced to 12.5 mg before to 
the first patient visit of Study GPGC if the first interim analysis of the ongoing Phase 2 
Study I8F-MC-GPGB indicates that the 15 mg dose is not well tolerated.  
7.4.1. Dose Escalation
The dose escalation decision will be made on the basis of the safety data at the 10-mg dose level 
of Cohort 1 to proceed to Cohort 2. The safety data up to Day 36 (predose procedure) of 
Cohort 1 from at least 8 patients (to include at least 5 on LY3298176) will be reviewed.  
Safety data will be the primary criteria for the dose escalation.  In addition, if available at the 
time of dose-escalation decision, PK results may be used as supporting data for dose escalation.  
No dose decision can occur without prior discussion and agreement between the investigator and 
the Lilly clinical pharmacologist, CRP, or CRS.
Safety data, in particular AEs, SAEs, and adverse laboratory abnormalities, will be 
independently assessed by the investigator and will be considered related to the IMP unless there 
is clear evidence that the event is not related.  
After review of these data, an agreement on the appropriate dose will be made by the investigator 
and sponsor for Cohort 2.
The planned dosing regimen of Cohort 2 may be changed to 2.5 mg for Days 1 and 8; followed 
by 5 mg for Days 15 and 22; and 8 mg for Days 29, 36, 43, and 50, or the corresponding volume-
matched placebo before the first dose of Cohort 2 if the safety assessment for the dose-escalation 
decision indicates that the 10-mg dose of Cohort 1 is not well tolerated.
If any of the following scenarios occur, dosing at the current level and dose-escalation from 
Cohort 1 to Cohort 2 will be discontinued:
1) if a single patient experiences an SAE other than anticipated pharmacology of 
LY3298176 (for example, GI-related AEs [particularly nausea, vomiting, and diarrhea] or 
hypoglycemia)
2) two clinically significant events (CSEs) in each cohort that are related to LY3298176
administration, with the exception of anticipated pharmacology of LY3298176
3) if 50% or more of patients in a cohort experience a symptomatic hypoglycemic episode 
with plasma/serum glucose levels of ≤3.0 mmol/L [54 mg/dL])


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4) if more than 4 patients in 1 cohort experience moderate treatment-related AEs that impair 
normal activities
5) if 2 or more patients experience an acute pancreatitis event (Appendix 6)
Examples of unrelated events could include but are not limited to: events occurring before 
LY3298176 dosing; events experienced after receiving placebo; personal injury accidents that
were not a result of hemodynamic changes or neurological symptoms (dizziness, visual
disturbance, numbness, loss of muscle control); events resulting from viral or bacterial
infections; or changes in clinical chemistry or liver enzymes as a result of documented acute 
viral hepatitis, alcohol, or other hepatotoxic drug use.  
A CSE will be determined by the investigator or suitable designee (Appendix 4) and may include 
findings that do not fulfill the criteria for SAEs.  Patients experiencing CSEs thought to be 
related to the IMP will be encouraged to complete a 28-day follow-up period before study 
discharge.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions (2C to 8C) have 
been maintained, as communicated by sponsor, during transit for all IMP received and any 
discrepancies are reported and resolved before use of the IMP.
Only participants enrolled in the study may receive IMP or study materials, and only authorized 
site staff may supply or administer IMP. All IMP should be stored in an environmentally 
controlled and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (such as receipt, 
reconciliation, and final disposition records).
7.6.
Treatment Compliance
The IMP will be administered at the clinical site, and documentation of treatment administration 
will occur at the CRU.
7.7.
Concomitant Therapy
Treatment with drugs that are excluded in the entry criteria (Section 6) is not permitted.
Patients on stable concomitant medication at the time of study entry should continue their 
regular, unchanged dose throughout the study.
In general, concomitant medication should be avoided; however, acetaminophen (1g/dose, 
maximum 2g/day) may be administered at the discretion of the investigator for treatment of 
headaches, etc.  If the need for concomitant medication (other than acetaminophen) arises, 
inclusion or continuation of the patient may be at the discretion of the investigator, preferably
after consultation with a Lilly clinical pharmacologist, CRP, or CRS. Stable doses (refer to 


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Section 6) of over-the-counter or prescription medications (for example, antihypertensive agents, 
aspirin, lipid-lowering agents) for treatment of concurrent medical conditions are allowed.
All concomitant medications used during the course of study will be recorded in the eCRF.
7.8.
Treatment after the End of the Study
Not applicable for this study.


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8. Discontinuation Criteria
Patients discontinuing from the treatment prematurely for any reason should complete AE and 
other follow-up procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Discontinuation of the IMP for abnormal pancreatic tests should be considered by the 
investigator when a patient meets the following condition:

lipase and/or amylase are confirmed to be ≥3× ULN.  Please refer to algorithm 
for the monitoring of pancreatic events in Appendix 6.
Discontinuation of the IMP for abnormal liver tests should be considered by the investigator 
when a patient meets 1 of the following conditions after consultation with the Lilly-designated 
medical monitor:

ALT or AST >8× ULN

ALT or AST >5× ULN sustained for more than 2 weeks 

ALT or AST >3× ULN and TBL >2× ULN or international normalized ratio 
>1.5 

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 TBL >2× ULN

ALP >2.5× ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
8.1.1. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly clinical pharmacologist, CRP, 
or CRS and the investigator to determine if the patient may continue in the study.  If both agree it 
is medically appropriate to continue, the investigator must obtain documented approval from the 
Lilly clinical pharmacologist, CRP, or CRS to allow the inadvertently enrolled patient to 
continue in the study with or without continued treatment with IMP.
8.2.
Discontinuation from the Study
Patients will be discontinued in the following circumstances:

enrollment in any other clinical study involving an IMP or enrollment in any 
other type of medical research judged not to be scientifically or medically 
compatible with this study

participation in the study needs to be stopped for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and good clinical 
practice

investigator decision


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o
the investigator decides that the patient should be discontinued from 
the study
o
if the patient, for any reason, requires treatment with another 
therapeutic agent that has been demonstrated to be effective for 
treatment of the study indication, then discontinuation from the study 
occurs before introduction of the new agent

patient decision
o
the patient or legal representative requests to be withdrawn from the study
8.3.
Patients Lost to Follow-up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  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.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the clinical laboratory tests that will be performed for this study.
Appendix 7 provides a summary of the maximum number and volume of invasive blood 
samples, for all sampling, during the study.
Unless otherwise stated in 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
This section is not applicable for this study.
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 IMP or the 
study, or that caused the patient to discontinue the IMP before completing the study.  The patient
should be followed up 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.
After the informed consent form 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.  Additionally, site personnel will 
record any change in the condition(s) and the occurrence and nature of any AEs.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatment, or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the IMP, study device, and/or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.


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If a patient’s IMP is discontinued as a result of an AE, study site personnel must report this to 
Lilly or its designee via eCRF.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above
Study site personnel must alert the Lilly clinical pharmacologist, CRP, CRS, or its designee of 
any SAE as soon as practically possible.
Additionally, study site personnel must alert Lilly Global Patient Safety 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 up with official notification 
on study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
Although all AEs are recorded in the eCRF after signing informed consent, SAE reporting to the 
sponsor begins after the patient has signed informed consent and has received IMP.  However, if 
an SAE occurs after signing informed consent, but before receiving IMP, AND is considered 
reasonably possibly related to a study procedure then it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued from and/or completed the study (the patient’s summary eCRF has been 
completed).  However, if the investigator learns of any SAE, including a death, at any time after 
a patient has been discharged from the study, and the investigator considers the event reasonably 
possibly related to the study treatment or study participation, he or she must promptly notify 
Lilly.  
Pregnancy (maternal or paternal exposure to IMP) 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.
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 reports as related to IMP or procedure.  Lilly has procedures 


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that will be followed for the recording and expedited reporting of SUSARs that are consistent 
with global regulations and the associated detailed guidances.
9.2.2. Complaint Handling
Lilly collects product complaints on IMPs and drug delivery systems used in clinical trials in 
order to ensure the safety of study participants, monitor quality, and to facilitate process and 
product improvements.
Patients should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the IMP so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY3298176 is considered any dose higher than the 
dose assigned through randomization.
Refer to the IB for LY3298176.
9.4.
Safety
9.4.1. Laboratory Tests
For each patient, clinical laboratory tests detailed in Appendix 2 should be conducted according 
to the Schedule of Activities (Section 2).
9.4.2. Vital Signs
For each patient, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).  
Blood pressure (BP) and pulse rate (PR) should be measured after approximately 5 minutes in 
the supine position.
If orthostatic measurements are required, patients should be supine for approximately 5 minutes 
and stand for at least 2 minutes.  If the patient feels unable to stand, supine vital signs only will 
be recorded.  
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted.
Body temperature will be measured as specified in the Schedule of Activities and as clinically 
indicated (Section 2).
9.4.2.1.
Body Weight
Weight will be measured in a consistent manner using a calibrated scale according to the 
Schedule of Activities (Section 2).  Patients will be weighed in light clothing at approximately 
the same time in the morning before dosing and after an overnight fast and evacuation of bowel 
and the bladder, if possible.  During the treatment period, weight will be measured twice on each 


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scheduled occasion, with the patient stepping off the scale between measurements.  Both weight 
measurements will be recorded in the source document and the eCRF.  Wherever possible, the 
same scale will be used for all weight measurements throughout the study.
9.4.3. Electrocardiograms
For each patient, 12-lead digital ECGs should be collected according to the Schedule of 
Activities (Section 2).
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
patient receives the first dose of the IMP should be reported to Lilly or its designee as an AE 
via eCRF.
For each patient, a single 12-lead ECG will be collected locally at screening and follow-up or 
early termination visit according to the Schedule of Activities (Section 2). At all other time 
points, ECGs will be collected and stored using an ECG machine provided by the central ECG 
vendor. The Day 1 predose ECG will be taken in triplicate every 15 minutes for 1 hour to 
establish a baseline.  At all other scheduled times, consecutive triplicate ECGs will be obtained
at approximately 1-minute intervals.  Electrocardiograms may be obtained at additional times 
when deemed clinically necessary.  Collection of more ECGs (more replicates) than expected at 
a particular time point is allowed to ensure high-quality records.  All ECGs recorded should be 
stored at the investigational site.
Electrocardiograms must be recorded before collecting any blood for safety or PK tests.  Patients
must be supine for approximately 5 to10 minutes before ECG collection and remain supine but 
awake during ECG collection.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon as possible after the time of ECG collection and ideally while the 
patient is still present to determine whether the patient meets entry criteria at the relevant visit(s) 
and for immediate patient management should any clinically relevant findings be identified.
If a clinically significant quantitative or qualitative change from baseline is identified (including, 
but not limited to, changes in QT interval/QT interval corrected for heart rate [QTc] using 
Fridericia’s formula [QTcF] from baseline) after enrollment, the investigator will assess the 
patient for symptoms (for example, palpitations, near syncope, syncope) 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 or her review 
of the ECG printed at the time of evaluation from at least one of the replicate ECGs from each 
time point.  Any new clinically relevant finding should be reported as an AE.
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will perform a basic quality control check (for example, 
demographics and study details) and then store the ECGs in a database.  At a future time, the 
stored ECG data may be overread at the central ECG laboratory for further evaluation of 
machine-read measurements or to meet regulatory requirements.  


