Clinical trial NCT03222427
Conditions: Healthy
Sponsor: AstraZeneca
Start date: 2018-01-15; Completion date: 2018-02-16
Enrollment: 8 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to measure how much LY3314814 gets into the bloodstream when it is given as a single dose by mouth and as an intravenous (IV) infusion over two hours. The study will last at least two weeks for each participant, not including screening.

Detailed description:

Arms: arm 1: Single 50 milligram (mg) dose of LY3314814 administered orally arm 2: Single 100 micrograms (μg) intravenous (IV) dose of \[13C415N3\] LY3314814 administered as an IV infusion.
Interventions: intervention 1: LY3314814 intervention 2: [13C415N3] LY3314814
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered as an IV infusion

Protocol documents:
Prot_000.pdf: 
Protocol I8D-MC-AZEP(d) 
 
An Absolute Bioavailability Study of LY3314814 in Healthy Subjects Using an Intravenous 
Tracer Method 
 
 
NCT03222427 
 
Approval Date: 13-OCT-2017 
 
 
 


I8D-MC-AZEP(d) Clinical Pharmacology Protocol
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LY3314814
Protocol I8D-MC-AZEP(d)
An Absolute Bioavailability Study of LY3314814 in Healthy 
Subjects Using an Intravenous Tracer Method
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 
LY3314814, 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 Exemption 4 and 
may not be reproduced or otherwise disseminated without the written approval of Eli Lilly 
and Company or its subsidiaries.  
LY3314814
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly:
07 November 2016
Amendment (a) Electronically Signed and Approved by Lilly on 07 June 2017.
Amendment (b) Electronically Signed and Approved by Lilly on 21 August 2017.
Amendment (c) Electronically Signed and Approved by Lilly on 06 September 2017.
Amendment (d) Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 13-Oct-2017 GMT


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LY3314814
Table of Contents
An Absolute Bioavailability Study of LY3314814 in Healthy 
Subjects Using an Intravenous Tracer Method
Section
Page
Protocol I8D-MC-AZEP(d) An Absolute Bioavailability Study of 
LY3314814 in Healthy Subjects Using an Intravenous Tracer 
Method ...............................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................7
2.
Schedule of Activities .........................................................................................................9
3.
Introduction ......................................................................................................................12
3.1.
Study Rationale............................................................................................................12
3.2.
Background..................................................................................................................12
Clinical Experience..............................................................................................12
3.2.1.
3.2.1.1.
Clinical Pharmacokinetic Data........................................................................12
3.2.1.2.
Clinical Safety Data........................................................................................13
3.3.
Benefit/Risk Assessment..............................................................................................13
4.
Objectives and Endpoints..................................................................................................15
5.
Study Design.....................................................................................................................16
5.1.
Overall Design .............................................................................................................16
5.2.
Number of Participants.................................................................................................16
5.3.
End of Study Definition ...............................................................................................16
5.4.
Scientific Rationale for Study Design...........................................................................16
5.5.
Justification for Dose ...................................................................................................17
6.
Study Population...............................................................................................................18
6.1.
Inclusion Criteria..........................................................................................................18
6.2.
Exclusion Criteria ........................................................................................................19
6.3.
Lifestyle and/or Dietary Requirements .........................................................................21
Meals and Dietary Restrictions.............................................................................21
6.3.1.
Caffeine, Alcohol, and Tobacco ...........................................................................21
6.3.2.
Activity................................................................................................................21
6.3.3.
6.4.
Screen Failures.............................................................................................................21
7.
Treatment..........................................................................................................................22
7.1.
Treatment Administered...............................................................................................22
Packaging and Labeling .......................................................................................22
7.1.1.
Retention Samples................................................................................................23
7.1.2.


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LY3314814
7.2.
Method of Treatment Assignment ................................................................................23
Selection and Timing of Doses.............................................................................23
7.2.1.
7.3.
Blinding .......................................................................................................................23
7.4.
Dose Modification........................................................................................................23
Special Treatment Considerations ........................................................................23
7.4.1.
7.4.1.1.
Premedication for Infusions ............................................................................23
7.4.1.2.
Management of Infusion Reactions.................................................................23
7.4.1.3.
Safety Protocol in the Event of a Retrospective Positive 
Sterility Finding from Extemporaneously Prepared Study 
Treatment .......................................................................................................24
7.5.
Preparation/Handling/Storage/Accountability...............................................................24
7.6.
Treatment Compliance .................................................................................................24
7.7.
Concomitant Therapy...................................................................................................24
7.8.
Treatment after the End of the Study............................................................................24
8.
Discontinuation Criteria ....................................................................................................25
8.1.
Discontinuation from Study Treatment.........................................................................25
Discontinuation of Inadvertently Enrolled Subjects ..............................................25
8.1.1.
8.2.
Discontinuation from the Study....................................................................................25
8.3.
Subjects Lost to Follow-up...........................................................................................25
9.
Study Assessments and Procedures ...................................................................................26
9.1.
Efficacy Assessments...................................................................................................26
9.2.
Adverse Events ............................................................................................................26
Serious Adverse Events........................................................................................27
9.2.1.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................27
Complaint Handling.............................................................................................28
9.2.2.
9.3.
Treatment of Overdose.................................................................................................28
9.4.
Safety...........................................................................................................................28
Laboratory Tests ..................................................................................................28
9.4.1.
Vital Signs ...........................................................................................................28
9.4.2.
Electrocardiograms ..............................................................................................29
9.4.3.
Physical Examination...........................................................................................29
9.4.4.
Body Weight........................................................................................................29
9.4.5.
Safety Monitoring ................................................................................................29
9.4.6.
9.4.6.1.
Hepatic Safety ................................................................................................30
9.5.
Pharmacokinetics .........................................................................................................30
Bioanalysis...........................................................................................................30
9.5.1.
9.6.
Pharmacodynamics ......................................................................................................31
9.7.
Genetics .......................................................................................................................31


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LY3314814
9.8.
Biomarkers...................................................................................................................31
9.9.
Health Economics ........................................................................................................31
10.
Statistical Considerations and Data Analysis .....................................................................32
10.1. Sample Size Determination ..........................................................................................32
10.2. Populations for Analyses..............................................................................................32
Study Participant Disposition ...............................................................................32
10.2.1.
Study Participant Characteristics ..........................................................................32
10.2.2.
10.3. Statistical Analyses ......................................................................................................32
Safety Analyses....................................................................................................32
10.3.1.
10.3.1.1.
Clinical Evaluation of Safety ..........................................................................32
10.3.1.2.
Statistical Evaluation of Safety .......................................................................33
Pharmacokinetic Analyses....................................................................................33
10.3.2.
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................33
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................33
Interim Analyses ..................................................................................................33
10.3.3.
11.
References ........................................................................................................................34


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LY3314814
List of Tables
Table
Page
Table AZEP.1.
Objectives and Endpoints .......................................................................15
Table AZEP.2.
Treatments Administered........................................................................22


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LY3314814
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................35
Appendix 2.
Clinical Laboratory Tests........................................................................38
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................39
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............42
Appendix 5.
Blood Sampling Summary......................................................................43
Appendix 6.
Protocol Amendment I8D-MC-AZEP(d) Summary 
An Absolute Bioavailability Study of LY3314814 in Healthy 
Subjects Using an Intravenous Tracer Method........................................44


