Clinical trial NCT03375463
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2017-12-19; Completion date: 2018-12-27
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study has four parts. Each participant will enroll in one part.

Part A: The purpose of Part A is to compare study drug tirzepatide solution formulation to a powder formulation mixed with water and given subcutaneously (SC) (just under the skin). Part A will measure how much of the study drug gets into the blood stream and how long it takes the body to get rid of it.

Part B: The purpose of Part B is to evaluate the safety and tolerability of tirzepatide intravenous (IV) formulation when administered into a vein.

Part C: The purpose of Part C is to evaluate the safety and tolerability of tirzepatide following multiple SC weekly doses of a solution.

Part D: The purpose of Part D is to evaluate the safety and tolerability of tirzepatide following single IV bolus dose of lyophilized formulation.

This study will last approximately 70 days for each part (Part A, Part B or Part D) and 92 days for Part C. This does not include screening. Screening is required within 28 days prior to the start of the study.

Detailed description:

Arms: arm 1: Participants received 5 milligrams (mg) of tirzepatide subcutaneous (SC) solution formulation. arm 2: Participants received 5 mg of tirzepatide SC lyophilized formulation. arm 3: Participants received Intravenous (IV) infusion of a single 0.5 mg dose of tirzepatide formulation. arm 4: Participants received tirzepatide subcutaneous solution at 5 mg on Days 1 (week 1) and 8 (Week 2), 7.5 mg on Day 15 (Week 3) and 10 mg on Day 22 (Week 4). arm 5: Participants received SC injection of placebo. arm 6: Participants received IV bolus of 0.5 mg tirzepatide lyophilized formulation.
Interventions: intervention 1: Tirzepatide intervention 2: Tirzepatide intervention 3: Placebo intervention 4: Tirzepatide
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered IV intervention 3: Administered SC intervention 4: Administered IV

Protocol documents:
SAP_002.pdf: 
Statistical Analysis Plan I8F-MC-GPGE
Pharmacokinetics, Safety, and Tolerability of a Solution Formulation of LY3298176 in 
Healthy Subjects 
NCT03375463 
Approval Date: 30-Nov-2017


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STATISTICAL ANALYSIS PLAN
Pharmacokinetics, Safety, and Tolerability of a Solution Formulation of LY3298176 in 
Healthy Subjects
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  27 November 2017
Study Drug:  LY3298176
Sponsor Reference:  I8F-MC-GPGE
Covance CRU Study: 1000071-8369709
Clinical Phase I
Approval Date: 30-Nov-2017 GMT


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1.
TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 4
3.
INTRODUCTION ......................................................................................................... 6
4.
STUDY OBJECTIVES.................................................................................................. 6
4.1
Part A...................................................................................................................... 6
4.2
Part B...................................................................................................................... 6
4.3
Part C...................................................................................................................... 7
5.
STUDY DESIGN........................................................................................................... 7
5.1
Part A...................................................................................................................... 7
5.2
Part B...................................................................................................................... 8
5.3
Part C...................................................................................................................... 8
6.
TREATMENTS............................................................................................................. 9
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 9
7.1
Part A...................................................................................................................... 9
7.2
Parts B and C........................................................................................................... 9
8.
DEFINITION OF ANALYSIS POPULATIONS.......................................................... 10
9.
STATISTICAL METHODOLOGY ............................................................................. 10
9.1
General.................................................................................................................. 10
9.2
Demographics and Subject Disposition.................................................................. 10
9.3
Pharmacokinetic Assessment................................................................................. 10
9.3.1
Pharmacokinetic Analysis............................................................................. 10
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 15
9.4
Safety and Tolerability Assessments...................................................................... 16
9.4.1
Adverse events ............................................................................................. 16
9.4.2
Concomitant medication............................................................................... 16
9.4.3
Clinical laboratory parameters...................................................................... 16
9.4.4
Vital signs .................................................................................................... 16
9.4.5
Electrocardiogram (ECG)............................................................................. 16
9.4.6
Injection-site assessment............................................................................... 17
9.4.7
Injection-site pain assessment....................................................................... 17
9.4.8
Immunogenicity ........................................................................................... 17
9.4.9
Blood glucose monitoring............................................................................. 17
9.4.10
Hypoglycemic episodes................................................................................ 17
9.4.11
Hepatic monitoring....................................................................................... 18
9.4.12
Other assessments......................................................................................... 18
9.4.13
Safety and tolerability statistical methodology.............................................. 18


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10. INTERIM ANALYSES ............................................................................................... 18
10.1 Part B tolerability assessment ................................................................................ 18
10.2 Interim database lock............................................................................................. 19
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 19
12. REFERENCES ............................................................................................................ 19
13. DATA PRESENTATION ............................................................................................ 19
13.1 Derived Parameters ............................................................................................... 19
13.2 Missing Data ......................................................................................................... 19
13.3 Insufficient Data for Presentation .......................................................................... 19


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2.
ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
%AUC(tlast-∞)
Percentage of AUC(0-∞) extrapolated
AE
Adverse event
ADA
Antidrug antibody
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
AUC(0-72)
area under the concentration versus time curve from time zero to 72 
hours postdose
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
AUC
Area under the concentration versus time curve during one dosing 
interval
BQL
Below the lower limit of quantitation
CI
Confidence interval
CL
Total body clearance of drug calculated after intravenous 
administration
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
Clast
Last observed quantifiable drug concentration
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
F
Absolute bioavailability (based upon geometric mean)


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GI
Gastrointestinal
GIP
Glucose-dependent insulinotropic polypeptide
GLP-1
Glucagon-like peptide 1
ICH
International Council on Harmonisation
IV
Intravenous
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MRE
Magnetic resonance elastography
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard deviation 
SOP
Standard Operating Procedure
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
TBL
Total bilirubin
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
VAS
Visual Analog Scale
Vss
Volume of distribution at steady state following intravenous 
administration
Vss/F
Apparent volume of distribution at steady state following 
extra-vascular administration
Vz
Volume of distribution during the terminal phase after intravenous 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


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3.
INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
01 September 2017).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) 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 and PK analyses of 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 subject 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
4.1
Part A
Primary Objective
To evaluate the PK of a single subcutaneous (SC) dose of LY3298176, administered as solution 
formulation (test) versus lyophilized formulation (reference) in healthy subjects.
Secondary Objective
To investigate the safety and tolerability of LY3298176, administered to healthy subjects.
4.2
Part B
Primary Objective
To evaluate the PK of a single intravenous (IV) dose of LY3298176 in healthy subjects.


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Secondary Objective
To investigate the safety and tolerability of LY3298176, administered to healthy subjects via IV 
formulation
4.3
Part C
Primary Objective
To evaluate the safety and tolerability of LY3298176, following multiple SC weekly doses of a 
solution formulation administered in healthy subjects.
Secondary Objective
To evaluate the PK of LY3298176, administered as a solution formulation.
5.
STUDY DESIGN
Study I8F-MC-GPGE (GPGE) is a single-center, Phase 1 study conducted in healthy subjects in 
3 parts:  Part A is a 2-period, 2-treatment, crossover design evaluating the relative bioavailability 
of 2 formulations of LY3298176; Part B, a single-arm design evaluating LY3298176 PK with IV
administration; and Part C is a placebo-controlled, single-arm design evaluating the safety,
tolerability, and PK of LY3298176 titrated, once-weekly for 4 weeks.
5.1
Part A
Part A is a randomized, 2-period, crossover study in healthy subjects to evaluate the relative 
bioavailability of 5 mg LY3298176, administered as a solution formulation (test), compared to a 
5-mg dose administered as lyophilized formulation (reference).
Each subject will provide informed consent for study participation, and will undergo a screening
examination within 28 days prior to enrollment.
In each treatment period, subjects will be admitted to the clinical research unit (CRU) on Day -1.  
On the morning of Day 1, following an overnight fast of at least 8 hours, subjects will receive a
single SC dose of LY3298176, administered according to their assigned treatment sequences.  
Blood samples will be collected predose and up to 480 hours postdose to measure LY3298176
concentrations. At a minimum, subjects will remain in the CRU for 8 days. The investigator (or
qualified designee) will review all available inpatient safety data before discharging subjects
from the CRU on the morning of Day 8, provided that the subjects are deemed medically fit.
Subjects may be required to remain in the CRU longer than Day 8, at the investigator’s
discretion. The subjects will return to the CRU for follow-up visits on Days 21 and 35.
There will be a washout period of at least 35 days between doses in Periods 1 and 2. Based on
the PK properties of LY3298176 (terminal half-life: approximately 5 days), a washout period of
at least 35 days between doses in Periods 1 and 2 is considered adequate. Period 2 will repeat


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the same schedule as Period 1 with the Day 35 visit being the final study visit, which will include
an antidrug antibody (ADA) sample at least 10 weeks after the first dose.
5.2
Part B
Part B is a single, 0.5-mg IV dose of LY3298176 solution formulation (or lyophilized
formulation in absence of solution formulation) administered to healthy subjects.
Each subject will provide informed consent for study participation, and will undergo a screening
examination within 28 days prior to enrollment.
Subjects will be admitted to the CRU on Day -1. On the morning of Day 1, following an
overnight fast of at least 8 hours, 2 subjects will receive a single IV dose of 0.5 mg LY3298176,
administered over 10 minutes. This dose is expected to be safe while also providing plasma
concentrations that can be adequately measured over the course of the sampling time period to
enable adequate characterization of the PK profile.

If the dose of 0.5 mg is found to be safe and well-tolerated, then a PK interim analysis
will be performed. Based on the results of the interim analysis, if it is noted that
LY3298176 concentrations can be adequately quantified, then 4 more subjects will be
dosed.

If the dose of 0.5 mg is found to be safe and well-tolerated, then a PK interim analysis
will be performed. Based on the results of the interim analysis, if it is noted that
LY3298176 concentrations cannot be adequately quantified, then a dose adjustment
(however less than 1 mg) may be considered for an additional 6 subjects.

If the dose is not tolerated due to extensive gastrointestinal (GI) events, a lower dose of 
0.25 mg (infused over 10 minutes) may be administered to an additional 6 subjects.
Plasma samples will be collected multiple times, including predose and up to 336 hours
postdose, to measure LY3298176 concentrations.
At a minimum, subjects will remain in the CRU for 8 days. The investigator (or qualified
designee) will review all available inpatient safety data before discharging subjects from the
CRU on the morning of Day 8, provided that the subjects are deemed medically fit. Subjects
may be required to remain in the CRU longer than Day 8, at the investigator’s discretion.
Each subject will be required to return to the CRU for a follow-up visit at least 35 days after the
LY3298176 dose. In addition, subjects will need to attend a study visit on Day ≥70 for an ADA
follow-up sample.
5.3
Part C
Part C is a randomized, titration study where healthy subjects will be assigned LY3298176 or 
placebo at a ratio of 3 LY subjects to 1 placebo subjects. The investigator and subject will be 
blinded to the treatment.
Subjects will receive a treatment regimen of either LY3298176 or placebo to be given as a SC
dose on Days 1, 8, 15, and 22, after an overnight fast (at least 8 hours). Subjects randomized to


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LY3298176 will receive a 5 mg dose on Day 1 and Day 8, a 7.5 mg dose on Day 15, and a 10 mg 
dose on Day 22, administered via solution formulation.
Each subject will be required to return to the CRU for outpatient visits and for a follow-up visit 
on Day ≥92.
6.
TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Part
Study Treatment Name
Treatment order in TFL
A
5 mg LY3298176 SC (lyophilized)
1
5 mg LY3298176 SC (solution)
2
B
0.5 mg LY3298176 IV
3
C
Placebo SC
4
5-10 mg LY3298176 SC1
5
1 Subjects receive 5 mg LY3298176 SC on Day 1 and Day 8, 7.5 mg LY3298176 SC on Day 15, and 
10 mg LY3298176 SC Day 22
7.
SAMPLE SIZE JUSTIFICATION
Approximately 20 healthy subjects may be enrolled in Part A in order that at least 16 subjects 
complete Part A.  Up to 10 subjects will be enrolled in Part B in order that at least 6 subjects 
complete Part B.  Approximately 16 healthy subjects may be enrolled in Part C in order that at 
least 12 subjects complete Part C (in a 3:1 ratio of LY3298176:placebo).
For each study part, any dropout may be replaced so that the targeted numbers of subjects for 
safety review and data collection may be achieved. The replacement subject will be assigned to 
receive the treatment of the dropout.
7.1
Part A
Assuming the intra-subject variability (coefficient of variation [CV]) is 30%.  Based on this 
assumption, 16 subjects will provide a precision of 0.227 on a log-scale for the area under the 
concentration versus time curve (AUC) or the maximum observed drug concentration (Cmax) 
with 90% coverage probability.  This would result in a 90% probability that the half-width of the 
90% confidence interval (CI) of the ratio of the geometric means for AUC and Cmax is no larger 
than 20% in natural scale.
7.2
Parts B and C
The sample size is customary for Phase 1 studies evaluating safety and PK.  The sample sizes are 
not based on statistical calculations.  The sample sizes for each part of the study are considered 
sufficient to evaluate the primary objectives of this study.


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8.
DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled subjects, whether or not they completed all 
protocol requirements.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
study drug and have evaluable PK data.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
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 CV% will also be presented. For categorical data, frequency count and 
percentages will be presented. Data listings will be provided for all subjects up to the point of 
withdrawal, with any subjects excluded from the relevant population highlighted. Summary 
statistics and statistical analyses will generally only be performed for subjects 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 subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’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 Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, country of 
enrolment, site ID, body weight, height and body mass index will be summarized and listed.
Changes from baseline in weight will also be listed, where baseline is defined as Day -1.
9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
The PK parameter estimates will be determined using non-compartmental procedures in 
validated software program (Phoenix WinNonlin Version 6.4 or later).


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Plasma concentrations of LY3298176 will be used to determine the following PK parameters, 
when possible:  
Parts A & B – LY3298176 PK Parameters
Parameter
Units
Definition
AUC(0-)
ng.h/mL
area under the concentration versus time curve from time zero to 
infinity
AUC(0-tlast)
ng.h/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
%AUC(tlast-)
%
percentage of AUC(0-∞) extrapolated
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
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration
CL
L/h
total body clearance of drug calculated after intravenous
administration
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vz
L
volume of distribution during the terminal phase after intravenous
administration
Vss/F
L
apparent volume of distribution at steady state following 
extra-vascular administration
Vss
L
volume of distribution at steady state following intravenous 
administration
F
NA
absolute bioavailability (based upon geometric mean)


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Part C – LY3298176 PK Parameters
Parameter
Units
Definition
AUC(0-τ)
ng.h/mL
area under the concentration versus time curve during one dosing 
interval (e.g., 168 hours)
AUC(0-72)
ng.h/mL
area under the concentration versus time curve from time zero to 
72 hours postdose
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
Additional PK parameters may be calculated, as appropriate.  The software and version used for 
the final analyses will be specified in the clinical study report. 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 time 
point, 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.  AUC(0-) values where the 
percentage of the total area extrapolated is more than 20% will be flagged.  Any 
AUC(0-) value excluded from summary statistics will be noted in the footnote of the 
summary table.

Half-life (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 subject 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.  Half-life will only be calculated when a reliable estimate for this 


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parameter can be obtained comprising of at least 3 data points.  If t½ is estimated over a 
time window of less than 2 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 the last observed quantifiable drug concentration (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 subject or from a subsequent 
dose period following a suitable wash-out period.
o
The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing.

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
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.


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
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 time point have quantifiable measurements that are within the 
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:

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.
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.  
2.
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.