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The machine-read ECG intervals and heart rate may be used for data analysis and report-writing 
purposes unless a cardiologist overread of the ECGs is conducted before completion of the final 
study report (in which case, the overread data would be used).
9.4.4. Safety Monitoring
The Lilly clinical pharmacologist, CRP, or CRS will monitor safety data throughout the course 
of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly clinical 
pharmacologist, CRP, or CRS will periodically review the following data:

trends in safety data

laboratory analytes

serious and nonserious AEs, including AEs of special interest (for example, GI events, 
hypoglycemia, injection-site reactions, and hypersensitivity reactions) and reported and 
adjudicated pancreatitis
When appropriate, the Lilly clinical pharmacologist, CRP, or CRS will consult with the 
functionally independent Global Patient Safety therapeutic area physician or clinical research 
scientist.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, additional analyses of the safety data will be conducted by the personnel 
included in the Blinding/Unblinding Plan (Appendix 8).
9.4.4.1.
Hepatic Safety
If a study patient experiences elevated ALT ≥3× ULN, ALP ≥2× ULN, or elevated TBL ≥2×
ULN, liver tests (Appendix 5) should be repeated within 3 to 5 days including ALT, AST, ALP, 
TBL, direct bilirubin, γ-glutamyl transferase, and creatinine kinase to confirm the abnormality 
and to determine if it is increasing or decreasing.  If the abnormality persists or worsens, clinical 
and laboratory monitoring should be initiated by the investigator on the basis of consultation 
with the Lilly clinical pharmacologist, CRP, or CRS.  Monitoring should continue until levels 
normalize and/or are returning to approximate baseline levels.  
Additional safety data should be collected if 1 or more of the following conditions occur:  

elevation of serum ALT to ≥5× ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2× ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests 

patient discontinued from treatment because of a hepatic event or abnormality of 
liver tests

hepatic event considered to be an SAE


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9.4.4.2.
Pancreatic Safety
Serum amylase and lipase measurements will be collected as part of the clinical laboratory 
testing at time points specified in the Schedule of Activities (Section 2).  Additional 
measurements may be performed at the investigator’s discretion.  Further diagnostic assessments 
will be recommended as per the algorithm (refer to Appendix 6) for the monitoring of pancreatic 
events whenever lipase and/or amylase is confirmed to be ≥3× ULN at any visit postdose, even if 
the patient is asymptomatic. If pancreatitis is suspected, the case will be further defined during 
an adjudication process.  Any patient who develops symptoms of pancreatitis must not receive 
further administration of LY3298176.
9.4.4.3.
Hypersensitivity Reactions
All hypersensitivity reactions will be reported by the investigator either as AEs or, if any serious 
criterion is met, as SAEs.  Dosing should be temporarily discontinued in any individual 
suspected of having a severe or serious allergic/hypersensitivity reaction to IMP.  Investigational 
medicinal product may be restarted if, in the opinion of the investigator, the event was not related 
to IMP and if/when it is safe to do so.  If dosing is permanently discontinued, the patient should 
remain in the study as needed per medical judgement.
The report of a clinically significant AE of drug reaction or injection-site reaction may prompt 
notification of the sponsor, clinical photography, and referral for dermatologic evaluation and 
consideration of a skin biopsy and laboratory evaluations (ALT, AST, complete blood count with 
percent eosinophils, and additional immunogenicity testing).
9.4.4.3.1. Injection-Site Reactions
If an injection-site reaction is present, it will be fully characterized (including erythema, 
induration, pain, itching, and swelling) and will be closely monitored until resolution.
Investigational site staff will be provided with separate instructions/training on how to 
consistently evaluate injection-site reactions and their severity.  Photographs of injection-site 
reactions may be taken in a standardized fashion for record-keeping purposes; however, the 
photographs will not be used to evaluate injection-site reaction severity.
9.4.4.4.
Glucose Monitoring
Patients will be instructed on how to use the glucose meter provided by the site and conduct 
SMPG tests.  In addition to the PG monitoring, patients will be educated on the symptoms of 
hypoglycemia.  Throughout their participation in the study, patients will monitor PG levels.  
Patients will be provided diaries and instructed to record PG results whenever the patient 
experiences symptoms of hypoglycemia, while not in the CRU.  The investigator or designee
will review PG results clinically indicative of hypoglycemia or hyperglycemia.
Additionally, patients who were taking metformin or a DPP-IV inhibitor (except for omarigliptin, 
trelagliptin, and linagliptin) at screening will be required to monitor their PG in the morning 
before breakfast during the 28-day washout period.


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9.4.4.4.1. Hyperglycemia and Hypoglycemia Reporting
Episodes of hyperglycemia (fasting plasma/serum glucose >270 mg/dL [15 mmol/L]) or
hypoglycemia (plasma/serum glucose ≤70 mg/dL [3.9 mmol/L]) will be reported by the 
investigator or designated physician who will be responsible for advising the patient on what 
further actions to take.  Additional monitoring may be requested at the investigator’s discretion.
If the fasting plasma/serum glucose during the dosing period exceeds the acceptable level,
defined as hyperglycemia on 3 or more separate days during any 2-week period between 
screening and the end of the dosing period, the patient will be evaluated further at the study site.  
If fasting plasma/serum glucose continues to exceed the acceptable level, IMP will be 
discontinued, and treatment with an appropriate antidiabetic agent may be initiated by the 
investigator.  The patient will continue to be followed up in the study (for safety, PK, and 
immunogenicity assessment) for at least 28 days after his or her last dose.  If hyperglycemia 
occurs during the follow-up period, the patient will remain in the study until completion of the 
planned follow-up.
Hypoglycemia episodes will be recorded on specific eCRF pages.  Hypoglycemia will be treated 
appropriately by the investigator and additional monitoring of plasma/serum glucose levels may 
be performed.  The following categories of the 2017 American Diabetes Association position 
statement on glycemic targets (American Diabetes Association 2017) on the basis of
recommendations of the International Hypoglycaemia Study Group (International 
Hypoglycaemia Study Group 2017) should be applied for reporting in the eCRF and evaluating 
hypoglycemic events.
The main categories of hypoglycemia are outlined below:
Documented Glucose Alert Level (Level 1):  plasma/serum glucose ≤70 mg/dL (3.9 mmol/L)

Documented symptomatic hypoglycemia:  with typical symptoms of hypoglycemia.

Documented asymptomatic hypoglycemia:  without typical symptoms of 
hypoglycemia.

Documented unspecified hypoglycemia:  with no information about symptoms of 
hypoglycemia available.  (This has also been called unclassifiable hypoglycemia.)
Documented Clinically Significant Hypoglycemia (Level 2): with similar criterion as above 
except for threshold plasma/serum glucose <54 mg/dL (3.0 mmol/L)

Level 2 documented symptomatic hypoglycemia 

Level 2 documented asymptomatic hypoglycemia

Level 2 documented unspecified hypoglycemia


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Severe Hypoglycemia (Level 3)

Severe hypoglycemia (in adults): Patients had altered mental status, and could not 
assist in their own care, or were semiconscious or unconscious, or experienced coma 
with or without seizures, and the assistance of another person was to actively 
administer carbohydrate, glucagon, or other resuscitative actions.  Plasma/serum
glucose measurements may not be available during such an event, but neurological 
recovery attributable to the restoration of plasma/serum glucose concentration to 
normal is considered sufficient evidence that the event was induced by a low 
plasma/serum concentration (plasma/serum glucose ≤70 mg/dL [3.9 mmol/L]).

Severe hypoglycemia requiring medical attention: Severe hypoglycemic events 
when patients require therapy by Health Care Providers (Emergency Medical 
Technicians, emergency room personnel, etc) are of particular interest to payers.  
Therefore, some clinical trials may collect data on this subset of severe hypoglycemia 
episodes, especially if economic outcomes analyses may be based on trial results.
Other Hypoglycemia

Nocturnal hypoglycemia:  Any documented hypoglycemic event (including severe 
hypoglycemia) that occurs at night and presumably during sleep.  At Lilly, this is 
captured as hypoglycemia that occurs between bedtime and waking.  This definition 
is more useful than the commonly used ~midnight to ~6 AM definition, which does 
not take patients’ individual sleep times into consideration and is consistent with the 
American Diabetes Association recommendations for reporting events that occur 
during sleep (American Diabetes Association 2005).  It is also important to collect the 
actual time when a hypoglycemic event occurred to allow further characterization of 
hypoglycemia timing (eg, to allow analysis of frequency of events occurring during a
24-hr time period).  Nocturnal hypoglycemia may occur at severity Levels 1, 2, or 3.

Relative hypoglycemia (also referred to as pseudohypoglycemia [Seaquist et al. 
2013]):  An event during which typical symptoms of hypoglycemia occur, that does 
not require the assistance of another person, and is accompanied by plasma/serum 
glucose >70 mg/dL (3.9 mmol/L).  The plasma/serum glucose value for patients with 
chronically poor glycemic control can decrease so rapidly that patients may report 
symptoms of hypoglycemia before their plasma/serum glucose concentration falls 
below 70 mg/dL (3.9 mmol/L).  Events with plasma/serum glucose ≤70 mg/dL should 
not be categorized as relative hypoglycemia.  Evaluation and statistical analysis of 
this category is optional.  However, if a patient reports a relative hypoglycemia event 
where assistance from another person was received or the patient experienced 
significant symptoms, the study team should clarify the circumstances to ensure the 
event is not a severe hypoglycemia event and report it appropriately.  

Probable symptomatic hypoglycemia: Symptoms of hypoglycemia were present, 
but plasma/serum glucose measurement was not reported.


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
Overall (or total) hypoglycemia:  This optional category combines most cases of 
hypoglycemia (documented hypoglycemia and probable symptomatic hypoglycemia, 
including severe hypoglycemia).  It does not include relative hypoglycemia.  
Nocturnal and severe hypoglycemia are special cases of documented or probable 
hypoglycemia.  If an event of hypoglycemia falls into multiple subcategories, that 
event should only be counted once in the category of overall (or total) hypoglycemia.
If a hypoglycemic event meets the criteria of severe, it needs to be recorded as serious in the 
eCRF (that is, recorded as an SAE).  In the case of a hypoglycemic event (other than severe), the 
actual glucose value, if measured, should be recorded in the eCRF, with any treatments 
administered, and not be recorded as an AE.  Cases of hypoglycemia may be treated with foods 
rich in carbohydrate such as fruit, juice, skimmed milk, or energy bars.  All episodes of 
hypoglycemia that are determined by the investigator to constitute severe hypoglycemia 
according to the definition above should be reported as SAEs.
9.4.4.5.
Nausea and Vomiting
Nausea and vomiting events are considered AEs of interest and will be recorded as AEs in the 
eCRF.  For each event assessment of severity, duration, and investigator’s opinion of relatedness 
to IMP and protocol procedure will be captured.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 3 mL each will be collected to determine the plasma concentrations of 
LY3298176.  A maximum of 3 samples may be collected at additional time points during the 
study if warranted and agreed upon between both the investigator and sponsor.  Instructions for 
the collection and handling of blood samples will be provided by the sponsor.  The actual date 
and time (24-hour time period) of each sampling will be recorded.
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of LY3298176 will be assayed using a validated liquid chromatography mass 
spectrometry method.  Analyses of samples collected from patients treated with placebo are not 
planned.
Bioanalytical samples collected to measure IMP concentrations will be retained for a maximum 
of 1 year after last patient visit for the study.  
9.6.
Pharmacodynamics
Assessment of LY3298176 pharmacology may include fasting PG levels; insulin; lipid profile 
(total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, triglycerides);
HbA1C; body weight; 7-point SMPG test; glucagon; and oral glucose tolerance test (OGTT;


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AUC for glucose and insulin).  Additional exploratory PD analysis may be analyzed as deemed 
appropriate.
Blood samples will be obtained for the measurement of PD.  The scheduled times for the 
collection of these samples are as listed in the Schedule of Activities (Section 2).  The timing of 
PD samples is intended to assess pharmacologic effects of LY3298176.  The sampling times may 
be modified at the discretion of the sponsor, but the total number of the samples or total blood 
volume will not increase.
The sample(s) will be stored for up to a maximum of 1 year after the last patient visit for the 
study at a facility selected by the sponsor.
9.6.1. Glucose Samples
Plasma/serum concentrations of glucose, as indicated in the Schedule of Activities (Section 2), 
will be assayed using validated analytical methods.  Instructions for the collection and handling 
of blood samples for these analyses will be provided by the sponsor.
9.6.1.1.
Oral Glucose Tolerance Test
Glucose and insulin will be measured by an OGTT to assess effects of LY3298176 on glycemic 
control, disposition index, and insulin sensitivity.  The schedule for OGTTs is indicated in the 
Schedule of Activities (Section 2).
Patients shall maintain adequate carbohydrate intake 3 days before the scheduled OGTT.  
Patients shall fast for at least 10 hours overnight before administration of the glucose.  A 75-g 
glucose dose will be given orally.  Patients should consume the glucose load within 5 minutes.  
Blood samples will be drawn for assessment of glucose and insulin at pretest, 0.5, 1, 1.5, and 
2 hours after the initiation of the glucose load.
9.6.1.2.
7-Point Glucose Monitoring
Patients will be asked to perform a 7-point PG profile according to the Schedule of Activities 
(Section 2).  Patients will be asked to test their self-monitored PG levels before each meal, 
approximately 2 hours after each meal, and at bedtime.  Patients will be asked to record their 
self-monitored PG levels in their diaries according to instructions.  The complete 7-point PG
profile must be completed in a single day.  If a patient does not complete the entire profile in a 
single day, all 7 points must be collected on a subsequent day. In the event that the baseline 7-
point SMPG is conducted on the day before Day -1, all 7 points must be completed on that day to 
avoid interference with the OGTT that will be administered on the subsequent day (Day -1).
9.6.2. Exploratory Sample Assessments and Storage
Samples will be collected and retained for a maximum of 15 years after the last patient visit, or 
for a shorter period if local regulations and/or ethical review boards (ERBs)/IRBs impose shorter 
time limits for the study, at a facility selected by the sponsor.  The duration allows the sponsor to 
explore the effects of LY3298176 on potential biomarkers such as adiponectin, cortisol, and 
bone biomarkers.  Blood samples will be collected as specified in the Schedule of Activities 
(Section 2).


