Clinical trial NCT02568423
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2015-12-02; Completion date: 2018-10-24
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to explore the safety and tolerability of mirikizumab in healthy Japanese and Caucasian participants. The study will also estimate how much mirikizumab gets into the blood stream and how long it takes the body to remove it. The study is expected to last about 16 weeks for each participant.

Detailed description:

Arms: arm 1: Participants received 200mg Mirikizumab by intravenously. arm 2: Participants received single dose of either 60mgor 200mg 0r 600mg or 1200mg or 2400mg Mirikizumab by subcutaneously. arm 3: Participants received placebo by intravenously. arm 4: Participants received placebo by subcutaneously.
Interventions: intervention 1: Mirikizumab - IV intervention 2: Mirikizumab - SC intervention 3: Placebo - IV intervention 4: Placebo - SC
Intervention descriptions: intervention 1: Administered IV intervention 2: Administered SC intervention 3: Administered IV intervention 4: Administered SC

Protocol documents:
Prot_000.pdf: 
 
I6T-JE-AMAD (a) Protocol 
 
 
A Single-Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of LY3074828 in 
Japanese and Caucasian Healthy Subjects. 
 
NCT02568423 
 
 Date: 23-Jan-2018 
 
 


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1. Protocol I6T-JE-AMAD(a)
A Single-Dose Study to Assess the Safety, Tolerability, and 
Pharmacokinetics of LY3074828 in Japanese and
Caucasian Healthy Subjects
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY3074828, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.  This document and its associated attachments are 
subject to United States Freedom of Information Act (FOIA) Exemption 4.
LY3074828
Study I6T-JE-AMAD is a single-site, subject- and investigator-blind, randomized, placebo-
controlled, single-dose study to assess the safety, tolerability, and pharmacokinetics of 
LY3074828 in Japanese and Caucasian healthy subjects.  The study will consist of 
6 planned dose cohorts:  5 intravenous cohorts (60 mg, 200 mg, 600 mg, 1200 mg, and 
2400 mg) and 1 subcutaneous cohort (200 mg). Subjects in each cohort will be 
randomized to receive LY3074828 or placebo.
Eli Lilly Japan K.K.
Kobe Hyogo Japan
Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 23-Jan-2018 GMT


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2. Synopsis
Clinical Pharmacology Protocol Synopsis:  Study I6T-JE-AMAD
Name of Investigational Product: LY3074828
Title of Study:  A Single-Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of LY3074828 in 
Japanese and Caucasian Healthy Subjects
Number of Planned Subjects:  approximately 50 subjects
Phase of Development:  1
Length of Study:  approximately 16 weeks
Objectives:  The primary objective is to explore the safety and tolerability of LY3074828 in healthy Japanese and 
Caucasian subjects to define an appropriate dose for further clinical research in Japan.  The secondary objectives of 
this study are to estimate the pharmacokinetic (PK) parameters of LY3074828 following intravenous (IV) and 
subcutaneous (SC) administration in healthy Japanese and Caucasian subjects and to explore the safety, 
tolerability, and PK of LY3074828 in Japanese subjects in relation to Caucasian subjects.
Study Design:  Study I6T-JE-AMAD is a single-site, subject- and investigator-blind, randomized, 
placebo-controlled, single-dose study to assess the safety, tolerability, and PK of LY3074828 in Japanese and 
Caucasian healthy subjects. The study will consist of 6 planned dose cohorts:  5 IV cohorts (60 mg, 200 mg, 
600 mg, 1200 mg, and 2400 mg) and 1 SC cohort (200 mg).  Subjects in each cohort will be randomized to receive 
LY3074828 or placebo. Subjects will be inpatient in the clinical research unit (CRU) for treatment administration 
and will then be discharged and followed as outpatients for 12 weeks after treatment administration.
Diagnosis and Main Criteria for Inclusion and Exclusion:  This study will enroll healthy male and female
subjects who are 20 years to 64 years, inclusive, with a body mass index of 18.0 kg/m2 to 32.0 kg/m2, inclusive, at 
screening.  Japanese subjects must be first-generation Japanese, defined as the subject, the subject’s biological 
parents, and the subject’s biological grandparents are all of exclusive Japanese descent and were born in Japan.
Investigational Product, Dosage, and Mode of Administration:  A single dose of LY3074828 will be 
administered IV at the planned dose levels of 60 mg, 200 mg, 600 mg, 1200 mg, and 2400 mg.  A single dose of 
LY3074828 will be administered SC at a planned dose of 200 mg.
Comparator, Dose, and Mode of Administration:  A single dose of placebo (sterile normal saline [0.9% sodium 
chloride]) will be given IV or SC, as per cohort.
Planned Duration of Treatment:  LY3074828 or placebo will be given as a single dose.
Criteria for Evaluation:  
Safety:  Adverse events (AEs), serious adverse events, physical examinations, vital signs, electrocardiograms 
(ECGs), and clinical laboratory evaluations including immunogenicity.
Bioanalytical:  Serum for the measurement of LY3074828 concentrations will be collected at select visits.
Pharmacokinetic:  The primary parameters for analysis will be maximum drug concentration (Cmax) and area under 
the concentration versus time curve (AUC) of LY3074828.  Other noncompartmental parameters, such as half-life, 
clearance, and volume of distribution (apparent clearance and apparent volume of distribution for SC 
administration) may be reported.  


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Evaluation Methods:
Statistical:  Up to 60 subjects may be enrolled in order that approximately 50 subjects complete the study.  It is 
intended that 10 subjects (6 Japanese and 4 Caucasian) will be randomized in Cohort 1, and 8 subjects (4 Japanese 
and 4 Caucasian) will be randomized in Cohorts 2, 3, 4, 5, and 6.  The sample size is customary for Phase 1 studies 
evaluating safety, tolerability, and PK parameters. The first interim analysis is scheduled to occur when safety and 
PK data through Day 15 become available from at least 8 subjects in Cohort 1, including at least 3 Japanese 
subjects on LY3074828.  An additional interim analysis may occur when safety and PK data through Day 15 
becomes available from at least 6 subjects in Cohort 6, including at least 3 Japanese subjects on LY3074828. All 
safety and PK data available by this time will be included in the interim analysis.  
Safety:  Safety parameters that will be assessed include vital signs, ECG parameters, and safety lab parameters.  
The parameters will be listed and summarized using standard descriptive statistics.  Additional analysis will be 
performed if warranted upon review of the data.  
Bioanalytical:  Serum concentrations of LY3074828 will be assayed using a validated enzyme-linked 
immunosorbent assay.
Pharmacokinetic:  PK parameter estimates for LY3074828 will be calculated by standard noncompartmental 
methods of analysis.  


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3. Table of Contents
A Single-Dose Study to Assess the Safety, Tolerability, and 
Pharmacokinetics of LY3074828 in Japanese and Caucasian 
Healthy Subjects
Section
Page
1.
Protocol I6T-JE-AMAD(a) A Single-Dose Study to Assess the 
Safety, Tolerability, and Pharmacokinetics of LY3074828 in 
Japanese and Caucasian Healthy Subjects ...........................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................4
4.
Abbreviations and Definitions...........................................................................................10
5.
Introduction ......................................................................................................................13
5.1.
General Introduction ....................................................................................................13
5.2.
Rationale and Justification for the Study ......................................................................16
6.
Objectives.........................................................................................................................17
6.1.
Primary Objective ........................................................................................................17
6.2.
Secondary Objectives...................................................................................................17
7.
Investigational Plan...........................................................................................................18
7.1.
Summary of Study Design............................................................................................18
7.2.
Discussion of Design and Control ................................................................................20
8.
Study Population...............................................................................................................21
8.1.
Criteria for Enrollment .................................................................................................21
8.1.1.
Inclusion Criteria .................................................................................................21
8.1.2.
Exclusion Criteria ................................................................................................22
8.1.3.
Rationale for Exclusion of Certain Study Candidates ...........................................24
8.2.
Discontinuation............................................................................................................24
8.2.1.
Discontinuation of Subjects..................................................................................25
8.2.1.1.
Subjects Inadvertently Enrolled ......................................................................25
8.2.1.2.
Discontinuations from Investigational Product or from 
the Study ........................................................................................................25
8.2.1.3.
Subjects Lost to Follow-up .............................................................................26
8.2.2.
Discontinuation of Study Sites .............................................................................26
8.2.3.
Discontinuation of the Study................................................................................26
9.
Treatment..........................................................................................................................27
9.1.
Treatment Materials and Supplies.................................................................................27
9.2.
Treatment Administration ............................................................................................27


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9.3.
Rationale for Selection of Dose....................................................................................28
9.4.
Dose Escalation............................................................................................................30
9.4.1.
Dose Escalation Method.......................................................................................31
9.5.
Specific Restrictions/Requirements ..............................................................................31
9.5.1.
Special Treatment Considerations ........................................................................32
9.5.1.1.
Premedication for Infusions............................................................................32
9.5.1.2.
Management of Infusion Reactions.................................................................32
9.6.
Blinding .......................................................................................................................32
9.7.
Concomitant Therapy...................................................................................................33
10.
Sample Collection and Safety Data Collection ..................................................................34
10.1. Laboratory Samples .....................................................................................................34
10.2. Samples for Pharmacokinetic and Pharmacodynamic Evaluations................................34
10.2.1.
Pharmacokinetic Samples.....................................................................................34
10.2.2.
Bioanalysis...........................................................................................................34
10.3. Samples for Biomarker Research..................................................................................35
10.3.1.
Samples for Genetic Biomarker Research.............................................................35
10.3.2.
Samples for Exploratory Evaluation.....................................................................35
10.4. Samples for Immunogenicity Research.........................................................................36
10.5. Safety Evaluations........................................................................................................36
10.5.1.
Adverse Events ....................................................................................................36
10.5.2.
Serious Adverse Events........................................................................................37
10.5.2.1.
Suspected Unexpected Serious Adverse Reactions..........................................38
10.5.3.
Other Safety Measures .........................................................................................38
10.5.3.1.
Physical Examination .....................................................................................38
10.5.3.2.
Vital Signs......................................................................................................38
10.5.3.3.
Body Weight and Height ................................................................................39
10.5.3.4.
Electrocardiograms.........................................................................................39
10.5.4.
Safety Monitoring ................................................................................................40
10.5.5.
Complaint Handling.............................................................................................40
10.6. Appropriateness and Consistency of Measurements......................................................40
10.7. Compliance..................................................................................................................40
11.
Sample Size and Data Analyses ........................................................................................42
11.1. Determination of Sample Size ......................................................................................42
11.2. Data Analysis Plans......................................................................................................42
11.2.1.
General Considerations ........................................................................................42
11.2.2.
Study Participant Disposition ...............................................................................42
11.2.3.
Study Participant Characteristics ..........................................................................42
11.2.4.
Pharmacokinetic Analyses....................................................................................43


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11.2.4.1.
Pharmacokinetic Parameter Estimation...........................................................43
11.2.4.2.
Pharmacokinetic Statistical Inference .............................................................43
11.2.5.
Pharmacodynamic Analyses.................................................................................43
11.2.6.
Pharmacokinetic/Pharmacodynamic Analyses......................................................43
11.2.7.
Safety Analyses....................................................................................................43
11.2.7.1.
Clinical Evaluation of Safety..........................................................................43
11.2.7.2.
Statistical Evaluation of Safety.......................................................................43
11.2.7.3.
Evaluation of Immunogenicity........................................................................44
11.3. Interim Analyses ..........................................................................................................44
12.
Data Management Methods...............................................................................................45
12.1. Data Quality Assurance................................................................................................45
12.2. Data Capture Systems ..................................................................................................45
12.2.1.
Source Data and Case Report Form......................................................................45
12.2.2.
Ancillary Data......................................................................................................46
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................47
13.1. Informed Consent.........................................................................................................47
13.2. Ethical Review.............................................................................................................47
13.3. Regulatory Considerations ...........................................................................................47
13.3.1.
Investigator Information.......................................................................................48
13.3.2.
Protocol Signatures ..............................................................................................48
13.3.3.
Final Report Signature .........................................................................................48
14.
References ........................................................................................................................49


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List of Tables
Table
Page
Table AMAD.1.
Investigational Product Regimens...........................................................28
Table AMAD.2.
Margin of Safety for Intravenous Administration of 2400 mg 
LY3074828 Based on Administered Dose and Predicted Exposure.........30


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List of Figures
Figure
Page
Figure AMAD.1.
Mean percentage change from baseline in the Psoriasis Area and 
Severity Index score by dose group.........................................................15
Figure AMAD.2.
Study design for Protocol I6T-JE-AMAD...............................................19


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List of Attachments
Attachment
Page
Attachment 1.
Protocol AMAD Study Schedule ............................................................51
Attachment 2.
Protocol AMAD Clinical Laboratory Tests.............................................54
Attachment 3.
Protocol AMAD Blood Sampling Summary...........................................55
Attachment 4.
Protocol AMAD Blinding/Unblinding Plan ............................................56
Attachment 5.
Protocol Amendment I6T-JE-AMAD(a) Summary: A Single-Dose 
Study to Assess the Safety, Tolerability, and Pharmacokinetics of 
LY3074828 in Japanese and Caucasian Healthy Subjects .......................58


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4. Abbreviations and Definitions
Term
Definition
ADA
antidrug antibody
AE
adverse event:  any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
AUC
area under the concentration versus time curve
audit
A systematic and independent examination of the trial-related activities and documents to 
determine whether the evaluated trial-related activities were conducted, and the data were 
recorded, analyzed, and accurately reported according to the protocol, sponsor’s standard 
operating procedures (SOPs), good clinical practice (GCP), and the applicable regulatory 
requirement(s).
blinding
a procedure in which one or more parties to the trial are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the subject is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and his staff and the subject are not. A double-blind study is one in 
which neither the subject nor any of the investigator or sponsor staff who are involved in 
the treatment or clinical evaluation of the subjects are aware of the treatment received.
CD
Crohn’s disease
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum drug concentration
complaint
a complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
adherence to all the 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.
CRF
case report form/electronic case report form:  sometimes referred to as clinical report form; 
a printed or electronic form for recording study participants’ data during a clinical study, as 
required by the protocol.


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CRU
clinical research unit
CSE
clinically significant event:  a moderate to severe adverse event (AE), abnormal clinical 
sign, or clinical laboratory finding that may pose a risk to the well-being of the subject
CTCAE
Common Terminology Criteria for Adverse Events
end of study
End of study is the date of the last visit or last scheduled procedure shown in the Study 
Schedule for the last patient/subject.
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/institutional review board:  a board or committee (institutional, 
regional, or national) composed of medical professionals and nonmedical members whose 
responsibility is to verify that the safety, welfare, and human rights of the subjects
participating in a clinical trial are protected
GCP
good clinical practice:  a standard for the design, conduct, performance, monitoring, 
auditing, recording, analyses, and reporting of clinical trials that provides assurance that the 
data and reported results are credible and accurate and that the rights, integrity, and 
confidentiality of trial subjects are protected
IB
Investigator’s Brochure:  a compilation of the clinical and nonclinical data on the 
investigational product(s) which is relevant to the study of the investigational product(s) in 
human subjects
IBD
inflammatory bowel disease
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IL-12
interleukin-12
IL-23
interleukin-23
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.  
interim analysis
An interim analysis is an analysis of clinical trial data, separated into treatment groups, that 
is conducted before the final reporting database is created/locked.
investigational 
product (IP)
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.