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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.
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
Part A
To assess the relative bioavailability of a single SC dose of LY3298176 administered as a 
solution formulation (test), compared to a lyophilized formulation (reference), AUC(0-), 
AUC(0-tlast) and Cmax will be log-transformed and analyzed using a linear mixed effects model 
with treatment, period, and sequence as fixed effects and subject as a random effect.  The 
difference in least squares means between the test formulation and reference formulation for 
each parameter will be exponentiated to yield ratios of geometric least squares means and their 
corresponding 90% CIs.
Example SAS code:
proc mixed data=DATA;
   class treatment period sequence subject;
   model log_pk = treatment period sequence / ddfm=kr;
   random subject;
   lsmeans treatment / pdiff cl alpha=0.1;
   ods output lsmeans=lsmeans;
   ods output diffs=diffs;
run;
The tmax will be analyzed non-parametrically for the same comparison stated above. The  
Wilcoxon rank-sum test will be used to account for any possible period effect .  The median of 
differences, approximate 90% CI, and p-values will be calculated.


Final, 27 November 2017
             Page 16 of 19
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 100071-8369709
Sponsor Reference I8F-MC-GPGE
Parts B and C
No formal statistical analysis will be performed. The PK parameters will be summarised by 
treatment, and listed.
9.4
Safety and Tolerability Assessments
9.4.1
Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (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 subject 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 is defined as an AE which occurs postdose or which is present prior to dosing and becomes 
more severe postdose. AEs by day of onset will be presented for Part C.
All AEs will be listed.  Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug. The frequency (the number AEs, the number of subjects 
experiencing an AE and the percentage of subjects experiencing an AE) of treatment-emergent 
AEs will be summarized by treatment, 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.
9.4.2
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2017).
Concomitant medication will be listed.
9.4.3
Clinical laboratory parameters
All clinical chemistry, hematology and 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 subject data listings.
9.4.4
Vital signs
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as Day 1 predose (of each period in Part A), and listed.
9.4.5
Electrocardiogram (ECG)
ECGs will be performed for safety monitoring purposes only and will not be presented.


Final, 27 November 2017
             Page 17 of 19
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 100071-8369709
Sponsor Reference I8F-MC-GPGE
9.4.6
Injection-site assessment
Injection-site assessment data (erythema, induration, categorical pain, pruritus and edema) will 
be listed and summarized in frequency tables.
9.4.7
Injection-site pain assessment
Injection-site pain for subjects receiving SC injections/infusions will be assessed using the 
Visual Analog Scale (VAS).  The data will be listed and summarized by treatment.
9.4.8
Immunogenicity
Immunogenicity data will be listed and frequency tables will be presented.  The frequency of 
treatment-emergent ADAs will also be calculated.  Treatment-emergent ADAs are those that are 
induced or boosted by exposure to study drug, with a 4-fold increase in titer compared to 
baseline if ADAs were detected at baseline or a titer 2-fold greater than the minimum required 
dilution if no ADAs were detected at baseline.
Clinically significant treatment-emergent ADAs will be flagged on the individual subject 
listings.  Clinically significant treatment-emergent ADAs will be defined as any 
treatment-emergent ADAs at the last visit with:

a high titer (≥1280) or an increasing titer from last measured value.

an association with a moderate-to-severe injection site reaction or infusion-related 
reaction.

cross-reactive and/or neutralizing binding of an ADA with endogenous glucagon-like 
peptide 1 (GLP-1) or glucose-dependent insulinotropic polypeptide (GIP).
To show the association of treatment-emergent ADAs with AEs, the frequency of 
treatment-emergent ADAs will be presented by MedDRA preferred term.  Relationship between 
the presence of antibodies and the PK parameters of  LY3074828 may be assessed graphically.
9.4.9
Blood glucose monitoring
Blood glucose data will be listed.
9.4.10
Hypoglycemic episodes
Episodes of hypoglycemia 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 events will be listed 
and summarized by treatment.  The categories of hypoglycaemia are defined in the Protocol 
(Section 9.4.7.1).


Final, 27 November 2017
             Page 18 of 19
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 100071-8369709
Sponsor Reference I8F-MC-GPGE
9.4.11
Hepatic monitoring
If a subject 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.
The subjects’ 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.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed.  Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual subject data listings.
9.4.12
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analysed.
9.4.13
Safety and tolerability statistical methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
10.1 Part B tolerability assessment
An interim analysis is planned after dosing 2 subjects in Part B of the study.
The possible outcomes following IV administration of a 0.5 mg dose of LY3298176 over 10 
minutes are:

LY3298176 tolerability is adequate; LY3298176 concentrations are measurable in the 2 
subjects.

LY3298176 tolerability is inadequate. To improve tolerability, the dose of LY3298176 
may be reduced to 0.25 mg, administered over 10 minutes.

LY3298176 tolerability is adequate; however, if LY3298176 concentrations cannot be 
adequately quantified, then a dose adjustment may be considered.


Final, 27 November 2017
             Page 19 of 19
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 100071-8369709
Sponsor Reference I8F-MC-GPGE
10.2 Interim database lock
An interim database lock will be performed after all subjects complete Part A, Period 2 up to 
Day 35.  All available data in Part B will also be included.   Database listings for the clinical 
laboratory, immunogenicity, and PK data will be created.
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.
13.3 Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects 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 = 0a938e35-0fb2-40d4-94ec-09aa3fd3bfe8
Approver: 
Approval Date & Time: 28-Nov-2017 14:02:10 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 28-Nov-2017 14:02:20 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 30-Nov-2017 14:54:54 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 30-Nov-2017 21:31:26 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD

Prot_001.pdf: 
 
 
Protocol I8F-MC-GPGE(a) 
 
 
Pharmacokinetics, Safety, and Tolerability of a Solution Formulation of LY3298176 in 
Healthy Subjects 
 
 
NCT03375463  
 
 
Approval Date: 23-Jan-2018 
 


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
Page 1
LY3298176
Protocol I8F-MC-GPGE(a)
Pharmacokinetics, Safety, and Tolerability of a Solution 
Formulation of LY3298176 in Healthy Subjects
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.
LY3298176
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly:  01-Sep-
2017
Amendment (a) Electronically Signed and Approved by Lilly on date provided below:
Approval Date: 23-Jan-2018 GMT


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
Page 2
LY3298176
Table of Contents
Section
Page
Protocol I8F-MC-GPGE Pharmacokinetics, Safety, and Tolerability of a 
Solution Formulation of LY3298176 in Healthy Subjects....................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................7
2.
Schedule of Activities .........................................................................................................9
2.1.
Study Schedule Protocol I8F-MC-GPGE, Part A..........................................................10
2.2.
Study Schedule Protocol I8F-MC-GPGE, Part B..........................................................14
2.3.
Study Schedule Protocol I8F-MC-GPGE Part C...........................................................17
3.
Introduction ......................................................................................................................20
3.1.
Study Rationale............................................................................................................20
3.2.
Background..................................................................................................................20
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.
Dose Justification.........................................................................................................25
5.5.1.
Part A...................................................................................................................25
5.5.2.
Part B...................................................................................................................25
5.5.3.
Part C...................................................................................................................26
6.
Study Population...............................................................................................................27
6.1.
Inclusion Criteria..........................................................................................................27
6.2.
Exclusion Criteria ........................................................................................................28
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................30
6.3.
Lifestyle and/or Dietary Requirements .........................................................................30
6.3.1.
Meals and Dietary Restrictions.............................................................................30
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................30
6.3.3.
Activity................................................................................................................30
6.4.
Screen Failures.............................................................................................................30
7.
Treatment..........................................................................................................................31
7.1.
Treatment Administered...............................................................................................31
7.1.1.
LY3298176 for Injection......................................................................................31


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
Page 3
LY3298176
7.1.2.
LY3298176 Solution Formulation Injection .........................................................31
7.2.
Method of Treatment Assignment ................................................................................32
7.2.1.
Selection and Timing of Doses.............................................................................32
7.3.
Blinding .......................................................................................................................32
7.4.
Dose Modification........................................................................................................33
7.4.1.
Management of Intravenous Infusion ...................................................................33
7.4.1.1.
Premedication for Infusions............................................................................33
7.4.1.2.
Management of Infusion Reactions.................................................................33
7.5.
Preparation/Handling/Storage/Accountability...............................................................34
7.6.
Treatment Compliance .................................................................................................34
7.7.
Concomitant Therapy...................................................................................................34
7.8.
Treatment after the End of the Study............................................................................35
8.
Discontinuation Criteria ....................................................................................................36
8.1.
Discontinuation from Study Treatment.........................................................................36
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................36
8.2.
Discontinuation from the Study....................................................................................36
8.3.
Subjects Lost to Follow-up...........................................................................................37
9.
Study Assessments and Procedures ...................................................................................38
9.1.
Efficacy Assessments...................................................................................................38
9.2.
Adverse Events ............................................................................................................38
9.2.1.
Serious Adverse Events........................................................................................39
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................39
9.2.2.
Complaint Handling.............................................................................................39
9.3.
Treatment of Overdose.................................................................................................40
9.4.
Safety...........................................................................................................................40
9.4.1.
Laboratory Tests ..................................................................................................40
9.4.2.
Vital Signs ...........................................................................................................40
9.4.3.
Electrocardiograms ..............................................................................................40
9.4.4.
Body Weight........................................................................................................41
9.4.5.
Safety Monitoring ................................................................................................41
9.4.5.1.
Hepatic Safety................................................................................................41
9.4.6.
Hypersensitivity Reactions...................................................................................42
9.4.6.1.
Injection-Site Reactions..................................................................................42
9.4.6.1.1.
Pain Measurements Using the Visual Analog Scale...................................42
9.4.7.
Glucose Monitoring (Part C)................................................................................42
9.4.7.1.
Hyperglycemia and Hypoglycemia Reporting.................................................43
9.4.8.
Nausea and Vomiting...........................................................................................45
9.4.9.
Elevated Lipase or Amylase.................................................................................45


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
Page 4
LY3298176
9.4.10.
Immunogenicity Assessments ..............................................................................45
9.5.
Pharmacokinetics .........................................................................................................46
9.5.1.
Bioanalysis...........................................................................................................46
9.6.
Pharmacodynamics ......................................................................................................46
9.7.
Genetics .......................................................................................................................47
9.8.
Biomarkers...................................................................................................................47
9.9.
Health Economics ........................................................................................................47
10.
Statistical Considerations and Data Analysis.....................................................................48
10.1. Sample Size Determination ..........................................................................................48
10.2. Populations for Analyses..............................................................................................48
10.2.1.
Study Participant Disposition ...............................................................................48
10.2.2.
Study Participant Characteristics ..........................................................................48
10.3. Statistical Analyses ......................................................................................................48
10.3.1.
Safety Analyses....................................................................................................49
10.3.1.1.
Clinical Evaluation of Safety..........................................................................49
10.3.1.2.
Statistical Evaluation of Safety.......................................................................49
10.3.1.3.
Injection Site Reaction....................................................................................49
10.3.2.
Pharmacokinetic Analyses....................................................................................49
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................49
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................49
10.3.2.2.1.
Part A .......................................................................................................49
10.3.2.2.2.
Part B .......................................................................................................50
10.3.2.2.3.
Part C .......................................................................................................50
10.3.3.
Evaluation of Immunogenicity .............................................................................50
10.3.4.
Data Review during the Study..............................................................................50
11.
References ........................................................................................................................51


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
Page 5
LY3298176
List of Tables
Table
Page
Table GPGE.4.1
Objectives and Endpoints .......................................................................22
Table GPGE.7.1
Treatments Administered........................................................................32


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
Page 6
LY3298176
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................53
Appendix 2.
Clinical Laboratory Tests........................................................................58
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................59
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............62
Appendix 5.
Blood Sampling Summary......................................................................63
Appendix 6.
Clinically Significant Adverse Effects ....................................................65
Appendix 7.
Pancreatic Monitoring ............................................................................67
Appendix 8.
Contraceptive Methods...........................................................................70


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
Page 7
LY3298176
1. Protocol Synopsis
Title of Study:
Pharmacokinetics, Safety, and Tolerability of a Solution Formulation of LY3298176 in Healthy Subjects 
Rationale: 
A solution formulation of LY3298176 will be evaluated in upcoming Phase 3 studies. This solution formulation has
a different composition from the lyophilized formulation for injection that was used in the Phase 1 study, and is 
being used in the ongoing Phase 2 studies. 
Part A: Investigate the relative bioavailability of the solution formulation (test), compared to the lyophilized 
formulation (reference). 
Part B: The pharmacokinetics (PK) of LY3298176 following administration via intravenous (IV) route will be 
investigated. 
Part C: The safety, tolerability, and PK of LY3298176, following administration of up to a 10-mg dose via a 
titration regimen using a solution formulation.
Objective(s)/Endpoints:  
Objectives
Endpoints
Part A:

Primary: To evaluate the PK of a single SC 
dose of LY3298176, administered as solution 
formulation (test) versus lyophilized 
formulation (reference) in healthy subjects

Secondary: To investigate the safety and 
tolerability of LY3298176, administered to 
healthy subjects 

PK parameters, including AUC and Cmax, 

AEs and injection site reactions
Part B: 

Primary: To evaluate the PK of a single IV
dose of LY3298176 in healthy subjects

Secondary: To investigate the safety and 
tolerability of LY3298176, administered to 
healthy subjects via IV formulation

PK parameters, including AUC 

AEs
Part C:

Primary: To evaluate the safety and 
tolerability of LY3298176, following multiple  
SC weekly doses of a solution formulation
administered in healthy subjects.

Secondary: To evaluate the PK of 
LY3298176, administered as a solution 
formulation 

AEs and injection site reactions

PK parameters including AUC and Cmax
Abbreviations:  AEs = adverse events; AUC = area under the drug plasma concentration versus time curve; 
Cmax = maximum observed concentration; IV = intravenous(ly); PK = pharmacokinetic(s); SC = subcutaneous(ly).


I8F-MC-GPGE(a)Clinical Pharmacology Protocol
Page 8
LY3298176
Summary of Study Design:  
Study I8F-MC-GPGE is a single-center, Phase 1,Part A is a 2-period crossover study in healthy subjects to evaluate 
the relative bioavailability of a 5-mg solution formulation (test) administered subcutaneously (SC), compared to 
reconstituted lyophilized formulation (reference).  Part B is a single-arm study in healthy subjects to evaluate the PK 
of 0.5-mg solution formulationofLY3298176 following IV administration.  Part C will be conducted in healthy 
subjectsevaluating safety, tolerability, and PK of doses up to 10mg, administered via titration, using a solution 
formulation.
Treatment Arms and Planned Durationfor an Individual:  
Part A: Subjectswill be screened over a28 dayperiod and will be randomized to 1 of 2treatment sequences,
according to the randomization table provided to the site.  Each subjectwill receive a single SCinjection of 
LY3298176 test formulation and a reference formulation in a 2 arm cross over design. Subjects will be admitted to 
the clinical research unit (CRU) on Day -1 and discharged on Day 8 of eachperiodand will return to the CRU for 
Day 15, Day 21, and Day 35-37procedures each period.  Each dose will be separated by a minimum of 35 days.  A
follow-up (or early discontinuatio
n)visit should occur 35-37days after the last dose of the study drug.
Part B: Subjects will be screened over a28-dayperiod. Subjects will be admitted to the CRU on Day -1. On 
Day1, following an overnight fast of at least 8 hours, subjects will receive a single IV dose of LY3298176solution 
formulation, administered over 10 minutes. At a minimum, subjects will remain inthe CRU for 8 days. Subjects 
may be required to remain inthe CRUforlonger than Day 8,at the investigator’s discretion. Subjects will return to 
the CRU onDay 15, Day 35-37and at greater than or equal to 70 dayspost-dose.
Part C: Subjectswill be screened over a28-day period.  Subjects willbe randomized toreceive LY3298176 or 
placebo in doses of 5mg (Day1), 5mg (Day 8), 7.5mg (Day 15), and 10mg(Day 22).Treatment will be
administered via solution formulationat each of the doses.Subjectswill be required to attend follow-upvisits35 
days after the last doseand at least 70 days after the last dose.
Number of Subjects:
Up to 46adult subjects will be enrolled to ensure that 34complete the study:
Up to 20 healthy subjects will be enrolled in order thatatleast 16 complete Part A
Up to 10 healthy subjects will be enrolled in order thatatleast 6complete Part B
Up to 16healthy subjectswill be enrolled inorder thatatleast 12complete Part C
Statistical Analysis:
Safety:
Continuous safety variables will be summarized using descriptive statistics.  Categorical safety variables will be 
summarized using countand percentage.  Vital signs data will be analyzed and summarized for each Part.
Pharmacokinetic:
Part A:   To evaluatethe PK for the 2formulations, area under the drug plasma concentration versus time curve 
from time zero to infinity (AUC[0-∞]), and maximum drug  plasma concentration (Cmax)will be log transformed and 
analyzedusing a linear mixed-effects model with treatment, period, and sequence as fixed effects,and subject as a 
random effect.  The treatment ratio and the corresponding 90% confidence intervals [CIs]of the ratios will be 
reported.
Part B:  Pharmacokineticparameters will be summarized descriptively.
Part C:  Pharmacokineticparameters will be summarized descriptively.