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1. Protocol Synopsis
Title of Study:
An Absolute Bioavailability Study of LY3314814 in Healthy Subjects Using an Intravenous Tracer Method
Rationale:  
Absolute bioavailability data are required by regulatory agencies in some geographical areas.  Knowledge of 
absolute bioavailability is helpful in the interpretation of pharmacokinetic (PK) data, and may be helpful in the 
design of clinical pharmacology studies.
Objectives/Endpoints:  
Objectives
Endpoints
Primary
The primary objective is to estimate the absolute 
bioavailability of LY3314814 following simultaneous 
administration of a single oral dose of 50 mg 
LY3314814 and a 2-hour intravenous (IV) infusion of 
approximately 100 g [13C4
15N3]-LY3314814(+)-
Camsylate (referred to as [13C4
15N3]-LY3314814 from 
this point forward) in healthy subjects.
The primary endpoint is LY3314814 absolute 
bioavailability, as calculated based on the ratio of the 
dose-adjusted area under the drug concentration-time 
curve (AUC) from zero to infinity (AUC[0-∞]) of 
LY3314814 and [13C4
15N3]-LY3314814.
Secondary
The secondary objectives are:
To assess the safety of LY3314814 following 
simultaneous administration of a single oral dose of 
50 mg LY3314814 and a 2-hour IV infusion of 
approximately 100 g [13C4
15N3]-LY3314814 in 
healthy subjects;
To characterize the PK parameters of LY3314814
and [13C4
15N3]-LY3314814 following simultaneous 
administration of a single oral dose of 50 mg 
LY3314814 and a 2-hour IV infusion of 
approximately 100 g [13C4
15N3]-LY3314814 in 
healthy subjects.
Secondary endpoints include:
Incidence of treatment-emergent adverse events
(AEs) and serious AEs;
LY3314814 and [13C4
15N3]-LY3314814 PK 
parameters:  AUC(0-∞), AUC from time zero to 
time tlast (AUC[0-tlast]), where tlast is the last time
point with a measurable concentration, maximum 
observed drug concentration (Cmax), time of 
maximum observed drug concentration (tmax), and 
half-life associated with the terminal elimination 
phase (t1/2).
Summary of Study Design:  
Study I8D-MC-AZEP is a Phase 1, single-center, open-label, single-period study to determine the absolute 
bioavailability of LY3314814 in healthy male and female subjects not of childbearing potential.
Treatment Arms and Duration:  
On Day 1, following an overnight fast of at least 8 hours, subjects will receive a single oral dose of 50 mg 
LY3314814 and at approximately the same time an IV infusion of approximately 100 g [13C4
15N3]-LY3314814 will 
be started.  The infusion will run for 2 hours.  


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LY3314814
Number of Subjects:  
Up to 8 subjects may be enrolled and dosed to ensure that at least 6 subjects complete and have evaluable PK data.  
Statistical Analysis:  
Pharmacokinetic:  To quantify the absolute bioavailability of LY3314814, a mixed-effect analysis of variance model 
will be applied to the log-transformed dose-adjusted AUC of LY3314814 obtained after oral dosing and that of the 
IV administered [13C4
15N3]-LY3314814.  The model will contain formulation (oral or IV) as a fixed effect and 
subject as a random effect.  The absolute bioavailability will be expressed as the ratio of the least-squares geometric 
means of the formulations (oral : IV) along with its corresponding 90% confidence interval.  The PK parameter 
estimates for LY3314814, and [13C4
15N3]-LY3314814 will be summarized using appropriate descriptive statistics.  
Additional analysis may be conducted if deemed appropriate.
Safety:  All investigational product and 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.  Each 
symptom will be classified by the most suitable term from the medical regulatory dictionary.  The number of 
investigational product-related serious AEs will be reported.  Safety parameters that will be assessed include clinical 
lab parameters, vital signs, and electrocardiograms. The clinical lab parameters will be listed.  Vital signs will be 
listed and summarized using standard descriptive statistics.  Electrocardiograms and physical examinations will be 
performed for safety monitoring purposes and will not be presented.  Additional analysis may be performed if 
warranted upon review of the data.


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LY3314814
2. Schedule of Activities


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LY3314814
Study Schedule Protocol I8D-MC-AZEP
Screening
Day
FU or 
ED
Comments
Procedure
Up to 
28 days 
prior to  
enrollment
-1
1
2
3
4
5
6
≥7 days 
after 
postdose 
or ED
Outpatient Visit
X
X
X
X
X
Subject Admission to 
CRU
X
Subject Discharge 
from CRU
X
Informed Consent
X
Medical History
X
Height and BMI
X
Weight
X
X
Drug and Alcohol 
Tests
X
X
Estimated GFR
X
Estimated GFR will be calculated using the 
Modification of Diet in Renal Disease equation.
Physical Exam
X
X
X
After screening exam, exams are to include only
medical review and targeted examination, as 
appropriate.
Pregnancy Test (if 
applicable)
X
(X)
X
Serum pregnancy tests will be performed at 
screening and at follow-up or early 
discontinuation for all females (if applicable).  A 
urine pregnancy test (X) may be performed upon 
admission and may be repeated during the study 
at the investigator’s discretion.
Vital Signs (supine) 
(hours) a
X
P, 2, 4, 
8, 12
24
X
X
X
X
Sampling times are relative to the time of oral 
dose administration (0 hour).  
Clinical Lab Tests
X
X
X
X
See Appendix 2 for details.  Follow-up sample is 
only if clinically indicated.
12-lead ECG (hours) a
X
X
X
X
X
Sampling times are relative to the time of oral 
dose administration (0 hour).


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LY3314814
Screening
Day
FU or 
ED
Comments
Procedure
Up to 
28 days 
prior to  
enrollment
-1
1
2
3
4
5
6
≥7 days 
after 
postdose 
or ED
Genetic Sample
P
Single sample for pharmacogenetic analysis.
LY3314814 Oral 
Administration (hours)
0
Dosed in the morning following an overnight fast 
of ≥8 hours.
[13C4
15N3]-LY3314814 
IV Administration 
(hours)
0-2
Infusion to start at approximately the same time 
as the oral dose and run for 2 hours.
PK Samples (hours) a
P, 0.25, 
0.5, 1, 
1.5,  
2*, 2.5, 
3, 4, 8, 
12
24
48
72
96
120
Sampling times are relative to the time of oral 
dose administration (0 hour).  Labeled and non-
labeled drug assessments will be conducted on 
the same sample at each time point.  During the 
infusion of [13C4
15N3]-LY3314814 and for at least 
4 hours post-infusion, the PK blood samples will 
be taken from the arm contralateral to the 
infusion site.
*The 2-hour sample will be collected 
immediately prior to the end of IV infusion.
AE Assessment
X
X
X
Abbreviations:  [13C4
15N3]-LY3314814 = [13C4
15N3]-LY3314814(+)-Camsylate; AE = adverse event; BMI = body mass index; CRU = clinical research unit; ECG 
= electrocardiogram; ED = early discontinuation; FU = follow-up; GFR = glomerular filtration rate; IV = intravenous; P = predose; PK = pharmacokinetics.  
a
Specified times are target and actual times will be recorded.  All attempts should be made to ensure that the actual sampling time does not exceed 1 hour prior 
to dosing for the predose sample or ±10% of the specified postdose sample time.


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3. Introduction
3.1.
Study Rationale
Absolute bioavailability data are required by regulatory agencies in some geographical areas.  
Knowledge of absolute bioavailability is helpful in the interpretation of pharmacokinetic (PK)
data, and may be helpful in the design of clinical pharmacology studies.
3.2.
Background
LY3314814, also known as AZD3293, is a brain-permeable inhibitor of human beta-site amyloid 
precursor protein cleaving enzyme 1 being developed to slow disease progression in patients 
with early Alzheimer’s disease (AD) (defined as the continuum of mild cognitive impairment 
due to AD and mild dementia of the Alzheimer’s type).  
Clinical Experience
3.2.1.
As of 28 November 2016, approximately 429 subjects/patients have been exposed to LY3314814
in completed Phase 1 trials, of which 417 were healthy subjects and 12 were patients with AD.  
Single oral doses ranging from 1 to 750 mg and multiple daily doses up to 150 mg were explored 
in 11 completed clinical pharmacology studies. 
An additional Phase 1 trial (I8D-MC-AZEB) evaluating the effect of LY3314814 on rosuvastatin 
in healthy subjects and 3 Phase 3 trials (Study I8D-MC-AZET, Study I8D-MC-AZES, Study
I8D-MC-AZFD) evaluating daily doses of 20 mg and 50 mg LY3314814 in patients with mild 
cognitive impairment and mild AD dementia, are currently ongoing.
LY3314814 has not previously been administered as an intravenous (IV) dose.
3.2.1.1.
Clinical Pharmacokinetic Data
LY3314814 PK have been evaluated following single oral doses of 1 to 750 mg and at 
steady-state from 15 to 150 mg.  Following oral dosing, LY3314814 time of maximum observed 
drug concentration (tmax) is approximately 1 to 2 hours postdose and then follows a 
bi-exponential elimination profile.  The LY3314814 half-life associated with the terminal 
elimination phase (t1/2) is approximately 18 hours.  Upon multiple dosing, exposure increases 
modestly with an accumulation ratio of approximately 1.46, based on area under the drug 
concentration-time curve (AUC).  Steady-state appears to be achieved 4 to 8 days following the 
initiation of dosing, consistent with LY3314814 t1/2.  Over the dose range from 15 to 150 mg, 
the PK of LY3314814 appears dose proportional.  No meaningful differences in PK have been 
observed between young and elderly healthy subjects, or between healthy subjects and patients 
with AD.  Renal clearance was approximately 1.0 to 1.5 L/h 5% to 10% of total body clearance), 
suggesting that renal clearance is a minor elimination pathway.  A food effect study was 
completed demonstrating that administration of 50 mg LY3314814 with food resulted in a 
minimal (approximately 17%) reduction in maximum observed drug concentration (Cmax),
although AUC was not impacted. These results suggest that food reduces the rate, although not 
the extent, of absorption.  The PK results for the major metabolite AZ13569724 mirrored those 
of the parent.


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LY3314814
LY3314814 is a substrate of CYP3A, as shown by drug interaction studies where strong 
inhibitors of CYP3A activity increased LY3314814 exposure by up to 2.85-fold. LY3314814
co-administration resulted in minor changes in exposure of the sensitive CYP3A4 substrate 
midazolam, suggesting that there is no clinically-meaningful effect of LY3314814 on CYP3A 
activity.
In vitro data suggests that LY3314814 is a substrate and inhibitor of Pgp.  A regimen of 50 mg 
LY3314814 once daily increased dabigatran mean AUC from zero to infinity (AUC[0-∞]) and 
Cmax by 15% and 17%, respectively, when a single 150-mg dose of dabigatran etexilate
(P-glycoprotein [Pgp] substrate) was administered at the same time as LY3314814 in healthy 
subjects.  These data suggest that LY3314814 is a relatively modest inhibitor of Pgp.  
Additional information regarding LY3314814 PK may be found in the Investigator’s Brochure 
(IB).
3.2.1.2.
Clinical Safety Data
No clinically significant safety or tolerability concerns have been identified to date in the 
LY3314814 Phase 1 program up to the highest dose given (750-mg single dose; 150-mg daily 
dosing for up to 12 days).  Across the 11 completed studies as of 28 November 2016, 2 serious 
adverse events (SAEs) were reported in 2 patients (severe ventricular tachycardia in a patient 
with a previously undisclosed cardiomyopathy, and cellulitis).  Both SAEs were judged by the 
investigator as not related to LY3314814.  
In completed studies, the most frequent treatment-emergent adverse events (TEAEs) reported by 
healthy subjects and patients with AD during LY3314814 treatment or wash-out (occurring in 
1% to 10% of subjects) periods include headache, orthostatic hypotension, dizziness, 
constipation, back pain, rash, dry skin, diarrhea, nausea, and pruritus. In general, there have 
been no clinical laboratory or ECG safety concerns identified in the completed Phase 1 studies.
Safety reviews of the ongoing Phase 3 trials are completed by an Independent Data Monitoring 
Committee (IDMC) which meets quarterly.  The recommendations of the IDMC at all meetings 
thus far for each study have been to continue without any modification.
More information about the known and expected benefits, risks, and reasonably anticipated AEs 
may be found in the IB.  
3.3.
Benefit/Risk Assessment
Study AZEP will include standard safety assessments, including spontaneous reporting of AEs, 
clinical laboratory tests, 12-lead ECGs, vital signs and physical examinations. Additionally, 
there are exclusion criteria in the protocol designed to prevent enrollment of subjects who may 
be at increased risk of potential adverse effects.
Potential risks of LY3314814 identified from non-clinical studies or completed phase 1 studies
include, but are not limited to, elevated liver enzymes, QT-prolongation in overdose, 
hypopigmentation of skin or hair, rash, retinal changes, and potential interactions with other 
drugs, including simvastatin, and strong CYP3A inducers or inhibitors, strong Pgp inducers or 
inhibitors, and BCRP inhibitors or inducers.  Of note, no LY3314814-related effects on male 


I8D-MC-AZEP(d) Clinical Pharmacology Protocol
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LY3314814
reproductive potential were identified in rats.  No additional safety signals or potential risks have 
been identified to date during Phase 3 development.
Overall, in the opinion of the sponsor, Study AZEP has been carefully designed to safeguard 
participants against potential risks. Although no benefit is expected for the healthy subjects 
participating in this study, the information obtained from this study will benefit the development 
of this molecule and patients with AD who may use this molecule for therapeutic benefit in the 
future, for whom there are currently no approved disease-modifying treatments.
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of LY3314814 may be found in the IB.  


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LY3314814
4. Objectives and Endpoints
Table AZEP.1 shows the objectives and endpoints of the study.
Table AZEP.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
The primary objective is to estimate the absolute 
bioavailability of LY3314814 following simultaneous 
administration of a single oral dose of 50 mg 
LY3314814 and a 2-hour intravenous (IV) infusion of 
approximately 100 g [13C4
15N3]-LY3314814(+)-
Camsylate (referred to as [13C4
15N3]-LY3314814 from 
this point forward) in healthy subjects.
The primary endpoint is LY3314814 absolute 
bioavailability, as calculated based on the ratio of the 
dose-adjusted AUC(0-∞) of LY3314814 and 
[13C4
15N3]-LY3314814.  
Secondary
The secondary objectives are:  
To assess the safety of LY3314814 following 
simultaneous administration of a single oral dose of 
50 mg LY3314814 and a 2-hour IV infusion of 
approximately 100 g [13C4
15N3]-LY3314814 in 
healthy subjects;
To characterize the PK parameters of LY3314814 and 
[13C4
15N3]-LY3314814 following simultaneous 
administration of a single oral dose of 50 mg 
LY3314814 and a 2-hour IV infusion of 
approximately 100 g [13C4
15N3]-LY3314814 in 
healthy subjects.
Secondary endpoints include:  
Incidence of TEAEs and SAEs;
LY3314814 and [13C4
15N3]-LY3314814 PK 
parameters:  AUC(0-∞); AUC from time zero to time 
tlast (AUC[0-tlast]), where tlast is the last time point
with a measurable concentration; Cmax; tmax; and half-
life associated with the terminal elimination phase 
(t1/2).


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LY3314814
5. Study Design
5.1.
Overall Design
This is a Phase 1, single-center, open-label, single-period study to estimate the absolute 
bioavailability of LY3314814 in healthy male and female subjects not of childbearing potential.
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 and will remain resident 
in the CRU for at least 48 hours after the start of infusion, followed by outpatient visits on Days
4, 5, 6, and 7 (follow-up visit).  On Day 1, following an overnight fast of at least 8 hours, 
subjects will receive a single oral dose of 50 mg LY3314814 and at approximately the same time 
an IV infusion of approximately 100 g [13C4
15N3]-LY3314814 will be started.  The infusion will 
run for 2 hours.  Blood samples will be collected predose and up to 120 hours postdose to 
measure LY3314814, and [13C4
15N3]-LY3314814 concentrations.  During the infusion and for at 
least 4 hours post-infusion, the PK blood samples will be taken from the arm contralateral to the 
infusion site.  A follow-up visit will occur at least 7 days postdose.
Safety and tolerability will be assessed throughout the study by means of vital sign 
measurements, clinical laboratory tests, ECGs, physical examinations (as indicated), and AE 
recording.
5.2.
Number of Participants
Up to 8 subjects may be enrolled and dosed to ensure that at least 6 subjects complete and have 
evaluable PK data.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
5.4.
Scientific Rationale for Study Design
This study will be open-label as the primary endpoint is objective rather than subjective; 
therefore, investigators and subjects do not need to be blinded.
The label or tracer method allows simultaneous oral and IV dosing which provides less 
variability in the absolute bioavailability estimate, and ensures the systemic clearance is 
equivalent for the IV and oral doses.  
The IV dose of [13C4
15N3]-LY3314814 will be administered at a constant rate of infusion over 
2 hours duration, so that the end of the IV dose occurs approximately at the tmax of the 
LY3314814 oral dose.  


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LY3314814
5.5.
Justification for Dose
An oral dose of 50 mg LY3314814 was selected based on current clinical data.  LY3314814 
doses up to 750 mg were well tolerated in the single ascending dose study.  The 50-mg dose of 
LY3314814 selected for this study is the highest dose that is being used in the ongoing Phase 3
studies.
The approximate 100-μg dose of [13C4
15N3]-LY3314814 to be delivered intravenously is 0.20%
of the 50-mg oral dose and is expected to have minimal impact on exposure and tolerability.  
This small fraction of the oral dose obviates the need for toxicology studies with IV 
administration.  In addition, the IV dose is within the anticipated sensitivity that can be achieved 
using liquid chromatography-tandem mass spectrometry (LC/MS/MS) for the tracer.  The 2-hour 
infusion duration is intended to align the oral and IV tmax (at 2 hours).


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6. Study Population
Eligibility of subjects for study enrollment will be based on the results of screening medical 
history, physical examination, vital signs, clinical laboratory tests, and safety ECG.  
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 inclusion 
criteria at screening and/or enrollment:
[1]
are overtly healthy males or females, as determined by medical history and 
physical examination  
[1a] female subjects:
women not of childbearing potential may participate and include those who 
are:
i.
infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as 
mullerian agenesis; or
ii.
postmenopausal – defined as women over 50 years of age with an 
intact uterus who have had 12 months of natural (spontaneous)
amenorrhea without an alternative medical cause and a serum
follicle-stimulating hormone level >40 mIU/mL 
[2]
are 18 to 65 years old, inclusive, at the time of screening 
[3]
have a body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, at the time of 
screening  
[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
[5]
have venous access sufficient to allow for blood sampling and IV 
administration of the investigational product as per the protocol
[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


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6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[8]
are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling.
[9]
are Lilly employees, AstraZeneca employees, or employees of third-party 
organizations involved with the study that require exclusion of their 
employees
[10] 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
[11] have participated, within the last 3 months, in a clinical trial involving an 
investigational product.  If the previous investigational product has a long 
half-life, 3 months or 5 half-lives (whichever is longer) should have passed.
[12] have previously completed or withdrawn from this study or any other study 
investigating LY3314814, and have previously received the investigational 
product 
[13] have known allergies to LY3314814, related compounds, or any components 
of the formulation, or history of significant allergic disease, as determined by 
the investigator
[14] have a history of significant ophthalmic disease, which includes subjects with 
clinically significant eye abnormalities, particularly any eye problem 
involving the retina, as determined by the investigator
[15] have vitiligo or any other clinically significant disorder of skin pigmentation,
as determined by the investigator
[16] have a history of previous or ongoing neuropsychiatric disease/condition 
including psychosis, affective disorder, anxiety disorder, borderline state, and 
personality disorder
[17] have a history of neurologic disease, including seizures (with the exception of 
febrile infantile seizures), or clinically significant head injury
[18] have a history of use of antipsychotic drugs, or chronic use of antidepressant 
or anxiolytic drugs, prescribed as well as non-prescribed use
[19] have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study, or 
have a history of significant dysrhythmias or atrioventricular (AV) block 
(including first degree AV block)  
[20] have Fridericia-corrected QT interval of >470 msec for females or >450 msec 
for males


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[21] have a personal or family history of prolonged QT syndrome
[22] have a clinically significant abnormal blood pressure or heart rate (supine), as 
determined by the investigator
[23] have estimated glomerular filtration rate ≤59 mL/min
[24] have a history of or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable 
of significantly altering the absorption, metabolism, or elimination of drugs; 
of constituting a risk when taking the investigational product; or of interfering 
with the interpretation of data
[25] regularly use known drugs of abuse and/or show positive findings on urinary 
drug screening
[26] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive HIV antibodies
[27] show evidence of hepatitis C and/or positive hepatitis C antibody
[28] show evidence of hepatitis B and/or positive hepatitis B surface antigen
[29] are women who are pregnant or lactating
[30] have donated blood of more than 500 mL within 1 month prior to Check-in
[31] are currently or have been smokers or users of tobacco- or nicotine-containing 
products within the 3 months prior to Check-in
[32] have used or intend to use prescription medication, oral over-the-counter 
medication, or herbal medications within 14 days prior to Check-in and during 
the study.  If this situation arises, inclusion of an otherwise suitable subject 
may be at the discretion of the investigator.
[33] use of any drugs or substances that are known strong inducers or inhibitors of 
cytochrome P450 (CYP) 3A, strong inhibitors or inducers of P-glycoprotein 
(Pgp), or inhibitors of breast cancer resistance protein (BCRP) are specifically 
excluded within 14 days prior to the administration of study drug and during 
the study
[34] are unwilling to comply with the dietary requirements/restrictions during the 
study:  (i) consume only the meals provided while resident in the CRU, and 
(ii) refrain from consuming any restricted food or beverages within 7 days 
prior to the study drug administration until the final PK sample is collected
[35] are unwilling to refrain from strenuous physical activity from 72 hours prior to 
dosing and during the study


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[36] have an average weekly alcohol intake that exceeds 21 units per week (males) 
and 14 units per week (females), or are unwilling to stop alcohol consumption 
from 48 hours prior to Check-in and while resident in the 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)
[37] are unwilling to refrain from consuming caffeine- or xanthine-containing food 
and drink from 24 hours prior to Check-in and while resident in the CRU
[38] in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
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.  
Meals and Dietary Restrictions
6.3.1.
Subjects will be required to fast overnight (at least 8 hours) prior to study drug administration on 
Day 1.  Fluids will be restricted from 1 hour prior to and until 1 hour after oral dosing, with the 
exception of water required for study drug administration.  Otherwise, water will be freely
available at all times.  A standard meal will be given to the subjects no sooner than 4 hours after 
the oral dose.  Meals will be provided as appropriate at all other times.
Subjects will refrain from consuming grapefruits or grapefruit-containing products, Seville 
oranges or Seville orange-containing products, star fruits or star fruit-containing products, 
pomelo, poppy seeds, or commercial apple juice or orange juice within 7 days prior to dosing
until the final PK sample is collected.  If this situation arises, inclusion or ongoing participation 
of the subject may be at the discretion of the investigator, in consultation with the sponsor or 
designee.
Caffeine, Alcohol, and Tobacco
6.3.2.
Subjects will refrain from consuming caffeine- or xanthine-containing food and drinks within 
24 hours prior to Check-in until discharge from the CRU.  
Alcohol will not be permitted from 48 hours prior to Check-in until discharge from the CRU.
Smoking will not be permitted throughout the study.  Subjects will not have used any tobacco- or 
nicotine-containing products (including, but not limited to, cigarettes, pipes, cigars, chewing 
tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 3 months prior to Check-in 
and during the entire study.
Activity
6.3.3.
No strenuous physical activity will be allowed for 72 hours prior to dosing and during the study.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened.  