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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
NOAEL
no-observed-adverse-effect level
PASI
Psoriasis Area and Severity Index
PK
pharmacokinetic
randomize
the process of assigning subjects to an experimental group according to the randomization 
schedule for the trial
rescreen
to screen a subject who was previously declared a screen failure for the same study
SAE
serious adverse event:  any untoward medical occurrence that at any dose results in death, is 
life threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability/incapacity, or is a congenital 
anomaly/birth defect
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.  In this study, screening 
involves invasive procedures and/or tests (for example, x-rays and blood draws).  For this 
type of screening, informed consent for these screening procedures and/or tests shall be 
obtained; this consent may be separate from obtaining consent for the study.
SC
subcutaneous
subject
an individual who is or becomes a participant in clinical research, either as a recipient of the 
investigational product(s) or as a control.  A subject may be either a healthy human or a 
patient.
SUSARs
suspected unexpected serious adverse reactions
TB
tuberculosis
Th17
T helper 17
TST
tuberculin skin test
TEAE
treatment-emergent adverse event:  any untoward medical occurrence that either occurs or 
worsens at any time after treatment baseline and which does not necessarily have to have a 
causal relationship with this treatment
TPO
third-party organization


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A Single-Dose Study to Assess the Safety, Tolerability, and 
Pharmacokinetics of LY3074828 in Japanese and Caucasian 
Healthy Subjects
5. Introduction
5.1.
General Introduction
Interleukin-23 (IL-23), a member of the interleukin-12 (IL-12) family of cytokines, is a 
heterodimeric protein composed of 2 subunits:  the p40 subunit, which IL-23 shares with IL-12, 
and the p19 subunit, which is believed to be specific to IL-23.  IL-23 is produced by antigen-
presenting cells, such as dendritic cells and macrophages (Oppmann et al. 2000; Andersson et al. 
2004).  IL-23 is critically involved in the maintenance and amplification of T helper 17 (Th17) 
cells.  In addition to Th17 cells, many innate immune cells respond to IL-23 and are important 
both in resistance to infection and in mediating pathology in many autoimmune or inflammatory 
diseases including ulcerative colitis and Crohn’s disease (CD) (Croxford et al. 2014).  
Treatment of autoimmune or inflammatory diseases with IL-23–targeted therapy is being 
pursued by many companies.  The first such biologic to demonstrate clinical benefit in 
autoimmune disease was ustekinumab, which is now an approved medicine for the treatment of 
patients with psoriasis and psoriatic arthritis (Stelara package insert, 2013) and CD (Toussirot et 
al. 2013).  Ustekinumab is a monoclonal antibody that recognizes the common p40 subunit of 
IL-12 and IL-23; therefore, it does not target IL-23 specifically.  Blockade of the IL-12 pathway
may prevent Th1 cell–induced interferon blockade of Th17 cell development, thus potentially 
limiting the clinical activity of p40 targeting antibodies.  Experimental studies suggest that 
blocking the IL-23/Th17/interleukin-17 immune axis (and not IL-12) is sufficient to treat 
autoimmune inflammation (Monteleone et al. 2009).  IL-23–specific medicines targeted to the 
IL-23 p19 subunit have demonstrated clinical activity in psoriasis and CD (Kopp et al. 2015; 
Sofen et al. 2014; Krueger et al. 2015; Sands et al. 2015).  Although clinical evaluation of an 
IL-23–targeted therapy in ulcerative colitis has yet to occur, the IL-23/Th17 pathway is 
suggested to have a significant role in patients with ulcerative colitis (Gheita et al. 2014; Globig 
et al. 2014; El-Bassat et al. 2014); therefore, evaluation of an IL-23 antibody in this disease 
would be the next logical step. Therefore, the planned Phase 2 study, I6T-MC-AMAC (AMAC), 
will evaluate the hypothesis that LY3074828 can induce significantly higher rates of clinical 
remission compared to placebo in subjects with moderate to severe ulcerative colitis.
LY3074828 is a humanized immunoglobulin G4–variant monoclonal antibody that is directed 
against the p19 subunit of IL-23 and does not bind IL-12.  LY3074828 is being developed for the 
treatment of autoimmune diseases in which the IL-23 pathway is thought to have a significant 
pathogenic role.  LY3074828 does not bind rodent IL-23, so a surrogate molecule was developed 
to neutralize mouse IL-23 for use in preclinical studies.  Neutralization of IL-23 with this 
surrogate antibody significantly reduced the development of arthritis and inhibited ileal 
inflammation in a mouse model of spondyloarthropathy with bowel inflammation (Ruutu et al. 
2012).  In addition, neutralization of IL-23 significantly reduced the disease score in the 


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relapsing-remitting experimental autoimmune encephalomyelitis (multiple sclerosis–like) model 
in mice.  Anti–IL-23 antibody also demonstrated some efficacy in preclinical arthritis models, 
depending on the timing of intervention (Cornelissen et al. 2013).  
One study, Study I6T-MC-AMAA (AMAA): A Phase 1, Randomized, Placebo-Controlled Study 
of LY3074828, an Anti-IL-23 Humanized Antibody in Subjects With and Without Psoriasis, has 
been completed.  This study evaluated LY3074828 in healthy volunteers and in subjects with 
plaque psoriasis.  Seven cohorts of subjects with active psoriasis received single doses of
intravenous (IV) LY3074828 (up to 600 mg) or placebo.  A single cohort of 5 healthy subjects 
received single subcutaneous (SC) doses of LY3074828 (120 mg).  A total of 33 subjects with 
psoriasis and 5 healthy subjects were administered LY3074828.  Seven subjects with psoriasis 
received placebo.

No deaths, serious adverse events (SAEs), or discontinuations due to an adverse event 
(AE) were reported.  Treatment-emergent adverse events (TEAEs) reported as related 
to investigational product (IP) included one Grade 1 event of headache experienced 
by a single subject in the 200-mg IV cohort and five Grade 1 events of injection site 
pain experienced by 3 subjects in the 120-mg SC cohort.  No LY3074828 TEAEs of 
Grade 2 or higher were reported.  No dose-dependent trends in adverse events (AEs) 
were seen.  No clinically important changes in vital signs, electrocardiograms 
(ECGs), or clinical laboratory results were observed.

Following single IV doses of LY3074828 in Study AMAA, the area under the curve 
(AUC) and maximum drug concentration (Cmax) increased in approximately a dose-
proportional manner.  The mean terminal phase half-life across all IV doses was 10.5 
days and did not appear to be dependent on dose, and the mean clearance is within the 
range expected for human monoclonal antibodies.  The overall mean clearance across 
all doses following IV administration was approximately 0.526 L/day and is within 
the range expected for human monoclonal antibodies.  Maximum concentrations were 
observed 3 days postdose following SC administration.  Based on the AUC, the SC 
bioavailability was 40% relative to IV administration. 

Immunogenicity evaluations were performed in Study AMAA.  Blood samples to 
evaluate anti-drug antibodies (ADA) were collected at baseline and approximately 22, 
43, and 85 days postdose.  ADA data were available for 45 subjects, 38 who received 
LY3074828 and 7 who received placebo.  All subjects who received placebo were 
ADA negative at baseline and postbaseline.  Only one subject who received 
LY3074828 was positive at baseline.  Thirty-one subjects who received LY3074828 
(81.6%) were negative at all postbaseline time points evaluated.  Seven subjects who 
received LY3074828 had a postbaseline positive titer; however, only 3 of those 
subjects (7.9% of LY3074828-treated individuals) developed treatment-emergent 
ADA, defined as a 4-fold or greater change in titer from baseline.  None of these 
cases of treatment-emergent anti-drug antibodies (TE-ADA) were associated with 
treatment-emergent adverse events (TEAEs). 


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
In Study AMAA, clinical activity was explored in subjects with psoriasis, with a 
follow-up period of approximately 12 weeks.  Figure AMAD.1 presents mean data by 
cohort for the percentage change in the Psoriasis Area and Severity Index (PASI) 
score.  The PASI measures the severity of disease on a scale from 0 to 72 (in which a 
score of 72 indicates extreme disease severity) by combining assessments of the 
extent of body surface involvement in the head, trunk, arms, and legs with the 
severities of desquamation, erythema, and plaque induration.  Preliminary PASI data 
show improvement of psoriasis after a single dose of LY3074828 in the higher-dose 
cohorts.
Figure AMAD.1.
Mean percentage change from baseline in the Psoriasis Area and 
Severity Index score by dose group.
Phase 2 studies investigating the efficacy of LY3074828 as a potential treatment for psoriasis 
(AMAF), ulcerative colitis (AMAC), and Crohn’s disease (AMAG) are currently ongoing.   
Phase 1 Study I6T-JE-AMAD (AMAD) will provide safety, tolerability, and pharmacokinetic 
(PK) data after IV and SC administration of LY3074828 in Japanese and Caucasian healthy 
subjects.
More information about the known and expected benefits, risks, and reasonably anticipated AEs
may be found in the Investigator’s Brochure (IB).  Information on AEs expected to be related to 
the IP may be found in Section 6 (Development Core Safety Information) of the IB.  
Change in PASI (%)
    -110
    -100
     -90
     -80
     -70
     -60
     -50
     -40
     -30
     -20
     -10
       0
      10
      20
Planned Study Day
Baseline
15
29
43
57
71
85
Placebo
5 mg
20 mg
60 mg
120 mg
200 mg
350 mg
600 mg


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LY3074828
5.2.
Rationale and Justification for the Study
This study intends to characterize the safety, tolerability, and PK of LY3074828 after single-dose 
administration in healthy Japanese and Caucasian subjects.  Characterization of safety and PK in 
Japanese subjects is essential for further clinical development in Japan.


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6. Objectives
6.1.
Primary Objective
The primary objective is to explore the safety and tolerability of LY3074828 in healthy Japanese 
and Caucasian subjects to define an appropriate dose for further clinical research in Japan.
6.2.
Secondary Objectives
The secondary objectives of this study are

to estimate the PK parameters of LY3074828 following IV and SC administration in healthy 
Japanese and Caucasian subjects

to explore the safety, tolerability, and PK of LY3074828 in Japanese subjects in relation to
Caucasian subjects


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LY3074828
7. Investigational Plan
7.1.
Summary of Study Design
This is a single-site, subject- and investigator-blind, randomized, placebo-controlled, single-dose 
study to assess the safety, tolerability, and PK of LY3074828 in Japanese and Caucasian healthy 
subjects. Subjects will be randomized to LY3074828 or placebo within 1 of 6 cohorts, as shown 
in Figure AMAD.2.  Cohort 1 will consist of 10 subjects (6 Japanese and 4 Caucasian) who will 
be randomized so that 5 Japanese subjects and 3 Caucasian subjects will receive LY3074828 
while 1 Japanese subject and 1 Caucasian subject will receive placebo.  Cohorts 2 through 6 will 
consist of 8 subjects (4 Japanese and 4 Caucasian) who are randomized in a 3:1 ratio of 
LY3074828 to placebo.  For each cohort, 3 Japanese subjects and 3 Caucasian subjects will 
receive LY3074828 while 1 Japanese subject and 1 Caucasian subject will receive placebo.  
Single doses up to 600 mg IV have been studied and shown to be well tolerated, therefore all 
cohorts, with the exception of Cohort 5 and Cohort 6, may be dosed in parallel if the site is able 
to accommodate more than 1 cohort at a time.  Cohort 5 will be dosed after confirming the safety 
and PK data from Cohort 1. Cohort 6 will be dosed last after confirming the safety and PK data 
from Cohort 5. Two additional Japanese subjects will be included in Cohort 1 to ensure that a 
sufficient number of Japanese subjects will have received LY3074828 at the time of the interim 
analysis.  An interim analysis is planned based on Cohort 1 data through Day 15 (see Section 
11.3) to support Japanese patients being included in the planned global Phase 2 study, Study I6T-
MC-AMAC (AMAC).


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LY3074828
Abbreviations:  FU = follow up; IV = intravenous; SC = subcutaneous.
Figure AMAD.2.
Study design for Protocol I6T-JE-AMAD.
Treatment:  
Four IV dose levels and 1 SC dose level of LY3074828 will be assessed in Cohorts 1 through 6.  
The following treatments are planned:
Cohort 1: a single dose of LY3074828 600 mg or placebo IV
Cohort 2: a single dose of LY3074828 200 mg or placebo IV
Cohort 3: a single dose of LY3074828 200 mg or placebo SC
Cohort 4: a single dose of LY3074828 60 mg or placebo IV
Cohort 5: a single dose of LY3074828 1200 mg or placebo IV
Cohort 6: a single dose of LY3074828 2400 mg or placebo IV
Study Procedures:  
Each subject will have a screening visit within 28 days prior to dosing, as shown in the Study 
Schedule (Attachment 1).  AEs, including injection-site reactions, will be assessed on all clinical 
research unit (CRU) visit days and when spontaneously reported. Physical examination, vital 


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LY3074828
signs, ECGs, laboratory tests, PK and other sample collections will be performed at times 
specified in the Study Schedule (Attachment 1).  
Subjects will report to the CRU on Day –2 and remain at the CRU until after the scheduled 
procedures have been completed on Day 2 (Attachment 1).  After randomization, study drug will 
be administered by either IV or SC injection in the morning of Day 1 after an overnight fast.
Extension of admission to the CRU and additional outpatient visits may be required for safety 
reasons at the discretion of the investigator.  If any safety findings warrant follow-up and/or 
preclude discharge from the study, further visits may be arranged as appropriate.
Sequential PK sampling and safety monitoring will occur through the end of study.  There will 
be outpatient visits over approximately 12 weeks after study drug administration, including an 
End of Study visit (Day 85) that will occur approximately 12 weeks after the dose.
7.2.
Discussion of Design and Control
This is a single-site, subject- and investigator-blind, randomized, placebo-controlled, single-dose 
study in healthy Japanese and Caucasian subjects.  Healthy Caucasian subjects are included in 
this study to enable comparison between healthy Japanese and Caucasian subjects, as most of the 
subjects in Study AMAA were Caucasian patients with psoriasis.  The number of subjects in 
Study AMAD is not sufficient for any formal ethnic comparison, but the safety, tolerability, and 
PK data will be assessed in both Japanese and Caucasian subjects and will be used to support the 
inclusion of Japanese subjects in future studies involving LY3074828.  The study will be 
subject- and investigator-blind, with the subjects, investigators, and site staff (except for site 
pharmacy staff) unaware of actual treatment (LY3074828 or placebo), but aware of dose level 
assigned to the cohort.  This design is being used to minimize bias in safety and tolerability 
assessments.
Dosing will begin with the 600 mg IV cohort because the timing of this cohort will determine the 
timing of the interim analysis and subsequent inclusion of Japanese subjects in the LY3074828 
global studies.  Single doses up to 600 mg have already been shown to be well tolerated in 
Study AMAA.  The dose levels included in this single-dose study are within the range of doses 
studied previously, with the exception of the planned 1200 mg and 2400 mg IV dose cohort.  
Preliminary population PK analyses of interim data from Study AMAA indicate that body 
weight has no clinically significant impact on clearance or volume of distribution of LY3074828.  
Therefore, the AUC and maximum drug concentration (Cmax) in Japanese subjects who may
have lower body weight are expected to be similar to those of subjects in Study AMAA.
The follow-up period will be 12 weeks for all cohorts after dosing. This duration will allow 
ample time for assessment of the PK of LY3074828 (>5 half-lives) and for an initial assessment 
of ADAs.  


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8. Study Population
8.1.
Criteria for Enrollment
Eligibility of subjects for study enrollment will be based on the results of a screening medical 
history, physical examination, vital signs, electrocardiogram (ECG), and clinical laboratory tests
(Attachment 1).  
A chest x-ray will be completed at screening unless one has been obtained within the past 
12 months, and the x-ray and/or report are available for the investigator’s review.
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to dosing.  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.
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.  However, if individuals have met the criteria for participation in this study but their 
screening assessments were collected outside of the 28-day screening window, those assessments 
may be repeated.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
8.1.1. Inclusion Criteria
Subjects are eligible for enrollment in the study only if they meet all of the following criteria:
[1]
are overtly healthy males or females, as determined by medical history and 
physical examination
[1a] male subjects:
will be sterile (including vasectomy) or agree to use a reliable method of 
birth control and will not donate sperm during the study and for 3 months 
following administration of the study drug
[1b] female subjects:
are women of childbearing potential who test negative for pregnancy before 
receiving study treatment based on serum pregnancy test and agree to use a reliable 
method of birth control (for example:  barrier methods such as condom, sponge, or 
diaphragm combined with spermicide in foam, gel, or cream; hormonal 
contraception [oral, intramuscular, implant, or transdermal], which includes 
Depo-Provera, Evra, and NuvaRing; intrauterine device; or complete abstinence
from sexual intercourse with men) during the study and for 3 months following
administration of the study drug
or


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are women not of childbearing potential due to surgical sterilization (at least 
6 weeks after bilateral oophorectomy and/or hysterectomy or at least 6 weeks after
tubal ligation) confirmed by medical history, or postmenopausal, defined as either:
1) spontaneous amenorrhea for at least 12 months, not induced by a medical 
condition or medications
or
2) spontaneous amenorrhea for 6 to 12 months with a follicle-stimulating hormone 
level greater than 40 mIU/mL at screening
[2]
are first-generation Japanese or are Caucasian.  
 