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9.6.3. Meal Intakeand Appetite
To explorethe effects of LY3298176 on meal intake and appetitesensation,patientswill be 
provided standardized lunchand dinner meals withan approximate total energy and 
macronutrient contents of 700 kCal and20% protein, 25% fat,and 55% carbohydrateaccording 
to the Schedule of Activities(Section 2).The meal intake will be recordedin the source 
document.  The subjective rating of appetitesensationsis measured by a 100-mm visual 
analogue scale (VAS)for parameters of hunger, fullness,satiety,and prospective food 
consumption before and 4to 5 hours afterthe standardized lunch and dinner meals.The 
standardized lunch and dinner meals will be provided at least 4 hours afterthe previous meal or
the ingestion of glucose in theOGTT.  The VAS is avalidated tool to assess appetite sensation 
parameters (Flintet al. 2000).  The VAS is presented as a 10-cm (100-mm) line, anchored by 
verbal descriptors, usually “extremely” and “not at all.”  Patients arerequired to rate their 
subjective sensations onfour100-mm scales combined with the questions:  “How hungry do you 
feel right now?”,“How satisfied do you feel right now?”, “How full do you feel right now?”, and 
“How much food do you think you could eat right now?”  A staff member will use a caliper to 
measure the distance from 0 to the mark that the patient placed on the VAS and record the 
measurement in the source document.  Overall appetite score iscalculated as the averageof the 4
individual scores—satiety +fullness +(100-prospective food consumption)+(100-hunger)/4
(van Can et al. 2014).  The higher overall appetite score indicatesless appetite,and the lower 
scoreindicatesmore appetite.
9.6.4. Immunogenicity Assessments
Samples from patients in each cohort will be tested for the development of treatment-emergent 
antidrug antibodies (TE-ADAs) againstLY3298176.  A blood sample will be collected at 
specific study visits according to the Schedule of Activities (Section2
CCI
).  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 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 afterthe event.  Instructions for the collection and handling of blood samples 
will be provided by the sponsor.  The actual date and 24-hour time periodof each sampling will 


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All patients will have an ADA sample measured at early discontinuation or at the follow-up visit 
(Day 85) approximately 5 weeks after the last dose of LY3298176.  A risk-based approach will 
be used to monitor patients who have clinically significant TE-ADAs at the last visit.  Treatment-
emergent ADAs are defined as those with a titer 2-fold (1 dilution) greater than the minimum 
required dilution if no ADAs were detected at baseline or those with a 4-fold (2 dilutions) 
increase in titer from baseline if ADAs were detected at baseline.  Clinically significant 
TE-ADAs will be defined as any TE-ADA at the follow-up visit (Day 85) with:

a high titer (1280) or an increasing titer from last measured value

an association of the 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-ADAs should be followed up with ADA testing 
every 3 months for up to approximately 1 year or until the ADA titers have returned to baseline 
ADA titer (defined as ADA titer within 2-fold of baseline), whichever occurs earlier.  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 up 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 are 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-ADAs 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, or for a shorter 
period if local regulations and ERBs allow, at a facility selected by the sponsor.  The duration 
allows the sponsor to respond to future regulatory requests related to LY3298176.  Any samples 
remaining after 15 years will be destroyed.
9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2), where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
LY3298176 and to investigate genetic variants thought to play a role in T2DM and related 
complications.  Assessment of variable response may include evaluation of AEs or differences in 
efficacy.  
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigative site personnel.  


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Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and/or ERBs impose shorter time limits, for the study 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 is commercially available.  
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section.  
9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of patient response (including safety), and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including DNA, RNA, proteins, lipids, 
and other cellular elements.  
Serum and plasma samples for nonpharmacogenetic biomarker research will be collected at the 
times specified in the Schedule of Activities (Section 2) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
LY3298176, pathways associated with T2DM, mechanism of action of LY3298176, and/or 
research method, or for validating diagnostic tools or assay(s) related to T2DM.
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and/or 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 or is commercially available.  
9.9.
Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
The sample size for the study was chosen to provide sufficient data to evaluate the primary 
objective of this study and is not intended to achieve any a priori statistical requirements.
Approximately 49 Japanese patients with T2DM may be enrolled so that approximately 
32 patients complete the study with compliant defined dosing regimen.  The estimated drop-out 
rates are 30% for Cohorts 1 and 3 and 50% for Cohort 2.  Patients will be administered 8 weekly 
SC doses of LY3298176 or placebo in a ratio of 12 LY3298176:3 placebo for Cohorts 1 and 3, 
and 16 LY3298176:3 placebo for Cohort 2. Considering the possibility of higher drop-out rate 
when administered the highest dose level of LY3298176, the number of patients to be enrolled in 
Cohort 2 is higher than those for the other 2 cohorts.
Replacement of discontinued patients is not planned because the sample size is determined 
considering the expected drop-out rate.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
All patients who discontinue from 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.
10.2.2. Study Participant Characteristics
The patient’s age, sex, weight, height, or other demographic characteristics will be recorded and 
may be used in the PK, PD, and safety analyses as quantitative or classification variables.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.  
PK and PD analyses will be conducted on data from all patients who receive at least 1 dose of 
the IMP and have evaluable PK and PD data.  
Patients treated with placebo within each cohort of the study will be pooled for PD and safety 
analyses. 
Safety analyses will be conducted for all enrolled patients, whether or not they completed all 
protocol requirements.  Primary safety analyses will be conducted by treatment group defined by 
intended titration regimen group.  Additional analyses will be conducted on the basis of the 
treatment groups defined by titration regimen as actually treated, if deemed necessary after data 
review.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Statistical 
analyses will be fully detailed in the statistical analysis plan.


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10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All IMP and protocol procedure–related AEs will be listed, and if the frequency of events allows, 
safety data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment group will be presented by severity and by 
association with IMP as perceived by the investigator.  Symptoms reported to occur before the 
first IMP dosing will be distinguished from those reported as new or increased in severity during 
the study.  Each symptom will be classified by the most suitable term from the Medical 
Dictionary for Regulatory Activities.
The number of IMP-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital signs, ECG 
parameters, injection-site reactions, and hypoglycemia.  The parameters will be listed and 
summarized using standard descriptive statistics.  
Laboratory measurements will be summarized with respect to observed values and change from 
baseline by treatment group at each time point using descriptive statistics.  In addition, all 
clinical chemistry, hematology, and urinalysis data outside the reference ranges will be tabulated 
by parameter and treatment group.
Vital signs will be summarized with respect to observed values and change from baseline (Day 1, 
Predose) by treatment at each time point using descriptive statistics.  For change from baseline 
values, a mixed-model repeated-measure model with treatment, time (of measurement), and 
treatment-by-time interaction as fixed effects, patient as random effect, and baseline as covariate 
will be used to determine the effects of LY3298176.  
Electrocardiogram parameters, including the pulse rate, QT interval, RR interval, and QTc using 
Fridericia’s formula (QTcF), QRS interval duration, and heart rate, will be summarized.  The 
number and percentage of patients with a maximum increase from baseline in QTcF will be 
summarized for each treatment group according to the following categories:  >30 milliseconds 
and >60 milliseconds.  In addition, the number and percentage of patients with QTcF postdose 
values according to the following categories:  >450 milliseconds, >480 milliseconds, and 
>500 milliseconds, will be summarized by treatment group.  Exploratory analyses may be
performed to determine the effects of LY3298176 concentration-response analysis of QTcF.
Additional analysis will be performed, if warranted, upon review of the data.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for LY3298176 will be calculated by standard 
noncompartmental methods of analysis.


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The primary parameters for analysis will be Cmax, AUC, and Tmax of LY3298176.  Other 
noncompartmental parameters, such as half-life, apparent clearance, and apparent volume of 
distribution may be reported.
Model-based analysis will be performed combined with data from other studies.  LY3298176 
concentration data will be analyzed using a population PK approach via nonlinear mixed-effects 
modeling with the NONMEM software (NONMEM, Dublin, Ireland).  Additionally, the effect of 
intrinsic and extrinsic patient factors such as age, weight, sex, and renal function on PK may be 
examined as needed.
10.3.2.2. Pharmacokinetic Statistical Inference
PK dose proportionality may be assessed in an exploratory manner in model-based analysis.  
The parameter Tmax of LY3298176 will be analyzed using a nonparametric method.
PK parameters will be summarized using descriptive statistics by dosing regimen.  
10.3.3. Pharmacodynamic Analyses 
10.3.3.1. Pharmacodynamic Parameter Estimation 
The ability of LY3298176 to reduce fasting or dynamic glucose and the effects on insulin will be 
assessed.  Such effects will be explored for different treatment regimens of LY3298176.
The AUC(0-2h) for glucose and insulin during an OGTT will be calculated using the trapezoidal 
rule.  The AUC(0-2h) as well as other derived parameters or observed concentration at specific 
time points for each patient on the study day will also be baseline-adjusted. The concentrations 
on Day -1 will be used as baseline.
10.3.3.2. Pharmacodynamic Statistical Inference
Statistical inference on PD parameters will be based on the patients who are compliant to each 
treatment regimen.  Pharmacodynamic parameters may be transformed before statistical analyses, 
if deemed necessary.
Absolute values, as well as change from baseline in each parameter, will be analyzed using
mixed-effects models to evaluate treatment effects as well as treatment comparisons. The model
will include treatment, or treatment regimen actually received, as fixed effects and the patient as 
a random effect. For repeated measured parameters, day and treatment-by-day interaction terms 
will be included in the model. Baseline (Day -1) values, as well as other influencing variables, 
may be used as covariates.  The main comparisons will be between each LY3298176-treated 
group and placebo group.
The individual observed and mean time profile of the postdose PD parameters will be plotted by
treatment group.