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7. Treatment
7.1.
Treatment Administered
This study involves a comparison of a single 50-mg oral dose of LY3314814 administered 
concurrently with an IV formulation containing approximately 100 g [13C4
15N3]-LY3314814
infused over 2 hours.  Table AZEP.2 shows the treatment administered.
On Day 1, 1 tablet of LY3314814 will be administered orally with approximately 240 mL of 
room temperature water in the morning in a sitting position.
On Day 1, approximately 100 g [13C4
15N3]-LY3314814 will be administered as an IV infusion 
over 2 hours at an approximate rate of 15 mL/hour, in the semi-recumbent position.  The IV 
infusion will be initiated at approximately the same time as the oral dose is administered.
Table AZEP.2.
Treatments Administered
Treatment Name
LY3314814
[13C4
15N3]-LY3314814a
Dosage Formulation
50-mg tablets
Solution
Dosage Level
50 mg
100 g
Route of Administration
Oral
Intravenous infusion
Dosing Instructions
1 tablet taken on Day 1
2-hour infusion
a
Dosage information and administration instructions for [13C4
15N3]-LY3314814 will be provided in a separate 
pharmacy manual.
The investigator or designee is responsible for:

explaining the correct use of the investigational product(s) to the site personnel, 

verifying that instructions are followed properly,

maintaining accurate records of investigational product dispensing and collection,

and returning all unused medication to Lilly or its designee at the end of the study.
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical trial materials.  
Packaging and Labeling
7.1.1.
Each LY3314814 tablet is oval, biconvex, plain, dark tan, and film-coated.  Tablets contain 
50 mg LY3314814 and excipients and will be provided in high-density polyethylene bottles.
Information regarding the [13C4
15N3]-LY3314814 solution for IV infusion will be provided in a 
separate pharmacy manual.  
Clinical trial materials will be labeled according to the country’s regulatory requirements.


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Retention Samples
7.1.2.
Samples of LY3314814 will be retained and stored according to the storage conditions listed on 
the product label by the site (or facility approved by Lilly) for at least 5 years following the date 
on which the last application or supplemental application to the Food and Drug Administration
(FDA) is approved, or, if such application or supplemental application is not approved, at least 5 
years following the date of completion of the study.
7.2.
Method of Treatment Assignment
All subjects will receive the same treatment; this study will not be subject to randomization.
Selection and Timing of Doses
7.2.1.
Doses will be administered on the morning of Day 1, preceded by an overnight fast of at least 
8 hours and followed by a fast of at least 4 hours post-oral-dose.  See Section 6.3.1 for meal and 
dietary restrictions.  
The actual time of all dose administrations will be recorded in the subject’s electronic case report 
form (eCRF).
7.3.
Blinding
This is an open-label study.
7.4.
Dose Modification
Dose adjustments are not allowed for this study.
Special Treatment Considerations
7.4.1.
7.4.1.1.
Premedication for Infusions
Premedication for the infusion is not planned.  However, if an infusion reaction occurs, 
appropriate medication may be used as determined by the study investigator.  
7.4.1.2.
Management of Infusion Reactions
The risk of an infusion reaction is anticipated to be small; however, because this is the first 
administration of IV [13C4
15N3]-LY3314814, 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 or stopped, depending on the 
symptoms/signs present
o
if slowed, the infusion should be completed at the slower rate, as tolerated
o
if stopped, no further attempts to administer the investigational product will be 
made


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o
supportive care should be employed in accordance with the symptoms/signs
7.4.1.3.
Safety Protocol in the Event of a Retrospective Positive Sterility Finding 
from Extemporaneously Prepared Study Treatment
If a positive sterility finding arises in the terminally sterile filtered product, the subjects who 
were dosed from the impacted batch should be immediately contacted and asked to return to the 
CRU for a full medical examination. This should include a physical examination/medical 
assessment, including blood pressure, pulse rate, and body temperature. Blood samples should 
be collected for culture and assayed for inflammatory markers such as C-reactive protein and 
elevations in white blood cell counts. If the signs and symptoms indicate a subject is suffering 
from possible infection(s), they will be clinically managed, treated, and followed up until 
resolution. Any AEs will be recorded as appropriate.
7.5.
Preparation/Handling/Storage/Accountability
Only participants enrolled in the study may receive investigational product and only authorized 
site staff may supply or administer study treatment.  All study treatments 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 records).
The [13C4
15N3]-LY3314814 solution for IV infusion will be prepared at the study site.  Details of 
the preparation and storage of the IV solution will be provided in separate instructions to the site.
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
Drugs or substances that are known strong inducers or inhibitors of CYP3A, strong inhibitors or 
inducers of Pgp, or inhibitors of BCRP are specifically excluded within 14 days prior to the 
administration of study drug and during the study.  Additional drugs are to be avoided during the 
study unless required to treat an AE or for the treatment of an ongoing medical problem.
If the need for concomitant medication arises, inclusion or continuation of the subject may be at 
the discretion of the investigator after consultation with a Lilly clinical pharmacologist (CP) or 
clinical research physician (CRP).  Occasional acetaminophen (paracetamol) up to a 2-gram dose 
in a 24-hour period may be used at the discretion of the investigator.  Any additional medication 
used during the course of the study must be documented.
7.8.
Treatment after the End of the Study
Not applicable for this study.


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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Subjects who discontinue the investigational product early will have procedures performed as 
shown in the Schedule of Activities (Section 2).
Discontinuation of Inadvertently Enrolled Subjects
8.1.1.
If the investigator identifies a subject who did not meet enrollment criteria and was inadvertently 
enrolled prior to any dosing, the subject will be discontinued from the study with no further data 
collection or study procedures performed.  If the investigator identifies a subject who did not 
meet enrollment criteria and was inadvertently enrolled and dosed, the subject will be 
discontinued from the study and early discontinuation procedures performed.
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study

participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

investigator decision
o
the investigator decides that the subject should be discontinued from the study

subject decision
o
the subject, requests to be withdrawn from the study
Subjects who discontinue the study early will have early discontinuation procedures performed 
as shown in the Schedule of Activities (Section 2).
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the clinical laboratory tests that will be performed for this study.
Appendix 4 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
Investigators must document their review of each laboratory safety report.
9.1.
Efficacy Assessments
This section is not applicable for this study.
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 event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the 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.  
Any clinically significant findings from ECGs, labs, vital sign measurements, and other 
procedures should be reported as an AE to Lilly or its designee.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the concomitant 
treatment or pathologies.  
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device, and/or study procedure and the AE.


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Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
If a subject’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF.
Serious Adverse Events
9.2.1.
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

events considered significant by the investigator based upon appropriate medical 
judgment
Study site personnel must alert Lilly, or its designee, of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed 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 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.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.  
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 identifies as related to investigational product or procedure.  
United States 21 Code of Federal Regulations 312.32 and European Union Clinical 
Trial Directive 2001/20/EC and the associated detailed guidances or national regulatory 


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requirements in participating countries require the reporting of SUSARs.  Lilly has procedures 
that will be followed for the recording and expedited reporting of SUSARs that are consistent 
with global regulations and the associated detailed guidances.
Complaint Handling
9.2.2.
Lilly will forward product complaints on LY3314814 to AstraZeneca in order to ensure the 
safety of study participants, monitor quality, and to facilitate process and product improvements.
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs

communicating the product complaint within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint correspondence with the product.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY3314814 is considered any dose higher than 
planned.  There is no specific antidote for LY3314814.  In case of known or suspected overdose, 
monitoring of cardiac and hepatic effects and appropriate standard supportive therapy should be 
initiated as clinically indicated.
9.4.
Safety
Laboratory Tests
9.4.1.
For each subject, clinical laboratory tests detailed in Appendix 2 should be conducted according 
to the Schedule of Activities (Section 2).  
Vital Signs
9.4.2.
For each subject, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2).  
Supine blood pressure and pulse rate should be measured after at least 5 minutes supine rest.  .
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 study if clinically
indicated or at the investigator’s discretion.
Body temperature will be measured as specified in the Schedule of Activities (Section 2) and as 
clinically indicated.


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Electrocardiograms
9.4.3.
For each subject, a single 12-lead digital ECG will be collected according to the Schedule of 
Activities (Section 2).  Electrocardiograms must be recorded before collecting any blood for 
safety or PK tests.  Subjects must be supine for at least 5 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 investigator (or designee) at the site as soon 
after the time of ECG collection as possible, and ideally while the 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 or 
corrected QT interval from baseline) after enrollment, the investigator will determine if 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 to Lilly, or its designee, as an AE.  
Physical Examination
9.4.4.
Physical examinations and medical review with targeted examinations will be conducted as 
specified in the Schedule of Activities (Section 2) and as clinically indicated.  
Body Weight
9.4.5.
Body weight will be recorded as specified in the Schedule of Activities (Section 2) and as 
clinically indicated.
Safety Monitoring
9.4.6.
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CP or 
CRP will consult with the functionally independent Global Patient Safety therapeutic area 
physician or clinical research scientist when appropriate, and periodically review:

trends in safety data

laboratory analytes 

AEs
In the event a subject experiences a suspected drug-induced rash, the following procedures 
should be followed:

The subject should be referred to a dermatologist for an expert opinion.

A photograph of the rash should be taken.


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
A blood sample should be drawn for PK analysis, if >12 hours since the last PK sample.
If treatment is discontinued due to a suspected drug-induced rash, the Lilly-designated medical 
monitor should be notified as soon as possible, even if the rash did not meet the definition of an 
SAE.
9.4.6.1.
Hepatic Safety
If a study subject experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated total 
bilirubin ≥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. 
Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥ [5X] ULN on two 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
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 2 mL each will be collected to determine the plasma concentrations of 
LY3314814, and [13C4
15N3]-LY3314814.  A maximum of 3 samples may be collected at 
additional time points during the study if warranted and agreed upon between both the 
investigator and sponsor.  Instructions for the collection and handling of blood samples will be 
provided by the sponsor.  The actual date and 24-hour clock time of each sampling will be 
recorded.
Bioanalysis
9.5.1.
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of LY3314814, and [13C4
15N3]-LY3314814 will be assayed using a validated 
LC/MS/MS method.  
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 2 years following last subject visit for the study.  During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses such as 
metabolism and/or protein binding work.


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9.6.
Pharmacodynamics
This section is not applicable for this study.
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 response to LY3314814 and to 
investigate genetic variants thought to play a role in AD.  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 ethical review boards (ERBs) impose shorter time limits, for 
the study at a facility selected by Lilly or its designee.  This retention period enables use of new 
technologies, response to regulatory questions, and investigation of variable response that may 
not be observed until later in the development of LY3314814 or after LY3314814 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
This section is not applicable for this study.  
9.9.
Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Up to 8 subjects may be enrolled and dosed to ensure that at least 6 subjects complete and have 
evaluable PK data.
This sample size is considered adequate for Phase 1 studies evaluating absolute bioavailability 
and is not intended to meet any a priori statistical requirement.
10.2. Populations for Analyses
Study Participant Disposition
10.2.1.
A detailed description of subject disposition will be provided at the end of the study. All 
subjects 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.
Study Participant Characteristics
10.2.2.
The subject’s age, sex, weight, height, BMI, race/sub-race, tobacco/nicotine habits, or other 
demographic characteristics will be recorded and may be used in the PK and safety analyses as 
quantitative or classification variables.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetic analyses will be conducted on the full analysis set.  This set includes all data 
from all subjects receiving the investigational product and who have evaluable data.  If a subject 
has an AE of vomiting that occurs at or before 2 times median tmax after dosing then that subject 
may be excluded from the PK summary statistics and statistical analysis.  Safety analyses will be 
conducted for all enrolled subjects, whether or not they completed all protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes.  
Safety Analyses
10.3.1.
10.3.1.1. Clinical Evaluation of Safety
All investigational product and 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 prior 
to enrollment will be distinguished from those reported as new or increased in severity during the 
study.  Each symptom will be classified by the most suitable term from the medical regulatory 
dictionary.


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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 clinical lab parameters, vital signs, and ECGs.  
The clinical lab parameters will be listed.  Vital signs will be listed and summarized using 
standard descriptive statistics.  Electrocardiogramsand physical examinationswill be performed 
for safety monitoring purposes and will not be presented.  Additional analysis maybe performed 
if warranted upon review of the data.
Pharmacokinetic Analyses
10.3.2.
10.3.2.1.Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for LY3314814, and [
13C4
15N3]-LY3314814will be 
calculated by standard noncompartmental methods of analysis.
The primary parameters for analysis will beAUC(0-∞) and AUC(0-t
last).  Secondary
 parameters 
will be Cmax, t
max, and t
1/2.  Other noncompartmental parameters, such as total body clearance 
of drug calculated after IV administration(CL), apparent clearance(CL/F), apparent volume of 
distribution during the terminal phase(Vz and Vz/F), and apparent volume of distributionat 
steady state (V
ssand Vss/F),may be reported.
The absolute bioavailability of LY3314814 will be calculated using the LY3314814 AUC 
estimates calculated after oral dosing with LY3314814 and IV administration of
[
13C4
15N3]-LY3314814, with adjustment for dose.
10.3.2.2.Pharmacokinetic Statistical Inference
To quantify the absolute bioavailability of LY3314814, a mixed-effect analysis of variance 
model will be applied to the log-transformed dose-adjusted AUC of LY3314814 obtained after 
oral dosing and that of the IV administered [
13C4
15N3]-LY3314814.  The model will contain 
formulation (oral or IV) as a fixed effect and subject as a random effect.  The absolute 
bioavailability will be expressed as the ratio of the least-squares geometric means of the 
formulations (oral :IV) along with its corresponding 90% confidence interval.
The PK parameter estimates for LY3314814, and [
13C4
15N3]-LY3314814will be summarized 
using appropriate descriptive statistics.
Additional analysis maybe conducted if deemed appropriate.
Interim Analyses
10.3.3.
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly CP, CRP/investigator, or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol.


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11.
References
Not applicable.


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Appendix 1.
Abbreviations and Definitions
Term
Definition
AD
Alzheimer’s disease
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.
AUC
area under the drug concentration-time curve
AUC(0-∞)
area under the drug concentration-time curve from zero to infinity
AUC(0-tlast)
area under the drug concentration-time curve from time zero to time tlast, where tlast is the 
last time point with a measurable concentration
AV
Atrioventricular
BCRP
breast cancer resistance protein
BMI
body mass index
Cmax
maximum observed drug concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-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.
CP
clinical pharmacologist
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
CYP
cytochrome P450


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ECG
Electrocardiogram
eCRF
electronic case report form
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the trial are those 
who have been assigned to a treatment.
enter
Subjects entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
GCP
good clinical practice
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonization
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular trial, after having been informed of all aspects of the trial that are relevant to the 
subject’s decision to participate.  Informed consent is documented by means of a written, 
signed and dated informed consent form.  
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form.
investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is conducted 
by a team of individuals at a trial site, the investigator is the responsible leader of the team 
and may be called the principal investigator.
IV
Intravenous
LC/MS/MS
liquid chromatography-tandem mass spectrometry
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.
Pgp
P-glycoprotein
PK
pharmacokinetic(s)
SAE
serious adverse event
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 trial.  


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SUSARs
suspected unexpected serious adverse reactions 
t1/2
half-life associated with the terminal elimination phase
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.  
tmax
time of maximum observed drug concentration
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Laboratory Tests
Hematologya
Clinical Chemistrya
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride 
Mean cell hemoglobin 
Calcium 
Mean cell hemoglobin concentration 
Glucose, random
Leukocytes (WBC)
Blood urea nitrogen 
Cell Morphology
Total protein
Absolute counts of:
Albumin
Neutrophils
Total bilirubin
Lymphocytes
Alkaline phosphatase 
Monocytes
Aspartate aminotransferase 
Eosinophils
Alanine aminotransferase 
Basophils
Creatinine
Platelets
Urinalysisa
Specific gravity
pH
Protein
Glucose
Ethanol testingc
Ketones
Urine drug screenc
Bilirubin
Hepatitis B surface antigend
Urobilinogen
Hepatitis C antibodyd
Blood
HIVd
Nitrite
Pregnancy test (females)e
Microscopic examination of sedimentb
FSH (females, if applicable)d
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
a
Performed by local laboratory.  Results will be validated by the laboratory at the time of initial testing.
b
Test only if dipstick result is abnormal (ie, positive for blood, protein, or nitrites).
c
Urine drug screen and ethanol testing will be performed by local laboratory at screening and at admission to the 
clinical research unit.
d
Performed by local laboratory at screening only.
e
Serum pregnancy tests will be performed for all females (if applicable) at screening and at follow-up or early 
discontinuation.  A urine pregnancy test may be performed on admission to the clinical research unit and may 
be repeated during the study at the investigator’s discretion. Serum and urine tests will be performed by local 
laboratory.


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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 potential risks and benefits of participating in 
the study.

ensuring that informed consent is given by each subject or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of investigational 
product.

answering any questions the 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 or her participation in the trial.
Ethical Review
The investigator must give assurance that the ERB was properly constituted and convened as 
required by International Conference on Harmonization (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 GCP.
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International
Organizations of Medical Sciences 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.


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LY3314814
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator 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 or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the eCRFs, 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 eCRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the 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.


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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 patients in consultation with Lilly or its designee 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 cell; WBC = white blood cell.
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.  Fewer 
venipunctures and blood draws may actually occur, but this will not require a protocol 
amendment.
Protocol I8D-MC-AZEP Sampling Summary
Purpose
Maximum Blood Volume 
per Sample (mL)
Maximum Number 
of Blood Samples
Maximum Total 
Volume (mL)
Screening testsa
11
1
11
Clinical laboratory testsa
7.5
3
22.5
Pharmacokineticsb
4
19
76
Pharmacogenetics
10
1
10
Total
119.5
Total for clinical purposes rounded up to nearest 10 mL
120
a
Additional samples may be drawn if needed for safety purposes.
b
Including the 3 additional pharmacokinetic samples, if needed.


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Appendix 6.
Protocol Amendment I8D-MC-AZEP(d) 
Summary 
An Absolute Bioavailability Study of LY3314814 in 
Healthy Subjects Using an Intravenous Tracer Method
Protocol I8D-MC-AZEP, An Absolute Bioavailability Study of LY3314814 in Healthy Subjects 
Using an Intravenous Tracer Method, has been amended. The new protocol is indicated by 
Amendment (d) and will be used to conduct the study in place of any preceding version of the 
protocol.
The protocol now states that 
If the investigator identifies a subject who did not meet enrollment criteria and was inadvertently 
enrolled prior to any dosing, the subject will be discontinued from the study with no further data 
collection or study procedures performed.  If the investigator identifies a subject who did not 
meet enrollment criteria and was inadvertently enrolled and dosed, the subject will be 
discontinued from the study and early discontinuation procedures performed (Section 8.1.1.).


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LY3314814
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
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 CP or CRP 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 CP or CRP to allow 
the inadvertently enrolled subject to continue in the study with or without continued treatment 
with investigational product.
If the investigator identifies a subject who did not meet enrollment criteria and was inadvertently 
enrolled prior to any dosing, the subject will be discontinued from the study with no further data 
collection or study procedures performed.  If the investigator identifies a subject who did not 
meet enrollment criteria and was inadvertently enrolled and dosed, the subject will be 
discontinued from the study and early discontinuation procedures performed.

SAP_001.pdf: 
Statistical Analysis Plan I8D-MC-AZEP 
 
An Absolute Bioavailability Study of LY3314814 in Healthy Subjects Using an Intravenous 
Tracer Method 
 
 
NCT03222427 
 
Approval Date: 09-JAN-2018 
 
 
 


Final, 05Jan 2018
             Page 1of 14
STATISTICAL ANALYSIS PLAN
An Absolute Bioavailability Study of LY3314814 in Healthy Subjects Using an Intravenous 
Tracer Method
Approval Date: 09-Jan-2018 GMT
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  05-January-2018
Study Drug:  LY3314814
Sponsor Reference:  I8D-MC-AZEP
Clinical Phase I
PPD


Final, 05Jan 2018
             Page 2of 14
Statistical Analysis Plan 
CONFIDENTIAL
Sponsor Reference I8D-MC-AZEP
1.TABLE OF CONTENTS
1. TABLE OF CONTENTS...............................................................................................2
2. ABBREVIATIONS........................................................................................................3
3. INTRODUCTION.........................................................................................................5
4. STUDY OBJECTIVES..................................................................................................5
4.1 Primary Objective....................................................................................................5
4.2 Secondary Objectives..............................................................................................5
5. STUDY DESIGN...........................................................................................................6
6. TREATMENT...............................................................................................................6
7. SAMPLE SIZE JUSTIFICATION.................................................................................6
8. DEFINITION OF ANALYSIS POPULATIONS............................................................6
9. STATISTICAL METHODOLOGY...............................................................................7
9.1 General....................................................................................................................7
9.2 Demographics and Subject Disposition....................................................................7
9.3 Pharmacokinetic Assessment...................................................................................7
9.3.1
Pharmacokinetic Analysis...............................................................................7
9.3.2
Pharmacokinetic Statistical Methodology.....................................................11
9.4 Safety and Tolerability Assessments......................................................................12
9.4.1
Adverse events.............................................................................................12
9.4.2
Concomitant medication...............................................................................12
9.4.3
Clinical laboratory parameters......................................................................12
9.4.4
Vital signs....................................................................................................13
9.4.5
Electrocardiogram (ECG).............................................................................13
9.4.6
Hepatic Monitoring......................................................................................13
9.4.7
Other assessments.........................................................................................13
9.4.8
Safety and Tolerability Statistical Methodology............................................13
10.INTERIM ANALYSES...............................................................................................13
11.CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES......13
12.REFERENCES............................................................................................................14
13.
PPD
DATA PRESENTATION............................................................................................14
13.1Derived Parameters...............................................................................................14
13.2Missing Data.........................................................................................................14
13.3Insufficient Data for Presentation..........................................................................14


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Statistical Analysis Plan 
CONFIDENTIAL
Sponsor Reference I8D-MC-AZEP
2.ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP)only (not thetables, figures and 
listings[TFLs]).
%AUC(tlast-∞) 
Percentage of AUC(0-∞) extrapolated
AE
Adverse event
ANOVA
Analysis of variance
AUC
Area under the concentration versus time curve
AUC(0-∞) 
Area under the concentration versus time curve from time zero to 
infinity
AUC(0-t
last) 
Area under the concentration versus time curve from time zero to 
time t, where t isthe last time point with a measurable concentration
BQL
Below the lower limit of quantitation
CL
Total body clearance of drug calculated after IV administration
Clast
Last quantifiable drug concentration
CL/F
Apparent total body clearance of drug calculated after extra vascular 
administration
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
CV
Coefficient of variation
DN
Dose normalised
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin:exempli gratia
PPD
)
ICH
International Council on Harmonisation
IV
Intravenous
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
SD
Standard deviation 


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             Page 4of 14
Statistical Analysis Plan 
CONFIDENTIAL
Sponsor Reference I8D-MC-AZEP
TFLs
Tables, Figures, and Listings
t
1/2
Half-life associated with the terminal rate constant (λ
z) in 
non-compartmentalanalysis
t
max
Time ofmaximum observed drugconcentration
WHO
World Health Organization
Vss
Volume of distribution at steady state after IV administration
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
Vz
Volume of distribution during the terminal phase after IV 
administration
Vz
PPD
/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration


Final, 05Jan 2018
             Page 5of 14
Statistical Analysis Plan 
CONFIDENTIAL
Sponsor Reference I8D-MC-AZEP
3.INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
07November2016), Protocol Amendment (a) (final version dated 07 June 2017), Protocol 
Amendment (b) (final version dated 21 August 2017), Protocol Amendment (c) (final version 
dated 06 September 2017), and Protocol Amendment (d) (finalversion dated 13October 2017).
This SAP describes the planned analysis of the safety, tolerability andpharmacokinetic(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 
.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 subjectadministration
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 supersedesthe 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 
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 Trials1and the ICH E3 Guideline entitled Guidance for Industry:
Structure and Content of Clinical Study Reports
2.
4.STUDY OBJECTIVES
4.1
PrimaryObjective
The primary objective is to estimate the absolutebioavailability of LY3314814 following 
simultaneousadministration of asingle oral dose of 50 mgLY3314814 and a 2-hour 
intravenous (IV) infusion ofapproximately 100 µg [13C4
15N3]-LY3314814(+)-Camsylate 
(referred to as [
13C4
15N3]-LY3314814 from this point forward) in healthy subjects.
4.2
SecondaryObjectives
The secondary objectives are:  
To assess the safety of LY3314814 following simultaneous administration of a single oral 
dose of 50 mgLY3314814 and a 2-hour IV infusion of approximately 
100µg[
13C4
15N3
PPD
]-LY3314814 in healthy subjects.
PPD
PPD