 
[3]
are 20 years to 64 years, inclusive, at the time of initial screening
[4]
have a body mass index (BMI) of 18.0 kg/m2 to 32.0 kg/m2, inclusive, at 
screening
[5]
have a body weight of 40.0 kg or higher for Cohorts 1 to 4 and 48.0 kg or 
higher for Cohort 5 and Cohort 6
[6]
have clinical laboratory test results within normal reference range for the 
population or investigator site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator
[7]
have venous access sufficient to allow for blood sampling and administration 
of IP as per the protocol
[8]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[9]
have given written informed consent approved by Lilly and the ethical review 
board (ERB) governing the site
8.1.2. Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria:
[10] are investigator site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.
[11] are Lilly employees or employees of the third-party organizations (TPOs)
involved with the study
[12] are currently enrolled in a clinical trial involving an IP or off-label use of a 
drug or device or are concurrently enrolled in any other type of medical 
research judged not to be scientifically or medically compatible with this 
study
CCI


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LY3074828
[13] have participated, within the last 30 days, in a clinical trial involving an IP. If 
the previous IP has a long half-life, 3 months or 5 half-lives (whichever is 
longer) should have passed.
[14] are persons who have previously completed or withdrawn from this study or 
any other study investigating LY3074828 or any other anti-IL-23 antibody
and have previously received the IP
[15] have known allergies to LY3074828, related compounds including humanized 
monoclonal antibodies, or any components of the formulation or history of 
significant atopy
[16] have clinically significant multiple or severe drug allergies, intolerance to 
topical corticosteroids, or severe posttreatment hypersensitivity reactions 
(including but not limited to erythema multiforme major, linear 
immunoglobulin A (IgA) dermatosis, toxic epidermal necrolysis, or 
exfoliative dermatitis)
[17] have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study
[18] have an abnormal blood pressure as determined by the investigator
[19] have a significant 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 study medication; or of 
interfering with the interpretation of data
[20] have known or ongoing psychiatric disorders
[21] regularly use known drugs of abuse and/or show positive findings on urinary 
drug screening
[22] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies at screening
[23] show evidence of hepatitis C and/or positive hepatitis C antibody at screening
[24] show evidence of hepatitis B and/or positive hepatitis B surface antigen or
positive hepatitis B core antibody (HBcAb+) at screening
[25] are women who are lactating
[26] have used or intend to use over-the-counter or prescription medication,
including herbal medications, within 14 days prior to dosing (stable doses of 
oral contraceptive, hormone replacement therapy, or vitamins at usual doses 
may be allowed as per judgment of the investigator)
[27] have donated blood of more than 500 mL within the last month


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LY3074828
[28] are subjects who have an average weekly alcohol intake that exceeds 21 units 
per week for males and 14 units per week for females or who are unwilling to 
abide by the alcohol restrictions described in Section 9.5
[29] are subjects whose tobacco consumption is more than 10 cigarettes per day or 
the equivalent or subjects who are not willing to refrain from smoking for 
approximately 2 hours prior to each ECG and vital-sign measurement during 
the study or who are unwilling to abide by the CRU smoking guidelines 
(Section 9.5)
[30] have had symptomatic herpes zoster within 3 months of screening
[31] show evidence of active or latent tuberculosis (TB), as documented by 
medical history and examination, chest x-rays (posterior anterior and lateral), 
and TB testing:  to qualify for the study, subject must have either a negative 
tuberculin skin test (TST; defined as a skin induration <5 mm at 48 hours to 
72 hours, regardless of BCG [Bacillus Calmette-Guerin] or other vaccination 
history), or a negative (not indeterminate) QuantiFERON®-TB Gold test.  The 
choice to perform a TST or a QuantiFERON-TB Gold test will be made by 
the investigator according to local licensing and standard of care.
[32] have received live vaccine(s) within 1 month of screening or intend to during 
the study
[33] are immunocompromised
[34] have received treatment with biologic agents (such as monoclonal antibodies, 
including marketed drugs) within 3 months or 5 half-lives (whichever is 
longer) prior to dosing
[35] have had lymphoma, leukemia, or any malignancy within the past 5 years 
except for basal cell or squamous epithelial carcinomas of the skin that have 
been resected with no evidence of metastatic disease for 3 years
[36] have had breast cancer within the past 10 years
[37] in the opinion of the investigator or sponsor are unsuitable for inclusion in the 
study for any reason
8.1.3. Rationale for Exclusion of Certain Study Candidates
Criteria [10] and [11] prevent conflict of interest in study participants.  Criteria [12] through [37] 
exclude medical conditions, medication intolerance, and concomitant medication use that may 
constitute a risk for the subject and/or may confound the assessment of study endpoints.
8.2.
Discontinuation
The reason for and date of discontinuation will be collected for all subjects.  All randomized
subjects who discontinue after receiving study drug will have procedures performed as shown in 
the Study Schedule (Attachment 1).


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LY3074828
8.2.1. Discontinuation of Subjects
8.2.1.1.
Subjects Inadvertently Enrolled
The criteria for enrollment must be followed explicitly.  If the investigator site identifies a 
subject who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor 
must be notified.  If the sponsor identifies a subject who did not meet enrollment criteria and 
who was inadvertently enrolled, the investigator site will be notified.  A discussion must occur 
between the Lilly clinical pharmacologist or clinical research physician and the investigator to 
determine whether the subject may continue in the study without IP.  The subject may not 
continue in the study if the Lilly clinical pharmacologist or clinical research physician does not 
agree with the investigator’s determination it is medically appropriate for the subject to continue.  
The investigator must obtain documented approval from Lilly clinical pharmacologist or clinical 
research physician to allow the inadvertently enrolled subject to continue in the study.
8.2.1.2.
Discontinuations from Investigational Product or from the Study
Subjects will be discontinued from the IP and/or from the study in the following circumstances:

enrollment in any other clinical trial involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study

investigator decision
o
the investigator decides that the subject should be discontinued from the study

subject decision
o
the subject requests to be discontinued from the study

sponsor decision
o
Lilly stops the study or stops the subject’s participation in the study for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and good clinical practice (GCP)

adverse event 
o
if a clinically significant event (CSE) occurs during the IV infusion or SC 
injection, the IP is to be discontinued and appropriate measures taken.  Lilly or its 
designee should be alerted immediately.  A CSE will be defined as a moderate to 
severe AE, abnormal clinical sign, or clinical laboratory finding that may pose a 
risk to the well-being of the subject.  Refer to Safety Evaluations (Section 10.5).
o
a clinically significant systemic hypersensitivity reaction occurs following 
administration of the IP (for example, drug-related symptomatic bronchospasm, 
allergy-related edema/angioedema, or hypotension) that requires parenteral 
medication, does not respond to symptomatic medication, or results in clinical 
sequelae or an anaphylactic reaction


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LY3074828
A dose group may be discontinued from the IP if the following are met:
2 or more subjects/cohort develop AEs that are severe, unless there is an obvious 
explanation other than IP or study procedures for the event(s)
OR
if greater than 40% of subjects in a cohort experience moderate treatment-related AEs 
that impair normal activities
OR
after the introduction of premedication in accordance with the protocol, 2 or more 
subjects develop (according to Common Terminology Criteria for Adverse Events 
[CTCAE], version 4.0) Grade 2 acute AEs related to the infusion, during or within 
2 hours of completing the infusion, that do not resolve with a reduced infusion rate and/or 
supportive care
Following the investigator’s determination that CSE criteria have been met and the investigator’s 
judgment of relatedness to the IP is documented, a decision will be made between the 
investigator and Lilly or its designee regarding subject discontinuation.
The nature of any conditions, clinical signs or symptoms, or abnormal laboratory values present 
at the time of discontinuation and any applicable follow-up procedures will be documented.
Refer to the Study Schedule (Attachment 1) for data collected at the time of discontinuation.
8.2.1.3.
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.
8.2.2. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for any reason consistent with applicable laws, regulations, and GCP.
8.2.3. Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.


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LY3074828
9. Treatment
9.1.
Treatment Materials and Supplies
LY3074828 will be supplied to the investigator by Lilly.  Clinical trial materials are 
manufactured in accordance with good manufacturing practices.  All IPs will be stored, 
inventoried, reconciled, and destroyed according to applicable regulations.
LY3074828 is supplied for clinical trial use as lyophilized powder in a glass vial and should be 
stored in refrigerated conditions (2ºC to 8ºC).  The vial is manufactured to deliver 75 mg of 
LY3074828 and will be reconstituted before administration.  Detailed instructions for the 
preparation and handling of LY3074828 will be provided by the sponsor.
When reconstituted and in a syringe, LY3074828 cannot be distinguished visually from placebo.  
Subjects and blinded site staff will not be able to see the difference because the label on the 
syringe will cover the solution. See Table AMAD.1 for additional details regarding the IP 
regimens. 
Placebo will be sterile normal saline (0.9% sodium chloride), which should be supplied by 
investigative site(s).
Clinical trial materials will be labeled according to the country’s regulatory requirements.
9.2.
Treatment Administration
The investigator or designee is responsible for:

explaining the correct use of the investigational agent(s) to the subject/site personnel, 

verifying that instructions are followed properly,

maintaining accurate records of IP 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 investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical trial materials.  
Subjects will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the IP so that the situation can be assessed.
All clinical trial material provided to the investigator will be stored in a secure place, and 
allocated and dispensed by appropriately trained persons.  The allocation and dispensing of the 
IPs will be fully documented and verified by a second person.  Detailed records of the amounts 
of the IP received, dispensed, and remaining at the end of the study will be maintained.
The actual time of all dose administrations will be recorded in the subject’s case report form 
(CRF).


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LY3074828
The IP will be administered as a slow IV infusion of at least 30 minutes.  SC administration of 
LY3074828 will be given as 2 injections of 1.4 mL into the skinfold of the left or right 
abdominal wall. Sites must have resuscitation equipment, emergency drugs, and appropriately 
trained staff available for at least 6 hours after the start of the infusion or postdose for SC 
administration.
Table AMAD.1.
Investigational Product Regimens
LY3074828 or Placebo
Cohort
Cohort 1
Cohort 2
Cohort 3
Cohort 4
Cohort 5
Cohort 6
Regimen
600 mg IV
200 mg IV
200 mg SC
60 mg IV
1200 mg IV
2400 mg IV
LY3074828 concentration
25 mg/mL
20 mg/mL
72 mg/mL
6 mg/mL
25 mg/mL
25 mg/mL
Volume per dose
24 mL
10 mL
2.8 mL
(1.4 mL ×
2 injections)
10 mL
48 mL
96 mL
Abbreviations:  IV = intravenous; SC = subcutaneous.
9.3.
Rationale for Selection of Dose
The 5 IV doses for this study are 60, 200, 600, 1200, and 2400 mg and the SC dose for this study 
is 200 mg.
The low dose of 60 mg IV for this study is chosen as one of the doses that was administered in 
the global single-dose study (Study AMAA) and is close to the low dose in the Phase 2 
ulcerative colitis study (Study AMAC).
The 200-mg IV dose is one of the starting doses in Study AMAC and is one of the doses that was 
administered in Study AMAA.  A dose of 200 mg SC is being administered in the maintenance
period of Study AMAC.
The 600-mg IV dose is the highest dose being tested in Study AMAC and is the highest dose that 
was administered in Study AMAA.
The original highest dose of 1200 mg IV was tested for safety and tolerability based on the safety 
results at each escalation cohort of this study. Findings from these results supported the highest 
dose of 1000 mg IV in the Phase 2 Crohn’s disease study (Study AMAG).
The amended maximum dose of 2400 mg IV is selected to support potential future studies in 
patients with ulcerative colitis and Crohn’s disease, where high IV doses (potentially beyond 
1200 mg) during induction treatment may be required to maximize efficacy (Sandborn et al. 
2012; Adedokun et al. 2016; Feagan et al. 2016).
The margin of safety at 2400 mg IV is 1.9-fold.  This value is based on the predicted exposure at
2400 mg compared to the observed exposure at 100 mg/kg IV, administered once weekly, in the 
4-week, repeat-dose monkey study.  In this study, 100 mg/kg was the no observed adverse-effect 
level (NOAEL) and also the highest dose tested. (see Table AMAD.2).
LY3074828 does not recognize rodent IL-23, which precludes its use in preclinical toxicity 
assessment and in efficacy disease models.  The monkey is a pharmacologically relevant species 


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LY3074828
for assessing nonclinical toxicity because LY3074828 binds with similar affinity to human and 
cynomolgus IL-23 (21 pM and 55 pM, respectively).  To assess the toxicity of LY3074828 and 
establish a margin of safety for clinical trials (Table AMAD.2), 4-week and 6-month toxicity 
studies in normal cynomolgus monkeys were performed with evaluation of safety pharmacology 
as part of the 4-week study. The weekly administration of LY3074828 to cynomolgus monkeys 
resulted in no adverse drug-related findings at doses of 0 mg/kg (vehicle), 1 mg/kg and 
30 mg/kg (SC), or 100 mg/kg (IV) for 4 weeks, with an 8-week recovery period, or at doses of 
0 mg/kg, 10 mg/kg, and 100 mg/kg (SC) for 6 months.  Therefore, the NOAEL was 
100 mg/kg/week for both studies; this was the highest dose tested. A safety pharmacology 
assessment performed during the 4-week monkey study included evaluation of body temperature, 
cardiovascular safety (including quantitative evaluation of ECG measurements and qualitative 
evaluation for abnormal waveform morphology and arrhythmias), observations for central 
nervous system signs with neurologic examinations, and qualitative assessments of respiratory 
depth with quantitative estimates of respiratory rate.  No drug-related changes occurred in any of 
these parameters.
Due to a lack of a preclinical disease model, the anticipated minimally effective dose for 
LY3074828 is unknown.  The clinical dose range for LY3074828 is not yet known, and the 
maximum planned LY3074828 dose level to be evaluated in Study AMAC is 600 mg.  However, 
it is possible that dose levels higher than 600 mg could be required in certain patients (for 
example, those with more severe disease activity) to achieve higher exposures in patients with 
inflammatory bowel disease (IBD), in part due to greater clearance observed in these patients 
(Ordás et al. 2012). Higher drug exposures, particularly during an induction dosing period
(Yarur et al. 2014), may be required to support the best clinical outcomes in many auto-
inflammatory disease indications, including IBD.  
Therefore, this study planned to evaluate the safety, tolerability, and PK of a 1200-mg IV dose of 
LY3074828.  The 1200-mg IV dose cohort (Cohort 5) was dosed after safety, tolerability, and 
PK data were confirmed from the 600-mg dose cohort (Cohort 1). Other dose levels were dosed 
concurrently in this study because these doses have already been shown to be well tolerated in 
Study AMAA. Evaluation of 1200-mg IV dose cohort (Cohort 5) provided safety and PK data to 
support the use of a higher dose level in Study AMAC and Study AMAG. 
In addition to the above evaluation, this study is amended to add the evaluation of safety, 
tolerability, and PK of a 2400-mg IV dose of LY3074828, since there is a possibility to evaluate 
a higher dose level up to 2400 mg IV in later clinical development.  The proposed dose of 
2400-mg IV infusion has a sufficient margin of safety in terms of dose. Moreover, the clinical 
safety profile of LY3074828 available to date supports 2400-mg IV administration in this study.  
Single doses of up to 1200 mg IV were evaluated in healthy subjects from Study AMAD and no 
dose-related safety or tolerability issues were observed.  Evaluation of the safety data available 
to date in the ongoing Study AMAC and Study AMAG that are evaluating higher and more 
frequent dose regimens of up to 1000 mg IV Q4W for up to 52 weeks has not revealed any 
differences in the safety profile.  The PK profile of this drug was found to be approximately
linear up to 1200-mg IV administration. Since the 2400-mg IV dose is only 2-fold of 1200 mg, it 