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10.3.4. Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic/pharmacodynamic modeling may be used to characterize the exposure-response 
relationships between LY3298176 concentrations and various PD endpoints, provided data are 
sufficient.
10.3.5. Evaluation of Immunogenicity
The frequency of antibody formation (presence and titers) to LY3298176 will be determined.  If 
any cross-reactive or neutralization assays are performed, the frequency of antibodies will be 
determined.  If there are a sufficient number of patients with positive antibodies to LY3298176, 
the change of antibodies (negative to positive) will be summarized using shift tables.
The relationship between the presence of antibodies, antibody titers, and clinical parameters (eg, 
AEs) may be assessed.  Likewise, the relationship between antibody titers, PK parameters, and 
PD response to LY3298176 may be assessed.
10.3.6. Data Review During the Study
Access to safety data is scheduled to occur at least once to review the safety data up to Day 36
(predose procedure) of Cohort 1 from at least 8 patients to proceed to Cohort 2.  The available 
PK data may be accessed at the review.  Pharmacokinetic data is not mandatory for the dose 
escalation or for moving to the next cohort.  The purpose of this review is to guide dose selection 
for the next dosing session, and/or to inform the design of subsequent studies.  The investigator 
and the Lilly sponsor team will make the determination regarding dose escalation based upon 
their review of the data.  The investigator will remain blinded, and the Lilly sponsor team will be 
unblinded during these reviews.
10.3.7. Interim Analyses
Interim analysis may be conducted when all data through Day 85 become available from all 
cohorts.  Additional interim analysis may be conducted to proceed to the subsequent Japan 
studies.  For this purpose, at least safety and PK data may be analyzed.


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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.
American Diabetes Association. Glycemic targets. Sec 6. In:  Standards of medical care in 
diabetes—2017. Diabetes Care. 2017;40(suppl 1):S48-S56. 
Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes:  
systematic review and meta-analysis. JAMA. 2007;298(2):194-206.
Baynes KC. The evolving world of GLP-1 agonist therapies for type 2 diabetes. Ther Adv 
Endocrinol Metab. 2010;1(2):61-67.
Bydureon [package insert]. Wilmington, DE:  AstraZeneca; 2015.
Drucker DJ, Nauck MA. The incretin system:  glucagon-like peptide-1 receptor agonists and 
dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696-1705.
Finan B, Ma T, Ottaway N, Müller TD, Habegger KM, Heppner KM, Kirchner H, Holland J, 
Hembree J, Raver C, Lockie SH, Smiley DL, Gelfanov V, Yang B, Hofmann S, Bruemmer D, 
Drucker DJ, Pfluger PT, Perez-Tilve D, Gidda J, Vignati L, Zhang L, Hauptman JB, Lau M, 
Brecheisen M, Uhles S, Riboulet W, Hainaut E, Sebokova E, Conde-Knape K, Konkar A, 
DiMarchi RD, Tschöp MH. Unimolecular dual incretins maximize metabolic benefits in 
rodents, monkeys, and humans. Sci Transl Med. 2013;5(209):209ra151.
Flint A, Raben A, Blundell JE, Astrup A. Reproducibility, power and validity of visual analogue 
scales in assessment of appetite sensations in single test meal studies. Int J Obes Relat Metab 
Disord. 2000;24(1):38-48.
International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 mmol/L 
(54 mg/dL) should be reported in clinical trials:  a joint position statement of the American 
Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 
2017;40(1):155-157. 
Irwin N, Hunter K, Frizzell N, Flatt PR. Antidiabetic effects of sub-chronic activation of the GIP 
receptor alone and in combination with background exendin-4 therapy in high fat fed mice. 
Regul Pept. 2009;153(1-3):70-76.
Kim SJ, Nian C, Karunakaran S, Clee SM, Isales CM, McIntosh CH. GIP-overexpressing mice 
demonstrate reduced diet-induced obesity and steatosis, and improved glucose homeostasis. 
PLoS One 7. 2012;7(7):e40156.
Nauck MA, Baller B, Meier JJ. Gastric inhibitory polypeptide and glucagon-like peptide-1 in the 
pathogenesis of type 2 diabetes. Diabetes. 2004;53(suppl 3):S190-S196.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller SR, Rodriguez H, 
Rosenzweig J, Vigersky R. Hypoglycemia and diabetes:  a report of a workgroup of the 
American Diabetes Association and the Endocrine Society. Diabetes Care. 
2013;36(5):1384-1395.
Trulicity [package insert]. Indianapolis, IN:  Eli Lilly and Company; 2017.


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van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. Effects of the once-daily GLP-1 
analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism 
in obese, non-diabetic adults. Int J Obes (Lond). 2014;38(6):784-93.


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
ADA
antidrug antibody
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase 
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
blinding
A procedure in which one or more parties to the study are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
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 patients are aware of the treatment received.
Cmax
maximum drug concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CRF
case report form
CRP
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician or other medical officer.
CRU
clinical research unit
CSE
clinically significant event
DPP
dipeptidyl peptidase


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ECG
electrocardiogram
eCRF
electronic case report form
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
GI
gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide
GLP-1
glucagon-like peptide-1
HbA1c
hemoglobin A1c
HIV
human immunodeficiency virus
IB
investigator’s brochure
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form.  
investigational 
medicinal product 
(IMP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, 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.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
legal 
representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the clinical study.
MAD
multiple-ascending dose
OGTT
oral glucose tolerance test
PG
plasma glucose
PK/PD
pharmacokinetic/pharmacodynamic
QTc
QT corrected for heart rate
QTcF
QTc using Fridericia’s formula


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randomize
the process of assigning patients to an experimental group on a random basis
SAE
serious adverse event
SMPG
self-monitored plasma glucose
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.  
TBL
total bilirubin level
TE-ADA
treatment-emergent antidrug antibody
T2DM
type 2 diabetes mellitus
Tmax
time to maximum drug concentration
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Laboratory Tests
Hematologya
Clinical Chemistry (fasting)a
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Chloride
Mean cell volume
Serum creatinine
Mean cell hemoglobin
Calcium
Mean cell hemoglobin concentration
Phosphorus
Leukocytes (WBC)
Glucose
Platelets
Blood urea nitrogen
Differential WBC Absolute counts of: 
Uric acid
Neutrophils
Total protein
Lymphocytes
Albumin
Monocytes
Total bilirubin
Eosinophils
Alkaline phosphatase
Basophils
Alanine aminotransferase
Aspartate aminotransferase
Urinalysisa
Lipase
Specific gravity
Amylase
pH
Total cholesterolf
Protein
Triglyceridef
Glucose
eGFRe
Ketones
Bilirubin
Biomarkersd
Urobilinogen
Fasting plasma glucose, insulin, glucagonc
Blood
OGTT serum glucose and insulinc
Leukocytes
Exploratory storage samplec
Microscopyb
Other Tests
Lipid Panelc,d
Pregnancy test (urine, serum)a,b
HDL-C
Follicle-stimulating hormone a,b,e
LDL-C (calculated)
Drug and alcohol screena
Total cholesterol
Hemoglobin A1cc,d
Triglycerides
Pharmacogenetic sample (storage)c,d
Nonpharmacogenetic sampling (storage)c,d
Serologya,e
LY3298176 Plasma levelsd,g
Hepatitis B surface antigen
Immunogenicityd,g
Hepatitis C antibody
HIV antibody and/or HIV antigen
Abbreviations:  eGFR = estimated glomerular filtrating ratio; HDL-C = high-density lipoprotein cholesterol; 
HIV = human immunodeficiency virus; LDL-C = low-density lipoprotein cholesterol; OGTT = oral glucose 
tolerance test; RBC = red blood cells, WBC = white blood cells.
a
Performed at local laboratories.
b
If clinically indicated, per investigator’s discretion.
c
Performed or stored at a central laboratory.


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d
These results will not be reported to investigator sites except for the screening hemoglobin A1c.
e
Performed at screening only.
f
Total cholesterol and triglyceride concentrations in the safety panel will not be required on the days that the lipid 
panel is performed.  
g
Assayed at Lilly-designated laboratory.


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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the informed consent form 
(ICF) before the performance of any protocol procedures and before the administration 
of investigational medicinal product.

answering any questions the patient may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the patient’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file.
Recruitment
Lilly is responsible for the central recruitment strategy for patients.  Individual investigators may 
have additional local requirements or processes.  Study-specific recruitment material should be 
approved by Lilly.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Council for Harmonisation (ICH)
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on good clinical practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current investigator’s brochure and updates during the course of the study

ICF

relevant curricula vitae


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Regulatory Considerations
This study will be conducted in accordance with the protocol and with:
1) consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
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 organization.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of 
the study.  
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator with the most enrolled patients will serve as the final report coordinating 
investigator.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the final report coordinating investigator.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
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

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the case report forms (CRFs), and 
study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection

conduct a quality review of the database


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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 and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.  
The purpose and use of patient personal information collected will be provided in a written 
document to the patient by the sponsor.
Study and Site Closure
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.
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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Appendix 4.
Clinically Significant Adverse Effects
The table below summarizes the type and severity of symptoms, clinical signs, and clinical 
laboratory findings that may qualify as a clinically significant event.  These are intended as a 
guideline to the investigator(s), not as a set of absolute criteria.  The underlying principle is to 
define a level of moderate to severe abnormality in safety findings that could cause harm to 
health and would preclude further dosing of a patient/subject who experiences this effect.  Safety 
parameters not included in this table may be interpreted in a similar fashion according to 
investigator judgment.


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Clinically Significant Adverse Effects
Parameter
CSE level
Symptoms
Severe hypoglycemia
One episode of severe hypoglycemia defined as low blood glucose with mental 
status impairment severe enough to require third-party assistance
Dizziness/hypotension
Orthostatic CNS symptoms (dizziness, confusion) that are not vasovagal responses 
to provocative stimuli (for example, phlebotomy, nausea, bowel or bladder 
function), and are associated with orthostatic SBP decrease >20 mm Hg or DBP 
decrease >10 mm Hg or heart rate >105 bpm, for >3 hours 
Sensorium
Disorientation to time, place, or identity.  Any abnormal ideation
Mood
Feelings of grief or loss that interfere with study procedures or activities of daily 
living; any suicidal ideation
Headache/pain
Any focal or generalized head pain that disrupts normal activities and is not 
responsive to medical therapies
Pruritus
Generalized itching for more than 24 hours that is unresponsive to oral antihistamine
Signs
Systolic blood pressure
>30 mm Hg increase from baseline values and an absolute level >190 mm Hg
Diastolic blood pressure
>20 mm Hg increase from baseline values and an absolute level >115 mm Hg
Heart rate
Resting (sitting or recumbent) HR >120 bpm
Cardiac rhythm
Any rhythm other than sinus rhythm, mild sinus bradycardia, or mild sinus 
tachycardia
QTc
>500 milliseconds or >60 milliseconds increase from baseline value
QRS morphology
Significant prolongation of QRS interval or new onset of bundle branch block
Tremor
Readily visible tremor during normal movement deemed unrelated to hypoglycemia
Reflexes
New onset of clonic reflexes
Clinical Laboratory
Confirmed by repeat measurements within 48 hours
Hemoglobin
Absolute value <10 g/dL and >2 g/dL reduction from baseline
Neutropenia
Absolute neutrophils <1,500/μL and >1,000 L decrease from baseline
Lymphopenia
Absolute lymphocyte count <800/μL and >500/L decrease from baseline
Platelet count
<75,000/μL and >50,000/L decrease from baseline
Creatinine
>2 mg/dL and >0.5 mg/dL increase from baseline value
Urea
>8 mmol/L and >3 mmol/L increase from baseline values
Alanine aminotransferase
>5-fold above laboratory reference upper limit value
Aspartate 
aminotransferase
>5-fold above laboratory reference upper limit value
Bilirubin (total)
>1.5-fold above laboratory reference upper limit value
Potassium
<2.5 or >5.5 mEq/L and >0.5 mEq/L change from baseline value
Sodium
<130 or >150 mEq/L and >10 mEq/L change from baseline value
Abbreviations:  BPM = beats per minute; CNS = central nervous system; CSE = clinically significant event; DBP = 
diastolic blood pressure; HR = heart rate; QTc = QT interval corrected for heart rate; SBP = systolic blood 
pressure.