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
Page 9
LY3298176
2. Schedule of Activities


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
Page 10
LY3298176
2.1.
Study Schedule Protocol I8F-MC-GPGE, Part A
Procedure (Part A) 
Screening
Periods 1 and 2
ET
Comments
Days
-28 to -2
-1
1
2
3
4
5
6
7
8
15
21
35 -
37 post 
dose 
period 1
35 -
37 post 
dose 
period 2
≥35 day washout 
between doses 1 
and 2. 
Informed Consent
X
Subject Admission to 
CRU
X
Subject Discharge from 
CRU
X
Subjects may stay 
longer according to 
investigator 
discretion
Outpatient Visit
X
X
X
X
X
X
Investigational Product 
Administration
X
There is a minimum 
of 35 days washout 
period between 
doses for Period 1 
and Period 2.   
Study drug will be 
administered SC 
after an overnight 
fast of at least 8 
hours.
Medical History
X
Height
X
Weight
X
X
X
X
X
Vital Signs 
(BP/PR/T) (supine) 
X
X
P
24
48
X
X
X
X
X
X
Time points may be 
added for each 
study period, if 
warranted and 
agreed upon 
between Lilly and 
the  investigator.


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
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LY3298176
Procedure (Part A) 
Screening
Periods 1 and 2
ET
Comments
Days
-28 to -2
-1
1
2
3
4
5
6
7
8
15
21
35 -
37 post 
dose 
period 1
35 -
37 post 
dose 
period 2
≥35 day washout 
between doses 1 
and 2. 
Clinical Laboratory Tests
X
X
X
X
X
X
See Appendix 2, 
Clinical Laboratory 
Tests, for details.  
Adverse Event
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Injection Site Reaction 
Assessment
P, 0, 
6h, 12h
24h
48h
0-hour assessment 
should be 
performed within 
5 minutes after 
subcutaneous 
injection.  
Additional 
assessments may be 
performed if 
deemed necessary 
by the investigator. 
Visual analog scale 
(VAS) score will be 
recorded
PK Samples 
P, 8h, 
12h,
24h
48h
72h
96h
120h
144h
168h
336h
480h
X
X
X
Sampling times are 
relative to the start 
of dose 
administration (0 
hr).  Predose sample 
must be collected 
before dose 
administration. If a 
subject withdraws 
from the study prior 
to completion of 
scheduled PK 
sampling for a 
given period, every 
effort will be taken 
to draw an 
unscheduled blood 
sample for PK 


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
Page 12
LY3298176
Procedure (Part A) 
Screening
Periods 1 and 2
ET
Comments
Days
-28 to -2
-1
1
2
3
4
5
6
7
8
15
21
35 -
37 post 
dose 
period 1
35 -
37 post 
dose 
period 2
≥35 day washout 
between doses 1 
and 2. 
assessment.  This 
will not be required 
if a sample has 
already been taken 
within the previous 
24 hours. For ET, 
a PK sample can be 
taken at any time 
during the visit 
timed close to the 
immunogenicity 
sample.
Pregnancy Test 
X
X
X
X
X
All females only.  
Serum pregnancy 
test will be 
performed at 
screening.  Urine 
pregnancy test will 
be performed at 
Day -1 for each 
period and at 
ET/Follow-up.
Physical Examination
X
X
X
X
X
X
After screening, 
medical assessment 
only performed to 
include medical 
review and targeted 
examination, as 
appropriate.
12-lead ECG
X
X
X
X
X
X
Single 12-lead ECG 
will be collected.  
ECGs must be 
recorded before 
collecting any blood 
samples.  Subjects 
must be supine for 


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
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LY3298176
Procedure (Part A) 
Screening
Periods 1 and 2
ET
Comments
Days
-28 to -2
-1
1
2
3
4
5
6
7
8
15
21
35 -
37 post 
dose 
period 1
35 -
37 post 
dose 
period 2
≥35 day washout 
between doses 1 
and 2. 
at least 5 minutes 
before ECG 
collection and 
remain supine but 
awake during ECG 
collection.
Genetic Sample
P
Single sample for 
pharmacogenetic 
analysis taken prior 
to dosing on Day 1 
in Period 1 only.
Immunogenicity Samples
P
X
X
X
X
All samples for 
immunogenicity 
should be taken 
predose for period 1 
and 2.  Day ≥35 
post dose 2 and at 
follow-up (Day 
≥70).  
Time-matched PK 
sample should be 
collected at each 
time point.
Abbreviations:  BP = blood pressure; CRU = clinical research unit; ECG = electrocardiogram; ET = early termination; h = hours; P = Predose; 
PK = pharmacokinetics; PR = pulse rate; T = Temperature; VAS = visual analog scale.
Note:  If multiple procedures take place at the same time point, the following order of the procedures should be used:  ECGs, vital signs, and venipuncture.


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
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LY3298176
2.2.
Study Schedule Protocol I8F-MC-GPGE, Part B
Procedure
(Part B)
Screening
Treatment
ET
Comments
Days
-28 to -2
-1
1
2
3
4
5
6
7
8
15
35 - 37
≥70 days
Informed 
Consent
X
Subject 
Admission to 
CRU
X
Subject 
Discharge from 
CRU
X
Subjects may stay 
longer according to 
investigator 
discretion
Outpatient Visit
X
X
X
X
X
Investigational 
Product 
Administration
X
Study drug will be 
administered after an 
overnight fast of at 
least 8 hours. Study 
drug will be 
administered over 10 
min IV infusion
Medical History
X
Height
X
Weight
X
X
X
X
Vital Signs 
(BP/PR/T) 
(supine) (hours)
X
X
P
24h
48h
X
X
X
Time points may be 
added for each study 
period, if warranted 
and agreed upon 
between Lilly and the 
investigator.
Clinical 
Laboratory 
Tests
X
X
X
X
X
Requires an 8 hour 
fast. See Appendix 2, 
for details.  
Adverse Event
X
X
X
X
X
X
X
X
X
X
X
X
X


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
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LY3298176
Procedure
(Part B)
Screening
Treatment
ET
Comments
Days
-28 to -2
-1
1
2
3
4
5
6
7
8
15
35 - 37
≥70 days
PK Samples 
P, 5 
min, 
10 
min, 
30 
min 
1h, 
2h, 
4h,  
8h, 
12h,
24 h, 
36 h
48 h
72h
96h
120h
144h
168h
336
h
X
X
X
All sampling times 
are from start of 
infusion. (0 hr). 
Predose sample must 
be collected before 
dose administration. 
If a subject withdraws 
from the study prior 
to completion of 
scheduled PK 
sampling, every effort 
will be taken to draw 
an unscheduled blood 
sample for PK 
assessment.   This 
will not be required if 
a sample has already 
been taken within the 
previous 24 hours.  
For ET, a PK sample 
can be taken at any 
time during the visit 
timed close to the 
immunogenicity 
sample.
Pregnancy Test 
X
X
X
X
All females only.  
Serum pregnancy test 
will be performed at 
screening.  Urine 
pregnancy test will be 
performed at Day -1  
and at ET/Follow-up.
Physical Exam
X
X
X
X
X
After screening, 
medical assessment 
only performed to 
include medical 
review and targeted 
examination, as 
appropriate.


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
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LY3298176
Procedure
(Part B)
Screening
Treatment
ET
Comments
Days
-28 to -2
-1
1
2
3
4
5
6
7
8
15
35 - 37
≥70 days
12-lead ECG
X
X
X
X
X
Single 12-lead ECG 
will be collected.  
ECGs must be 
recorded before 
collecting any blood 
samples.  Subjects 
must be supine for at 
least 5 minutes before 
ECG collection and 
remain supine but 
awake during ECG 
collection.
Genetic Sample
P
Single sample for 
pharmacogenetic 
analysis taken prior to 
dosing on Day 1.
Immunogenicity 
Samples
P
X
X
X
X
All samples for 
immunogenicity 
should be taken 
predose and follow 
up.  Time-matched 
PK sample should be 
collected at each time 
point.
Abbreviations:  BP = blood pressure; CRU = clinical research unit; ECG = electrocardiogram; ET = early termination; hr = hour(s); IV = intravenous(ly); 
min = minute(s); P = Predose; PK = pharmacokinetic(s); PR = pulse rate; T= Temperature
Note:  If multiple procedures take place at the same time point, the following order of the procedures should be used:  ECG, vital signs, and venipuncture.


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
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LY3298176
2.3.
Study Schedule Protocol I8F-MC-GPGE Part C
Procedure (Part 
C)
Screen
Prestudy
Treatment
ET/Follow-
up
Days
-28 to -2
Before −2
−1
1
2
3
4
8a
9
10
15 a
16
17
18
22 a
23
24
25
57
≥92
Informed consent
X
Admission to 
CRUc
X
X
X
X
Discharge from 
CRU
X
X
X
X
Outpatient visits 
to CRU
X
X
X
X
X
Distribution of 
glucose meters, 
test strips, diary, 
and GM training
X
Distribution of 
additional test 
strips, and diary. 
X
X
X
Administer study 
drugd
X
X
X
X
Medical history
X


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
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LY3298176
Procedure (Part 
C)
Screen
Prestudy
Treatment
ET/Follow-
up
Days
-28 to -2
Before −2
−1
1
2
3
4
8a
9
10
15 a
16
17
18
22 a
23
24
25
57
≥92
Height and 
weighte
X
X
P
P
P
P
X
Physical 
examination
X
Medical 
assessmentf
X 
P
P
P
P
X
Vital signs 
(BP/PR/T)g
(hours)
X
X
P
X
X
P
X
X
P
X
X
P
X
X
X
ECGh
X
P
P
X
PK sampling
(hours)
P,
8h
2
4
h
48
h
72h
P
P, 
8h
24
h
48
h
72
h
P, 
8h
24
h
48
h
72
h
X
X
Clinical laboratory 
testsi
X
P
P
X
AEs/concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Injection site 
reactionsb
P, 
0, 
6h , 
12h
2
4
h
P, 
0, 
6h
, 
12
h
24
P, 
0, 6,
12
24
P, 
0, 6, 
12
24


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
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LY3298176
Procedure (Part 
C)
Screen
Prestudy
Treatment
ET/Follow-
up
Days
-28 to -2
Before −2
−1
1
2
3
4
8a
9
10
15 a
16
17
18
22 a
23
24
25
57
≥92
Pharmacogenomic 
sample
X
Immunogenicity
P
P
X
X
Abbreviations:  AEs = adverse events; BP = blood pressure; CRU = clinical research unit; ECG = electrocardiogram; ET = early termination; GM = glucose 
monitoring; h = hours; P = Predose; PK = pharmacokinetic(s); PR = pulse rate; T= temperature.
a
Dosing day – subjects will be admitted to CRU the day prior to dosing.
b
Visual analog scale (VAS) score will be recorded
c
For each CRU admission, subjects must remain at the CRU at least 72 hours postdose or per medical judgment.
d
Study drug will be administered after an overnight fast of at least 8 hours.
e
Height measured at screening only.  Weight will be measured twice in a consistent way, each predose.  Scale needs to be calibrated (refer to Section 9.4.4).
f
Medical assessment will include a physical examination.
g
Vital signs(BP/PR/T) measurements:  for each dose day: predose, 24 hr, 48 hr, and on or after Day 92 (follow-up/ET).
h
Single local safety ECGs will be measured at screening, predose Day 1, predose Day 22, predose Day 50 and follow-up/ET to take place on or after Day 92
(follow-up).  Electrocardiograms must be recorded before collecting any blood for safety or PK samples and close to the time of the blood draw.  Subjects 
must be supine for approximately 5 to 10 minutes before ECG collection and remain supine, but awake, during ECG collection.
i
Clinical safety laboratory measures include chemistry, hematology, and urinalysis panels.  Blood samples will be taken predose on all dosing days.  Subjects
will be required to fast for at least 8 hours before each blood sample is drawn.


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3. Introduction
3.1.
Study Rationale
Study I8F-MC-GPGE is a single-center, Phase 1, 3-part study to be conducted in healthy 
subjects.
A new solution formulation of LY3298176 will be evaluated in upcoming Phase 3 studies.
This formulation has a different composition from the lyophilized formulation for injection that 
was used in the Phase 1 study and is also being used in the ongoing Phase 2 studies.
In Part A of the study, the study will evaluate the relative bioavailability of a 5-mg dose of 
LY3298176, administered subcutaneously (SC) as solution formulation (test), compared to a 
5-mg dose, administered after reconstituting a lyophilized formulation (reference). These data 
will support Phase 3 clinical development.
LY3298176 has not been administered to subjects via the intravenous (IV) route to date;
therefore, in Part B of the study, we will evaluate the pharmacokinetics (PK) of LY3298176 
following IV administration.  This information will enable us to calculate the absolute 
bioavailability of LY3298176 following SC administration (using prior SC PK data from 
Phase 1), which was the route utilized in the Phase 1 study, and is the intended route of 
administration for this drug as a therapeutic. 
Part C will evaluate the safety, tolerability, and PK of LY3298176 doses up to 10 mg.
Doses will be administered via a weekly titration regimen in healthy subjects. These data will 
support Phase 3 clinical development.
3.2.
Background
LY3298176 is being investigated for its potential use in the treatment of type 2 diabetes mellitus 
(T2DM).  LY3298176 is a long-acting, dual incretin receptor co-agonist that binds to both the 
glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 
(GLP-1) receptor.  As a co-agonist, LY3298176 combines the signaling of each receptor for 
potentially improved glycemic control.  LY3298176 consists of a peptide component, which is 
based on the GIP sequence, conjugated to a C20 fatty acid moiety that prolongs the duration of 
action, allowing for once weekly (QW) SC administration.  Because it is a co-agonist, 
LY3298176 has the potential of reaching high efficacy in target tissues (such as the insulin-
producing pancreatic -cells that express both GIP and GLP-1 receptors) before reaching its 
therapeutic limitation.  Furthermore, LY3298176 may attain additional efficacy by recruiting 
metabolically active tissues (eg, adipose tissue) not targeted by classical GLP-1 receptor 
agonists.  This may result in increased energy utilization and greater weight loss in T2DM 
patients than that observed with GLP-1 receptor agonists (GLP-1 RAs) alone (Baggio and 
Drucker 2007).
The safety, tolerability, and pharmacokinetics/pharmacodynamics (PK/PD) of LY3298176 were 
evaluated in the Phase 1 clinical pharmacology trial, I8F-MC-GPGA (GPGA).  Preliminary data 
are available. In Study GPGA, LY3298176 was administered as an SC injection in a single dose 
(0.25 to 8 mg) and in 4 QW doses (0.5 to 10 mg with doses >5 mg reached through dose 


I8F-MC-GPGE(a)Clinical Pharmacology Protocol
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LY3298176
titration) to healthy subjects.  LY3298176 was also administered SC to patients with T2DM in 
4QW doses (0.5 to 15mg with doses >5 mg reached through dose titration).  In both healthy 
volunteers and patients with T2DM, there was a suppression of serum glucose and a reduction of 
postprandial glucose that was generally dose-dependent.  There was also a decrease in body 
weight that was generally dose-dependent.  Nausea, vomiting, and diarrhea were frequently 
reported adverse events (AEs).  Higher doses were better tolerated using a dose titration scheme 
of administration.  Increases in heart rate were observed following administration of LY3298176,
compared with placebo.  There were no clinically significant changes in systolic or diastolic 
blood pressure or QT/corrected QT (QTc)interval prolongation observed in either healthy 
volunteers or patients with T2DM.  No subject appeared to develop neutralizing antibodies to 
LY3298176.
In summary, LY3298176 has exhibited the expected GLP-1 pharmacological effects on glucose 
suppression.  The body weight loss may be due to pharmacology of higher GLP-1 doses or due 
to contribution of the GIP part of the molecule.  The reported gastrointestinal-(GI-)related AEs 
are consistent with GLP-1 pharmacology and those observed previously following administration 
of GLP-1 RAs (Nauck et al. 2009; Dungan et al. 2014; Giorgino et al. 2015; Jendle et al. 2016; 
Nauck et al. 2016).  The effects observed on heart rate have also been observed with other GLP-1
RAs and have not been associated withadverse cardiovascular (CV) outcomes (Herbst et al. 
2017).
3.3. Benefit/Risk Assessment
The nonclinical dataand preliminary clinical data (See Section 3.2) from Study GPGA support 
furtherclinical development for LY3298176. 
Predicted exposure multiples were derived from repeat-dose toxicology studies,using the highest
proposed clinical dose of 15 mg/week. 
 