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is unlikely that an unexpected PK profile will be observed after administration of a 2400-mg IV 
dose. Therefore, evaluation of this additional higher dose cohort (2400 mg) will provide safety 
and PK data to support the use of a higher dose level beyond 1200 mg during the clinical 
development of this compound.
Table AMAD.2.
Margin of Safety for Intravenous Administration of 2400 mg 
LY3074828 Based on Administered Dose and Predicted Exposure
Dose (mg/kg)
Dose Multiplea
AUC0-672h,ss
(gh/mL)
Margin of Safetyb
Human highest 
dose (2400 mg)c
36.9 (IV)
110000
Monkey NOAELd
6-month study
100 (SC)
2.7
85800e
0.78
Monkey NOAELf
4-week study
100 (IV)
2.7
204200g
1.9
Abbreviations:  AUC = area under the concentration vs time curve; AUC0-672h,ss = AUC over 672 hours at steady 
state; AUC0-168h = AUC over 168 hours; AUC0-∞  = AUC from time zero to infinity; Cmax = maximum drug 
concentration; IV = intravenous; NOAEL = no observed-adverse-effect level; SC = subcutaneous.
a
Dose multiple is the dose in animals divided by dose in humans.
b
Margin of safety is the calculated mean AUC in animals divided by predicted mean AUC in humans after 
adjusting for differences in dosing frequency.
c
Highest proposed dose in this study; a body weight of 65 kg is assumed.  Human AUC0-672h,ss is equivalent to 
the expected AUC0-∞following a single dose.  Human AUC0-672h,ss at 2400 mg IV is predicted on the basis of 
the average IV clearance (0.526 L/day) from Study I6T-MC-AMAA.  AUC and Cmax were observed to increase 
in proportion to dose in Study I6T-MC-AMAA.
d
NOAEL was determined in a 6-month repeat dose toxicity study (Study 20043324).
e
Monkey AUC value was based on average of male and female Day 176 means of AUC0-168h and has been 
multiplied by 4 to align with the 4-week AUC interval projected for humans and planned for Phase 2 
Study I6T-MC-AMAC.
f
NOAEL was determined in a 1-month repeat-dose toxicity study (Study 20029153).  
g
Monkey AUC value was based on average of male and female Day 29 means of AUC0-168h and has been 
multiplied by 4 to align with the 4-week AUC interval projected for humans and planned for Phase 2 
Study I6T-MC-AMAC.
9.4.
Dose Escalation
All doses in this study, with the exception of the 1200-mg and 2400-mg doses, have been
previously tested and shown to be well tolerated in Study AMAA.  The only dose escalation 
decisions in this study will be made to proceed from the 600-mg cohort (Cohort 1) to the 1200-
mg cohort (Cohort 5) and the 1200-mg cohort (Cohort 5) to the 2400-mg dose cohort (Cohort 6).
Safety and PK data reviewed at the time of the first interim analysis will be used for the 
escalation decision to the 1200-mg dose.  Safety and PK data up to the 1200-mg dose cohort will 
be reviewed before dose escalation to 2400 mg.  The dose escalation cannot occur without prior 
discussion and agreement between the investigator and the Lilly clinical pharmacologist.  


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9.4.1. Dose Escalation Method
Safety data, in particular AEs, SAEs, and adverse laboratory abnormalities, will be 
independently assessed by the investigator, and will be considered related to the IP unless there 
is clear evidence that the event is not related.  The assessment of AE relatedness is detailed in 
Section 10.5.1.  PK data included in the interim analysis will also be assessed.  
After review of the data, an agreement on the appropriate dose escalation will be made by the 
investigator and sponsor for Cohort 6. None of the following scenarios occurred at 1200-mg 
LY3074828:
2 or more subjects develop AEs that are severe, unless there is an obvious explanation 
other than IP or study procedures for the event(s)
OR
if greater than 40% of subjects experience moderate treatment-related AEs that impair 
normal activities
OR
after the introduction of premedication in accordance with the protocol, 2 or more 
subjects develop (according to Common Terminology Criteria for Adverse Events 
[CTCAE]) Grade 2 acute AEs related to the infusion, during or within 2 hours of 
completing the infusion, that do not resolve with a reduced infusion rate and/or 
supportive care.
9.5.
Specific Restrictions/Requirements
Prior to beginning the study, the subjects will complete informed consent. Throughout the study, 
subjects may undergo medical assessments and review of compliance with restrictions before 
continuing in the study.
Meals/Diet—Subjects should fast overnight for at least 8 hours before dosing (water permitted)
and before each laboratory test.
Caffeine—Subjects should not be allowed caffeine consumption for 12 hours prior to CRU 
admissions and when in the CRU. At other times during the outpatient period, subjects will be 
allowed to maintain their regular caffeine consumption.
Alcohol—Alcohol consumption is not allowed from 12 hours prior to all study visits and during 
CRU stays.  At all other times, alcohol consumption should be limited to 21 units per week for 
males and 14 units per week for females (1 unit = 12 oz or 360 mL of beer, 5 oz or 150 mL of 
wine, 1.5 oz or 45 mL of distilled spirits).
Smoking—Subjects who smoke should maintain a stable smoking habit throughout the study.  
Subjects will be asked to refrain from smoking for approximately 2 hours prior to each ECG and
vital sign measurements as well as abide by the CRU smoking guidelines.


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Exercise—Strenuous activity should be avoided from 24 hours prior to admission until discharge 
from the CRU.
Contraception—Subjects with partners of childbearing potential must agree to use a reliable 
method of birth control during the study and until 3 months after the subject’s dose.
9.5.1. Special Treatment Considerations
9.5.1.1.
Premedication for Infusions
Premedication for the infusions is not planned.  However, if an infusion reaction occurs, 
appropriate medication may be used as determined by the study investigator(s) (see Section 9.7).  
If infusion reactions are observed but review of the data suggests that dose escalation may 
continue, administration of acetaminophen 500 mg to 1000 mg, and/or an antihistamine, such as
diphenhydramine (Benadryl®), may be administered orally 30 minutes to 60 minutes prior to the 
start of infusion for subsequent subjects.
The decision to implement premedication for infusions in subsequent cohorts will be made by 
the investigator and sponsor and recorded in the study documentation, along with the dose-
escalation decision.
Any premedications given will be documented as a concomitant therapy (see Section 9.7).
9.5.1.2.
Management of Infusion Reactions
Due to the risk of an infusion reaction with any biological agent, 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 IP 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 IP will be made

supportive care should be employed in accordance with the symptoms/signs
9.6.
Blinding
This is a subject- and investigator-blind study.  The sponsor and site pharmacists will be 
unblinded.  
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomization table and treatment assignments before the study is complete.  The Lilly clinical 
pharmacologist will have open access to this table.  Subject randomization codes and drug 
accountability records will be held in a secure location at the CRU, accessible only by 
individuals involved with study drug preparation.  Individuals involved with study drug
preparation will not be involved in any clinical aspects of the study including study drug


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administration and AE assessments. Refer to Attachment 4 for details on the blinding/unblinding 
plan.
Emergency codes will be available to the investigator. A code, which reveals the treatment
group for a specific study subject, may be opened during the study only if the subject’s well-
being requires knowledge of the subject’s treatment assignment.  
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted.  Subject safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the Lilly clinical pharmacologist 
or clinical research physician prior to unblinding a study subject’s treatment assignment.  If a 
study subject’s treatment assignment is unblinded, Lilly must be notified immediately.  Upon 
completion of the study, all codes must be returned to Lilly or its designee.
9.7.
Concomitant Therapy
Over-the-counter or prescription medication, including herbal medications, are not permitted 
within 14 days prior to dosing and throughout the study.  However, stable doses of oral 
contraceptive, hormone replacement therapy, or vitamins at usual doses may be allowed as per 
judgment of the investigator.  Any other drugs are to be avoided during the study unless required 
to treat an AE.  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 or clinical research physician. Any additional medication used during the course 
of the study must be documented.


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10.
Sample Collection and Safety Data Collection
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the clinical laboratory tests that will be performed for this study.
Attachment 3 summarizes the blood volumes for all blood sampling during the study.  
10.1. Laboratory Samples
Blood and urine samples will be collected to determine whether subjects meet 
inclusion/exclusion criteria and to monitor subject health at the visits and times specified in the 
Study Schedule (Attachment 1).  Routine clinical laboratory tests will be analyzed by a local 
laboratory.  
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.2. Samples for Pharmacokinetic and Pharmacodynamic 
Evaluations
10.2.1. Pharmacokinetic Samples
At the visits and times specified in the Study Schedule (Attachment 1), blood samples of 
approximately 2 mL each will be collected to determine the serum concentrations of 
LY3074828.  A maximum of 3 samples may be collected at additional time points during the 
study if warranted and agreed upon between both the investigator and sponsor.  Instructions for 
the collection and handling of blood samples will be provided by the sponsor.  The actual date 
and time (24-hour clock time) of each sampling will be recorded.
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
10.2.2. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of LY3074828 will be assayed using a validated enzyme-linked immunosorbent 
assay.  Analyses of samples collected from placebo-treated subjects are not planned.
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
1 year following last subject visit for the study.


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10.3. Samples for Biomarker Research
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, mechanism of action, variability of patient response (including 
safety), and clinical outcome.  Sample collection is incorporated into clinical studies to enable 
examination of these questions through measurement of biomolecules including DNA, RNA, 
proteins, lipids, and other cellular elements.
10.3.1. Samples for Genetic Biomarker Research
A blood sample will be collected for pharmacogenetic analysis as specified in the Study 
Schedule (Attachment 1) 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 LY3074828.  
Assessment of variable response may include evaluation of AEs or differences in efficacy.
All pharmacogenetic samples will be coded with the subject number.  These samples and any 
data generated can be linked back to the subject only by the investigator site personnel.
Samples will be retained for a maximum of 15 years after the last subject visit for the study, or 
for a shorter period if local regulations and/or ERBs impose shorter time limits, at a facility 
selected by the sponsor.  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 LY3074828 or after LY3074828 becomes 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, and candidate gene studies.  Regardless of 
technology utilized genotyping data generated will be used only for the specific research scope 
described in this section.
10.3.2. Samples for Exploratory Evaluation
Samples will be collected for potential nonpharmacogenetic biomarker research where local 
regulations allow. Samples may be used for research on IL-23, pathways associated with IL-23 
biology, mechanism of action of LY3074828, and/or research method or in validating diagnostic 
tools or assay(s) related to ulcerative colitis.
Whole blood mRNA, serum, and plasma will be collected at the times specified in the study 
schedule (Attachment 1). Proteomic, gene-expression, genomic, epigenetic, or metabolomic 
analysis may be performed on these samples.
Samples will be identified by the subject number (coded) and stored for up to a maximum of 
15 years after the last subject visit for the study at a facility selected by the sponsor.


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10.4. Samples for Immunogenicity Research
Blood samples for immunogenicity testing will be collected as specified in the Study Schedule
(Attachment 1) to determine antibody production against the IP.  Additional samples may be 
collected if there is a possibility that an AE is immunologically mediated.  Immunogenicity will 
be assessed by a validated assay designed to detect antidrug antibodies in the presence of the IP.  
Antibodies may be further characterized and/or evaluated for their ability to neutralize the 
activity of the IP.  Immunogenicity samples may also be analyzed for LY3074828 concentrations 
to facilitate in the interpretation of immunogenicity data.
Samples may be stored for a maximum of 15 years following last subject visit for the trial at a 
facility selected by the sponsor to enable further analysis of immune responses to the IP.  The 
duration allows the sponsor to respond to regulatory requests related to the IP.
10.5. Safety Evaluations
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.  
Planned safety assessments and measures are detailed in Section 10.5.3, but additional 
assessments and safety tests may be performed at the investigator’s discretion.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to study treatment or the study, or that caused the subject
to discontinue before completing the study.  The subject should be followed until the event is 
resolved or explained.  Frequency of follow-up evaluation is left to the discretion of the 
investigator.
In addition to records of observations made at specific times, unexpected signs and symptoms 
and concomitant medications will be recorded in the clinical trial records throughout the study.
10.5.1. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.
Cases of pregnancy that occur during maternal or paternal exposures to the IP should be 
reported.  Data on fetal outcome and breast-feeding are collected for regulatory reporting and 
drug safety evaluation.
After the informed consent form (ICF) is signed, site personnel will record any change in the 
condition(s) and the occurrence and nature of any AEs.  All AEs related to protocol procedures 
are reported to Lilly or designee.
Any clinically significant findings from ECGs, laboratory values, vital sign measurements, and 
other procedures should be reported as an AE to Lilly or its designee.


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In addition, all AEs occurring after the subject receives the first dose of the IP must be reported 
to Lilly or its designee via CRF.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure, IP, and/or drug delivery system via the CRF.
The investigator decides whether he or she interprets the observed AEs as either related to 
disease, study medication, study procedure, or other concomitant treatment or pathologies.  To 
assess the relationship of the AE to the IP, the following terminologies are defined:

Related:  A direct cause and effect relationship between the study treatment and 
the AE is likely.

Possibly related:  A cause and effect relationship between the study treatment 
and the AE has not been demonstrated at this time and is not probable but is also 
not impossible.

Unrelated:  Without question, the AE is definitely not associated with the study 
treatment.
As per Lilly’s standard operating procedures all “related” and “possibly related” AEs and SAEs 
will be defined as related to the IP.
If a subject’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via CRF the circumstances and data leading 
to any such dosage reduction or discontinuation of treatment.
10.5.2. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.


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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.  
SAE collection begins after the subject has signed informed consent and has received IP.  If a 
subject experiences an SAE after signing informed consent but prior to receiving IP, the event 
will NOT be reported as serious unless the investigator feels the event may have been caused by 
a protocol procedure.
SAEs occurring up to and including the subject’s last study visit will be collected, regardless of 
the investigator’s opinion of causation, in the clinical data collection database and the 
pharmacovigilance system at the sponsor.
The investigator does not need to actively monitor subjects for AEs once the trial has ended 
unless specified in the protocol.  However, if an investigator becomes aware of SAEs occurring 
to a subject after the subject’s participation in the trial has ended, the investigator should report 
them to the sponsor, regardless of the investigator’s opinion of causation, and the SAEs will be 
entered in the pharmacovigilance system at the sponsor.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.  
10.5.2.1. 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 IP or procedure.  United States 21 
CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the associated 
detailed guidances or national regulatory requirements in participating countries require the 
reporting of SUSARs.  Lilly has procedures that will be followed for the recording and expedited 
reporting of SUSARs that are consistent with global regulations and the associated detailed 
guidances.
10.5.3. Other Safety Measures
10.5.3.1. Physical Examination
Physical examinations and routine medical assessments will be conducted as specified in the 
Study Schedule and as clinically indicated (Attachment 1).
10.5.3.2. Vital Signs
Blood pressure and pulse rate will be measured as specified in the Study Schedule and as 
clinically indicated (Attachment 1).
Blood pressure and pulse rate should be measured after at least 5 minutes supine.