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Appendix 5.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with Lilly clinical pharmacologist, clinical 
research physician, or clinical research scientist.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils
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
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Antinuclear Antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti–Smooth Muscle Antibody (or Antiactin 
Antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = γ-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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Appendix 6.
Pancreatic Monitoring
Glucagon-like peptide-1 agonists have been associated with a possible risk of acute pancreatitis.  
In 2006, the US prescribing information for exenatide was revised to include the event of 
pancreatitis.  In 2007, the US prescribing information for this medication was amended to 
include pancreatitis under precautions.  Epidemiologic studies have indicated that there is an 
increased incidence and prevalence of pancreatitis in persons with type 2 diabetes mellitus 
(T2DM).
To enhance understanding of the natural variability of pancreatic enzymes in the T2DM 
population and to assess for any potential effects of LY3298176 on the exocrine pancreas, 
amylase and lipase values will be monitored in all current and future clinical trials with 
LY3298176.
Additional monitoring will be requested for amylase or lipase values ≥3× the upper limit of 
normal (ULN) at any visit after randomization, even in asymptomatic patients (see figure below).  
Lipase and amylase may also be obtained at any time, at the investigator’s discretion, during the 
clinical trials for any patient suspected of having symptoms suggestive of pancreatitis (eg, severe 
gastrointestinal signs and/or symptoms).
Acute pancreatitis is an adverse event (AE) defined as an acute inflammatory process of the 
pancreas that may also involve peripancreatic tissues and/or remote organ systems.  The 
diagnosis of acute pancreatitis requires 2 of the following 3 features:

abdominal pain characteristic of acute pancreatitis

serum amylase and/or lipase >3× ULN

characteristic findings of acute pancreatitis on computed tomography scan or 
magnetic resonance imaging
Most patients with acute pancreatitis experience abdominal pain that is located generally in the 
epigastrium and radiates to the back in approximately half of cases.  The pain is often associated 
with nausea and vomiting.  However, experience with glucagon-like peptide-1 agonists has 
demonstrated that some patients/subjects asymptomatic for classic pancreatitis may demonstrate 
significant elevations of lipase and/or amylase.  For patients considered by investigators to be 
asymptomatic for pancreatitis, but whose value(s) for lipase and/or amylase are ≥3× ULN, an 
algorithm is in place to follow up with these patients safely and to quickly reach or not reach a 
diagnosis of pancreatitis.


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Abbreviations:  A/L = amylase and/or lipase; CBC = complete blood count; CT = computed 
topography; LFTs = liver function tests; LY = LY3298176; MRI = magnetic resonance imaging; 
ULN = upper limit of normal.
Pancreatic Enzymes:  Safety Monitoring Algorithm
In Patients without Symptoms of Pancreatitis1,2
Follow this algorithm when the value(s) for serum amylase and/or lipase are = 3x upper limit of normal (ULN)
Test A/L every 4 Weeks 
(More Frequently if Protocol Visit  
Schedule is < 4 weeks)
Negative Imaging Results
Stop Injectable Study Drug5
Consult for Assessment and Management 
Assess for Causes of Pancreatitis 
Notify Lilly
Retest within 24 - 72 hours
Send sample to Laboratory
Amylase and/or Lipase (A/L3) = 3X ULN
A/L Not Decreasing
4.  Abdominal imaging is most valuable when performed 
at the time of elevated enzyme values.  If in the opinion 
of the radiologist or investigator, it is safe for the 
patient/subject to receive contrast, an enhanced 
abdominal CT is preferred. MRI is also an acceptable 
imaging modality.
3. A/L = amylase and/or lipase. Either or both 
enzymes can be used to meet the algorithm criteria.   
5. At a minimum, order a CBC and a pancreatic 
panel (which includes LFTs, calcium and 
triglycerides). Record all concomitant 
medications.
A/L Decreasing
Repeat Abdominal Imaging4
as Soon as Possible After 
Confirmation of Laboratory Values  
1. Symptomatic – related primarily to abdominal pain 
consistent with pancreatitis; however, in the opinion of 
the investigator severe nausea and vomiting plus
other symptoms consistent with pancreatitis may be
considered symptomatic as well.  
2. If in the opinion of the investigator, the patient 
has symptoms of acute pancreatitis:
(a) Stop injectable study drug 
(b) Consult for assessment and management 
(c) Assess for causes of pancreatitis 
(d) Notify Lilly
If A/L = 3X ULN, perform 
Abdominal Imaging4
Stop Injectable Study Drug5
Consult for Assessment and Management 
Assess for Causes of Pancreatitis
Notify Lilly
Test A/L Every 4 Weeks Until 
A/L = 3X ULN, 
Then Follow Protocol Schedule
Positive Imaging Results
Negative Imaging Results
Positive Imaging Results
Test A/L Every 4 Weeks Until 
A/L = 3X ULN, 
Then Follow Protocol Schedule
5
5


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Patients diagnosed with pancreatitis will be discontinued from the study.  Investigators will be 
responsible for following up, through an appropriate health care option, these pancreatitis AEs 
until the events resolve or are explained.  AEs that meet the diagnostic criteria of acute 
pancreatitis will be captured as serious AEs.  For all other pancreatic AEs (eg, idiopathic or 
asymptomatic pancreatic enzyme abnormalities), the investigator will be responsible for 
determining the seriousness of the event (AE or serious AE) and the relatedness of the event to 
investigational medicinal product.


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Appendix 7.
Blood Sampling Summary
This table summarizes the approximate number of samples and blood volumes for all blood 
sampling (screening, safety laboratories, bioanalytical assays, and the other tests) during the
study.
Protocol I8F-JE-GPGC Sampling Summary
Purpose
Blood Volume 
per Sample 
(mL)
Number of Blood Samples
Total Volume (mL)
Cohort 1 or 2
Cohort 3
Cohort 1 or 2
Cohort 3
Screening serology and 
Serum pregnancy testsa
9b
1
1
9
9
Clinical safety laboratory 
testsa
10b
20
16
200
160
Lipid panel
2.5
3
3
7.5
7.5
LY3298176
pharmacokinetics
3
18
18
54
54
Potential additional 
LY3298176 
pharmacokinetic samples
3
3
3
9
9
Glucagon
2
15
13
30
26
Fasting plasma glucose and 
insulin
4.5
15
13
67.5
58.5
Oral glucose tolerance test
(serum glucose and insulin)
2.5
10
10
25
25
HbA1c
2
4
4
8
8
Immunogenicity
6
4
4
24
24
Exploratory storage sampled
Adiponectin
2
2
2
4
4
Cortisol
2.5
3
3
7.5
7.5
Bone biomarkers
3.5
2
2
7
7
Pharmacogenetics
6
1
1
6
6
Nonpharmacogenetics 
Storage sample
4.5
6
6
27
27
Total
485.5c
432.5c
Abbreviation: HbA1c = hemoglobin A1c.
a
Additional samples may be drawn if needed for safety purposes.
b Because screening and safety (chemistry and hematology) tests are performed at local laboratories at each site, 
this volume is an estimate and will vary depending on the local laboratory’s testing requirements.
c The maximum blood volume will increase if follow-up visits for antidrug antibody testing are needed.
d
Blood volumes for this storage sample is calculated based on the assumption that the following biomarkers will 
be assayed for. 


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
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LY3298176
Appendix 8.
Protocol I8F-JE-GPGC 
Blinding/Unblinding Plan
Levels of unblinding are indicated in the table below.  This table provides general guidance as to 
who will be allowed access to randomization codes at various steps of the trial.  The information 
in the protocol will always take precedence over this table.  
Randomization data are kept strictly confidential and are accessible only by authorized personnel 
until unblinding of the trial as described below.  All measures possible must be taken to maintain 
the blinded portion of the study, which means that access to the randomization code must be 
restricted to authorized personnel as described in the protocol and summarized in the 
table below.
If there is a need for unblinding of select people from Lilly and/or the third-party organization 
who are not dealing with the site, the detailed process, including formation of the unblinded 
team, creating restricted access electronic folders, and measures taken to guard against 
inappropriate dissemination of treatment codes (for example, by maintaining no contact with the 
study team until team is unblinded), will be described in the Unblinding Plan or another 
appropriate document, and approval will be sought from Lilly and Covance team statisticians.


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
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LY3298176
Study I8F-JE-GPGC Blinding and Unblinding Plan
Study Timelines
Study Team Member
Screening
Randomization
Treatment 
Phase
Follow-Up
Database 
Lock (up to 
Day 85)
General
Drug supply
NA
U
U
U
U
Randomization statisticians
NA
U
U
U
U
ECG reader
NA
B
B
B
U
Bioanalysis lab/sample analysis
NA
U
U
U
U
Clinical Site
Pharmacist
NA
U
U
U
U
Dosing staff
NA
B
B
B
U
Patient
NA
B
B
B
U
Investigator
NA
B
B
B
U
Study monitor 
NA
U
U
U
U
Covance
Project integration
NA
U
U
U
U
Data management
NA
U
U
U
U
Programming
NA
U
U
U
U
Statistician
NA
U
U
U
U
Medical writing 
NA
U
U
U
U
Pharmacokinetic scientist/associate
NA
U
U
U
U
Lilly
CPM
NA
U
U
U
U
CPA
NA
U
U
U
U
DSA
NA
U
U
U
U
SDTM core team
NA
U
U
U
U
Statistician
NA
U
U
U
U
Medical writing
NA
U
U
U
U
Clinical pharmacologist
NA
U
U
U
U
Pharmacokinetic scientist/associate
NA
U
U
U
U
Abbreviations:  B = blinded; CPA = clinical pharmacology associate; CPM=clinical project management; DSA = 
data sciences associate; ECG = electrocardiogram; lab = laboratory; NA = not applicable; SDTM = study data 
tabulation model; U = unblinded.


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
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LY3298176
Appendix 9.
Protocol Amendment I8F-JE-GPGC(a) 
Summary
A Multiple-Ascending Dose Study in Japanese Patients 
with Type 2 Diabetes Mellitus to Investigate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics 
of LY3298176
Overview
Protocol I8F-JE-GPGC, A Multiple-Ascending Dose Study in Japanese Patients with Type 2 
Diabetes Mellitus to Investigate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of LY3298176, has been amended.  The new protocol is indicated by 
Amendment (a) and will be used to conduct the study in place of any preceding version of the 
protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

The study will be unblinded triggered by the database lock with data up to Day 85 to
initiate the subsequent Japan clinical studies.


I8F-JE-GPGC(a) Clinical Pharmacology Protocol
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LY3298176
The overall changes and rationale for the changes made to this protocol are described in the 
following table:
Table GPGC.3.
Amendment Summary for Protocol I8F-JE-GPGC Amendment(a)
Section # and Name
Description of Change
Brief Rationale
7.3. Blinding
and
Appendix 8. Protocol I8F-JE-GPGC 
Blinding/Unblinding Plan
Blinded period ends when the 
database is locked with data up to 
Day 85.
To initiate the subsequent clinical 
studies, the unblinded data of GPGC 
study up to Day 85 will be provided 
to ERBs and investigators for better 
understanding the profile of 
LY3298176 in Japanese patients 
with T2DM.