 
The effects in rats and monkeys included decreases 
in body weight and/or body weight loss, decreases in food consumption, and dehydration. All of 
the changes were consistent with, or secondary to, GLP-1 pharmacology,and wereeasily 
monitoredin clinical studies. Furthermore, there was no evidence of target organ toxicity in either 
species. For more information, reference the Investigator’s Brochure(IB).
No clinically significant safety or tolerabilityconcerns were identified up to the highest single 
dose level of 8 mgor following 4 QW doses titrated up to 10 mg in Study GPGA. Based on this 
information,doses to be administeredin Study GPGE will be tolerable to healthy subjects.
Anyidentified potential risks are similar with the risks associated with currently available long-
acting GLP-1 receptor agonists (See Section 3.2)
CCI
, are considered to be manageable,and areable 
to be monitored.
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated AEs ofLY3298176is found in the compound IB.  


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
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LY3298176
4. Objectives and Endpoints
Table GPGE.4.1 shows the objectives and endpoints of the study.
Table GPGE.4.1
Objectives and Endpoints
Objectives
Endpoints
Part A:

Primary: To evaluate the PK of a single SC 
dose of LY3298176, administered as solution 
formulation (test) versus lyophilized 
formulation (reference) in healthy subjects.

Secondary: To investigate the safety and 
tolerability of LY3298176, administered to 
healthy subjects.

PK parameters, including AUC and Cmax, 

AEs and injection site reactions
Part B: 

Primary: To evaluate the PK of a single IV
dose of LY3298176 in healthy subjects.

Secondary: To investigate the safety and 
tolerability of LY3298176, administered to 
healthy subjects via IV formulation.

PK parameters, including AUC 

AEs
Part C:

Primary: To evaluate the safety and 
tolerability of LY3298176, following multiple 
SC weekly doses of a solution formulation
administered in healthy subjects.

Secondary:  To evaluate the PK of 
LY3298176, administered as a solution 
formulation.

AEs and injection site reactions

PK parameters including AUC and Cmax
Abbreviations:  AEs = adverse events; AUC = area under the drug plasma concentration versus time curve; 
Cmax= maximum observed concentration; IV = intravenous(ly); PK = pharmacokinetic(s); SC = subcutaneous(ly).


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
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5. Study Design
5.1.
Overall Design
Study I8F-MC-GPGE (GPGE) is a single-center, Phase 1 study conducted in healthy subjects in 
3 parts: Part A is a 2-period, 2-treatment, crossover design evaluating the relative bioavailability 
of 2 formulations of LY3298176; Part B, a single-arm design evaluating LY3298176 PK with IV 
administration; and Part C is a placebo-controlled, single-arm design evaluating the safety, 
tolerability, and PK of LY3298176 titrated, once-weekly for 4 weeks.
Part A: Part A is a randomized, 2-period, crossover study in healthy subjects to evaluate the 
relative bioavailability of 5 mg LY3298176, administered as a solution formulation (test),
compared to a 5-mg dose administered SC as lyophilized formulation (reference). Treatment 
sequences and randomization are described in Section 7.2.
Each subject will provide informed consent for study participation, and will undergo a screening 
examination within 28 days prior to enrollment.
In each treatment period, subjects will be admitted to the clinical research unit (CRU) on Day -1.  
On the morning of Day 1, following an overnight fast of at least 8 hours, subjects will receive a 
single SC dose of LY3298176, administered according to their assigned treatment sequences.  
Blood samples will be collected predose and up to 480 hours postdose to measure LY3298176
concentrations. At a minimum, subjects will remain in the CRU for 8 days.  The investigator (or 
qualified designee) will review all available inpatient safety data before discharging subjects 
from the CRU on the morning of Day 8, provided that the subjects are deemed medically fit. 
Subjects may be required to remain in the CRU longer than Day 8, at the investigator’s 
discretion. The subjects will return to the CRU for follow-up visits on Days 21 and 35-37.
There will be a washout period of at least 35 days between doses in Periods 1 and 2. Based on 
the PK properties of LY3298176 (terminal half-life: approximately 5 days), a washout period of 
at least 35 days between doses in Periods 1 and 2 is considered adequate. Period 2 will repeat 
the same schedule as Period 1 with the Day 35 visit being the final study visit, which will include 
an antidrug antibody (ADA) sample at least 10 weeks after the first dose.  
Part B:  Part B is a single, 0.5-mg IV dose of LY3298176 solution formulation (or lyophilized 
formulation in absence of solution formulation) administered to healthy subjects.
Each subject will provide informed consent for study participation, and will undergo a screening 
examination within 28 days prior to enrollment.
Subjects will be admitted to the CRU on Day -1. On the morning of Day 1, following an 
overnight fast of at least 8 hours, 2 subjects will receive a single IV dose of 0.5 mg LY3298176, 
administered over 10 minutes. This dose is expected to be safe while also providing plasma 
concentrations that can be adequately measured over the course of the sampling time period to 
enable adequate characterization of the PK profile.

If the dose of 0.5 mg is found to be safe and well-tolerated, then a PK interim analysis 
will be performed.  Based on the results of the interim analysis, if it is noted that 


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
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LY3298176
LY3298176 concentrations can be adequately quantified, then 4 more subjects will be 
dosed.

If the dose of 0.5 mg is found to be safe and well-tolerated, then a PK interim analysis 
will be performed. Based on the results of the interim analysis, if it is noted that 
LY3298176 concentrations cannot be adequately quantified, then a dose adjustment
(however less than 1 mg) may be considered for an additional 6 subjects.

If the dose is not tolerated due to extensive GI events, a lower dose of 0.25 mg (infused 
over 10 minutes) may be administered to an additional 6 subjects. 
Plasma samples will be collected multiple times, including predose and up to 336 hours 
postdose, to measure LY3298176 concentrations.  
At a minimum, subjects will remain in the CRU for 8 days.  The investigator (or qualified 
designee) will review all available inpatient safety data before discharging subjects from the 
CRU on the morning of Day 8, provided that the subjects are deemed medically fit.  Subjects 
may be required to remain in the CRU longer than Day 8, at the investigator’s discretion.
Each subject will be required to return to the CRU for a follow-up visit at least 35 days after the 
LY3298176 dose.  In addition, subjects will need to attend a study visit on Day ≥70 for an ADA
follow-up sample.
Part C:  Part C is a randomized, titration study where healthy subjects will be assigned 
LY3298176 or placebo at a ratio of 3 LY subjects to 1 placebo subjects. The investigator and 
subject will be blinded to the treatment. .
Subjects will receive a treatment regimen of either LY3298176 or placebo to be given as a SC 
dose on Days 1, 8, 15, and 22, after an overnight fast (at least 8 hours). Subjects randomized to
LY3298176 will receive a 5-mg dose on Day 1 and Day 8, a 7.5-mg dose on Day 15, and a 10-
mg dose on Day 22, administered via solution formulation (treatment specifics can be found in 
Section 7.1).
Each subject will be required to return to the CRU for outpatient visits and for a follow-up visit  
on Day ≥92.
For all parts of this study pharmacokinetic sampling and safety assessments, including AE
recording, medical assessments, clinical laboratory tests, vital signs measurement, and 
electrocardiograms (ECGs), will be performed according to the Schedule of Activities 
(Section 2). 
Subjects will be admitted the day before dosing.  The investigator (or qualified designee) will 
review all available inpatient safety data before discharging subjects from the CRU on Day 3 
after the final study procedures, provided that the subjects are deemed medically fit. More 
information is outlined in the Schedule of Activities (Section 2.3). 


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
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LY3298176
5.2.
Number of Participants
Part A: Approximately 20 healthy subjects will be enrolled so that at least 16 complete 
this part.
Part B:  Approximately 10 healthy subjects will be enrolled so that at least 6 complete 
this part.
Part C:  Approximately 16 healthy subjects will be enrolled so that at least 12 complete 
this part.
For purposes of this study, a subject completes the study when all scheduled procedures shown 
in the Schedule of Activities (Section 2) have been finished.
5.3.
End of Study Definition
The end of the study is the date of the last visit or last scheduled procedure shown in the 
Schedule of Activities (Section 2) for the last subject entered into any part of the study.
5.4.
Scientific Rationale for Study Design
In this study, a population of healthy subjects is selected based on the likelihood of less 
physiologic variability in the absence of disease states that may affect multiple organ systems 
and absence of other confounding factors, such as concomitant medications.  Part A is a
randomized, open-label, single-dose, crossover-design study. The use of a crossover design 
allows each subject to serve as his/her own control, thereby, reducing variability.
Part B, will investigate the PK of LY3298176 following administration via a single IV dose.
An interim analysis will be performed after dosing the first 2 subjects to review safety and 
tolerability, and to check if there is a need for dose adjustment prior to dosing the rest of the 
subjects. 
Part C will evaluate the safety, tolerability, and PK of doses up to 10 mg attained via a 4-week 
titration regimen in healthy subjects, when administered via a solution formulation planned for 
use in the Phase 3 study, compared to placebo. The titration algorithms have been chosen based 
on safety and tolerability data from the Phase 1 study, GPGA.
5.5.
Dose Justification
5.5.1. Part A
A 5-mg LY3298176 dose is selected for Part A of the study to enable comparison of the solution 
formulation (test) versus the lyophilized formulation (reference). A 5-mg dose has been 
previously studied in healthy subjects and T2DM patients (Study GPGA), and was found to be 
safe and tolerable. 
5.5.2. Part B
A starting dose of 0.5 mg LY3298176 (administered IV over 10 minutes) is chosen because this 
dose is expected to lead to a measureable PK profile with a modest observed peak drug 


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
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LY3298176
concentration (Cmax), while still leading to peak and overall exposures notably lower than those 
observed following administration of a 5-mg SC dose (which has been studied in the Phase 1 
study, GPGA). This dose will be administered such that up to 2 subjects will receive an initial 
dose of 0.5 mg, administered over 10 minutes. If this dose is found to be safe in the first 
2 subjects, an interim analysis will be performed to evaluate the PK data in these subjects.
After the interim analysis, it will be decided whether to administer the same 0.5-mg dose to all 
the remaining subjects in this arm or to evaluate a different dose. If it is noted that LY3298176
concentrations cannot be adequately quantified, then a dose adjustment may be considered for an 
additional 6 subjects.
If the 0.5-mg dose is not tolerated, a lower dose of 0.25 mg (infused over 10 minutes) may be 
administered to an additional 6 subjects. 
5.5.3. Part C
The planned dose-titration scheme to be tested in healthy subjects in this part of the study will be 
comprised of a QW titration dosing regimen of 5 mg, 5 mg, 7.5 mg, and 10 mg, compared to 
placebo. The titration algorithms have been chosen based on safety and tolerability data from the 
Phase 1 study, GPGA.


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LY3298176
6. Study Population
Eligibility of subjects for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and ECGs.  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 prior to enrollment.  Subjects 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
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening:
[1]
are overtly healthy males or females, as determined by medical history and 
physical examination.
[1a] Male subjects:
agree to use an effective method of contraception for the duration of the 
study and for 3 months following the last dose of investigational product
(see Appendix 8 for acceptable methods of contraception).
[1b] Female subjects:
women not of childbearing potential due to surgical sterilization 
(hysterectomy or bilateral oophorectomy or tubal ligation) or 
menopause.  Women with an intact uterus are deemed postmenopausal if 
they are ≥45 years old,
AND
have not taken hormones or oral contraceptives within the last year and 
had cessation of menses for at least 1 year.
OR
have had at least 6 months of amenorrhea with follicle-stimulating hormone 
levels consistent with a postmenopausal state.
[2]
are males or females between 18 and 70 years old.
[3]
have a screening body mass index of >18.5 and ≤32.0 kg/m2.
[4]
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.


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[5]
have blood pressure of <160/90 mmHg and pulse rate of 50 to 90 bpm
(supine) at screening, or with minor deviations judged to be acceptable by the 
investigator.
[6]
are reliable and willing to make themselves available for the duration of the 
study, and are willing to follow study procedures.
[7]
are able and willing to give signed informed consent.
[8]
have venous access sufficient to allow for blood sampling as per the protocol.
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[9]
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.
[10] are Lilly employees.
[11] are currently enrolled in a clinical trial involving an investigational product or 
any other type of medical research judged not to be scientifically or medically 
compatible with this study.  
[12] have received treatment with a drug that has not received regulatory approval 
for any indication within 30 days of screening.
[13] have previously completed or withdrawn from this study or any other study 
investigating LY3298176, and have previously received the investigational 
product.
[14] have had any exposure to dulaglutide, other GLP-1 analogs, or other related 
compounds within the prior 3 months, or any history ever of allergies to these 
medications.
[15] have a history of heart block, or a PR interval >200 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.
[16] have a significant history of or current cardiovascular (eg, myocardial 
infarction, congestive heart failure, cerebrovascular accident, venous 
thromboembolism, etc.), 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.
[17] have evidence of significant active neuropsychiatric disease, as determined by 
the investigator.


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[18] regularly use known drugs of abuse and/or show positive findings on drug 
screening.
[19] have evidence of human immunodeficiency virus (HIV) infection and/or are 
positive for HIV antibodies.
[20] have evidence of hepatitis C and/or are positive for hepatitis C antibodies.
[21] have evidence of hepatitis B and/or are positive for hepatitis B surface 
antigen.
[22] smoke >10 cigarettes per day, or the equivalent, or are unable or unwilling to 
refrain from nicotine during CRU admission.
[23] have used or plan to use over-the-counter or prescription medication, and/or 
herbal supplements (with the exception of vitamin/mineral supplements, any 
hormone replacement therapy, and/or thyroid replacement therapy) within 
14 days prior to dosing and for the duration of the study, including any 
medications that reduce GI motility, including, but not limited to, 
anticholinergics, antispasmodics, 5-hydroxytryptamine-3 receptor antagonists, 
dopamine antagonists, and opiates.
[24] have had a blood donation of 450 mL or more in the last 3 months, or have 
had any blood donation within the last month prior to screening.
[25] have an average weekly alcohol intake that exceeds 21 units per week (males)
or 14 units per week (females), or are unwilling to stop alcohol consumption 
24 hours before dosing until discharge from CRU.
(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)
[26] have a history or presence of pancreatitis (history of chronic pancreatitis or 
idiopathic acute pancreatitis), elevation in serum amylase or lipase (>1.5-fold 
the upper limit of normal [ULN]), GI disorder (eg, relevant esophageal reflux 
or gall bladder disease), or any GI disease which impacts gastric emptying 
(eg, gastric bypass surgery, pyloric stenosis [with the exception of 
appendectomy]) or could be aggravated by GLP-1 analogs or dipeptidyl 
peptidase IV (DPP-IV) inhibitors.  Subjects with dyslipidemia and subjects
who had cholecystolithiasis (with removal of gallstones) and/or 
cholecystectomy (removal of the gall bladder) in the past, with no further 
sequelae, may be included in the study, at the discretion of the investigator.
[27] have a history of atopy or clinically significant multiple or severe drug
allergies, intolerance to topical corticosteroids, or severe posttreatment
hypersensitivity reactions (including, but not limited to, erythema multiforme
major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, or
exfoliative dermatitis).
[28] have a personal or family history of medullary thyroid carcinoma or have
multiple endocrine neoplasia syndrome type 2.


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[29] have serum aspartate aminotransferase (AST) or alanine aminotransferase
(ALT) >2X the ULN or total bilirubin (TBL) >1.5X ULN.
[30] have a history of malignancy within 5 years prior to screening.
[31] have a serum triglyceride (TG) ≥5 mmol/L (442.5 mg/dL) at screening.
[32] are deemed unsuitable by the investigator for any other reason.
6.2.1. Rationale for Exclusion of Certain Study Candidates
Conflict of interest in study participants is outlined in Criteria [9] and [10].  Excluded medical 
conditions, medication intolerance, and concomitant medication use that may constitute a risk for 
the subject and/or may confound the assessment of study endpoints are described in Criteria [11] 
through [32].
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
Subjects will be required to fast overnight for at least 8 hours before taking a SC or IV dose of 
LY3298176, and when clinical safety laboratory samples are taken (see Schedule of Activities
[Section 2]). Water may be consumed freely. Standard meals will be administered in the CRU.
6.3.2. Caffeine, Alcohol, and Tobacco
No alcohol will be allowed for at least 24 hours before each CRU admission and each outpatient
visit, and throughout the duration of each CRU visit. Between CRU visits, daily alcohol 
consumption should not exceed 3 units for males and 2 units for females (a unit is defined in 
Exclusion Criterion [25], Section 6.2). No nicotine use will be permitted while in the CRU.
While not resident in the CRU, subjects must consume no more than 10 cigarettes or the 
equivalent per day.
Subjects will be allowed to maintain their regular caffeine consumption throughout the study 
period.
6.3.3. Activity
Subjects should not engage in strenuous physical exercise or activities from 48 hours prior to the 
first dose, and for duration of the study.  When certain study procedures are in progress at the site, 
subjects may be required to remain recumbent or sitting.
6.4.
Screen Failures
Subjects who do not meet the criteria for participation in this study (screen failure) may not be
rescreened.


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7.Treatment
7.1. TreatmentAdministered
This study involves a comparison of drug product LY3298176,for injection thatis being used in 
the Phase1 and ongoing Phase 2 trials to the intended solution formulation of LY3298176 drug 
productfor Phase 3trials over a planned dose range,administered by SC injection. In addition,
the PK of a single IV dose of LY3298176 will be evaluated. Table GPGE.7.1illustrates the 
treatment regimens.
7.1.1. LY3298176 for Injection
LY3298176 for injection, 5 mg, is supplied as lyophilized formulation in a glass vial for SC and 
IV infusion administration.  
 
 
 
  The 
reconstituted product solution in the vial(s) may be held at room temperature and/or refrigerated 
(2°C to 8°C),and should be administered within 4 hours from the time of reconstitution.  
LY3298176 for injection, 5-mg vials,are intended for single-dose administration.
7.1.2. LY3298176 Solution Formulation Injection
CCI
LY3298176 injection is prepared by sterile compounding,and is for SC and IV administration.  
 
 The LY3298176 drug 
product solution vials may be held refrigerated (2°C to 8°C) for not more than 72 hours.The 
drug product solution must be administered within 4 hours after it is removed from refrigerated
(2°C to 8°C) storage.  LY3298176 compounded sterile drug product vials are intended for single-
dose administration.   
All investigational product provided to the investigator will be stored in a secure location, and 
allocated and dispensed by appropriately trained persons.  The allocation and dispensing of the 
investigational products will be fully documented and verified by a second person.  Detailed 
records of the amounts of investigational product received, dispensed,and remaining at the end 
of the study will be maintained. Detailed instructions for the preparation and handling of 
LY3298176 will be provided by the Sponsor in a pharmacy manual.
CCI


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Table GPGE.7.1
Treatments Administered
Treatment Name
LY3298176 
LY3298176 Solution
Placebo to Match 
LY3298176 Solution
Dosage Formulation
Reference lyophilized 
powder in glass vial
Test solution formulation in
a glass vial
Test solution formulation
in a glass vial
Unit Dose Strength(s) / 
Dosage Level(s)
Each vial can deliver 5 mg 
LY3298176
Concentration ranging from
10 mg/mL to 30 mg/mL
Placebo
Route of Administration
Subcutaneous injection
and intravenous infusion
Subcutaneous injection and 
intravenous infusion
Subcutaneous injection
Dosing Instructions
Single-dose administration
Single-dose administration
Single-dose
administration
7.2.
Method of Treatment Assignment
Part A: the treatment to be injected for each period will be determined according to a 
randomization schedule.
Part B:  a fixed, single-arm treatment.
Part C: the treatment to be injected on a given treatment day will be determined according to a 
randomization schedule.
7.2.1. Selection and Timing of Doses
Part A: Subjects will be randomized to 1 of 2 treatment sequences to be administered over 
2 consecutive study periods.  Each treatment period will consist of the reference lyophilized
formulation and a test-solution formulation. The sequence of treatments will be administrated 
according to the randomization schedule. The doses will be administered at approximately the 
same time of the day during both periods. The actual time of all dose administrations will be 
recorded in the subject’s electronic case report form (eCRF). Injections will be administered into 
the SC tissue of the abdominal wall.
Part B: A single, 0.5-mg IV dose of LY3298176 will be administered in the morning following 
an 8-hour, overnight fast. The actual start and stop time of IV dose administration will be 
recorded in the subject’s eCRF.
Part C: Dosing will commence at approximately the same time of day at each dosing instance.
The actual time of all dose administrations will be recorded in the subject’s eCRF. All injections 
will be administered into the SC tissue of the abdominal wall. Injection sites will be alternated 
weekly between 4 sites (ie, right and left upper quadrants and right and left lower quadrants) on 
the abdominal wall.
7.3.
Blinding
Parts A and B are open label. Part C is investigator- and subject-blinded.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event.  The 
subject’s safety must always be the first consideration in making such a determination.  If the 


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investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
7.4.
Dose Modification
Part B: An 0.5-mg LY3298176 dose is planned to be administered over 10 minutes to the first 
2 subjects. If vomiting is noted in the first 2 subjects, to the extent that treatment with 
antiemetics and intravenous fluids is required, a reduced dose (0.25 mg) may be administered to 
the next 6 subjects planned in this part. If there are no safety concerns, then, following an 
interim PK analysis, the same planned dose of 0.5 mg will be administered to the next 4 subjects 
enrolled in this part. If, following the interim analysis, it is noted that the LY3298176
concentrations cannot be adequately measured, then a different dose may be considered for an 
additional 6 subjects. 
7.4.1. Management of Intravenous Infusion
7.4.1.1.
Premedication for Infusions
Premedication for the infusions is not planned.  However, if an infusion reaction occurs, 
appropriate medication may be used, as determined by the study investigator(s).  If infusion 
reactions are observed, but a review of the data suggests that dose escalation may continue, 
administration of acetaminophen, 500 to 1000 mg, and/or an antihistamine may be administered 
orally, 30 to 60 minutes prior to the start of infusion for subsequent subjects.
The decision to implement premedication for infusions in subsequent cohorts will be made by 
the investigator and Sponsor, and recorded in the study documentation along with the dose-
escalation decision.
Any premedications given will be documented as a concomitant therapy (see Section 7.7).
7.4.1.2.
Management of Infusion Reactions
There is a risk of infusion reaction with any biological agent; therefore, all subjects should be 
monitored closely.  Symptoms and signs that may occur as part of an infusion reaction include, 
but are not limited to: fever, chills, nausea, headache, bronchospasm, hypotension, angioedema, 
throat irritation, rash, pruritus, myalgia, and dizziness.  
In the event that a significant infusion reaction occurs, the following guidance should be followed:

The investigational product infusion should be slowed (eg, reduce infusion rate by 50%
[ie, an infusion rate of 12 mL/hr becomes 6 mL/hr or slower]) or stopped, depending on 
the symptoms/signs present:
o
If slowed, the infusion should be completed at the slower rate, as tolerated.
o
If determined by the investigator that the infusion should no longer continue, no 
further attempts to dose the subject should be made.

Supportive care should be employed in accordance with the symptoms/signs.


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
If a subject’s infusion reaction is sufficiently severe to discontinue the infusion, 
subsequent infusions may be administered with premedication, at the discretion of the 
investigator, following agreement with the Lilly clinical research physician (CRP) or 
clinical pharmacologist.

If a subject’s infusion rate is reduced due to an infusion reaction, subsequent infusions 
may be administered, at the discretion of the investigator, following agreement with the 
Lilly CRP or clinical pharmacologist.  If further infusions are administered, the infusion 
rate must not exceed the slowest rate used to complete the infusion on the occasion when 
the infusion reaction occurred.  Premedication may be administered at the discretion of 
the investigator.

If it is determined that the subject should not receive further doses of investigational 
product, the subject should complete AE and other follow-up procedures, per Section 2 of 
this protocol.
If the signs and symptoms indicate that a subject is suffering from possible infection(s), he/she 
will be clinically managed, treated, and followed up until resolution. Any AEs will be recorded,
as appropriate.
7.5.
Preparation/Handling/Storage/Accountability
The investigator (or designee) must confirm that appropriate temperature conditions have been 
maintained, as communicated by the Sponsor, during transit for all investigational product
received, and that any discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive investigational product or study materials, 
and only authorized site staff may supply or administer investigational product.
All investigational product 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 study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation, and final disposition of records).
7.6.
Treatment Compliance
The investigational product will be administered at the clinical site, and documentation of 
treatment administration will occur at the site.
7.7.
Concomitant Therapy
Subjects should not use over-the-counter or prescription medication, and/or herbal supplements, 
with the exception of vitamin/mineral supplements, any hormone replacement therapy, and/or 
thyroid replacement therapy, within 14 days prior to dosing and for the duration of the study.
The use of topical medication may be permitted if no evidence of chronic dosing with the risk of
systemic absorption exists.


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Because LY3298176 may be associated with nausea and vomiting, symptomatic care (eg, 
antiemetic drugs [except 5-hydroxytryptamine 3 antagonists] and antacids) can be used as per 
usual standard of care, but should be avoided if possible. Signs and symptoms of dehydration 
should be evaluated and, if present, appropriately managed. 
Additional drugs are to be avoided during the study, unless required to treat an AE. Any drug 
given for treatment of an AE should be documented as such.
If the need for any other concomitant medication (eg, nonsteroidal anti-inflammatory drugs, 
acetaminophen, or antihistamines) arises, inclusion or continuation of the subject may be at the 
discretion of the investigator, preferably after consultation with a Lilly CRP or clinical 
pharmacologist. Any additional medication used during the course of the study must be 
documented in the eCRF.
7.8.
Treatment after the End of the Study
LY3298176 will not be made available to subjects after the conclusion of the study.


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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Discontinuation of the investigational product for abnormal pancreatic tests and liver function 
tests (LFTs) should be considered by the investigator when a subject meets any of the following 
conditions:

ALT or AST >5X ULN in healthy subjects

ALT or AST >3X ULN sustained for more than 2 weeks in healthy subjects

ALT or AST >3X ULN and TBL >2X ULN or international normalized ratio (INR) >1.5.

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

Lipase and/or amylase are confirmed to be ≥3X ULN (please refer to algorithm for 
the monitoring of pancreatic events in Appendix 7)

Drug-related vomiting requiring IV hydration treatment or causing severe distress 
(prevents daily activities and results in no appetite, or requires an emergency department 
visit or hospitalization)
The criteria for enrollment must be followed explicitly.  If a subject who does not meet 
enrollment criteria is inadvertently enrolled, that subject must be discontinued from the 
investigational product, but may be allowed to continue in the study to provide the follow-up 
data.
Subjects who discontinue the investigational product early will have procedures performed, as 
shown in the Schedule of Activities (Section 2).
8.1.1. Discontinuation of Inadvertently Enrolled Subjects
If the Sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly clinical pharmacologist and the 
investigator to determine if the subject 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 to allow the inadvertently enrolled subject to continue in the study, with or 
without continued treatment with investigational product.  
8.2.
Discontinuation from the Study
Subjects will be discontinued under the following circumstances:

Enrollment in any other clinical study involving an investigational product, or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study.

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP).


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
Investigator Decision:
o
The investigator decides that the subject should be discontinued from the study.
o
If the subject, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent.

Subject Decision
o
The subject (or legal representative) requests to be withdrawn from the study.
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits, and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for scheduled visits or who 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 laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.
Unless, otherwise, stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
Not applicable.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study,
and for alerting Lilly (or its designee) to any events that seem unusual, even if those events may 
be considered an unanticipated benefit to the subjects.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate healthcare option, 
AEs that are serious or, otherwise, medically important, considered related to the investigational 
product or the study, or which caused the subject to discontinue the investigational product 
before completing the study.  The subject should be followed until the event resolves, stabilizes
with appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
After the informed consent form (ICF) is signed, study site personnel will record, via eCRF, the 
occurrence and nature of each subject’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 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 investigational product, 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 subject’s investigational product is discontinued as the 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 (ie, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization, but that may jeopardize the subjects or may require intervention to 
prevent one of the other outcomes listed in the definition above
Study site personnel must alert the Lilly CRP/clinical pharmacologist (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 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 subject has signed informed consent and has received investigational 
product.  However, if an SAE occurs after signing informed consent, but prior to receiving 
investigational product, and is considered reasonably possibly related to a study procedure, then 
it must be reported.
Pregnancy (maternal or paternal exposure to investigational product) does not meet the definition 
of an AE.  However, to fulfill regulatory requirements, any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus.
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 investigational product or procedure.  Lilly 
has procedures that will be followed for the recording and expedited reporting of SUSARs that 
are consistent with global regulations and the associated detailed guidance.
9.2.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, to monitor quality, and to 
facilitate process and product improvements.


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Subjects should be instructed to contact the investigator as soon as possible if they have 
complaints or problems with the investigational product (or drug delivery system), so that the 
situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY3298176 is considered to be any dose higher 
than the dose assigned through randomization.  Treatment for overdose is supportive care. For 
detailed information, refer to the IB for LY3298176.
9.4.
Safety
9.4.1.Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted, according to the 
Schedule of Activities (Section 2).
9.4.2. Vital Signs
For each subject, vital signs (blood pressure, pulse rate, temperature) measurements should be 
conducted, according to the Schedule of Activities (Section 2).
Blood pressure and pulse rate should be measured after the subject is supine for at least 
5 minutes.
If orthostatic measurements are required, the subject should be supine for at least 5 minutes and 
stand for at least 3 minutes.
If the subject 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.
9.4.3. Electrocardiograms
For each subject, 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 
subject receives the first dose of the investigational product, should be reported to Lilly (or its 
designee) as an AE via eCRF.
For each subject, a single12-lead digital ECG will be collected, according to the Schedule of 
Activities (Section 2).  Electrocardiograms must be recorded before collecting any blood 
samples. Subjects must be supine for approximately 5 to 10 minutes before ECG collection, and 
remain supine, but awake, during ECG collection.  Electrocardiograms may be obtained at 
additional times, when deemed clinically necessary.  All ECGs recorded should be stored at the 
investigational site.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 


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subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings be 
identified.  
If a clinically significant finding is identified (including, but not limited to, changes in 
QT/corrected QT [QTc] interval from baseline) after enrollment, the investigator will determine 
whether the subject can continue in the study.  The investigator (or qualified designee) is 
responsible for determining if any change in subject management is needed, and must document
his/her review of the ECG printed at the time of collection.  Any new clinically relevant finding 
should be reported as an AE.
9.4.4. Body Weight
Weight will be measured, as indicated in the Schedule of Activities (Section 2). Subjects will be 
weighed in light clothing at approximately the same time in the morning, before dosing and after 
an overnight fast and evacuation of the bowel and bladder, if possible. During the treatment 
period, weight will be measured twice on each scheduled occasion, with the subject 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, and the scale will not be moved or recalibrated.
9.4.5. Safety Monitoring
The Lilly clinical pharmacologist or CRP 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 or CRP will periodically review the following data:

trends in safety data

laboratory analytes 

serious and nonserious AEs, including AEs of special interest (GI events, hypoglycemia, 
injection-site reactions, and hypersensitivity reactions) and reported and adjudicated
pancreatitis
When appropriate, the Lilly clinical pharmacologist or CRP will consult with the functionally 
independent Global Patient Safety therapeutic area physician or clinical research scientist.
9.4.5.1.
Hepatic Safety
If a study subject experiences elevated ALT ≥3X ULN, alkaline phosphatase (ALP) ≥2X ULN, 
or elevated TBL ≥2X ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days 
including ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase (GGT), 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, based on consultation with the Lilly clinical pharmacologist or CRP.  
Monitoring should continue until levels normalize and/or are returning to approximate baseline 
levels.