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If orthostatic measurements are required, subjects should be supine for at least 5 minutes and 
stand for at least 3 minutes.
If the subject feels unable to stand, supine vital signs only will be recorded.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period as 
per judgment of the investigator.
Body temperature (oral) will be measured as specified in the Study Schedule and as clinically 
indicated (Attachment 1).
10.5.3.3. Body Weight and Height
Body weight will be recorded as specified in the Study Schedule and as clinically indicated 
(Attachment 1).  Height will be measured only at screening; subject is to remove shoes.
10.5.3.4. Electrocardiograms
For each subject, a 12-lead digital electrocardiogram (ECG) will be collected as replicates 
(triplicates) except for screening visit according to the Study Schedule (Attachment 1).  
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.  Consecutive replicate ECGs will be obtained at approximately 
1-minute intervals.  Electrocardiograms may be obtained at additional times, when deemed 
clinically necessary.  Collection of additional ECGs at a particular time point is allowed to 
ensure high-quality records.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible and ideally while the 
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 quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the subject for symptoms (for example, palpitations, near 
syncope, syncope) to determine whether the subject can continue in the study.  The investigator 
or qualified designee is responsible for determining if any change in subject management is 
needed and must document his/her review of the ECG printed at the time of evaluation from at 
least 1 of the replicate ECGs from each time point.
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will perform a basic quality control check (for example, 
demographics and study details) then store the ECGs in a database.  At a future time, the stored 
ECG data may be overread at the central ECG laboratory for further evaluation of machine-read 
measurements or to meet regulatory requirements.
The machine-read ECG intervals and heart rate may be used for data analysis and report writing 
purposes unless a cardiologist overread of the ECGs is conducted prior to completion of the final 
study report (in which case the overread data would be used).


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10.5.4. Safety Monitoring
The Lilly clinical pharmacologist or clinical research physician/scientist will monitor safety data 
throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly clinical 
pharmacologist or research physician 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 including monitoring of incidence of and nature of any infections, infusion reactions, 
and injection-site reactions
10.5.5. Complaint Handling
Lilly collects product complaints on IPs and drug delivery systems used in clinical trials in order 
to ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements.
Complaints related to unblinded comparator drugs or concomitant drugs/drug delivery systems 
are reported directly to the manufacturers of those drugs/devices in accordance with the package 
insert.
For blinded studies, all product complaints associated with material packaged, labeled, and
released by Lilly or its designee will be reported. 
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 using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form 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 form with the product.
10.6. Appropriateness and Consistency of Measurements
For this study, the safety and PK assessments are appropriate and follow standard practice during 
Phase 1 drug development.
10.7. Compliance
Every attempt will be made to select subjects who have the ability to understand and comply 
with instructions.  Noncompliant subjects may be discontinued from the study.  The time and day 
of drug administration will be recorded.  Drug accountability records will be maintained by the 
study site.


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The specifications in this protocol for the timings of safety and PK sampling are given as targets 
to be achieved within reasonable limits.  Modifications may be made to the time points based 
upon the safety and PK information obtained.  The scheduled time points may be subject to 
minor alterations; however, the actual time must be correctly recorded in the CRF.
Any major modifications that might affect the conduct of the study, subject safety, and/or data 
integrity will be detailed in a protocol amendment.


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11.
Sample Size and Data Analyses
11.1. Determination of Sample Size
Up to 60 subjects may be enrolled in order that approximately 50 subjects complete the study.  It 
is intended that 10 subjects (6 Japanese and 4 Caucasian) will be randomized in Cohort 1, and 
8 subjects (4 Japanese and 4 Caucasian) will be randomized in Cohorts 2, 3, 4, 5, and 6.  The 
sample size is customary for Phase 1 studies evaluating safety, tolerability, and PK parameters.  
Subjects who are randomized but not administered treatment or do not provide sufficient safety 
and/or PK data may be replaced if judged necessary by the Lilly clinical pharmacologist. The 
replacement subject should be assigned to the same treatment as the discontinued subject and 
should be Japanese or Caucasian to match the discontinued subject.
11.2. Data Analysis Plans
11.2.1. General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
PK analyses will be conducted on the full analysis set.  This set includes all data from all 
randomized subjects receiving at least one dose of the IP according to the treatment the subjects
actually received.  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.  Analyses 
will be fully detailed in the statistical analysis plan.  Study results may be pooled with the results 
of other studies for population PK analysis purposes to avoid issues with post-hoc analyses and 
incomplete disclosures of analyses.
Data from subjects receiving placebo in the IV cohorts will be pooled to form 1 placebo group.
Data will be also summarized by race (Japanese and Caucasian) where appropriate.
11.2.2. Study Participant Disposition
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.
11.2.3. Study Participant Characteristics
The subject’s age, sex, weight, BMI, height, race/subrace, or other demographic characteristics 
will be recorded and summarized by treatment group as well as overall.


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11.2.4. Pharmacokinetic Analyses
11.2.4.1. Pharmacokinetic Parameter Estimation
PK parameter estimates for LY3074828 will be calculated by standard noncompartmental 
methods of analysis.
The primary parameters for analysis will be Cmax and AUC of LY3074828.  Other 
noncompartmental parameters, such as half-life, clearance, and volume of distribution (apparent 
clearance and apparent volume of distribution for SC administration) may be reported.
11.2.4.2. Pharmacokinetic Statistical Inference
PK parameter estimates following IV administration will be evaluated to delineate effects of 
dose proportionality.  Log-transformed Cmax and AUC estimates will be evaluated in a power 
model with log-transformed dose as the explanatory variable. The treatment differences will be 
back-transformed to present the ratios of geometric means and the corresponding 90%
confidence interval (CI).  Exploratory power model analysis based on the model including race 
and race-by-dose interaction terms will be also performed to examine the effect of the race on 
dose proportionality.
For the SC dose, the bioavailability relative to IV infusion at the same dose will be evaluated via 
a log-transformed model.  The log-transformed Cmax and AUC will be the response variable, and 
route of administration (IV or SC) is the explanatory variable and ratio (SC/IV), and its 90% CI 
will be calculated based on the model to assess the absolute bioavailability.
11.2.5. Pharmacodynamic Analyses
Not applicable.
11.2.6. Pharmacokinetic/Pharmacodynamic Analyses
Not applicable.
11.2.7. Safety Analyses
11.2.7.1. Clinical Evaluation of Safety
All IP 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 IP 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.
11.2.7.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include vital signs, ECG parameters, and safety lab 
parameters.  The parameters will be listed and summarized using standard descriptive statistics.  
Additional analysis will be performed if warranted upon review of the data.


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11.2.7.3. Evaluation of Immunogenicity 
The frequency of antibody formation to LY3074828 and ADA titer will be determined.  If a 
neutralization assay is performed, the frequency of neutralizing antibodies will be determined.  
The relationship between the presence (or absence) of antibodies and clinical parameters (AEs,
etc.) will be assessed.  Likewise, the relationship between the presence of antibodies and PK
parameters will be assessed.
11.3. Interim Analyses
The Lilly study team is unblinded.  Data may be analyzed while the trial is ongoing, but no 
changes to the study design are planned.  An assessment committee will not be formed.
The first interim analysis is scheduled to occur when safety and PK data through Day 15 become
available from at least 8 subjects in Cohort 1 including at least 3 Japanese subjects on 
LY3074828.  All safety and PK data available from other cohorts by this time will be included in 
the interim analysis.  The purpose of the interim analysis is to support the future inclusion of
Japanese subjects in Study AMAC and to determine if dose escalation to 1200 mg should occur.
The investigator and the Lilly study team will review the safety and tolerability data.  The 
investigator will remain blinded and the Lilly study team will be unblinded during this interim 
review.
The data review for dose escalation to 2400 mg will not be included in the interim review.
An additional interim analysis may occur when safety and PK data through Day 15 becomes 
available from at least 6 subjects in Cohort 6, including at least 3 Japanese subjects.  The purpose 
of this interim analysis is to support a future potential higher dosage in Study AMAG.  The 
investigator and the Lilly study team will review the safety and tolerability data.  The 
investigator will remain blinded and the Lilly study team will be unblinded during this interim 
review.
If ADA follow-up described in the Protocol Addendum 1 is needed for subjects in Cohort 6, 
another interim analysis may occur when all procedures of the main protocol for Cohort 6 are 
completed, even if the ADA follow-up is in process.  The investigator and the Lilly study team 
will review all available data.  The investigator will remain blinded and the Lilly study team will 
be unblinded during this interim review.


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12.
Data Management Methods
12.1. Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the CRFs, and study 
procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate CRF data and/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.
12.2. Data Capture Systems
12.2.1. Source Data and Case Report Form
A source document is the first record of data.  These can be paper (for example, ECG tracing or 
patient diary), a paper CRF on which the data is initially recorded, or data captured directly on an 
investigator site electronic system (for example, Holter monitor record data files or electronic 
health record).  The site must retain all source records and must maintain a record of any data 
where source data are directly entered into the paper CRF.
Data may then be entered into either an electronic or paper CRF, and the process will be 
documented and communicated by the sponsor to the investigator site before first patient visit.
Some investigator site data may be collected directly in the paper CRF whereas other data that is 
collected by the site on paper or electronic records may be transferred to the paper CRF.
Lilly does not allow direct source data entry into Lilly computer systems, with the exception of 
the investigator site systems at the Lilly clinical research unit.


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For data handled by a data management TPO, CRF data and some or all data that are related will 
be managed and stored electronically in the TPO system.  Subsequent to the final database lock, 
validated data will be transferred to the sponsor.
For data handled internally, CRF data and some or all data that are related will be managed by 
the sponsor and stored electronically in the sponsor’s system.
12.2.2. Ancillary Data
Data managed by a central vendor will be stored electronically in the central laboratory’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly 
generic labs system and the TPO’s system.
Bioanalytical data will be stored electronically in the bioanalytical laboratory’s database.  Data 
will subsequently be transferred from the bioanalytical laboratory to the Lilly generic labs 
system and the TPO’s system.
ECG data will be stored electronically in the central database system of Lilly’s central review 
organization.  Data will subsequently be transferred from the central review organization system 
to the Lilly generic labs system and the TPO’s system.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


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13.
Informed Consent, Ethical Review, and Regulatory
Considerations
13.1. Informed Consent
The investigator is responsible for ensuring that the subject understands the potential risks and 
benefits of participating in the study, including 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.
The ICF will be used to explain the potential risks and benefits of study participation to the 
subject in simple terms before the subject is entered into the study and to document that the 
subject is satisfied with his or her understanding of the potential risks and benefits of 
participating in the study and desires to participate in the study.
The investigator is ultimately responsible for ensuring that informed consent is given by each 
subject before the study is started.  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 
the IP.
13.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites.  All 
ICFs must be compliant with the International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline on GCP.
The investigator must give assurance that the ERB was properly constituted and convened as 
required by 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.  The ERB(s) will review the protocol as required.
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
13.3. Regulatory Considerations
This study will be conducted in accordance with:
1) consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences
(CIOMS) International Ethical Guidelines 
2) ICH GCP Guideline (E6)
3) applicable laws and regulations


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The investigator or designee will promptly submit the protocol to applicable ERB(s).
Some of the obligations of the sponsor will be assigned to a TPO.
An identification code assigned by the investigator to each subject will be used in lieu of the 
subject’s name to protect the subject’s identity when reporting AEs and/or other trial-related 
data.
13.3.1. Investigator Information
Site-specific contact information may be provided in a separate document.
13.3.2. 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.
13.3.3. 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.


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14.
References
Adedokun OJ, Xu Z, Gasink C, Friedman J, Szapary P, Lang Y, Johanns J, Gao L-L, Miao Y, 
Davis H, Hanauer S, Feagan B, Sandborn W. Pharmacokinetics and exposure-response 
relationships of intravenously administered ustekinumab during induction treatment in patients 
with Crohn’s disease: results from the UNITI-1 and UNITI-2 studies. Oral presentation at: 
11th Congress of European Crohn’s and Colitis Organisation (ECCO): Inflammatory Bowel 
Diseases; Mar 16-19, 2016; Amsterdam: The Netherlands. Oral presentation (OP) 028.
Andersson A, Kokkola R, Wefer J, Erlandsson-Harris H, Harris RA. Differential macrophage 
expression of IL-12 and IL-23 upon innate immune activation defines rat autoimmune 
susceptibility. J Leukoc Biol. 2004;76(6):1118-1124.
Cornelissen F, Asmawidjaja PS, Mus AM, Corneth O, Kikly K, Lubberts E. IL-23 dependent and 
independent stages of experimental arthritis: no clinical effect of therapeutic IL-23p19 
inhibition in collagen-induced arthritis. PLoS One. 2013;8(2):e57553.
Croxford AL, Kulig P, Becher B. IL-12-and IL-23 in health and disease. Cytokine Growth Factor 
Rev. 2014;25(4):415-421.
El-Bassat H, Ali LA, El Yamany S, Al Shenawy H, Al Din RA, Taha A. Interleukin 23 P 19 
expression in patients with ulcerative colitis and its relation to disease severity. J Mol Biomark 
Diagn. 2014;5(5):1000191.
Feagan BG, Sandborn W, Panés J, Ferrante M, Louis E, D’Haens GR, Franchimont D, Kaser A, 
Dewit O, Seidler U, Kim K-J, Neurath M, Scholl P, Visvanathan S, Padula S, Herichova I, 
Soaita A, Hall D, Böcher WO. Efficacy and safety of induction therapy with the selective IL-
23 inhibitor BI 655066, in patients with moderate-to-severe Crohn’s disease: results of a 
randomized, double-blind, placebo-controlled Phase II study. Gastroenterology. 2016;150(4) 
suppl 1:S1266. Abstract 812a.
Gheita TA, El Gazzar II, El-Fishawy HS, Aboul-Ezz MA, Kenawy SA. Involvement of IL-23 in 
enteropathic arthritis patients with inflammatory bowel disease: preliminary results. Clin 
Rheumatol. 2014;33(5):713-717.
Globig AM, Hennecke N, Martin B, Seidl M, Ruf G, Hasselblatt P, Thimme R, Bengsch B. 
Comprehensive intestinal T helper cell profiling reveals specific accumulation of IFN-+IL-
17+coproducing CD4+ T cells in active inflammatory bowel disease. Inflamm Bowel Dis. 
2014;20(12):2321-2329.
Kopp T, Riedl E, Bangert C, Bowman EP, Greisenegger E, Horowitz A, Kittler H, Blumenschein 
WM, McClanahan TK, Marbury T, Zachariae C, Xu D, Hou XS, Mehta A, Zandvliet AS, 
Montgomery D, van Aarle F, Khalilieh S. Clinical improvement in psoriasis with specific 
targeting of interleukin-23. Nature. 2015;521(7551):222-226.
Krueger JG, Ferris LK, Menter A, Wagner F, White A, Visvanathan S, Lalovic B, Aslanyan S,  
Wang EE, Hall D, Solinger A, Padula S, Scholl P.  Anti–IL-23A mAb BI 655066 for treatment 
of moderate-to-severe psoriasis: safety, efficacy, pharmacokinetics, and biomarker results of a 
single-rising-dose, randomized, double-blind, placebo-controlled trial. J Allergy Clin 
Immunol. 2015;136(1);116-124.e7.


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Monteleone I, Pallone F, Monteleone G. Interleukin-23 and Th17 cells in the control of gut 
inflammation. Mediators Inflamm. 2009;2009:297645.
Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, 
Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams 
JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA. Novel 
p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as 
well as distinct from IL-12. Immunity. 2000;13(5):715-725.
Ordás I, Mould DR, Feagan BG, Sandborn WJ. Anti-TNF monoclonal antibodies in 
inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther. 
2012;91(4):635-646.
Ruutu M, Thomas G, Steck R, Degli-Esposti MA, Zinkernagel MS, Alexander K, Velasco J, 
Strutton G, Tran A, Benham H, Rehaume L, Wilson RJ, Kikly K, Davies J, Pettit AR, Brown 
MA, McGuckin MA, Thomas R. β-glucan triggers spondylarthritis and Crohn's disease-like 
ileitis in SKG mice. Arthritis Rheum. 2012;64(7):2211-2222.
Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J, Guzzo C, Sands BE, Hanauer SB,
Targan S, Rutgeerts P, Ghosh S, de Villiers WJ, Panaccione R, Greenberg G, Schreiber S,
Lichtiger S, Feagan BG; CERTIFI Study Group. Ustekinumab induction and maintenance
therapy in refractory Crohn’s disease. N Engl J Med. 2012;367(16):1519-1528.
Sands BE, Chen J, Penney M, Newhold P, Faggioni R, van der Merwe R, Patra K, Klekotka P, 
Pulkstenis E, Drappa J, Gasser RA Jr. A randomized, double-blind placebo-controlled phase 
2a induction study of MEDI2070 (anti-p19 antibody) in patients with active Crohn’s disease 
who have failed anti-TNF antibody therapy. J Crohns Colitis. 2015;9(suppl 1):S15-S16.
Sofen H, Smith S, Matheson RT, Leonardi CL, Calderon C, Brodmerkel C, Li K, Campbell K, 
Marciniak SJ Jr, Wasfi Y, Wang Y, Szapary P, Krueger JG. Guselkumab (an IL-23-specific 
mAb) demonstrates clinical and molecular response in patients with moderate-to-severe 
psoriasis. J Allergy Clin Immunol. 2014;133(4):1032-1040.
Stelara (ustekinumab) [package insert]. Horsham, PA: Janssen Biotech Inc; 2013.
Toussirot E, Michel F, Béreau M, Binda D. Ustekinumab in chronic immune-mediated diseases: 
a review of long term safety and patient improvement. Patient Prefer Adherence. 
2013;7:369-377.
Yarur AJ, Abreu MT, Deshpande AR, Kerman DH, Sussman DA. Therapeutic drug monitoring 
in patients with inflammatory bowel disease. World J Gastroenterol. 2014;20(13):3475-3484.