I8F-JE-GPGC Clinical Pharmacology Protocol
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LY3298176
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
7.3.
Blinding
Blinding will be maintained until the database is locked with data up to Day 85 (blinded period)
throughout the conduct of the study as described in the separate Blinding Plan (Appendix 8).
If a patient’s study treatment assignment is unblinded during the blinded period, the patient must 
be discontinued from the study unless the investigator obtains specific approval from a Lilly 
clinical pharmacologist, CRP, or CRS for the study participant to continue in the study.  During 
the study, emergency unblinding should occur only by accessing the study patient’s emergency 
code.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event.  The 
patient’s safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding during the blinded period is warranted, it is the responsibility 
of the investigator to promptly document the decision and rationale and notify Lilly as soon as 
possible.
Appendix 8.
Protocol I8F-JE-GPGC Blinding/Unblinding Plan
Study Timelines
Study Team Member
Screening
Randomization
Treatment 
Phase
Follow-Up
Database 
Lock (up to 
Day 85)
General
Drug supply
NA
U
U
U
U
Randomization statisticians
NA
U
U
U
U
ECG reader
NA
B
B
B
UB
Bioanalysis lab/sample analysis
NA
U
U
U
U
Clinical Site
Pharmacist
NA
U
U
U
U
Dosing staff
NA
B
B
B
UB
Patient
NA
B
B
B
UB
Investigator
NA
B
B
B
UB
Study monitor 
NA
U
U
U
U


PPD
Leo Document ID = 0cb9e08a-d783-42f0-97e6-8c6c45ee1db0
Approver: 
Approval Date & Time: 15-Oct-2018 01:38:16 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 15-Oct-2018 04:19:51 GMT
Signature meaning: Approved
PPD

SAP_001.pdf: 
Statistical Analysis Plan I8F-JE-GPGC 
A Multiple-Ascending Dose Study in Japanese Patients with Type 2 Diabetes Mellitus to Investigate 
the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of LY3298176
NCT03322631
Approval Date: 22-Nov-2017


Final, 16 Nov 2017
             Page 1 of 25
STATISTICAL ANALYSIS PLAN
A Multiple-Ascending Dose Study in Japanese Patients with Type 2 Diabetes Mellitus to 
Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of
LY3298176
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  16-November-2017
Study Drug: LY3298176
Sponsor Reference:  I8F-JE-GPGC
Covance CRU Study: 1000071-8355248
Clinical Phase I
Approval Date: 22-Nov-2017 GMT


Final, 16 Nov 2017
             Page 2 of 25
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8355248
Sponsor Reference I8F-JE-GPGC
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 4
3.
INTRODUCTION ......................................................................................................... 6
4.
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 6
4.1
Primary Objective.................................................................................................... 6
4.2
Secondary Objectives .............................................................................................. 6
4.3
Exploratory Objectives ............................................................................................ 7
5.
STUDY DESIGN........................................................................................................... 7
6.
TREATMENTS............................................................................................................. 9
7.
SAMPLE SIZE JUSTIFICATION ............................................................................... 10
8.
DEFINITION OF ANALYSIS POPULATIONS.......................................................... 10
9.
STATISTICAL METHODOLOGY ............................................................................. 11
9.1
General.................................................................................................................. 11
9.2
Demographics and Patient Disposition................................................................... 11
9.3
Pharmacokinetic Assessment................................................................................. 11
9.3.1
Pharmacokinetic Analysis............................................................................. 11
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 15
9.4
Pharmacodynamic Assessment .............................................................................. 15
9.4.1
Pharmacodynamic Analysis.......................................................................... 15
9.4.2
Pharmacodynamic Statistical Methodology .................................................. 16
9.4.3
Pharmacokinetic/Pharmacodynamic Analyses .............................................. 17
9.5
Safety and Tolerability Assessments...................................................................... 17
9.5.1
Adverse events ............................................................................................. 17
9.5.2
Concomitant medication............................................................................... 18
9.5.3
Clinical laboratory parameters...................................................................... 18
9.5.4
Vital signs .................................................................................................... 18
9.5.5
Electrocardiogram (ECG)............................................................................. 19
9.5.6
Body weight ................................................................................................. 20
9.5.7
Hepatic Monitoring ...................................................................................... 20
9.5.8
Pancreatic Safety.......................................................................................... 21
9.5.9
Hypersensitivity and Injection Site Reactions ............................................... 21
9.5.10
Glucose Monitoring and Hyperglycemia/Hypoglycemia Reporting............... 21
9.5.11
Immunogenicity ........................................................................................... 23
9.5.12
Other assessments......................................................................................... 24


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8355248
Sponsor Reference I8F-JE-GPGC
10. INTERIM ANALYSES ............................................................................................... 24
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 24
12. REFERENCES ............................................................................................................ 24
13. DATA PRESENTATION ............................................................................................ 24
13.1 Derived Parameters ............................................................................................... 24
13.2 Missing Data ......................................................................................................... 24
13.3 Insufficient Data for Presentation .......................................................................... 25


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8355248
Sponsor Reference I8F-JE-GPGC
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
ADA
Antidrug antibody
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
AUC(0-)
Area under the concentration versus time curve during one dosing 
interval (168 hours)
BQL
Below the lower limit of quantitation
CI
Confidence interval
Cmax
Maximum observed drug concentration
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
CRF
Case Report Form
CRP
Clinical research physician
CRS
Clinical research scientist
CSR
Clinical Study Report
CRU
Clinical Research Unit
CV
Coefficient of variation
DPP
Dipeptidyl peptidase
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
HbA1c
hemoglobin A1c
ICH
International Council on Harmonisation
IMP
Investigational medicinal product
LLOQ
Lower limit of quantification
MAD
Multiple ascending dose
MedDRA
Medical Dictionary for Regulatory Activities


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8355248
Sponsor Reference I8F-JE-GPGC
MRE
Magnetic resonance elastography
OGTT
Oral glucose tolerance test  
PD
Pharmacodynamics 
Peak to trough
Ratio of Cmax to Cmin (at 168 hours)
PG
Plasma glucose
PK
Pharmacokinetic
QW
Once a week
RA
Accumulation ratio based on AUC(0-τ)
SAE
Serious AE
SAP
Statistical Analysis Plan
SC
Subcutaneous 
SD
Standard deviation 
SMPG
Self monitored plasma glucose
TBL
Total bilirubin
T2DM
Type 2 diabetes mellitus
TEAE
Treatment-emergent adverse event
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


Final, 16 Nov 2017
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8355248
Sponsor Reference I8F-JE-GPGC
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
24 August 2017).
This SAP describes the planned analysis of the safety, tolerability, pharmacokinetic (PK) and 
pharmacodynamic (PD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document.
The intent of this document is to provide guidance for the statistical analyses of PK and PD data. 
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement between Eli Lilly and Company and Covance Early Clinical (EC)
Biometrics. A limited amount of information concerning this study (e.g., objectives, study 
design) is given to help the reader’s interpretation. This SAP must be signed off prior to first 
patient administration for this study. When the SAP and TFL shells are agreed upon and 
finalized, they will serve as the template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and Covance EC Biometrics and identified in the CSR. Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Council on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES AND ENDPOINTS
4.1
Primary Objective

To investigate the safety and tolerability of LY3298176 after multiple subcutaneous (SC)
doses administered to Japanese patients with type 2 diabetes mellitus (T2DM).
Endpoint: Adverse events (AEs)
4.2
Secondary Objectives

To characterize the PK of LY3298176 after multiple SC doses in Japanese patients with 
T2DM.
Endpoints: Area under the concentration versus time curve (AUC) and maximum 
observed drug concentration (Cmax) of LY3298176


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8355248
Sponsor Reference I8F-JE-GPGC

To investigate the PD effect of LY3298176 after multiple SC doses administered to 
Japanese patients with T2DM.
Endpoints: Fasting plasma glucose levels
4.3
Exploratory Objectives

To investigate the exploratory PD effects of LY3298176 after multiple SC doses 
administered to Japanese patients with T2DM.
Endpoints: Body weight, oral glucose tolerance test (OGTT) (serum glucose and insulin), 
7-point self-monitored plasma glucose (7-p SMPG), hemoglobin A1C (HbA1c), lipids, 
glucagon, subjective appetite sensation

To evaluate the impact of formation of antidrug antibodies (ADAs) on LY3298176 after 
multiple SC doses administered to Japanese patients with T2DM.
Endpoint: Presence of ADAs to LY3298176
5. STUDY DESIGN
This study is a Phase 1, multiple-site, patient- and investigator-blind, placebo-controlled,
randomized, parallel dose–group, 8-week multiple ascending dose (MAD) study in Japanese 
patients with T2DM.
Figure 1 illustrates the study design.
Figure 1. Illustration of study design
This study consists of 3 cohorts. Patients will be randomized to 3 treatment regimens or placebo 
within each cohort, including up to 3 dose levels of LY3298176 in each regimen, as shown in 
Figure 1. Patients will be administered 8 weekly SC doses of LY3298176 or placebo.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8355248
Sponsor Reference I8F-JE-GPGC
Screening to Prestudy
Patient eligibility for this study will be determined at a screening visit. Eligible patients will visit
the clinical research unit (CRU) before Day -1 to receive training on the 7p-SMPG, glucose 
meters, test strips, and diaries. Patients will conduct the 7-point SMPG until the day before Day 
-1. In addition, patients treated with metformin or dipeptidyl peptidase intravenous (DPP-IV)
inhibitors (except for omarigliptin, trelagliptin, and linagliptin) will be required to withdraw their 
treatment and have at least a 28-day washout period before dosing with investigational medicinal 
product (IMP). These patients will be required to monitor their plasma glucose (PG) levels 
during the washout period. 
Treatment Period
Patients will be admitted to the CRU on Day -1. If the investigator decides not to administer the
first dose to a patient on a particular day based on the results of medical assessments, vital signs,
or electrocardiograms (ECGs), the patient may be rescheduled to participate in the study, and any
procedures performed up to that point may be repeated.
Patients will be given SC doses of LY3298176 (or placebo) on Days 1, 8, 15, 22, 29, 36, 43, and
50 after an overnight fast (at least 8 hours). Even if there are visit allowances of ±1 day, the
interval of each IMP administration must be at least 6 days.
Patients in Cohort 1 will receive either LY3298176 with titration regimen starting from 2.5 mg
for Days 1 and 8 followed by 5 mg for Days 15 and 22, and 10 mg for Days 29, 36, 43, and 50,
or corresponding volume-matched placebo. Patients in Cohort 2 will receive either LY3298176
with titration regimen starting from 5 mg for Days 1 and 8 followed by 10 mg for Days 15, 22,
29, and 36, and 15 mg for Days 43 and 50, or corresponding volume-matched placebo. Patients
in Cohort 3 will receive either 5 mg LY3298176 or placebo for 8 weeks. The planned highest 
dose or dosing regimen of Cohort 2 may be changed for the reason of tolerability.
If the investigator decides not to up-titrate the dose level of IMP for individual patients in the
titration regimen in Cohorts 1 or 2 for the reason of safety and/or tolerability, patients may keep
current dose level to the planned last dose at Day 50 and will no longer be allowed up-titration
during the treatment period. Down-titration is not allowed during the treatment period for any
patients in Cohorts 1, 2, or 3.
Safety, as assessed by AEs, vital signs, 12-lead ECGs, concomitant medications, safety
laboratory measurements, and medical assessments from at least 8 patients (to include at least 5
on LY3298176) up to Day 36 predose procedure of Cohort 1, will be reviewed by the sponsor
and investigator before dose-escalation decision to Cohort 2.
Dosing will be staggered in Cohorts 1 and 2 so that an initial group of up to 6 patients receiving
LY3298176 and 2 patients receiving placebo will be dosed. On Days 4 and 32 of Cohort 1 and
on Days 4, 18, and 46 of Cohort 2, the investigator and Lilly clinical pharmacologist, clinical
research physician (CRP), or clinical research scientist (CRS) will review available safety data
from these patients, and if no relevant safety signals are noted, the remaining patients will be
dosed. Patients in Cohort 3 will be dosed after evaluation of safety data of the initial staggered
group of Cohort 2.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8355248
Sponsor Reference I8F-JE-GPGC
PK sampling and safety assessments, including AEs,/concomitant medications, medical
assessments, clinical laboratory tests, vital signs, and ECGs, will be performed according to the
Schedule of Activities.
The investigator or qualified designee will review all available inpatient safety data before
discharging patients from the CRU on the morning of each planned discharging day provided
they are deemed medically fit by the investigator. Patients may be required to remain at the
CRU longer than the planned discharging day at the investigator’s discretion to assure patients’ 
safety or to provide additional safety monitoring. Patients will be discharged after the review of
all final safety assessments from the last follow-up visit is completed by the investigator.
Follow-Up Period
Safety follow-up visits will occur approximately 2 and 5 weeks after the last dose of IMP.
Patients who have treatment-emergent LY3298176 ADAs at the planned follow-up visit 
(Day 85) or early termination visit may be monitored until return to baseline.
6. TREATMENTS
The following is a list of the study treatment abbreviations and treatment regimens that will be 
used in the TFLs.
Cohort
Study Treatment Name
Treatment order in TFL
1-3
Placebo
1
1
2.5 mg LY3298176
2
5 mg LY3298176
3
10 mg LY3298176
4
2
5 mg LY3298176
5
10 mg LY3298176
6
15 mg LY3298176
7
3
5 mg LY3298176
8