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Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2X ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests 

subject discontinued from treatment due to a hepatic event or abnormality of liver 
tests

hepatic event considered to be a SAE
9.4.6. Hypersensitivity Reactions
All hypersensitivity reactions will be reported by the investigator as either 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 investigational 
product.  Investigational product may be restarted if, in the opinion of the investigator, the event 
was not related to study drug and when/if it is safe to do so.  If dosing is permanently 
discontinued, the subject should remain in the study, as needed, per medical judgment.
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).
9.4.6.1.
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.
9.4.6.1.1. Pain Measurements Using the Visual Analog Scale
Pain measurements will be assessed using a 100-mm validated visual analog scale (VAS) for 
pain.  The VAS is a well-validated tool (Williamson and Hoggart 2005) to assess injection-site 
pain.  The VAS is presented as a 10-cm (100-mm) line, anchored by verbal descriptors, usually 
“no pain” and “worst imaginable pain.”  The subject will be asked to mark the 100-mm line to 
indicate pain intensity at time points according to the Schedule of Activities (Section 2) and as 
clinically indicated.  A staff member will use a caliper to measure the distance from 0 to the 
mark that the subject placed on the VAS, and to record the measurement in the source document.
9.4.7. Glucose Monitoring (Part C)
Subjects will be instructed on how to use the glucose meter provided by the site, and to conduct 
self-blood glucose-monitoring tests; subjects will be also educated on the symptoms of 
hypoglycemia.  Throughout their participation in the study, subjects will monitor blood-glucose 


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levels.  Subjects will be provided a diary card and instructed to record blood-glucose results
premeal and at bedtime on at least 2 days per week during the dosing phase of the study, and
whenever the subject experiences symptoms of hypoglycemia. Investigator review of glucose 
results clinically indicative of hypoglycemia is required.
9.4.7.1.
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 subject 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 over any 2-week period between screening 
and the end of the dosing period, the subject will be evaluated further at the study site. If fasting 
plasma/serum glucose continues to exceed the acceptable level, the investigational product will 
be discontinued, and treatment with an appropriate antidiabetic agent may be initiated by the 
investigator. If hyperglycemia occurs during the follow-up period, the subject 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) based on recommendations 
of the International Hypoglycaemia Study Group (IHSG 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 (also called unclassifiable hypoglycemia).
Documented Clinically Significant Hypoglycemia (Level 2): 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.
Severe Hypoglycemia (Level 3):

Severe hypoglycemia (in adults): Subjects 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


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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 
subjects require therapy by healthcare providers (emergency medical technicians, 
emergency room personnel, etc.) are of particular interest to payers. Therefore, some 
clinical trials may want to 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 approximately midnight to approximately 6 AM 
definition which does not take subjects’ individual sleep times into consideration, 
and is consistent with the American Diabetes Association recommendations of 
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 across a 24-hr clock). 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 of patients with chronically 
poor glycemic control can decrease so rapidly that subjects 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 subject 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.

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 
eECRF (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 eECRF, together with any 


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treatments administered and not be recorded as an AE.Cases of hypoglycemia may be treated 
with foods rich in carbohydrate such as fruit, juice, skim 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.
9.4.8. 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 study drug and protocol procedure will be captured.
9.4.9. Elevated Lipase or Amylase
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 7) for the monitoring of pancreatic
events whenever lipase and/or amylase is confirmed to be ≥3XULN at any visit
postrandomization, even if the subject is asymptomatic.
9.4.10.Immunogenicity Assessments
At the visits and times specified in the Schedule of Activities(Section 2), venous bloodsamples 
will be collected to determine antibody production against LY3298176.  To interpret the results 
of immunogenicity, a PK sample will be collected at the same time points. All samples for 
immunogenicity should be taken predose,when applicable. In the event of drug hypersensitivity 
reactions (immediate or nonimmediate), additional samples will be collectedas close to the onset 
of the eventas possible, at the resolution of the event, and 30 days following the event.  
Instructions for the collection and handling of blood samples will be provided by the sponsor.  
The actual date and time (24-hour clock time) of each sampling will be recorded.  
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of LY3298176at a laboratory approved by the Sponsor. Positive ADA samples may be 
evaluated for neutralizing antibodies to LY3298176. Positive ADA samples may also be tested 
for cross-reactivity with native GLP-1 and GIP, and,if positive, then,additional testing for 
neutralizing antibodies against native GLP-1 may also be conducted.  
All subjects will have an ADA sample measured at early discontinuation or at the follow-up visit
(date of visit outlined in the Schedule of Activities [Section 2]
CCI
).A risk-based approach will be 
used to monitor subjects who have clinically significant treatment-emergent ADAs (TE-ADAs)
at the last visit.
 
 
 
 


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A PK sample may be collected at the 
follow up immunogenicity assessment(s),if warranted and agreed upon by the investigator and 
Sponsor.
Every attempt should be made to contact subjectsfor the follow-up immunogenicity assessment; 
however, if subjectsare unwilling or unable to return for the visit, this is not considered a 
protocol violation.
Subjectsfollowed 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 arerecognized by the 
clinical team, no further follow-up will be required.Subjectswho have clinical sequelae that are 
considered potentially related to the presence of TE-ADAsmay also be asked to return for 
additional follow-up testing.
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and ethical review boards (ERBs) allow,at a facility selected by the 
Sponsor.  The duration allows the Sponsor to respond to future regulatory requests related to 
LY3298176.  Any samples remaining after 15 years will be destroyed.
9.5. Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples
of approximately 3mL 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 byboth 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 clock time) of each sampling will be recorded.
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 massspectrometry (LC/MS) method.  Analyses of samples collected 
from placebo-treatedsubjects are not planned.Bioanalytical samples collected to measure 
investigational product concentrations will beretained for a maximum of 1 year following last 
subject visit for the study. 
9.6. Pharmacodynamics
CCI
Not applicable.


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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.  Assessment of 
variable response may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or ERBs/investigational review board (IRBs) 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
Not applicable.
9.9.
Health Economics
Not applicable.


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10. Statistical Considerations and Data Analysis
10.1.Sample SizeDetermination
Approximately20 healthy subjects may be enrolled in Part A in order that at least 16 subjects 
complete Part A.  Up to 10 subjects will be enrolled in Part B in order that at least 6subjects 
complete Part B.  Approximately 16healthy subjectsmay be enrolled in Part C in order that at 
least 12subjectscomplete Part C(in a 3LY3298176:1placeboratio).
For each study part, any dropout may be replaced so that the targeted numbers of subjects for 
safety review and data collection maybe achieved.  The replacement subjectwill be assigned to 
receivethe treatment of the dropout.
Part A:
 
 
PartsB and C:  The sample size is customary for Phase 1 studies evaluating safety and PK.  
Thesample sizes are not based on statistical calculations.  The sample sizes for each part of the 
study are considered sufficient to evaluate the primary objectives ofthis study.
10.2.Populations for Analyses
10.2.1.Study Participant Disposition
A detailed description of subject disposition will be providedat the end of the study. 
Allsubjects 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 subject’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
CCI
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (or its 
designee).
Pharmacokineticanalyses will be conducted on data from all subjectswho receiveat least 1dose 
of the investigational productand who have evaluable PK.  
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.
Unless,otherwise,noted, all tests of treatment effects will be conducted at a 2-sided alpha level 
of0.1, and 90% CIs will be calculated.


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Additional exploratory analyses of the data will be conducted,as deemed appropriate.  
Studyresults may be pooled with the results of other studies for post-hoc analyses.  
10.3.1.Safety Analyses
10.3.1.1.Clinical Evaluation of Safety
All investigational productand protocol procedure 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 will be presented by severity and by association 
with investigational product,as perceived by the investigator.  Symptoms reported to occur 
before the first study drug dosingwill 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 investigational product-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,and 
ECG parameters.  The parameters will be listed. Continuous safety variables will be summarized 
using descriptive statistics.Categorical safetyvariables will be summarized using countand 
percentage.  Vital signs data will be analyzed and summarized for each Part.  Body weight data 
will be summarized.
Additional analysis will be performed,if warranted,upon review of the data.
10.3.1.3.Injection Site Reaction
For Part A and Part C, incidence of erythema, induration, pain, itching, and swelling will be 
listed and summarized by treatment.
The post-injection pain score will be summarized by treatment.  Additional analyses may be 
performed,if appropriate.
10.3.2.PharmacokineticAnalyses
10.3.2.1.Pharmacokinetic Parameter Estimation
Pharmacokineticparameter estimates for LY3298176 will be calculated by standard 
noncompartmentalmethods of analysis. The primary parameters for analysis will be: Cmax, and 
AUCfLY3298176for PartsA, B,and C of the study. Other parameters, such as half-life, 
apparent clearance, and apparent volume ofdistribution, may be reported, as appropriate. 
10.3.2.2.Pharmacokinetic Statistical Inference
10.3.2.2.1.Part A
To assess the relative bioavailability of a single SC dose of LY3298176 administered as a 
solution formulation (test),compared to a lyophilizedformulation (reference), AUC from time 
zero to infinity (AUC0-∞), AUC from time zero to thetime of last measured concentration 
(AUC0-tlast)and C
maxwill be log-transformed and analyzed using a linear mixed effects model 


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with treatment, period, and sequence as fixed effects and subject as a random effect. The 
difference in least squares means (LSMeans) between the test formulation and reference
formulation for each parameter will be exponentiated to yield ratios of geometric LSMeans and 
their corresponding 90% CIs. Time to maximum observed concentration will be analyzed using 
a nonparametric method. The Wilcoxon rank-sum test will be performed.  Median difference 
and 90% CI will be reported.
10.3.2.2.2.Part B
No formal statistical analysis will be performed for the IV formulation evaluation part of the 
study. A descriptive summary of PK parameters will be reported.
10.3.2.2.3.Part C
A descriptive summary of PK parameters, by treatment, will be presented.
10.3.3. Evaluation of Immunogenicity
The frequency and percentage of subjects with preexisting ADAs, ADAs at any time 
postbaseline, and TE-ADAs to LY3298176 will be tabulated. Correspondingly, the frequency 
and percentage of subjects with preexisting or treatment-emergent neutralizing antibodies, and/or 
cross-reacting antibodies to LY3298176 may be tabulated.
The relationship between the presence of antibodies to LY3298176 and the PK parameters and
safety (such as AEs, injection site reactions, formulation, and/or route of administration) may be 
assessed.
10.3.4. Data Review during the Study
An interim analysis is planned after dosing 2 subjects in Part B of the study.
The possible outcomes following IV administration of a 0.5-mg dose of LY3298176 over 
10 minutes are:

LY3298176 tolerability is adequate; LY3298176 concentrations are measurable in the 
2 subjects.

LY3298176 tolerability is inadequate. To improve tolerability, the dose of LY3298176 
may be reduced to 0.25 mg, administered over 10 minutes.

LY3298176 tolerability is adequate; however, if LY3298176 concentrations cannot be 
adequately quantified, then a dose adjustment may be considered. 
Following completion of Parts A and B of this study, an interim database lock may be 
performed.


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11.
References
[ADA] American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a
report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care.
2005;28(5):1245-1249.
[ADA] American Diabetes Association. 2017 Standards of medical care in diabetes: glycemic 
targets position statement. Diabetes Care. 2017:40(Suppl 1):S48-S56. Available at:
https://doi.org/10.2337/dc17-S009. Accessed August 22, 2017.
Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 
2007;132(6):2131-2157.
Dungan KM, Povedano ST, Forst T, González JG, Atisso C, Sealls W, Fahrbach JL. 
Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with 
type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 
2014;384(9951):1349-1357.
Giorgino F, Benroubi M, Sun JH, Zimmermann AG, Pechtner V. Efficacy and safety of 
once-weekly dulaglutide versus insulin glargine in patients with type 2 diabetes on metformin 
and glimepiride (AWARD-2). Diabetes Care. 2015;38(12):2241-2249.
Herbst R, Bolton W, Shariff A, Green JB. Cardiovascular outcome trial update in diabetes: new 
evidence, remaining questions. Curr Diab Rep. 2017;17(9):67.
[IHSG] 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. Available at: https://doi.org/10.2337/dc16-2215. Accessed
January 10, 2016.
Jendle J, Grunberger G, Blevins T, Giorgino F, Hietpas RT, Botros FT. Efficacy and safety of 
dulaglutide in the treatment of type 2 diabetes: a comprehensive review of the dulaglutide 
clinical data focusing on the AWARD phase 3 clinical trial program. Diabetes Metab Res Rev.
2016;32(8):776-790
Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, Zdravkovic M, Düring M, 
Matthews DR; LEAD-2 Study Group. Efficacy and safety comparison of liraglutide, 
glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD 
(liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009;32(1):84-90.
Nauck MA, Petrie JR, Sesti G, Mannucci E, Courrèges JP, Lindegaard ML, Jensen CB, 
Atkin SL; Study 1821 Investigators. A phase 2, randomized, dose-finding study of the novel 
once-weekly human GLP-1 analog, semaglutide, compared with placebo and open-label 
liraglutide in patients with type 2 diabetes. Diabetes Care. 2016;39(2):231-241.
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.


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Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin 
Nurs. 2005;14(7):798-804.


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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
assent
Agreement from a child or other individual who is not legally capable of providing consent, 
but who can understand the circumstances and potential risks involved in participating in a 
study (required by some institutional review boards [IRBs]/ethical review boards [ERBs]). 
AST
aspartate aminotransferase
AUC
area under the drug plasma concentration versus time curve
AUC(0-∞)
area under the drug plasma concentration versus time curve from time zero to infinity
AUC(0-tlast)
area under the drug plasma concentration versus time curve from time zero to the time of 
last measured concentration
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/subject is not, or vice versa, or when the Sponsor is aware of the 
treatment but the investigator and/his staff and the patient/subject are not.  A double-blind 
study is one in which neither the patient/subject nor any of the investigator or Sponsor staff 
who are involved in the treatment or clinical evaluation of the subjects are aware of the 
treatment received
BP
blood pressure
CBC
complete blood count
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum observed (peak) concentration
CNS
central nervous system
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.


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Term
Definition
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.
CPK
creatinine phosphokinase
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 effect
CT
computed tomography
CV
coefficient of variation
DBP
diastolic blood pressure
DPP-IV
dipeptidyl peptidase IV
ECG
electrocardiogram
eCRF
electronic case report form
enroll
The act of assigning a patient/subject to a treatment.  Patients/Subjects who are enrolled in 
the study are those who have been assigned to a treatment.
enter
Patients/Subjects entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives.
ERB
ethical review board
FOIA
Freedom of Information Act
FSH
follicle-stimulating hormone
GCP
good clinical practice
GGT
gamma-glutamyltransferase
GI
gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide


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Term
Definition
GLP-1
glucagon-like peptide 1
GLP-1 RA
glucagon-like peptide 1 receptor agonist
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
Ig
immunoglobulin
informed consent
A process by which a patient/subject 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/subject’s decision to participate.  Informed consent is documented 
by means of a written, signed and dated informed consent form.  
INR
international normalized ratio
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
Investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical 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.
IRB
institutional review board
IV
intravenous administration
LC/MS
liquid chromatography-mass spectrometry
Legal 
Representative
An individual or judicial or other body authorized under applicable law to consent, on behalf of 
a prospective a patient/subject, to the a patient/subject’s participation in the clinical study.
LFT
liver function test
LSMean
least squares mean
MRI
magnetic resonance imaging
NOAEL
no-observed-adverse-effect level


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Term
Definition
open-label
A study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study participant are aware of the drug therapy received during the 
study.
PD
pharmacodynamic
PK
pharmacokinetic
PR
pulse rate
QTc
corrected QT interval
QW
once weekly administration
randomize
the process of assigning subjects/patients to an experimental group on a random basis
RBC
red blood cell
SAE
serious adverse event
SBP
systolic blood pressure
SC
subcutaneous administration
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.  
SUSARs
suspected unexpected serious adverse reactions 
T
temperature
T2DM
type 2 diabetes mellitus
TBL
total bilirubin level
TE-ADA
treatment-emergent antidrug antibody
TEAE
treatment-emergent adverse event:  any untoward medical occurrence that emerges during a 
defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this treatment
TG
triglyceride
ULN
upper limit of normal
US
United States
USP
United States Pharmacopoeia
VAS
Visual Analog Scale
WBC
white blood cell


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Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology
Clinical Chemistry (Fasting)
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume
Chloride
Mean cell hemoglobin
Serum creatinine
Mean cell hemoglobin concentration
Calcium
Leukocytes (WBC)
Phosphorus
Absolute counts of: 
Glucose, fasting
Neutrophils
Blood urea nitrogen
Lymphocytes
Uric acid
Monocytes
Total protein
Eosinophils
Albumin
Basophils
Total bilirubin
Platelets
Alkaline phosphatase
Alanine aminotransferase
Urinalysis
Aspartate aminotransferase
Specific gravity
Lipase, fasting
pH
Amylase
Protein
Triglycerideb
Glucose
Total cholesterolb
Ketones
Bilirubin
Serologyc
Urobilinogen
Follicle-stimulating hormonea
Blood
Hepatitis B surface antigen
Leukocytes
Hepatitis C antibody
Microscopya
HIV antibody
Pregnancy test (urine, serum) d
Drug and alcohol screene
Abbreviations:  HIV = human immunodeficiency virus; RBC = red blood cell; WBC = white blood cell.
Note:  Results of these assays will be validated by the central or local laboratory at the time of testing.  Additional 
tests may be performed or autocalculated by the laboratory as part of its standard panel that cannot be removed.  
Some of the above parameters are calculated from measured values.  Omission of calculated values will not be 
considered as a protocol violation.
a
If clinically indicated, per investigator’s discretion.
b
Triglyceride and total cholesterol concentrations in the safety panel will not be required on the days that the lipid 
panel is performed.
c
At screening only (unless previously performed within the last 6 months with reports available for review).
d
Pregnancy tests (females, as appropriate) will be performed at the investigator’s discretion.
e
Drug screen and ethanol level may be repeated prior to admission to the clinical research unit and at other times 
indicated in the Schedule of Activities (Section 2).
f
Performed at a local laboratory only at site(s) located in the United States.


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Appendix 3.
Study Governance, Regulatory, and 
Ethical Considerations
Informed Consent
The investigator is responsible for:

Ensuring that the subject understands the nature of the study, the potential risks and 
benefits of participating in the study, and that his/her participation is voluntary.

Ensuring that informed consent is given by each subject or legal representative.  This 
includes obtaining the appropriate signatures and dates on the informed consent form
(ICF) prior to the performance of any protocol procedures and prior to the administration 
of investigational product.

Answering any questions, the subject may have throughout the study, and sharing, in a 
timely manner, any new information that may be relevant to the subject’s willingness to 
continue his/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 (or its designee) is responsible for the central recruitment strategy for subjects.  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 Conference on 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:

Current Investigator’s Brochure (IB) and updates during the course of the study

Informed consent form

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 (CIOMS) International Ethical Guidelines 
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations
Some of the obligations of the Sponsor will be assigned to a third party organization.
Protocol Signatures
The Sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his/her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator (or designee) will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
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/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 subject 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 subject personal information collected will be provided in a written 
document to the subject by the Sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly (or its designee), the investigator, or the 
ERB of the study site judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly (or its designee) judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality, and 
may be required in follow-up with subjects in consultation with Lilly (or its designee clinical 
research physician [CRP]).
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
Anti-nuclear antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/Confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol I8F-MC-GPGE Sampling Summary Part A
Type of Sample
Volume per Sample
(mL)
Number of Samples 
per Subject
Total Volume
(mL)
Screening testsa
17.0
1
17.0
Clinical laboratory testsa
6.5
6
39.0
Pharmacokinetics
3.0
29
87.0
Immunogenicity
6.0
6
36.0
Genetic
10.0
1
10.0
Loss by use of indwelling, 
intravenous cannula
1.0
3
3.0
Total:
192.0
a
Additional samples may be drawn, if needed, for safety purposes.
Protocol I8F-MC-GPGE Sampling Summary Part B
Type of Sample
Volume per Sample
(mL)
Number of Samples 
per Subject
Total Volume
(mL)
Screening testsa
17.0
1
17.0
Clinical laboratory testsa
6.5
4
26.0
Pharmacokinetics
3.0
23
69.0
Immunogenicity
6.0
4
24.0
Genetic
10.0
1
10.0
Loss by use of indwelling, 
intravenous cannula
1.0
9
9.0
Total:
155.0
a
Additional samples may be drawn, if needed, for safety purposes.


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Protocol I8F-MC-GPGE Sampling Summary Part C
Type of Sample
Volume per Sample
(mL)
Number of Samples 
per Subject
Total Volume
(mL)
Screening testsa
17.0
1
17.0
Clinical laboratory testsa
6.5
3
19.5
Pharmacokinetics
3.0
21
63.0
Immunogenicity
6.0
4
24.0
Pharmacogenomic
10.0
1
10.0
Loss by use of indwelling, 
intravenous cannula
1.0
6
6.0
Total:
139.5
a
Additional samples may be drawn, if needed for safety, purposes.


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Appendix 6.
Clinically Significant Adverse Effects
The following table summarizes the type and severity of symptoms, clinical signs, and clinical 
laboratory findings that may qualify as a clinically significant effect (CSE).  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 subjects 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 thirdparty assistance.
Dizziness/hypotension
Orthostatic CNS symptoms (dizziness, confusion) that are not vasovagal responses 
to provocative stimuli (eg, phlebotomy, nausea, bowel or bladder function), and are 
associated with orthostatic SBP decrease >20 mmHg or DBP decrease >10 mmHg 
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 over >24 hours that is unresponsive to oral antihistamine.
Signs
SBP
>30 mmHg increase from baseline values and an absolute level >190 mmHg.
DBP
>20 mmHg increase from baseline values and an absolute level >115 mmHg.
Heart rate
Resting (sitting or recumbent) >120 bpm.
Cardiac Rhythm
Any rhythm other than sinus rhythm, mild sinus bradycardia, or mild sinus 
tachycardia.
QTc
>500 msec or >60 msec 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 <1500/μL and >1000 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.
ALT
>5-fold above laboratory reference upper limit value.
AST
>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 >10mEq/L change from baseline value.
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CNS = central nervous system, 
CSE = clinically significant effect, DBP = diastolic blood pressure, QTc = corrected QT interval; SBP = systolic 
blood pressure.


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Appendix 7.
Pancreatic Monitoring
Glucagon-like peptide 1 (GLP-1) agonists have been associated with a possible risk of acute 
pancreatitis.  In 2006, the United States (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, in order 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 ≥3X the upper limit of 
normal (ULN) at any visit after randomization, even in asymptomatic subjects (see figure 
below).  Lipase and amylase may also be obtained at any time during the clinical trials for any 
patient/subject suspected of having symptoms suggestive of pancreatitis (such as severe 
gastrointestinal [GI] signs and/or symptoms), at the investigator’s discretion.
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 >3X ULN

characteristic findings of acute pancreatitis on computed tomography scan or 
magnetic resonance imaging
Most subjects with acute pancreatitis experience abdominal pain that is located generally in the 
epigastrium, and radiates to the back in approximately one-half of the cases.  The pain is often 
associated with nausea and vomiting.  However, experience with GLP-1 agonists has 
demonstrated that some subjects asymptomatic for classic pancreatitis may demonstrate 
significant elevations of lipase and/or amylase.  For subjects considered by investigators to be 
asymptomatic for pancreatitis, but whose value(s) for lipase and/or amylase are ≥3X ULN, an 
algorithm is in place to follow these subjects safely and to quickly reach (or not reach) a 
diagnosis of pancreatitis.


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Abbreviations:  CBC = complete blood count; CT = computed tomography; LFTs = liver function 
tests; MRI = magnetic resonance imaging.
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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Subjects diagnosed with pancreatitis will be discontinued from the study.  Investigators will be 
responsible for following, through an appropriate healthcare option, these pancreatitis AEs until 
the events resolve or are explained.  Adverse events that meet the diagnostic criteria of acute 
pancreatitis will be captured as serious adverse events (SAEs).  For all other pancreatic AEs 
(such as idiopathic or asymptomatic pancreatic enzyme abnormalities), the investigator will be 
responsible for determining the seriousness of the event (AE or SAE) and the relatedness of the 
event to study drug.


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Appendix 8.
Contraceptive Methods
Male subjects with female partners of childbearing potential will be required to use a condom in 
conjunction with a spermicidal gel, foam, cream, or suppository.  In addition, the female partner, 
as well as female subjects of childbearing potential, will be requested to use an additional 
effective form of contraception, which can be any of the following:

female condom with spermicide

diaphragm with spermicide

cervical sponge

cervical cap with spermicide

combined oral contraceptive pill and mini-pill

NuvaRing

implantable contraceptives

injectable contraceptives (such as Depo-Provera)

intrauterine device (such as Mirenaand ParaGard)

true abstinence, when in line with the preferred and usual lifestyle of the patient
Men who have had a vasectomy with appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate are not required to use contraception.  In addition, Inclusion 
Criterion 1b provides a specific definition of women not of childbearing potential; these subjects 
will not be required to use contraception.  Male subjects with a female partner meeting the 
definition of a woman not of childbearing potential will not be required to use contraception.


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Appendix 9.
Protocol Amendment I8F-MC-GPGE(a) 
Summary Pharmacokinetics, Safety, and Tolerability of a 
Solution Formulation of LY3298176 in Healthy Subjects
Overview
Protocol I8F-MC-GPGE(a) Pharmacokinetics, Safety, and Tolerability of a Solution Formulation 
of LY3298176 in Healthy Subjects 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:

Part C of the protocol has been amended to remove any clinical activities occurring on 
Day -2.  

Reference to a study period in Part B of the protocol is misleading.  Language in the 
protocol referencing a study period is removed.

Clarify that clinical assessments will be taken on Day 92 as part of follow-up activities 
rather than Day 84 for Part C.

Clarify that patients will return to the CRU for study days 35-37 inclusive consistent with 
the Schedule of Activities for Part A.

Clarify that patients will be admitted to the CRU on Day -1 in order to fulfill the 
completion of study assessments scheduled to occur on Day -1.

Added descriptor for each Part A – C to the top row for each SoA page to facilitate ease 
of use

Clarified that LY will be administered subcutaneously for Part A


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
The numbering system used for inclusion and exclusion criteria provides a unique number for 
each criterion and allows for efficiency in data collection.
In case an amendment to the protocol adds a criterion, that criterion will receive the next 
available number, regardless of whether it is an inclusion or exclusion criterion.


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2.1
Study Schedule Protocol I8F-MC-GPGE Part A
Procedure (Part A)
Screening
Periods 1 and 2
ET
Comments
Days
-28 to -2
-1
1
2
3
4
5
6
7
8
15
21
35 -
37 post 
dose 
period 1
35 -
37 post 
dose 
period 2
≥35 day washout 
between doses 1 
and 2. 
Informed Consent
X
Subject Admission to 
CRU
X
Subject Discharge from 
CRU
X
Subjects may stay 
longer according to 
investigator 
discretion
Outpatient Visit
X
X
X
X
X
X
Investigational Product 
Administration
X
There is a minimum 
of 35 days washout 
period between 
doses for Period 1 
and Period 2.   
Study drug will be 
administered SC
after an overnight 
fast of at least 8 
hours.


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2.2
Study Schedule Protocol I8F-MC-GPGE Part B
Procedure
(Part B)
Screening
Treatment
ET
Comments
Days
-28 to -2
-1
1
2
3
4
5
6
7
8
15
35 - 37
≥70 days
PK Samples 
P, 5 
min, 
10 
min, 
30 
min 
1h, 
2h, 
4h,  
8h, 
12h,
24 h, 
36 h
48 h
72h
96h
120h
144h
168h
336
h
X
X
X
All sampling times 
are from start of 
infusion. (0 hr). 
Predose sample must
be collected before 
dose administration. 
If a subject withdraws 
from the study prior 
to completion of 
scheduled PK 
sampling for a given 
period, every effort 
will be taken to draw 
an unscheduled blood 
sample for PK 
assessment.   This 
will not be required if 
a sample has already 
been taken within the 
previous 24 hours.  
For ET, a PK sample 
can be taken at any 
time during the visit 
timed close to the 
immunogenicity 
sample.
Pregnancy Test 
X
X
X
X
All females only.  
Serum pregnancy test 
will be performed at 
screening.  Urine 
pregnancy test will be 
performed at Day -1 
for each period and at 
ET/Follow-up.


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2.3
Study Schedule Protocol I8F-MC-GPGE Part C
Procedure (Part 
C)
Screen
Prestudy
Treatment
ET/Follow-
up
Days
-28 to -2
Before −2
−2
−1
1a
2
3
4
8a
9
10
15 a
16
17
18
22 a
23
24
25
57
≥92
Informed consent
X
Admission to 
CRUc
X
X
X
X
X
X
Discharge from 
CRU
X
X
X
X
Outpatient visits 
to CRU
X
X
X
X
X
Distribution of 
glucose meters, 
test strips, diary, 
and GM training
X
Distribution of 
additional test 
strips, and diary. 
X
X
X
Administer study 
drugd
X
X
X
X
Medical history
X


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
Page 76
LY3298176
Procedure (Part 
C)
Screen
Prestudy
Treatment
ET/Follow-
up
Days
-28 to -2
Before −2
−2
−1
1a
2
3
4
8a
9
10
15 a
16
17
18
22 a
23
24
25
57
≥92
Height and 
weighte
X
X
P
P
P
P
X
Physical 
examination
X
Medical 
assessmentf
X 
P
P
P
P
X
Vital signs 
(BP/PR/T)g
(hours)
X
X
P
X
X
P
X
X
P
X
X
P
X
X
X
ECGh
X
P
P
X
PK sampling
(hours)
P,
8h
24
h
4
8
h
72h
P
P, 
8h
24
h
48
h
72
h
P, 
8h
24
h
48
h
72
h
X
X
Clinical laboratory 
testsi
X
P
P
X
AEs/concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Injection site 
reactionsb
P, 
0, 
6h , 
12h 
24
h
P, 
0, 
6h 
, 
12
h 
24
P, 
0, 6,
12
24
P, 
0, 6, 
12
24


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
Page 77
LY3298176
Procedure (Part 
C)
Screen
Prestudy
Treatment
ET/Follow-
up
Days
-28 to -2
Before −2
−2
−1
1a
2
3
4
8a
9
10
15 a
16
17
18
22 a
23
24
25
57
≥92
Pharmacogenomic 
sample
X
Immunogenicity
P
P
X
X
g
Vital signs(BP/PR/T) measurements:  for each dose day: predose, 24 hr, 48 hr, and on or after Day 9284 (follow-up/ET).
h
Single local safety ECGs will be measured at screening, predose Day 1, predose Day 22, predose Day 50 and follow-up/ET to take place
on or after Dday 9284 (follow-up).  
5.1
Overall Design
…
Part A:  Part A is a randomized, 2-period, crossover study in healthy subjects to evaluate the relative bioavailability of 5 mg 
LY3298176, administered as a solution formulation (test), compared to a 5-mg dose administered SC as lyophilized formulation 
(reference).  Treatment sequences and randomization are described in Section 7.2.
Each subject will provide informed consent for study participation, and will undergo a screening examination within 28 days prior to 
enrollment.
In each treatment period, subjects will be admitted to the clinical research unit (CRU) on Day -1.  On the morning of Day 1, following 
an overnight fast of at least 8 hours, subjects will receive a single SC dose of LY3298176, administered according to their assigned 
treatment sequences.  Blood samples will be collected predose and up to 480 hours postdose to measure LY3298176 concentrations. 
At a minimum, subjects will remain in the CRU for 8 days.  The investigator (or qualified designee) will review all available inpatient 
safety data before discharging subjects from the CRU on the morning of Day 8, provided that the subjects are deemed medically fit.  
Subjects may be required to remain in the CRU longer than Day 8, at the investigator’s discretion. The subjects will return to the 
CRU for follow-up visits on Days 21 and 35-37.
…
Part C:  Part C is a randomized, titration study where healthy subjects will be assigned LY3298176 or placebo at a ratio of 3 LY 
subjects to 1 placebo subjects.  The investigator and subject will be blinded to the treatment.  .


I8F-MC-GPGE(a) Clinical Pharmacology Protocol
Page 78
LY3298176
Subjects will receive a treatment regimen of either LY3298176 or placebo to be given as a SC dose on Days 1, 8, 15, and 22, after an 
overnight fast (at least 8 hours). Subjects randomized to LY3298176 will receive a 5-mg dose on Day 1 and Day 8, a 7.5-mg dose on 
Day 15, and a 10-mg dose on Day 22, administered via solution formulation (treatment specifics can be found in Section 7.1).
Each subject will be required to return to the CRU for outpatient visits and for a follow-up visit  on Day ≥92.
For all parts of this study pharmacokinetic sampling and safety assessments, including AE recording, medical assessments, clinical
laboratory tests, vital signs measurement, and electrocardiograms (ECGs), will be performed according to the Schedule of Activities 
(Section 2). 
For each dose after the first dose, the sSubjects will be admitted the day before dosing.  The investigator (or qualified designee) will 
review all available inpatient safety data before discharging subjects from the CRU on Day 3 after the final study procedures, provided 
that the subjects are deemed medically fit. More information is outlined in the Schedule of Activities (Section 2.3). 


PPD
Leo Document ID = 5a9ca3a1-6686-4589-90a3-b6019fc907fb
Approver: 
Approval Date & Time: 22-Jan-2018 19:43:15 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 23-Jan-2018 17:02:53 GMT
Signature meaning: Approved
PPD

Prot_000.pdf: 
Protocol Addendum I8F-MC-GPGE(1)
Pharmacokinetics, Safety, and Tolerability of a Solution Formulation of LY3298176 in 
Healthy Subjects 
NCT03375463 
Approval Date: 31-Aug-2018


I8F-MC-GPGE(1) Clinical ProtocolAddendum
Page 1
LY3298176
1.Protocol Addendum I8F-MC-GPGE(1)
Pharmacokinetics, Safety, and Tolerability of a Solution
Formulation of LY3298176 in Healthy Subjects
Confidential Information
The information contained in this protocol addendum 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.  This document and its associated 
attachments are subject to United States Freedom of Information Act (FOIA) Exemption 4. 
Approval Date: 31-Aug-2018 GMT
LY3298176
This addendum is to be performed in addition to all procedures required by protocol 
I8F-MC-GPGEor any subsequent amendments to that protocol.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Addendum (1) Electronically Signed and Approved by Lilly on date provided 
below.


I8F-MC-GPGE(1) Clinical Protocol Addendum
Page 2
LY3298176
2. Table of Contents
Protocol Addendum I8F-MC-GPGE(1)
Pharmacokinetics, Safety, and Tolerability of a Solution 
Formulation of LY3298176 in Healthy Subjects
Section
Page
1.
Protocol Addendum I8F-MC-GPGE(1) Pharmacokinetics, Safety, 
and Tolerability of a Solution Formulation of LY3298176 in Healthy 
Subjects ..............................................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Rationale for Addendum .....................................................................................................4
4.
Protocol Additions ..............................................................................................................5
4.1.
Study Schedule...............................................................................................................5
4.2.
Objectives and Endpoints...............................................................................................9
4.3.
Overall Design ...............................................................................................................9
4.4.
Number of Participants.................................................................................................10
4.5.
Scientific Rationale for Study Design...........................................................................10
4.6.
Justification of Dose and Route of Administration........................................................10
4.7.
Inclusion and Exclusion Criteria...................................................................................10
4.8.
Treatment Administered...............................................................................................10
4.9.
Blinding .......................................................................................................................11
4.10. Dose Modification........................................................................................................11


I8F-MC-GPGE(1) Clinical Protocol Addendum
Page 3
LY3298176
List of Tables
Table
Page
Table GPGE(1).4.1.
Objectives and Endpoints......................................................................9


I8F-MC-GPGE(1) Clinical ProtocolAddendum
Page 4
LY3298176
3.Rationale for Addendum
CCI
Dosing has been completed in all 3 existing parts (A, B, and C) of Study I8F-MC-GPGE 
(GPGE).  This protocol addendum adds a fourth part, D.
Part D will evaluate the pharmacokinetics (PK) of LY3298176 following bolus intravenous (IV)
administration.  This information will enable the study teamto calculate the absolute 
bioavailability of LY3298176 following subcutaneous (SC)administration (using prior SC PK 
data from Phase1Study I8F-MC-GPGA[GPGA]).  Subcutaneousadministration is the intended 
route for this drug as a therapeutic.
Part D will mimicthe design and study population of Part B.  Part B wasanIV arm, with 0.5 mg 
LY3298176administered as infusion via pumpover 10 minutes.  Evaluation of IV PK in Part B 
led to inconclusive results:  LY3298176 exposurefollowing 0.5-mg IV infusion was lower than 
expected in all 8 subjects.Expectation wasbased on prior understanding of LY3298176 PK,
 
 
 
 The reason for the lower-than-expected exposure 
is currently unclear despite a completedinvestigation.
The aim of Part D is to provide IV PK data to estimatethe absolute bioavailabilityof 
LY3298176.Part D will use0.5 mgLY3298176 lyophilized drug product (GPGE protocol 
Section 7.1.1).  This contrasts with Part B, which used LY3298176 solution drug product (GPGE 
protocol Section 7.1.2).


I8F-MC-GPGE(1) Clinical Protocol Addendum
Page 5
LY3298176
4. Protocol Additions
4.1.
Study Schedule


I8F-MC-GPGE(1) Clinical Protocol Addendum
Page 6
LY3298176
Study Schedule Protocol I8F-MC-GPGE, Part D
Procedure
(Part D)
Screening
Treatment
ET
Comments
Days
-28 to -2
-1
1
2
3
4
5
6
7
8
15
35 - 37
≥70 days
Informed 
Consent
X
Subject 
Admission to 
CRU
X
Subject 
Discharge from 
CRU
X
Subjects may stay 
longer according to 
investigator’s
discretion
Outpatient Visit
X
X
X
X
X
X
X
X
X
Investigational 
Product 
Administration
X
Study drug will be 
administered after an 
overnight fast of at 
least 8 hours. Study 
drug will be 
administered through
bolus IV infusion
Medical History
X
Height
X
Weight
X
X
X
X
Vital Signs 
(BP/PR/T) 
(supine) (hours)
X
X
P
24h
48h
X
X
X
X
Time points may be 
added if warranted 
and agreed upon 
between Lilly and the 
investigator
Clinical 
Laboratory 
Tests
X
X
X
X
X
X
Requires an 8-hour 
fast. See GPGE 
protocol Appendix 2 
for details.
Adverse Event
X
X
X
X
X
X
X
X
X
X
X
X
X


I8F-MC-GPGE(1) Clinical Protocol Addendum
Page 7
LY3298176
Procedure
(Part D)
Screening
Treatment
ET
Comments
Days
-28 to -2
-1
1
2
3
4
5
6
7
8
15
35 - 37
≥70 days
PK Samples 
P, 5 
min, 
10 
min, 
30 
min 
1h, 
2h, 
4h,  
8h, 
12h
24 h, 
36 h
48 h
72h
96h
120h
144h
168h
336h
X
X
X
All sampling times 
are from start of dose 
administration.
Predose sample must 
be collected before 
dose administration. 
If a subject withdraws 
from the study prior 
to completion of 
scheduled PK 
sampling, every effort 
will be taken to draw 
an unscheduled blood 
sample for PK 
assessment. This will 
not be required if a 
sample has already 
been taken within the 
previous 24 hours.  
For ET, a PK sample 
can be taken at any 
time during the visit 
timed close to the 
immunogenicity 
sample.
Pregnancy Test 
X
X
X
X
All females only.  
Serum pregnancy test 
will be performed at 
screening.  Urine 
pregnancy test will be 
performed at Day -1 
and at ET/Follow-up.
Physical 
Examination
X
X
X
X
X
After screening, 
medical assessment is 
performed only to 
include medical 
review and targeted 
examination, as 
appropriate.


I8F-MC-GPGE(1) Clinical Protocol Addendum
Page 8
LY3298176
Procedure
(Part D)
Screening
Treatment
ET
Comments
Days
-28 to -2
-1
1
2
3
4
5
6
7
8
15
35 - 37
≥70 days
12-lead ECG
X
X
X
X
X
Single 12-lead ECG 
will be collected.  
ECGs must be 
recorded before 
collecting any blood 
samples.  Subjects 
must be supine for at 
least 5 minutes before 
ECG collection and 
remain supine but 
awake during ECG 
collection.
Genetic Sample
P
Single sample for 
pharmacogenetic 
analysis taken prior to 
dosing on Day 1.
Immunogenicity 
Samples
P
X
X
X
X
All samples for 
immunogenicity 
should be taken 
predose and follow 
up.  Time-matched 
PK sample should be 
collected at each time 
point.
Abbreviations:  BP = blood pressure; CRU = clinical research unit; ECG = electrocardiogram; ET = early termination; hr = hour(s); IV = intravenous(ly); 
min = minute(s); P = Predose; PK = pharmacokinetic(s); PR = pulse rate; T= Temperature
Note:  If multiple procedures take place at the same time point, the following order of the procedures should be used:  ECG, vital signs, and venipuncture.


I8F-MC-GPGE(1) Clinical Protocol Addendum
Page 9
LY3298176
4.2.
Objectives and Endpoints
Table GPGE(1).4.1 shows the objectives and endpoints of Part D of the study.
Table GPGE(1).4.1.
Objectives and Endpoints
Objectives
Endpoints
Part D: 

Primary:  To evaluate the PK of a single 
bolus IV dose of LY3298176, lyophilized 
formulation, in healthy subjects.

Secondary:  To investigate the safety and 
tolerability of LY3298176, administered to 
healthy subjects via bolus IV.

PK parameters, including AUC 

AEs
Abbreviations:  AE = adverse event; AUC = area under the concentration versus time curve; IV = intravenous(ly); 
PK = pharmacokinetic(s).
4.3.
Overall Design
Study GPGE is a single-center, Phase 1 study in 4 parts.  Parts A, B, and C are detailed in 
Protocol I8F-MC-GPGE.  
Part D is a single, 0.5-mg bolus IV dose of LY3298176 lyophilized formulation administered to 
healthy subjects.
In Part D, each subject will provide informed consent for study participation, and will undergo a 
screening examination within 28 days prior to enrollment.
Subjects will be admitted to the clinical research unit (CRU) on Day -1. On the morning of 
Day 1, following an overnight fast of at least 8 hours, 2 subjects will receive a single bolus IV
dose of 0.5 mg LY3298176.  This dose is expected to be safe while also providing plasma 
concentrations that can be adequately measured over the course of the sampling time period to 
enable adequate characterization of the PK profile.

If the dose of 0.5 mg is found to be safe and well tolerated, then 6 more 
subjects will be dosed.

If the dose is not tolerated due to extensive gastrointestinal events, a lower 
dose of 0.25 mg may be administered to an additional 8 subjects. 
Plasma samples will be collected multiple times, including predose and up to 336 hours 
postdose, to measure LY3298176 concentrations.  
At a minimum, subjects will remain in the CRU for 4 days.  The investigator (or qualified 
designee) will review all available inpatient safety data before discharging subjects from the 
CRU on the morning of Day 4, provided that the subjects are deemed medically fit.  Subjects 
may be required to remain in the CRU longer than Day 4, at the investigator’s discretion.
Each subject will be required to return to the CRU for a follow-up visit at least 35 days after the 
LY3298176 dose.  In addition, subjects will need to attend a study visit on Day ≥70 for an 
antidrug antibody follow-up sample.


I8F-MC-GPGE(1) Clinical ProtocolAddendum
Page 10
LY3298176
4.4. Number of Participants
Part D:  Approximately 10 healthy subjects will be enrolled so that at least 6complete this part
of the study.
4.5. Scientific Rationale for Study Design
Similarlytoother parts of Study GPGE, apopulation of healthy subjects will be enrolledfor Part 
D because it is likelythere will be lessphysiologic variabilitythan in a patient population.  This 
is due to the absence of disease states that may affect multiple organ systems, and the absence of 
other confounding factorssuch as concomitant medications.
Part Dwill investigate the PK of LY3298176 following administration via a single IV dose
administered as a bolus.
Safety and tolerability of LY3298176 were established by data from Study GPGA.  
Asafety reviewwill be performedafter dosing the first 2 subjects to review safety and 
tolerabilityfollowing discharge from the CRU on Day 4of the study, and to check if there is a 
need for dose adjustment prior to dosing the remainingsubjects.
4.6. Justificationof Dose and Route of Administration
A dose of 0.5 mg LY3298176 (administered via bolus IV) is chosen because this dose is 
expected to lead to measureable PK profile, since PK was quantifiable following a 0.5-mg IV 
10-minute infusion dose in Part B of the study.Preliminary data from Part B indicate that 
administration of LY3298176via infusion pump was well tolerated by the 8 subjects, with no
adverse events being reported.
The IV bolus route in Part D is expected to provide data to estimatetheabsolute bioavailability
of LY3298176.  Pharmacokineticexposure following IV infusion of a 0.5-mg dose in Part B was 
lower than anticipated, in all 8 subjects dosed
 
 
4.7. Inclusion and Exclusion Criteria
There are no additional inclusion or exclusion criteria, or other study populationrequirements,
for Part D of thestudy.
4.8. Treatment Administered
CCI
LY3298176 lyophilized formulation will be used in Part D.  See GPGE protocol Section 7.1.1 
for details.
No randomization is required for Part D.  A single, 0.5-mg bolus IVdose of LY3298176will be 
administered in the morning following an 8-hour, overnight fast.Theactual time of dose 
administration will be recorded in the subject’selectronic case report form.


I8F-MC-GPGE(1) Clinical Protocol Addendum
Page 11
LY3298176
4.9.
Blinding
Part D is open-label.
4.10. Dose Modification
A 0.5-mg LY3298176 dose is planned to be administered to the first 2 subjects of Part D.  If 
vomiting is noted in the first 2 subjects, to the extent that treatment with antiemetics and IV
fluids is required, a reduced dose (0.25 mg) may be administered to the next 8 subjects planned 
in this part.  If there are no safety concerns, then the same planned dose of 0.5 mg will be 
administered to the next 6 subjects enrolled in this part. 


PPD
Leo Document ID = 09836199-1f2f-4c11-a490-d47c3459306a
Approver: 
Approval Date & Time: 30-Aug-2018 13:30:45 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 31-Aug-2018 04:02:11 GMT
Signature meaning: Approved
PPD