Pharmacokinetics, Safety, and Tolerability of a Solution Formulation of LY3298176 in Healthy Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

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
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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.

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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

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List of Tables
Table
Page
Table GPGE(1).4.1.
Objectives and Endpoints......................................................................9

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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).

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4. Protocol Additions
4.1.
Study Schedule

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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

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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.

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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.

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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.

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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.

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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