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8355248
Sponsor Reference I8F-JE-GPGC
The treatment regimens used will be:
Study Treatment Regimen
Treatment order in TFL
Placebo QW
1
2.5 mg – 10 mg LY3298176 QW 
2
5 mg – 15 mg LY3298176 QW 
3
5 mg LY3298176 QW
4
7. SAMPLE SIZE JUSTIFICATION
The sample size for the study was chosen to provide sufficient data to evaluate the primary 
objective of this study and is not intended to achieve any a priori statistical requirements.
Approximately 49 Japanese patients with T2DM may be enrolled so that approximately 32 
patients complete the study with compliant defined dosing regimen. The estimated drop-out
rates are 30% for Cohorts 1 and 3 and 50% for Cohort 2. Patients will be administered 8 weekly
SC doses of LY3298176 or placebo in a ratio of 12 LY3298176 : 3 placebo for Cohorts 1 and 3,
and 16 LY3298176 : 3 placebo for Cohort 2. Considering the possibility of higher drop-out rate
when administered the highest dose level of LY3298176, the number of patients to be enrolled in
Cohort 2 is higher than those for the other 2 cohorts.
Replacement of discontinued patients is not planned because the sample size is determined
considering the expected drop-out rate.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled patients, whether or not they completed all 
protocol requirements.
The “Pharmacokinetic” population will consist of all patients who received at least one dose of 
IMP and have evaluable PK data.  
The “Pharmacodynamic” population will consist of all patients who received at least one dose of 
IMP and have evaluable PD data.
Patients treated with placebo will be pooled for PD and safety analyses.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when patients are assigned to analysis populations.
Additional analyses will be conducted on the basis of the treatment groups defined by titration 
regimen as actually treated, if deemed necessary, after data review.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8355248
Sponsor Reference I8F-JE-GPGC
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: AUCs and Cmax) the geometric 
mean and geometric coefficient of variation (CV%) will also be presented. For categorical data, 
frequency count and percentages will be presented. Data listings will be provided for all patients
up to the point of withdrawal, with any patients excluded from the relevant population 
highlighted. Summary statistics and statistical analyses will generally only be performed for 
patients included in the relevant analysis population. For the calculation of summary statistics 
and statistical analysis, unrounded data will be used. 
Mean change from baseline is the mean of all individual patients’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual patient’s
baseline value from the value at the timepoint. The individual patient’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.2
Demographics and Patient Disposition
Patient disposition will be listed. The demographic variables age, sex, race, ethnicity, country of 
enrolment, site ID, body weight, height, body mass index, screening HbA1c levels, fasting 
plasma glucose (Day 1, Predose for each cohort), duration of diabetes, and baseline vital signs
(pulse rate and blood pressure, Day -1 for each cohort) will be summarized by treatment 
regimen, and listed.
9.3
Pharmacokinetic Assessment
9.3.1 Pharmacokinetic Analysis
Model-based analysis will be performed combined with data from other studies by Global 
PK/PD and Pharmacometrics group in Eli Lilly and Company.  Details will be described in a 
separate analysis plan.
PK parameter estimates will be determined using non-compartmental procedures in validated 
software program (Phoenix WinNonlin Version 6.4 or later).
Plasma concentrations of LY3298176 will be used to determine the following PK parameters, 
when possible:  


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8355248
Sponsor Reference I8F-JE-GPGC
Parameter
Units
Definition
AUC(0-τ)
ng.h/mL
area under the concentration versus time curve during one dosing 
interval (e.g. 168 hours)
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
t½
h
half-life associated with the terminal rate constant (λz) in non 
compartmental analysis (Week 8 dose only)
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration (Week 8 dose only)
RA
n/a
accumulation ratio based on AUC(0-τ)
Peak to trough
n/a
ratio of Cmax to Cmin (at 168 hours)
Additional PK parameters may be calculated, as appropriate.  The software and version used for 
the final analyses will be specified in the CSR.  Any exceptions or special handling of data will 
be clearly documented within the final study report.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool 
effective at the time of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero. For non-bolus, 
multiple dose profiles, the pre-dose time will be set to zero unless a time deviation falls 
outside of the protocol blood collection time window which is considered to impact PK 
parameter derivation.

Cmax and tmax will be reported from observed values.  If Cmax occurs at more than one 
timepoint, tmax will be assigned to the first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule).  The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantification (LLOQ), with 
at least one of these concentrations following Cmax. 

t½ will be calculated, when appropriate, based on the apparent terminal log-linear portion 
of the concentration-time curve. The start of the terminal elimination phase for each 
patient will be defined by visual inspection and generally will be the first point at which 
there is no systematic deviation from the log linear decline in plasma concentrations.  t½
will only be calculated when a reliable estimate for this parameter can be obtained 
comprising of at least 3 data points.  If t½ is estimated over a time window of less than 2 


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half-lives, the values will be flagged in the data listings. Any t½ value excluded from 
summary statistics will be documented in the footnote of the summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal 
log-linear portion of the concentration-time curve.

The parameters based on predicted Clast will be reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL).  Plasma concentrations reported as BQL will be set to a value of zero 
when all of the following conditions are met: 
o
The compound is non-endogenous.
o
The samples are from the initial dose period for a patient or from a subsequent 
dose period following a suitable wash-out period.
o
The timepoints occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing. 
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times. 

The average concentration profiles will be graphed using arithmetic average 
concentrations.

The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero.  Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations.

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the final study 
report.

A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the timepoint have quantifiable measurements that are within the 


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sampling time window specified in the protocol or ± 10%. An average concentration 
estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all PK analyses is not a requirement. Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate. This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis.  The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:

During the terminal elimination phase, the concentration is quantifiable and follows 2
consecutive concentrations that are BQL.

For PK profiles during multiple dosing, the concentration of the pre-dose sample exceeds 
all measured concentrations for that individual in the subsequent post-dose samples.

For PK profiles during single dosing of non endogenous compounds, the concentration in 
a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum. 
Data between Individual Profiles
1. A value within an individual profile, (e.g. plasma concentrations obtained at the same point in 
identically treated individuals), may be excluded from analysis if it falls outside the range of 
acceptable values calculated as described in the methods below.
2. If n<6, then the dataset is too small to conduct a reliable range test.  Data will be analyzed 
with and without the atypical value, and both sets of results will be reported.  
3. If n6, then an objective outlier test will be used to compare the atypical value to other values 
included in that calculation:
a. Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log transformed values and 
exclude that value from the dataset.
c. Calculate the lower and upper bounds of the range defined by the arithmetic mean ±3*SD 
of the remaining log-transformed values.


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d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is not an outlier 
and will be retained in the dataset.
e. If the extreme value is outside the range of arithmetic mean ±3*SD, then it is an outlier and 
will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values.
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final report.  Approval of the 
final report will connote approval of the exclusion.
9.3.2 Pharmacokinetic Statistical Methodology
PK parameters will be summarized using descriptive statistics by dose level.
PK dose proportionality may be assessed in an exploratory manner in model-based analysis
performed by Eli Lilly.
9.4
Pharmacodynamic Assessment
9.4.1 Pharmacodynamic Analysis
The ability of LY3298176 to reduce fasting or dynamic glucose and the effects on insulin will be 
assessed. Such effects will be explored for different treatment regimens of LY3298176.
The following data will be summarized by treatment regimen and day, and listed:

Fasting glucose concentrations

Glucose concentrations and AUC(0-2h) during OGTT

Insulin concentrations and AUC(0-2h) during OGTT

Lipid panel (including high-density lipoprotein cholesterol, low-density lipoprotein 
cholesterol, total cholesterol, and triglycerides)

Adiponectin concentrations (if available)

Blood urea nitrogen concentrations

Cortisol concentrations (if available)


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
HbA1c concentrations 

7-point glucose profile 

Markers of bone metabolism (if available)

Meal intake and subjective rating of appetite sensation
The AUC(0-2h) for glucose and insulin during an OGTT will be calculated using the trapezoidal 
rule. The AUC(0-2h) as well as other derived parameters or observed concentration at specific 
timepoints for each patient on the study day will also be baseline-adjusted. The concentrations 
on Day 1, predose will be used as baseline.
9.4.2 Pharmacodynamic Statistical Methodology
Statistical inference on PD parameters (fasting blood glucose, OGTT glucose, and insulin) will 
be based on the patients who are included in the PD population. PD parameters may be 
transformed before statistical analyses, if deemed necessary.
The observed results, as well as change from baseline, will be analyzed by treatment regimen, 
using mixed-effects models to evaluate treatment effects, as well as treatment comparisons. The 
model will include treatment regimen actually received, as a fixed effect and the patient as a 
random effect. For repeated measured parameters, day and treatment regimen-by-day interaction 
terms will be included in the model. Baseline (Day -1) values, as well as other influencing 
variables, may be used as covariates. An unstructured covariance structure will be applied.  If 
the model fails to converge, alternative structures shall be examined using Akike’s criteria. The 
main comparisons will be between each LY3298176-treated group and placebo group.  Least-
squares means as well as 95% CIs will be reported. 


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Example SAS code for repeated measures analysis:
proc mixed data=pd; 
   class subject trtreg day; 
   model chg = base trtreg day trtreg*day / residual ddfm=kr; 
   repeated day / subject=subject type=un; 
   lsmeans trtreg / alpha=0.05 cl pdiff; 
   ods output lsmeans=lsm; 
   ods output diffs=diff; 
run;
where ‘chg’ is the change from baseline, ‘base’ is the baseline value, and ‘trtreg’ is the treatment 
regimen.
Example SAS code for mixed-effects analysis:
proc mixed data=pd; 
   class subject trtreg; 
   model pd = trtreg / residual ddfm=kr; 
   random subject; 
   lsmeans trtreg / alpha=0.05 cl pdiff; 
   ods output lsmeans=lsm; 
   ods output diffs=diff; 
run;
where ‘trtreg’ is the treatment regimen.
The individual observed and mean (SD) time profile of the postdose PD parameters will be 
plotted by treatment regimen. Additional exploratory analyses of PD parameters may be 
performed to understand dose response using relevant model considering titration scheme, as 
deemed appropriate.
9.4.3 Pharmacokinetic/Pharmacodynamic Analyses
PK/PD modeling may be used to characterize the exposure-response relationships between 
LY3298176 concentrations and various PD and key safety endpoints, provided data are
sufficient, and will be reported separately.
9.5
Safety and Tolerability Assessments
9.5.1 Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings, only the most severe will be used in the summary 
tables. A pre-existing condition is defined as an AE that starts before the patient has provided 
written informed consent and is ongoing at consent. A non-treatment emergent AE is defined as 
an AE which starts after informed consent but prior to dosing. A treatment-emergent AE
(TEAE) is defined as an AE which occurs postdose or which is present prior to dosing and 
becomes more severe postdose. AEs will also be presented by day of onset.