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Attachment 1.
Protocol AMAD Study Schedule


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Study Schedule Protocol I6T-JE-AMAD
Study Day
Screening
28 days
–2
–1
1
2
4
8
11a
15
22
29
43
57
71
85
ED
Visit Window
± 1 d
± 1 d
± 1 d
± 2 d
± 2 d
± 2 d ± 3 d ± 3 d ± 3 d ±3 d
Informed consent
X
Admission to CRU
X
Discharge from CRU
X
Review/confirm I/E criteria
X
X
Complete medical history
X
LY3074828 or placebo 
administration
X
Weight
X
X
X
X
X
Height
X
Complete physical examination
X
X
X
X
Directed physical examination
X
X
X
X
X
X
X
X
X
X
Chest x-ray
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review preexisting 
conditions/AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (pulse rate, blood 
pressure, and temperature)b,c
X
0, EId, 
2e, 6
0, EId, 
2e, 6
24
72
168
240
336
504
672
1008 1344 1680 2016
X
12-lead ECGsc,f
X
0, EId, 
2e, 6
0, EId, 
2e, 6
24
72
168
240
336
504
672
1008 1344 1680 2016
X
Laboratory Tests
QuantiFERON-TB Gold or TST
X
HIV/HBV/HCV testing
X
FSHg
X
Serum pregnancy testg
X
Urine pregnancy testg
X
X
X
X
X
Serum chemistry, hematology,
and urinalysis
X
X
X
X
X
X
X
X
X
Exploratory storage samples
(serum, plasma, RNA)
X
X
X
X
X
X
X
Pharmacogenetics storage 
sample (DNA)
X


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Study Schedule Protocol I6T-JE-AMAD
Study Day
Screening
28 days
–2
–1
1
2
4
8
11a
15
22
29
43
57
71
85
ED
Visit Window
± 1 d
± 1 d
± 1 d
± 2 d
± 2 d
± 2 d ± 3 d ± 3 d ± 3 d ±3 d
Immunogenicity
X
X
X
X
LY3074828 (PK) 
concentrationh
0, EId, 
2e, 6
24
72
168
240
336
504
672
1008 1344 1680 2016
X
Abbreviations:  0 = predose; AE = adverse event; CRU = clinical research unit; d = day; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ED = early 
discontinuation; EI = end of infusion; FSH = follicle-stimulating hormone; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; I/E = inclusion/exclusion; IL = interleukin; lab = laboratory; PK = pharmacokinetic; TST = tuberculin skin test.
a
Day 11 required for subjects receiving subcutaneous dosing only.
b Vital signs should be taken following an approximate 5-minute rest in supine position. Vital signs on days without dosing should be taken close to the Day 1 
dosing time where possible.
c
Time from starting infusion in hours, with the exception of Day –1.  Time-matched ECGs and vital signs on Day –1 should approximately match the times 
planned on Day 1.  Vital signs and ECG recording should occur prior to PK sampling, except at the end of infusion, at which time PK sampling will occur 
first.
d Required for intravenous cohorts only.  PK samples will be collected precisely at end of infusion.  Vital signs and ECGs should be taken approximately 
10 minutes after the end of infusion.
e
Not done for Cohort 3.
f
ECGs should be taken after an approximate 5-minute rest in supine position. ECGs on days without dosing should be taken close to the Day 1 dosing time, 
where possible. ECGs will be collected in triplicate except for screening visit.
g All female subjects of childbearing potential will have serum pregnancy test at screening.  For women who are considered to be postmenopausal, FSH should 
be drawn to confirm postmenopausal status as defined in inclusion criterion [1b] and to be considered exempt for further pregnancy tests during the study.
h Time from starting infusion in hours.  Samples are requested to be taken at the specified time and on days without dosing should be taken close to the Day 1 
dosing time where possible.  Actual times of doses and samples are to be recorded accurately to the minute on the appropriate forms.


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Attachment 2.
Protocol AMAD Clinical Laboratory Tests
Laboratory Tests 
Hematology:a
Clinical Chemistrya
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Calcium
Mean cell volume 
Glucose fasting
Mean cell hemoglobin 
Blood urea nitrogen (BUN)
Mean cell hemoglobin concentration 
Uric acid 
Leukocytes (WBC)
Total cholesterol
Cell Morphology
Total protein
Absolute counts of:
Albumin
Neutrophils
Total bilirubin
Lymphocytes
Alkaline phosphatase
Monocytes
Aspartate aminotransferase (AST)
Eosinophils
Alanine aminotransferase (ALT)
Basophils
Creatinine
Platelets
Urinalysisa
Ethanol testingc,d
Specific gravity
Urine drug screenc,d
pH
Hepatitis B surface antigenc
Protein
Hepatitis B core antibodyc
Glucose
Hepatitis C antibodyc
Ketones
HIV antibodiesc
Bilirubin
Pregnancy test (seruma and urine)
Urobilinogen
FSHc
Blood
QuantiFERON-TB Gold testa,c
Nitrite
Microscopic examination of sedimentb
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
a
Results will be validated by the local laboratory at the time of initial testing.
b
Test only if dipstick result is abnormal.
c
Performed at screening only.
d
Urine drug screen and ethanol level may be repeated prior to admission to the clinical research unit as per 
judgment of investigator.


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Attachment 3.
Protocol AMAD 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 I6T-JE-AMAD Sampling Summary
Purpose
Maximum Blood Volume 
per Sample (mL)
Maximum Number 
of Blood Samples
Maximum Total 
Volume (mL)
Screening testsa
45
1
45
Clinical laboratory testsa
12.5
7
87.5
Pharmacokinetics
2
15+3
36
Immunogenicity
10
3
30
Pharmacogenetics
10
1
10
Exploratory storage samples 
(serum, plasma, RNA)
14.5
6
87
Total
295.5
Total for clinical purposes
300
a
Additional samples may be drawn if needed for safety purposes.


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Attachment 4.
Protocol AMAD Blinding/Unblinding Plan 
Levels of unblinding are indicated in the table below. This table provides general guidance as to
who will be allowed access to randomization codes at various steps of the trial. The information 
in the protocol will always take precedence over this table.  For interim analysis (IA), 
appropriate IA team members, including statistician, programmer, and data manager will be 
identified and agreed upon between Lilly and the TPO.  
Randomization data are kept strictly confidential and are accessible only by authorized personnel 
until unblinding of the trial as described below.  All measures possible must be taken to maintain 
the blind, which means that access to the randomization code must be restricted to authorized 
personnel as described in the protocol and summarized in the table below.
If there is a need for unblinding of select people from Lilly and/or the TPO who are not dealing 
with the site, the detailed process including formation of the unblinded team, creating restricted 
access electronic folders, and measures taken to guard against inappropriate dissemination of 
treatment codes (for example, by maintaining no contact with the study team until team is 
unblinded) will be described in the unblinding plan or another appropriate document and 
approval sought from Lilly and Covance team statisticians.


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Study I6T-JE-AMAD Blinding and Unblinding Plan
Study Timelines
Study Team Member
Screening
Randomization
Treatment 
Phase
Follow-Up
Database 
Lock
General
Drug supply
NA
U
U
U
U
Randomization statisticians
NA
U
U
U
U
ECG reader (if read later)
NA
B
B
B
B
BioAnalysis lab/sample analysis
NA
U
U
U
U
Clinical Site
Pharmacist
NA
U
U
U
U
Dosing staff
NA
B
B
B
B
Subject
NA
B
B
B
B
Investigator
NA
B
B
B
B
Study monitor 
NA
U
U
U
U
Covance/CDARO
Project integration
NA
U
U
U
U
Data management
NA
U
U
U
U
Programming
NA
U
U
U
U
Statistician
NA
U
U
U
U
Medical writing 
NA
U
U
U
U
Pharmacokinetic scientist/associate
NA
U
U
U
U
Lilly
BioPharm coordinator
NA
U
U
U
U
CPA
NA
U
U
U
U
DSA
NA
U
U
U
U
SDTM core team
NA
U
U
U
U
Statistician
NA
U
U
U
U
Medical writing
NA
U
U
U
U
Clinical pharmacologist
NA
U
U
U
U
Pharmacokinetic scientist/associate
NA
U
U
U
U
Abbreviations:  B = blinded; CPA = clinical pharmacology associate; DSA = data sciences associate; ECG = 
electrocardiogram; NA = not applicable; SDTM = study data tabulation model; U = unblinded.


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Attachment 5.Protocol Amendment I6T-JE-AMAD(a)
Summary: A Single-Dose Study to Assess the Safety, 
Tolerability, and Pharmacokinetics of LY3074828 in 
Japanese and Caucasian Healthy Subjects
Overview
Protocol I6T-JE-AMAD, A Single-Dose Study to Assess the Safety, Tolerability, and 
Pharmacokinetics of LY3074828 in Japanese and Caucasian Healthy Subjects, has been 
amended. The new protocol is indicated by Amendment (a) and will be used to conduct the 
study in place of any preceding version of the protocol.
The overall changes made to this protocol are due to the implementation of Cohort 6, which 
contains the additional higher dose of 2400 mg IV, which will be the new maximum dose in the 
study. Editorial changes and formatting corrections were made throughout the protocol, but not 
necessarily documented below. The rationale for the changes is as follows:
The original protocol assesses the safety, tolerability, and pharmacokinetic profile up to 1200 mg 
IV of LY3074828 in Japanese and Caucasian healthy subjects. Single doses of up to 1200 mg IV 
support the highest dose of 1000 mg IV in Phase 2 studies for patients with ulcerative colitis 
(Study AMAC) and Crohn’s disease (Study AMAG), in that the safety data to date does not 
reveal any dose-related safety or tolerability issues with dose regimens of up to 1000 mg IV 
Q4W for up to 52 weeks.
Dose levels higher than 1000 mg may be required to support the best clinical outcomes in many 
auto-inflammatory disease indications, including IBD. Study 20029153 (4-week repeat-dose 
monkey study) showed the margin of safety for 2400 mg IV to be 1.9-fold. This value is based 
on the predicted exposure at 2400 mg in humans after a single dose compared to the observed 
exposure at 100 mg/kg IV, administered once weekly in monkeys.  In this study, 100 mg/kg, the 
highest dose tested, was the NOAEL.
The 2400-mg IV dose was selected to support potential future studies in patients with ulcerative 
colitis and Crohn’s disease, where higher IV doses (potentially beyond 1200 mg) during 
induction treatment may be required to maximize efficacy. Because the drug is degraded via the 
catabolic pathway (same as IgG) and the amount of drug is much smaller than the endogenous 
IgG in the body, it is unlikely that an unexpected PK profile will be observed after implementing 
a 2400-mg IV dose. 


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The overall changes and rationale for the changes made to this protocol are described in the 
following table:
Amendment Summary for Protocol I6T-JE-AMAD Amendment (a)
Section # and Name
Description of Change
Brief Rationale
Cover page
Approval date removed
New date will be timestamped 
upon approval of protocol 
amendment
Cover page
Cohort 6 added with 2400-mg 
dosage

Single doses of up to 
1200 mg IV to date did not 
reveal any safety or 
tolerability issues. 

Dose levels higher than 
1000 mg may be required to 
support the best clinical 
outcomes in many auto-
inflammatory disease 
indications, including IBD.

Because the drug is 
degraded via the catabolic 
pathway (same as IgG) and 
the amount of drug is much 
smaller than the endogenous 
IgG in the body, it is 
unlikely that an unexpected 
PK profile will be observed 
after implementing a 
2400-mg IV dose. 
2. Synopsis, Number of 
Planned Subjects
Number of planned subjects
increased from 42 to 50
2. Synopsis, Study Design
Cohort 6 added with 2400-mg 
dosage
2. Synopsis, Investigational 
Product, Dosage, and Mode of 
Administration  
Cohort 6 added with 2400-mg 
dosage
2. Synopsis: Evaluation 
Methods
Cohort 6 added (n=8); number of 
planned subjects completing study 
increased from 42 to 50; 
added information regarding a 
possible interim analysis for 
Cohort 6 subjects
Table of Contents: List of 
Attachments, Attachment 5
Protocol amendment section added
Added as per template
5.1 General Introduction
Updated per IB
Consistent with IB
7.1. Summary of Study Design
Cohort 6 added; both Cohorts 5 
and 6 will be dosed after 
confirming the safety and PK from 
Cohort 1 and Cohort 5, 
respectively

Single doses of up to 1200 
mg IV to date did not reveal 
any safety or tolerability 
issues. 

Dose levels higher than 
1000 mg may be required to 
support the best clinical 
outcomes in many auto-
inflammatory disease 
indications, including IBD.

Because the drug is 
degraded via the catabolic 
pathway (same as IgG) and 
the amount of drug is much 
smaller than the endogenous 
IgG in the body, it is 
unlikely that an unexpected 
7.1. Summary of Study 
Design, Figure AMAD.2. 
Study design for Protocol I6T 
JE AMAD.
Cohort 6 added with details 
7.1. Summary of Study 
Design; Treatment
Cohort 6 description added, safety 
and PK assessment added between 
Cohort 1 and 5, then 5 and 6
7.2. Discussion of Design and 
Control
Cohort 6 2400-mg dosage added
8.1.1. Inclusion Criteria
Cohort 6 added to Exclusion 
Criterion [5]
9.2. Treatment Administration; 
New column added to table with 


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Table AMAD. 1.
Cohort 6 description 
PK profile will be observed 
after implementing a 
2400-mg IV dose. 
9.3. Rationale for Selection of 
Dose
Cohort 6 description added, safety 
and PK assessment added between 
Cohort 1 and 5, then 5 and 6
9.3. Rationale for Selection of 
Dose, Table AMAD.2
Cohort 6 added, paragraphs moved 
within this same section and added 
to for readability. Table AMAD.2
updated with 2400-mg dosing 
information
9.4. Dose Escalation
Cohort 6 description added, safety 
and PK assessment added between 
Cohort 1 and 5, then 5 and 6
9.4.1. Dose Escalation Method
11.1. Determination of Sample 
Size
Cohort 6 added, sample size 
increased from 42 subjects to 
50 subjects
11.3 Interim Analyses
Interim analysis information added 
for Cohort 6
Cohort 6 added 
14. References
References added
References added to reflect 
higher dosing


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LY3074828
Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Amendment Summary for Protocol I6T-JE-AMAD Amendment (a)
Section # and Name
Additions and Deletions
Cover page
The study will consist of 5 6 planned dose cohorts:  4 5
intravenous cohorts (60 mg, 200 mg, 600 mg, and 1200 mg,
and 2400 mg) 
Cover page
Approval Date: 11-Aug-2015 GMT
2. Synopsis, Number of Planned 
Subjects
approximately 4250
2. Synopsis, Study Design
The study will consist of 5 6 planned dose cohorts:  4 5 IV 
cohorts (60 mg, 200 mg, 600 mg, and 1200 mg, and 2400 
mg) and 1 SC cohort (200 mg).  
2. Synopsis, Investigational Product, 
Dosage, and Mode of Administration  
A single dose of LY3074828 will be administered IV at the 
planned dose levels of 60 mg, 200 mg, 600 mg, and 1200 mg, 
and 2400 mg.  
2. Synopsis: Evaluation Methods
Up to 60 subjects may be enrolled in order that approximately 
42 50 subjects complete the study.  It is intended that 10 
subjects (6 Japanese and 4 Caucasian) will be randomized in 
Cohort 1, and 8 subjects (4 Japanese and 4 Caucasian) will be 
randomized in Cohorts 2, 3, 4,5, and 56. 
…
The first iInterim analysis is scheduled to occur when safety 
and PK data through Day 15 become available from at least 
8 subjects in Cohort 1, including at least 3 Japanese subjects 
on LY3074828.  An additional interim analysis may occur 
when safety and PK data through Day 15 becomes available 
from at least 6 subjects in Cohort 6, including at least 
3 Japanese subjects on LY3074828. 
Table of Contents: List of Attachments, 
Attachment 5
List of Attachments 
Attachment 5. Protocol Amendment I6T-JE-AMAD 
Summary: A Single-Dose Study to Assess the Safety, 
Tolerability, and Pharmacokinetics of LY3074828 in 
Japanese and Caucasian Healthy Subjects…..58
5.1 General Introduction
…
The first such biologic to demonstrate clinical benefit in 
autoimmune disease was ustekinumab, which is now an 
approved medicine for the treatment of patients with psoriasis 
and psoriatic arthritis (Stelara package insert, 2013) and is 
being evaluated in Phase 3 trials for treatment of CD 
(Toussirot et al. 2013).  
...
One study, Study I6T-MC-AMAA (AMAA): A Phase 1, 
Randomized, Placebo-Controlled Study of LY3074828, an 
Anti-IL-23 Humanized Antibody in Subjects With and 


I6T-JE-AMAD(a) Protocol
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LY3074828
Without Psoriasis, has been completed conducted to 
dateevaluating.  This study evaluated LY3074828 in healthy 
volunteers and in subjects with plaque psoriasis.  
...

No deaths, serious adverse events (SAEs), or 
discontinuations due to an adverse event (AE) were 
reported.  

Preliminary data from subjects administered single 
doses of up to 600 mg IV indicate that LY3074828 
has linear pharmacokinetics (PK), a low IV 
clearance (approximately 0.02 L/h), and long half-
life (~10 days), all of which are consistent with 
expectations for a monoclonal antibody.  SC 
bioavailability was 40% to 50%.

Treatment-emergent antidrug antibodies (ADAs) 
developed in 3 subjects after administration of single 
IV doses of LY3074828, (120 mg, 2 subjects; 350 
mg, 1 subject).  No subject had ADAs after SC 
administration.  There was no correlation between 
ADA titers and the doses of LY3074828.

There have not yet been any studies conducted for 
LY3074828 with efficacy as a primary objective.  
However, Following single IV doses of LY3074828 
in Study AMAA, the area under the curve (AUC) 
and maximum drug concentration (Cmax) increased in 
approximately a dose-proportional manner.  The 
mean terminal phase half-life across all IV doses 
was 10.5 days and did not appear to be dependent on 
dose, and the mean clearance is within the range 
expected for human monoclonal antibodies.  The 
overall mean clearance across all doses following IV 
administration was approximately 0.526 L/day and 
is within the range expected for human monoclonal 
antibodies.  Maximum concentrations were observed 
3 days postdose following SC administration.  Based 
on the AUC, the SC bioavailability was 40% relative 
to IV administration.

Immunogenicity evaluations were performed in 
Study AMAA.  Blood samples to evaluate anti-drug 
antibodies (ADA) were collected at baseline and 
approximately 22, 43, and 85 days postdose.  ADA 
data were available for 45 subjects, 38 who received 
LY3074828 and 7 who received placebo.  All 
subjects who received placebo were ADA negative 
at baseline and postbaseline.  Only one subject who 
received LY3074828 was positive at baseline.  
Thirty-one subjects who received LY3074828 


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LY3074828
(81.6%) were negative at all postbaseline time points 
evaluated.  Seven subjects who received LY3074828 
had a postbaseline positive titer; however, only 3 of 
those subjects (7.9% of LY3074828-treated 
individuals) developed treatment-emergent ADA, 
defined as a 4-fold or greater change in titer from 
baseline.  None of these cases of treatment-emergent 
anti-drug antibodies (TE-ADA) were associated with 
treatment-emergent adverse events (TEAEs).
…
Phase 2 studies investigating the efficacy of LY3074828 as a 
potential treatment for psoriasis (AMAF), ulcerative colitis 
(AMAC), and Crohn’s disease (AMAG) are currently 
ongoing.  However, Iin Study AMAA, clinical activity was 
explored…
…
Information on AEs expected to be related to the IP may be 
found in Section 7 6 (Development Core Safety Information) 
of the IB.   
7.1. Summary of Study Design
Subjects will be randomized to LY3074828 or placebo within
1 of 56 cohorts, as shown in Figure AMAD.2.
…
Cohorts 2 through 5 6 will consist of 8 subjects (4 Japanese 
and 4 Caucasian) who are randomized in a 3:1 ratio of 
LY3074828 to placebo.
…
Single doses up to 600 mg IV have been studied and shown 
to be well tolerated, therefore all cohorts, with the exception 
of Cohort 5 and Cohort 6, may be dosed in parallel if the site 
is able to accommodate more than 1 cohort at a time.  Cohort 
5 will be dosed after confirming the safety and PK data from 
Cohort 1.  Cohort 6 will be dosed last after confirming the 
safety and PK data from Cohort 1 5.  
7.1. Summary of Study Design, Figure 
AMAD.2. 
Cohort 6 added, arrow showing safety and PK assessment 
between Cohort 1 and 5, then 5 and 6
7.1. Summary of Study Design; 
Treatment
…
Treatment:
…
Cohort 6: a single dose of LY3074828 2400 mg or placebo 
IV
7.2 Discussion of Design and Control
The dose levels included in this single-dose study are within 
the range of doses studied previously, with the exception of 
the planned 1200 mg and 2400 mg IV dose cohort, for which 
the expected exposure has an appropriate safety margin based 
on the preclinical toxicity data (see Section 9.3 for additional 
information).
8.1.1. Inclusion Criteria
[5] have a body weight of 40.0 kg or higher for Cohorts 1 to 4 
and 48.0 kg or higher for Cohort 5 and Cohort 6


I6T-JE-AMAD(a) Protocol
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9.2. Treatment Administration; Table 
AMAD. 1.
Cohort 6, 2400 mg IV; 25 mg/mL, 96 mL
9.3. Rationale for Selection of Dose
The 4 5 IV doses for this study are 60, 200, 600, and 1200, 
and 2400 mg and the SC dose for this study is 200 mg.
…
The low dose of 60 mg IV for this study is was chosen as one 
of the doses that was administered in the global…
...
The 200-mg IV dose is one of the starting doses in Study 
AMAC and is one of the doses that was administered in 
Study AMAA.  It is also the SC dose that will A dose of 200 
mg SC is being administered in the maintenance period of 
Study AMAC.
The 600-mg IV dose is the highest dose being tested in Study 
AMAC and is the highest dose that was administered in 
Study AMAA.
The original highest dose of 1200 mg, IV was tested for 
safety and tolerability, based on the safety results at each 
escalation cohort of this study. Findings from these results 
supported the highest dose of 1000 mg IV in the Phase 2 
Crohn’s disease study (Study AMAG).
The amended maximum dose of 2400 mg IV is selected to 
support potential future studies in patients with ulcerative 
colitis and Crohn’s disease, where high IV doses (potentially 
beyond 1200 mg) during induction treatment may be required 
to maximize efficacy (Sandborn et al. 2012; Adedokun et al. 
2016; Feagan et al. 2016). 
The margin of safety at 2400 mg IV is 1.9-fold.  This value is 
based on the predicted exposure at 2400 mg compared to the 
observed exposure at 100 mg/kg IV, administered once 
weekly, in the 4-week, repeat-dose monkey study.  In this 
study, 100 mg/kg was the no observed adverse-effect level 
(NOAEL) and also the highest dose tested. (see Table 
AMAD.2).
…
Due to a lack of a preclinical disease model, the anticipated 
minimally effective dose for LY3074828 is unknown.  The 
clinical dose range for LY3074828 is not yet known, and the 
maximum planned LY3074828 dose level to be evaluated in
the Phase 2 ulcerative colitis Study AMAC is 600 mg.  
…
Therefore, this study plansplanned to evaluate the safety, 
tolerability, and PK of a 1200-mg IV dose of LY3074828.  
Evaluation of this additional higher dose cohort will provide 
safety and PK data to support the use of a higher dose level in 


I6T-JE-AMAD(a) Protocol
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LY3074828
later clinical development.  The 1200-mg dose cohort (Cohort 
5) will be dosed after safety, tolerability, and PK data are 
confirmed from the 600-mg dose cohort (Cohort 1).  A 2 fold 
dose escalation will provide the most informative PK data, as 
there is minimal overlap between the 600-mg and 1200-mg 
doses on the basis of data obtained from simulations.  Other 
dose levels may be dosed concurrently in this study because 
these doses have already been shown to be well tolerated in 
Study AMAA.  As shown in Table AMAD.2, the proposed 
maximum dose of 1200 mg IV infusion has a sufficient 
margin of safety both in terms of dose and exposure. The 
1200-mg IV dose cohort (Cohort 5) was dosed after safety, 
tolerability, and PK data were confirmed from the 600-mg 
dose cohort (Cohort 1). Other dose levels wereas dosed 
concurrently in this study because these doses have already 
been shown to be well tolerated in Study AMAA.  Evaluation 
of 1200-mg IV dose cohort (Cohort 5) provided safety and 
PK data to support the use of a higher dose level in Study 
AMAC and Study AMAG. 
In addition to the above evaluation, this study is amended to 
add the evaluation of safety, tolerability, and PK of a 2400-
mg IV dose of LY3074828, since there is a possibility to 
evaluate a higher dose level up to 2400 mg IV in later clinical 
development.  The proposed dose of 2400 mg IV infusion has 
a sufficient margin of safety in terms of dose.  Moreover, the 
clinical safety profile of LY3074828 available to date 
supports 2400-mg IV administration in this study.  Single 
doses of up to 1200 mg IV were evaluated in healthy subjects 
from Study AMAD and no dose-related safety or tolerability 
issues were observed.  Evaluation of the safety data available 
to date in the ongoing Study AMAC and Study AMAG that 
are evaluating higher and more frequent dose regimens of up 
to 1000 mg IV Q4W for up to 52 weeks has not revealed any 
differences in the safety profile.  The PK profile of this drug 
was found to be approximately linear up to 1200-mg IV 
administration.  Since the 2400-mg IV dose is only 2-fold of 
1200 mg, it is unlikely that an unexpected PK profile will be 
observed after administration of a 2400-mg IV dose.  
Therefore, evaluation of this additional higher dose cohort 
(2400 mg) will provide safety and PK data to support the use 
of a higher dose level beyond 1200 mg during the clinical 
development of this compound.
9.3. Rationale for Selection of Dose, 
Table  AMAD.2
[Title]: Margin of Safety for Intravenous Administration of 
1200 2400 mg
Human highest dose: (1200 2400 mg):
Dose: 18.5 36.9 (IV); AUC0-672h,ss 53800 110000


I6T-JE-AMAD(a) Protocol
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LY3074828
Monkey NOAELd 6-month study: Dose Multiple: 5.4 2.7; 
Margin of Safety: 1.6 0.78
Monkey NOAELd: Dose Multiple: 5.4 2.7; Margin of Safety:
3.8 1.9
Footnote c:… Human AUC0-672h,ss at 1200 2400 mg IV is 
predicted on the basis of the average IV clearance 
(0.526L/day) observed in from Study I6T-MC-AMAA.  
for doses between 5 mg and 350 mg.  
9.4. Dose Escalation
All doses in this study, with the exception of the 1200-mg 
and 2400-mg doses, have been previously tested and shown 
to be well tolerated in Study AMAA.  The only dose 
escalation decisions in this study will be made to proceed 
from the 600-mg cohort (Cohort 1) to the 1200-mg cohort 
(Cohort 5) and the 600 1200-mg cohort (Cohort 1 5) to the 
1200 2400-mg dose cohort (Cohort 5 6).  Safety and PK data 
reviewed at the time of the first interim analysis will be used
for the escalation decision to the 1200-mg dose. Safety and 
PK data up to the 1200-mg dose cohort will be reviewed 
before dose escalation to 2400 mg.  
9.4.1. Dose Escalation Method
…
After review of the data, an agreement on the appropriate 
dose escalation will be made by the investigator and sponsor 
for the 1200-mg cohort (Cohort 56).  The planned dose for 
Cohort 5 is 1200  mg, but depending on the observations 
from the 600 mg cohort (Cohort 1), the magnitude of the dose 
escalation may be reduced following data review;  the 
maximum dose for the study will be 1200  mg.  
If any of the following scenarios occur at 600 mg 
LY3074828, dose escalation to 1200  mg will not take place, 
and the dose for Cohort 5  may be reduced or the cohort will 
be canceled:
None of the following scenarios occurred at 1200-mg 
LY3074828,
11.1. Determination of Sample Size
Up to 60 subjects may be enrolled in order that approximately 
42 50 subjects complete the study.  It is intended that 10 
subjects (6 Japanese and 4 Caucasian) will be randomized in 
Cohort 1, and 8 subjects (4 Japanese and 4 Caucasian) will be 
randomized in Cohorts 2, 3, 4, and 5, and 6.  
11.3 Interim Analyses
The first Iinterim analysis is scheduled to occur when when 
safety and PK data through Day 15 become available …
…
The data review for dose escalation to 2400 mg will not be 
included in the interim review.
An additional interim analysis may occur when safety and PK 
data through Day 15 becomes available from at least 6 
subjects in Cohort 6, including at least 3 Japanese subjects.  
The purpose of this interim analysis is to support a future 


I6T-JE-AMAD(a) Protocol
Page 67
LY3074828
potential higher dosage in Study AMAG.  The investigator 
and the Lilly study team will review the safety and 
tolerability data.  The investigator will remain blinded and the 
Lilly study team will be unblinded during this interim review.
If ADA follow-up described in the Protocol Addendum 1 is 
needed for subjects in Cohort 6, another interim analysis may 
occur when all procedures of the main protocol for Cohort 6 
are completed, even if the ADA follow-up is in process.  The 
investigator and the Lilly study team will review all available 
data.  The investigator will remain blinded and the Lilly study 
team will be unblinded during this interim review. 
14. References
Adedokun OJ, Xu Z, Gasink C, Friedman J, Szapary P, Lang 
Y, Johanns J, Gao L-L, Miao Y, Davis H, Hanauer S, Feagan 
B, Sandborn W. Pharmacokinetics and exposure-response 
relationships of intravenously administered ustekinumab 
during induction treatment in patients with Crohn’s disease: 
results from the UNITI-1 and UNITI-2 studies. Oral 
presentation at: 11th Congress of European Crohn’s and 
Colitis Organisation (ECCO): Inflammatory Bowel Diseases; 
Mar 16-19, 2016; Amsterdam: The Netherlands. Oral 
presentation (OP) 028.
…
Feagan BG, Sandborn W, Panés J, Ferrante M, Louis E, 
D’Haens GR, Franchimont D, Kaser A, Dewit O, Seidler U, 
Kim K-J, Neurath M, Scholl P, Visvanathan S, Padula S, 
Herichova I, Soaita A, Hall D, Böcher WO. Efficacy and 
safety of induction therapy with the selective IL-23 inhibitor 
BI 655066, in patients with moderate-to-severe Crohn’s 
disease: results of a randomized, double-blind, placebo-
controlled Phase II study. Gastroenterology. 2016;150(4) 
suppl 1:S1266. Abstract 812a.
…
Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J, 
Guzzo C, Sands BE, Hanauer SB, Targan S, Rutgeerts P, 
Ghosh S, de Villiers WJ, Panaccione R, Greenberg G, 
Schreiber S, Lichtiger S, Feagan BG; CERTIFI Study Group. 
Ustekinumab induction and maintenance therapy in refractory 
Crohn’s disease. N Engl J Med. 2012;367(16):1519-1528.


Leo Document ID = fd22d648-6b60-4d2c-ade1-38a575f42ba1
Approver: 
Approval Date & Time: 23-Jan-2018 03:00:15 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 23-Jan-2018 14:08:22 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
 
I6T-JE-AMAD Statistical Analysis Plan 
 
 
A Single-Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of LY3074828 in 
Japanese and Caucasian Healthy Subjects. 
 
NCT02568423 
 
 Date: 03-May-2018 
 


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             Page 1 of 12
STATISTICAL ANALYSIS PLAN
A Single-Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of 
LY3074828 in Japanese and Caucasian Healthy Subjects
Statistical Analysis Plan Status:  Final Version 2
Statistical Analysis Plan Date:  25 April 2018
Study Drug: LY3074828
Sponsor Reference:  I6T-JE-AMAD
Covance CRU Study: 1001215-8326494
Clinical Phase I
Approval Date: 03-May-2018 GMT


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8326494
Sponsor Reference I6T-JE-AMAD
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS .....................................................................................................2
2.
ABBREVIATIONS..............................................................................................................3
3.
INTRODUCTION ...............................................................................................................4
4.
STUDY OBJECTIVES........................................................................................................4
Primary Objective ..................................................................................................................4
Secondary Objectives.............................................................................................................4
5.
STUDY DESIGN.................................................................................................................5
6.
TREATMENTS...................................................................................................................6
7.
SAMPLE SIZE JUSTIFICATION .......................................................................................6
8.
DEFINITION OF ANALYSIS POPULATIONS..................................................................7
9.
STATISTICAL METHODOLOGY .....................................................................................7
9.1
General..........................................................................................................................7
9.2
Demographics and Subject Disposition..........................................................................8
9.3
Pharmacokinetic Assessment.........................................................................................8
9.3.1
Pharmacokinetic Analysis.....................................................................................8
9.3.2
Pharmacokinetic Statistical Methodology .............................................................8
9.4
Safety and Tolerability Assessments..............................................................................9
9.4.1
Adverse events .....................................................................................................9
9.4.2
Concomitant medication.......................................................................................9
9.4.3
Clinical laboratory parameters..............................................................................9
9.4.4
Immunogenicity .................................................................................................10
9.4.5
Vital signs ..........................................................................................................10
9.4.6
Electrocardiogram (ECG)...................................................................................10
9.4.7
Other assessments...............................................................................................10
9.4.8
Safety and Tolerability Statistical Methodology..................................................10
10. INTERIM ANALYSES .....................................................................................................11
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............11
12. REFERENCES ..................................................................................................................11
13. DATA PRESENTATION ..................................................................................................11
13.1 Derived Parameters .....................................................................................................11
13.2 Missing Data ...............................................................................................................12
13.3 Insufficient Data for Presentation ................................................................................12


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8326494
Sponsor Reference I6T-JE-AMAD
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
ADA
Antidrug antibody
AE
Adverse event
AUC
Area under the concentration versus time curve
AUC(0-∞)
Area under the concentration versus time curve from zero to infinity
BMI
Body Mass Index
Cmax
Maximum observed drug concentration
CI
Confidence Interval
CRF
Case Report Form
CSR
Clinical Study Report
CRU
Clinical Research Unit
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
FU
Follow Up
ICH
International Conference on Harmonisation
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard deviation 
TFLs
Tables, Figures, and Listings
WHO
World Health Organization


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8326494
Sponsor Reference I6T-JE-AMAD
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
11 August 2015), and Amendment (a) (final version dated 23 January 2018).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) data 
from this study. A detailed description of the planned TFLs to be presented in the clinical study 
report (CSR) is provided in the accompanying TFL shell document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Eli Lilly and Company and Covance Early Clinical (EC) Biometrics. A 
limited amount of information concerning this study (e.g., objectives, study design) is given to 
help the reader’s interpretation. This SAP must be signed off prior to first subject administration
for this study. When the SAP and TFL shells are agreed upon and finalized, they will serve as 
the template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and Covance EC Biometrics and identified in the CSR. Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
Primary Objective
The primary objective is to explore the safety and tolerability of LY3074828 in healthy Japanese 
and Caucasian subjects to define an appropriate dose for further clinical research in Japan.
Secondary Objectives
The secondary objectives of this study are

to estimate the PK parameters of LY3074828 following intravenous (IV) and 
subcutaneous (SC) administration in healthy Japanese and Caucasian subjects.

to explore the safety, tolerability, and PK of LY3074828 in Japanese subjects in relation 
to Caucasian subjects.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8326494
Sponsor Reference I6T-JE-AMAD
5. STUDY DESIGN
This is a single-site, subject- and investigator-blind, randomized, placebo-controlled, single-dose
study to assess the safety, tolerability, and PK of LY3074828 in Japanese and Caucasian healthy
subjects. Subjects will be randomized to LY3074828 or placebo within 1 of 6 cohorts, as shown
in Figure 1. Cohort 1 will consist of 10 subjects (6 Japanese and 4 Caucasian) who will be 
randomized so that 5 Japanese subjects and 3 Caucasian subjects will receive LY3074828 while 
1 Japanese subject and 1 Caucasian subject will receive placebo. Cohorts 2 through 6 will
consist of 8 subjects (4 Japanese and 4 Caucasian) who are randomized in a 3:1 ratio of
LY3074828 to placebo. For each cohort, 3 Japanese subjects and 3 Caucasian subjects will
receive LY3074828 while 1 Japanese subject and 1 Caucasian subject will receive placebo.
Single doses up to 600 mg IV have been studied and shown to be well tolerated, therefore all
cohorts, with the exception of Cohort 5 and Cohort 6, may be dosed in parallel if the site is able 
to accommodate more than 1 cohort at a time. Cohort 5 will be dosed after confirming the safety 
and PK data from Cohort 1. Cohort 6 will be dosed last after confirming the safety and PK data 
from Cohort 5. Two additional Japanese subjects will be included in Cohort 1 to ensure that a 
sufficient number of Japanese subjects will have received LY3074828 at the time of the interim 
analysis. An interim analysis is planned based on Cohort 1 data through Day 15 to support 
Japanese patients being included in the planned global Phase 2 study, Study I6T-MC-AMAC 
(AMAC).
Abbreviations: FU = follow up; IV = intravenous; SC = subcutaneous
Figure. 1   Study design


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8326494
Sponsor Reference I6T-JE-AMAD
Treatment
Five IV dose levels and 1 SC dose level of LY3074828 will be assessed in Cohorts 1 through 6.
The following treatments are planned:
Cohort 1: a single dose of LY3074828 600 mg or placebo IV
Cohort 2: a single dose of LY3074828 200 mg or placebo IV
Cohort 3: a single dose of LY3074828 200 mg or placebo SC
Cohort 4: a single dose of LY3074828 60 mg or placebo IV
Cohort 5: a single dose of LY3074828 1200 mg or placebo IV
Cohort 6: a single dose of LY3074828 2400 mg or placebo IV
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Study Treatment Name
Treatment order in TFL
Placebo SC
1
Placebo IV
2
Pooled Placebo
3
60 mg LY3074828 IV
4
200 mg LY3074828 SC
5
200 mg LY3074828 IV
6
600 mg LY3074828 IV
7
1200 mg LY3074828 IV
8
2400 mg LY3074828 IV
9
Pooled LY3074828
10
7. SAMPLE SIZE JUSTIFICATION
Up to 60 subjects may be enrolled in order that approximately 50 subjects complete the study. It
is intended that 10 subjects (6 Japanese and 4 Caucasian) will be randomized in Cohort 1, and 8 
subjects (4 Japanese and 4 Caucasian) will be randomized in Cohorts 2, 3, 4, 5, and 6. The
sample size is customary for Phase 1 studies evaluating safety, tolerability, and PK parameters.  


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8326494
Sponsor Reference I6T-JE-AMAD
Subjects who are randomized but not administered treatment or do not provide sufficient safety
and/or PK data may be replaced if judged necessary by the Lilly clinical pharmacologist. The
replacement subject should be assigned to the same treatment as the discontinued subject and
should be Japanese or Caucasian to match the discontinued subject.
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 data from all randomized subjects receiving 
at least one dose of the study drug according to the treatment the subjects actually received.  
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: area under the concentration 
versus time curve [AUCs] and 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 from subjects receiving placebo in the IV cohorts will be pooled to form 1 placebo group. 
Data will be also summarized by population (overall, Japanese and Caucasian) where 
appropriate. The clinical chemistry and hematology, vital signs, and electrocardiogram (ECG) 
data will only be summarized by population if a trend is observed.
Data analysis will be performed using SAS® Version 9.4.


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Covance Clinical Study No. 8326494
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9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, population, ethnicity,
race, body weight, height and body mass index (BMI) will be summarized by population and 
treatment and listed.  All other demographic data will be listed only.
9.3
Pharmacokinetic Assessment
9.3.1 Pharmacokinetic Analysis
The PK parameter estimates for LY3074828 will be calculated by standard noncompartmental 
methods of analysis.
The primary parameters for analysis will be Cmax and area under the concentration versus time 
curve from zero to infinity [AUC(0-∞)]  of LY3074828.  Other noncompartmental parameters, 
such as half-life, clearance, and volume of distribution (apparent clearance and apparent volume 
of distribution for SC administration) may be reported.
9.3.2 Pharmacokinetic Statistical Methodology
The PK parameter estimates following IV administration will be evaluated to delineate effects of 
dose proportionality.  Log-transformed Cmax and AUC(0-∞) estimates will be evaluated in a 
power model with log-transformed dose as the explanatory variable.  The treatment differences 
will be back-transformed to present the ratios of geometric means and the corresponding 90% 
confidence interval (CI). 
Example SAS code 1:
proc mixed data=pk;
    by parameter;
    model lpk = ldose / alpha=0.1 residual ddfm=kr;
    estimate 'xx mg' intercept 1 ldose yy / cl; /* Log value of xx */
    estimate 'zz mg - xx mg' ldose pp / alpha=0.1 cl; /* Difference in 
log values of zz and xx */
    ods output solutionf=est;
    ods output estimates=estims;
run;
The above analysis will also be repeated for each population separately to examine the effect of 
the population on dose proportionality.
For the SC dose, the bioavailability relative to IV infusion at the same dose will be evaluated via 
a log-transformed model.  The log-transformed Cmax and AUC(0-∞) will be the response 
variables, and route of administration (IV or SC) is the explanatory variable and ratio (SC/IV), 
and its 90% CI will be calculated based on the model to assess the absolute bioavailability.
Example SAS code 2:
proc mixed data=pk;


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Covance Clinical Study No. 8326494
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    by parameter;
    class route;
    model log_pk = route / residual ddfm=kr;
    lsmeans route / alpha=0.1 cl pdiff;
    ods output lsmeans=lsmeans;
    ods output diffs=diffs;
run;
Additional analysis will be conducted if deemed appropriate.
9.4
Safety and Tolerability Assessments
9.4.1 Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (AE) will be reported in the listings, only the most severe will be used in the 
summary tables. A pre-existing condition is defined as an AE that starts before the subject has 
provided written informed consent and is ongoing at consent. A non-treatment emergent AE is 
defined as an AE which starts after informed consent but prior to dosing. A treatment-emergent 
AE is defined as an AE which occurs postdose or which is present prior to dosing and becomes 
more severe postdose.
All AEs will be listed.  Treatment-emergent AEs will be summarized by population, treatment, 
severity and relationship to the study drug. The frequency (the number of AEs, the number of 
subjects experiencing an AE and the percentage of subjects experiencing an AE) of 
treatment-emergent AEs will be summarized by population, treatment, Medical Dictionary for 
Regulatory Activities (MedDRA) version 18.0 system organ class and preferred term. The 
summary and frequency AE tables will be presented for all causalities and those considered 
related to the study drug. Any serious AEs will be tabulated.
9.4.2 Concomitant medication
Concomitant medication will be coded using the World Health Organization (WHO) drug 
dictionary (Version March 2015).  Concomitant medication will be listed.
9.4.3 Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by parameter and treatment
together with changes from baseline, where baseline is defined as Day -1.  Individual values for 
clinical chemistry, hematology and urinalysis data will be listed.  Additionally clinical chemistry, 
hematology and urinalysis data outside the reference ranges will be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.


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Covance Clinical Study No. 8326494
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9.4.4 Immunogenicity
Immunogenicity data will be listed and the frequency of positive results will be summarized.  
Overlaying individual profiles of titer values will also be presented over time.
9.4.5 Vital signs
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as Day 1, predose. Figures of mean vital signs and mean changes from 
baseline profiles by treatment will be presented by treatment. Furthermore, values for individual 
subjects will be listed.
9.4.6 Electrocardiogram (ECG)
The ECG data will be obtained directly from the 12-lead ECG traces.  These data include the PR,
RR, QT, QTcB intervals, QRS duration and heart rate, where QTcB is the QT interval corrected 
using Bazett’s formula. In addition, QTcF (the QT interval corrected using Fridericia’s formula) 
will be calculated as follows:


3 60HR
QT
QTcF 
The ECG data will be summarized by treatment together with changes from baseline, where 
baseline is defined as Day 1 predose.  Figures of mean ECG data and mean changes from 
baseline will be presented by treatment.  The frequency of subjects with a maximum increase 
from baseline in QTcB and QTcF interval will be summarized for each treatment according to 
the following categories: >30 ms and >60 ms.  In addition, the frequency of subjects with QTcB 
and QTcF postdose values, according to the following categories: >450 ms, >480 ms and >500 
ms, will be summarized by treatment. 
The relationship between concentrations of LY3074828 and changes from baseline QTcF 
(ΔQTcF) will be explored to assess the effect of LY3074828 concentration on the ΔQTcF.  
Where results are taken in triplicate, the mean of the measurements will be used in the analysis.  
A scatter plot of the change from baseline in QTcF versus the concentrations with the fitted lines 
will be plotted.  A linear mixed-effects model will be fitted with the ΔQTcF as the response, the 
time-matched concentration as a covariate and subject as a random effect.  The intercept and 
slope from the model along with their 90% CI will be reported.
9.4.7 Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.4.8 Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.


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Covance Clinical Study No. 8326494
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10.
INTERIM ANALYSES
The frist interim analysis is scheduled to occur when safety and PK data through Day 15 become 
available from at least 8 subjects in Cohort 1 including at least 3 Japanese subjects on 
LY3074828.  All safety and PK data available from other cohorts by this time will be included in 
the interim analysis.  The purpose of the interim analysis is to support the future inclusion of 
Japanese subjects in Study AMAC and to determine if dose escalation to 1200 mg should occur. 
The investigator and the Lilly study team will review the safety and tolerability data. The 
investigator will remain blinded and the Lilly study team will be unblinded during this interim 
review.
The data review for dose escalation to 2400 mg will not be included in the interim review.  
An additional interim analysis may occur when safety and PK data through Day 15 becomes 
available from at least 6 subjects in Cohort 6, including at least 3 Japanese subjects.  The purpose 
of this interim analysis is to support a future potential higher dosage in Study AMAG. The 
investigator and the Lilly study team will review the safety and tolerability data.  The 
investigator will remain blinded and the Lilly study team will be unblinded during this interim 
review.  
If antidrug antibody (ADA) follow-up described in the Protocol Addendum 1 is needed for 
subjects in Cohort 6, another interim analysis may occur when all procedures of the main 
protocol for Cohort 6 are completed, even if the ADA follow-up is in process. The investigator 
and the Lilly study team will review all available data. The investigator will remain blinded and 
the Lilly study team will be unblinded during this interim review.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received.  N and percentage 


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Covance Clinical Study No. 8326494
Sponsor Reference I6T-JE-AMAD
values should be reported as whole numbers.  Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings and will be treated as missing for calculation of 
descriptive statistics.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = 3d205509-ddfc-479a-a8c7-0d616985ed4f
Approver: 
Approval Date & Time: 03-May-2018 10:50:19 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 03-May-2018 10:50:19 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 03-May-2018 10:50:19 GMT
Signature meaning: Approved
PPD
PPD
PPD