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Statistical Analysis Plan 
CONFIDENTIAL
Sponsor Reference I8D-MC-AZEP
To characterize the PK parameters of LY3314814 and [13C4
15N3]-LY3314814 following 
simultaneous administration of a single oral dose of 50 mg LY3314814 and a 2-hour IV 
infusion of approximately 100 µg [13C4
15N3]-LY3314814 in healthy subjects.
5.STUDY DESIGN
This is a Phase 1, single-center, open-label, single-period study to estimate the absolute 
bioavailability of LY3314814 in healthy male and female subjects not of childbearing potential. 
Subjects will be admitted to the clinical research unit (CRU) on Day -1 and will remain resident 
in the CRU for at least 48 hours after the start of infusion, followed by outpatient visits on 
Days4, 5and6.  A follow-up visit will occur at least 7 days postdose.On Day 1, following an 
overnight fast of at least 8 hours, subjects will receive a single oral dose of 50 mg LY3314814 
and at approximately the same time an IV infusion of approximately 100 µg [
13C4
15N3]-
LY3314814 will be started. The infusion will run for 2 hours.Blood samples will be collected 
predose and up to 120 hours postdose to measure LY3314814 and [13C4
15N3]-LY3314814 
concentrations.
6.TREATMENT
The following label forstudy treatment will be used in the TFLs: 50 mg LY3314814 oral + 
100µg [13C4
15N3]-LY3314814 IV.  PK data will summarised separately for each administration.
7.SAMPLE SIZE JUSTIFICATION
Up to 8 subjects may be enrolled and dosed to ensure that at least 6 subjects complete and have 
evaluable PK data.
This sample size is considered adequate for Phase 1 studies evaluating absolute bioavailability 
and is not intended to meet any a priori statistical requirement.
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.  Subjects may be excluded from the PK summary 
statistics and statistical analysis if a subject has an adverse event(AE)of vomiting that occurs at 
or before 2 times medianof the time ofmaximum observed drug concentration(t
max
PPD
).
All protocoldeviations 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.


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9.STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all datathat isdatabased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include thearithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; forlog-normal data (e.g. the PK parameters: Area under the concentration 
versus time curve[AUC]and the maximum observed drug concentration[Cmax]the geometric 
mean and geometric coefficient of variation [CV%]will also be presented. For categorical data, 
frequency count and percentages will be presented. Data listings will be provided for all 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 9.4or greater.
9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity,body 
weight, height and body mass index will be summarized and listed.  All other demographics will 
be listedonly.
9.3
Pharmacokinetic Assessment
9.3.1Pharmacokinetic Analysis
ThePK parameter estimates will be determined using non-compartmental procedures in
validated software program (Phoenix WinNonlin Version 6.4.1 or later).
Plasmaconcentrations of LY3314814 and [
13C4
15N3
PPD
]-LY3314814 will be used to determine the 
following PK parameters, when possible:  


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Parameter
Units
Definition
AUC(0-t
last)
ng.h/mLand
ng equiv•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(0-∞)
ng.h/mLand
ng equiv•h/mL
area under the concentration versus time curve from time zero 
to infinity
DN 
AUC(0-t
last)
ng.h/mL/mgand
ng equiv•h/mL/mg
dose normalised AUC(0-t
last)
DN 
AUC(0-∞)
ng.h/mL/mgand
ng equiv•h/mL/mg
dose normalised AUC(0-∞)
%AUC(tlast-) %
percentage of AUC(0-∞) extrapolated
Cmax
ng/mLand
ng equiv/mL
maximum observed drug concentration
t
max
h
time of maximum observed drug concentration
t
1/2
h
half-life associated with the terminal rate constant (λz) in 
non-compartmentalanalysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration (LY3314814 only)
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration (LY3314814 only)
Vss/F
L
apparent volume of distribution at steady state after extra-
vascular administration (LY3314814 only)
CL
L/h
total body clearance of drug calculated after IV administration 
([
13C4
15N3]-LY3314814only)
Vz
L
volume of distribution during the terminal phase afterIV 
administration ([
13C4
15N3]-LY3314814  only)
Vss
L
volume of distribution at steady state after IV administration 
([
13C4
15N3]-LY3314814only)
Dose normalised (DN) PK parameters DN AUC(0-t
last) and DN AUC(0-∞)will be calculated by 
dividing the PK parameter value by dose in mg.
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

PPD
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. 


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Cmaxand t
maxwill be reported from observed values.  If Cmaxoccurs at more than onetime 
point, tmaxwill be assigned to the first occurrence of Cmax. 
AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidalmethods (linear-log trapezoidal rule).  The linear trapezoidal method will be 
applied up to t
maxand then the logarithmic trapezoidal method will be used after t
max. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above thelower 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 (t
½) 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 
parameter can be obtained comprising of at least 3data points.  If t½is estimated over a 
time window of less than 2half-lives, the values will be flagged in the data listings. Any 
t
½value 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 observed last 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: 
The compound is non-endogenous.
The samples are from the initial dose period for a subject or from a subsequent 
dose period following a suitable wash-out period.
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. 

PPD
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 


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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 concentrationswill beplotted utilizing actual sampling times.
The terminalpoint selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles
The average concentration profiles will be graphed using scheduled (nominal) sampling 
times. 
The average concentration profiles will be graphed using arithmetic average 
concentrations.
The pre-dose averageconcentration 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 3data 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:

PPD
For PK profiles during single dosing of non-endogenous compounds, the concentration in 
a pre-dose sample is quantifiable.


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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.
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 ofthe 
final report will connote approval of the exclusion.
9.3.2Pharmacokinetic Statistical Methodology
To quantify the absolute bioavailability of LY3314814, a mixed-effect analysis of variance
(ANOVA) model will be applied to the log-transformed DNAUC(0-∞)of LY3314814 obtained 
after oral dosing and that of the IV administered [
13C4
15N3
PPD
]-LY3314814.The model will contain 
formulation (oral or IV) as a fixed effect and subject as a random effect.The absolute 
bioavailability will be expressed as theratio of the least-squares geometric means of the 
formulations (oral:IV) along with its corresponding 90% confidence interval.


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Example SAS code:
proc mixed data=DATA alpha=0.1;
   class treatment subject;
   model log_pk = treatment / ddfm=kr;
   random subject;
   lsmeans treatment / pdiff cl alpha=0.1;
   ods output lsmeans=lsmeans;
   ods output diffs=diffs;
run;
Additional analysis may be conducted if deemed appropriate.
9.4
Safety and Tolerability Assessments
9.4.1Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AEwill 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 consentand is ongoing at consent. A non-treatment emergent AE is defined as 
an AE which startsafter 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.
All AEs will be listed.  Treatment-emergentAEs will be summarized by severity and 
relationship to the study drug. The frequency (the number of AEs, the number of subjects 
experiencing an AEand the percentage of subjects experiencing an AE) of treatment-emergent 
AEswill be summarized by Medical Dictionary for Regulatory Activities (MedDRA)version
20.1system organ class and preferred term. The summary and frequency AEtables will be 
presented for all causalities and those considered related to the study drug.Any serious AEswill 
be tabulated.  Onset time of AEs will derived relative to the oral administration.
9.4.2Concomitant medication
Concomitant medication will be coded using the World Health Organization(WHO)drug 
dictionary (VersionMarch 2017). Concomitant medication will be listed.
9.4.3Clinical laboratory parameters
PPD
Allclinical chemistry, hematologyand urinalysis data will be listed.Additionally clinical 
chemistry, hematologyand 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.


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9.4.4Vital signs
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as Day 1 predose. 
Furthermore, values for individual subjects will be listed.
9.4.5Electrocardiogram (ECG)
ECGs will be performed for safety monitoring purposes only and will not be presented.
9.4.6Hepatic 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.
9.4.7Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analysed.  Prior therapydata will be listed.
9.4.8Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
PPD
There were no changes from the protocol specified statistical analyses.


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12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for HumanUse, 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. Observedtime data, e.g. tmax, should be reported as received. N and percentage 
valuesshould 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
PPD
Some of the TFLs maynot 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.”