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All AEs will be listed.  TEAEs will be summarized by treatment regimen, severity, and 
relationship to the study drug. The frequency (the number of AEs, the number of patients
experiencing an AE and the percentage of patients experiencing an AE) of TEAEs will be 
summarized by treatment regimen, Medical Dictionary for Regulatory Activities (MedDRA)
version 20.0 system organ class, and preferred term. The summary and frequency AE tables will 
be presented for all causalities and those considered related to the study drug. Any serious AEs
will be tabulated.
9.5.2 Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2017 
Enhanced Dictionary B2 Format). Concomitant medication will be listed.
9.5.3 Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by treatment regimen and 
parameter together with changes from baseline, where baseline is defined as Day -1, and listed.
Urinalysis data will be listed. Additionally clinical chemistry, hematology, and urinalysis data 
outside the reference ranges will be listed.
Values for any clinical chemistry, hematology, and urinalysis values outside the reference ranges 
will be flagged on the individual patient data listings.
9.5.4 Vital signs
Vital signs data will be summarized by treatment regimen together with changes from baseline, 
where baseline is defined as Day 1, predose. Figures of mean vital signs and mean changes from 
baseline profiles will be presented by treatment regimen. Furthermore, values for individual 
patients will be listed.
For change from baseline in vital signs, a mixed-model repeated-measure model with treatment
regimen, time (of measurement), and treatment regimen-by-time interaction as fixed effects, 
patient as random effect, and baseline as covariate will be used to determine the effects of 
LY3298176.  An unstructured covariance structure will be applied.  If the model fails to 
converge, alternative structures shall be examined using Akike’s criteria. Least-squares means, 
as well as 95% CIs, will be reported.


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Example SAS code:
proc mixed data=safety; 
   class subject trtreg day; 
   model chg=trtreg day trtreg*day base / residual ddfm=kr; 
   repeated day / subject=subject type=un; 
   lsmeans trtreg*day / alpha=0.05 cl pdiff; 
   ods output lsmeans=lsmeans; 
   ods output diffs=diffs; 
run;
where ‘chg‘ is the change from baseline, ‘base’ is the baseline value, and ‘trtreg’ is the treatment 
regimen.
9.5.5 Electrocardiogram (ECG)
The ECG data will be obtained directly from the 12-lead ECG traces.  These data include the PR, 
QT, QTcB intervals, QRS duration and heart rate, where QTcB is the QT interval corrected using 
Bazett’s formula. In addition, QTcF (the QT interval corrected using Fridericia’s formula) will 
be calculated as follows:


3 60HR
QT
QTcF 
The ECG data will be summarized by treatment regimen together with changes from baseline, 
where baseline is defined as the mean of all measurements on Day 1 predose of the treatment 
period. Figures of mean ECG data and mean changes from baseline  will be presented by 
treatment regimen.
A plasma LY3298176 concentration-QT analysis will be performed to assess the changes from 
baseline (Day 1 predose) and placebo in the (double delta) QTcF interval relative to plasma 
LY3298176 concentrations across all active treatments. The change from baseline adjustment 
will be based on individual subject’s Day 1 predose value, and the change from placebo 
adjustment will be based on the mean of time-matched placebo values. 
Further details on how these will be calculated:

Calculate the arithmetic mean of the triplicate QTcF for each subject at each timepoint 
and use this in all subsequent calculations below.

Calculate the change from baseline at each timepoint for each individual subject who 
received LY3298176.

Calculate the mean change from baseline across all the placebo subjects at each 
timepoint.


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
For each subject that received LY3298176 at each corresponding timepoint subtract the 
mean placebo change from their own individual change from baseline.

BLQ LY3298176 concentration data will be imputed to 50% of the LLOQ for the 
purposes of the analysis.
The analysis will be performed by plotting double delta QTcF against LY3298176 
concentrations, including all post Day 1 dosing timepoints. 
A mixed effects analysis model will be performed on the double delta QTcF values and will 
include LY3298176 concentration as a covariate and subject as a random effect. The results of 
the model and associated 90% CI will be fitted on the plot and the p-value for the slope reported.  
Estimated double delta QTcF and 90% CI at the geometric mean Cmax will also be presented.
Additional analysis to evaluate effects of AE (such as gastrointestinal or hypoglycemia events) 
QTcF may be performed if deem necessary.
9.5.6 Body weight
Body weight data and changes from baseline (Day 1, predose) will be summarized by treatment
regimen, and listed.  Figures of mean body weight and mean changes from baseline profiles will 
be presented by treatment  regimen over time.
9.5.7 Hepatic Monitoring
If a patient experiences elevated alanine aminotransferase (ALT) ≥3× upper limit of normal 
(ULN), alkaline phosphatase (ALP) ≥2× ULN, or elevated total bilirubin (TBL) ≥2× ULN, liver 
tests will be performed to confirm the abnormality.  
Additional safety data will be collected if 1 or more of the following conditions occur:

Elevation of serum ALT to ≥5× ULN on 2 or more consecutive blood tests

Elevated serum TBL to ≥2× ULN (except for cases of known Gilbert’s syndrome)

Elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests

Patient discontinued from treatment because of a hepatic event or abnormality of liver 
tests

Hepatic event considered to be an SAE
The patient’s liver disease history and associated person liver disease history data will be listed.  
Any concomitant medication of acetaminophen/paracetamol will be listed.  Results from any 
hepatic monitoring procedures, such as a magnetic resonance elastography (MRE) scan, and a 
biopsy assessment will be listed, if performed.


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Hepatic risk factor assessment data will be listed.  Liver related signs and symptoms data will be 
summarized by treatment regimen, and listed.  Alcohol and recreational drug use data will also 
be listed.
All hepatic chemistry, hematology, coagulation, and serology data, as well as haptoglobin, will 
be listed.  Values outside the reference ranges will be flagged on the individual patient data 
listings.
9.5.8 Pancreatic Safety
If a patient experiences elevated serum amylase or lipase values ≥3× ULN, additional monitoring 
and tests will be performed to confirm the abnormality, even in asymptomatic patients.  
All serum amylase and lipase data will be summarized by treatment regimen, and listed.
9.5.9 Hypersensitivity and Injection Site Reactions
Hypersensitivity reaction data will be listed and summarized in frequency tables by treatment
regimen, and timepoint.
Injection-site reaction data, including erythema, induration, pain, pruritus, and edema, will also 
be listed and summarized in frequency tables by treatment regimen, and timepoint .
9.5.10
Glucose Monitoring and Hyperglycemia/Hypoglycemia Reporting
Hypoglycemic events will be appropriately recorded in the CRF. In the case of a hypoglycemic 
event, the actual blood glucose value, if measured, will be recorded in the CRF, together with 
any treatments administered. Each category of hypoglycemic event (defined below) will be 
listed and summarized by treatment regimen.
Blood glucose levels will be listed for individual patients and summarized by treatment regimen.
Hyperglycemia and Hypoglycemia
Hyperglycemic events will be reported by the investigator or designated physician who will be 
responsible for advising the patient on what further actions to take.  Hypoglycemic events will be 
recorded in the CRF, together with any treatments administered.
The main categories of hypoglycemia are as follows:

Documented Glucose Alert Level (Level 1): plasma/serum glucose ≤70 mg/dL 
(3.9 mmol/L)
o
Documented symptomatic hypoglycemia: with typical symptoms of 
hypoglycemia.
o
Documented asymptomatic hypoglycemia: without typical symptoms of 
hypoglycemia.


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o
Documented unspecified hypoglycemia: with no information about symptoms 
of hypoglycemia available.  (This has also been called unclassifiable 
hypoglycemia.)

Documented Clinically Significant Hypoglycemia (Level 2): with similar criterion as 
above except for threshold plasma/serum glucose <54 mg/dL (3.0 mmol/L)
o
Symptomatic hypoglycemia: an event during which typical symptoms of 
hypoglycemia are accompanied by PG <54 mg/dL (3.0 mmol/L)
o
Asymptomatic hypoglycemia: an event not accompanied by typical symptoms 
of hypoglycemia but with PG <54 mg/dL (3.0 mmol/L)
o
Unspecified hypoglycaemia: an event during which PG <54 mg/dL 
(3.0 mmol/L) but no information relative to symptoms of hypoglycemia was 
recorded

Severe Hypoglycemia (Level 3)
o
Severe hypoglycemia (in adults): Patients had altered mental status, and could 
not assist in their own care, or were semiconscious or unconscious, or experienced 
coma with or without seizures, and the assistance of another person was to 
actively administer carbohydrate, glucagon, or other resuscitative actions.  
Plasma/serum glucose measurements may not be available during such an event, 
but neurological recovery attributable to the restoration of plasma/serum glucose 
concentration to normal is considered sufficient evidence that the event was 
induced by a low plasma/serum concentration (plasma/serum glucose ≤70 mg/dL 
[3.9 mmol/L]).
o
Severe hypoglycemia requiring medical attention: Severe hypoglycemic 
events when patients require therapy by Health Care Providers (Emergency 
Medical Technicians, emergency room personnel, etc) are of particular interest to 
payers.  Therefore, some clinical trials may collect data on this subset of severe 
hypoglycemia episodes, especially if economic outcomes analyses may be based 
on trial results.


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
Other Hypoglycemia
o
Nocturnal hypoglycemia: Any documented hypoglycemic event (including 
severe hypoglycemia) that occurs at night and presumably during sleep. At Lilly, 
this is captured as hypoglycemia that occurs between bedtime and waking.  This 
definition is more useful than the commonly used ~midnight to ~6 AM definition, 
which does not take patients’ individual sleep times into consideration and is 
consistent with the American Diabetes Association recommendations for 
reporting events that occur during sleep (American Diabetes Association 2005).  
It is also important to collect the actual time when a hypoglycemic event occurred 
to allow further characterization of hypoglycemia timing (e.g., to allow analysis 
of frequency of events occurring during a 24-hr time period).  Nocturnal 
hypoglycemia may occur at severity Levels 1, 2, or 3.
o
Relative hypoglycemia (also referred to as pseudohypoglycemia [Seaquist et 
al. 2013]): An event during which typical symptoms of hypoglycemia occur, that 
does not require the assistance of another person, and is accompanied by 
plasma/serum glucose >70 mg/dL (3.9 mmol/L).  The plasma/serum glucose 
value for patients with chronically poor glycemic control can decrease so rapidly 
that patients may report symptoms of hypoglycemia before their plasma/serum 
glucose concentration falls below 70 mg/dL (3.9 mmol/L).  Events with 
plasma/serum glucose ≤70 mg/dL should not be categorized as relative 
hypoglycemia.  Evaluation and statistical analysis of this category is optional.  
However, if a patient reports a relative hypoglycemia event where assistance from 
another person was received or the patient experienced significant symptoms, the 
study team should clarify the circumstances to ensure the event is not a severe 
hypoglycemia event and report it appropriately.
o
Probable symptomatic hypoglycemia: Symptoms of hypoglycemia were 
present, but plasma/serum glucose measurement was not reported.
o
Overall (or total) hypoglycemia: This optional category combines most cases of 
hypoglycemia (documented hypoglycemia and probable symptomatic 
hypoglycemia, including severe hypoglycemia).  It does not include relative 
hypoglycemia.  Nocturnal and severe hypoglycemia are special cases of 
documented or probable hypoglycemia.  If an event of hypoglycemia falls into 
multiple subcategories, that event should only be counted once in the category of 
overall (or total) hypoglycemia. 
9.5.11
Immunogenicity
The frequency of antibody formation (presence and titers) to LY3298176 will be determined. If
any cross-reactive or neutralization assays are performed, the frequency of antibodies will be
determined. If there are a sufficient number of patients with positive antibodies to LY3298176,
the change of antibodies (negative to positive) will be summarized using shift tables.


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The relationship between the presence of antibodies, antibody titers, and clinical parameters 
(e.g., AEs) may be assessed. Likewise, the relationship between antibody titers, LY3298176 
concentration (or PK parameters), and PD response to LY3298176 may be assessed.
Furthermore, immunogenicity data will be listed for individual patients.
9.5.12 Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
10.
INTERIM ANALYSES
Interim analysis may be conducted when all data through Day 85 become available from all
cohorts. Additional interim analysis may be conducted to proceed to the subsequent Japan
studies. For this purpose, at least safety and PK data may be analyzed.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.


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13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of patients or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = 02c785bb-d359-4063-bb04-9049f06895d2
Approver: 
Approval Date & Time: 17-Nov-2017 16:52:14 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 20-Nov-2017 01:42:20 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 20-Nov-2017 08:12:17 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 22-Nov-2017 13:19:27 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD