Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 66
Healthy volunteers: yes

Brief summary:
The purpose of this study is to learn about the effects of LY3074828 when given as an injection just under the skin by two different devices. The study will last about 12 weeks for each participant.

Detailed description:

Arms:
arm 1: Reference 1: Participants received 125 mg LY3074828 solution formulation subcutaneously (SC) via 1-mL pre-filled syringe (PFS) administered in the arm.

Reference 2: Participants received 125 mg LY3074828 solution formulation SC via 1-mL PFS administered in the thigh.

Reference 3: Participants received 125 mg LY3074828 solution formulation SC via 1-mL PFS administered in the abdomen. arm 2: Test 1: Participants received 125 mg LY3074828 solution formulation SC via 1-mL Autoinjector (AI) administered in the arm.

Test 2: Participants received 125 mg LY3074828 solution formulation SC via 1-mL AI administered in the thigh.

Test 3: Participants received 125 mg LY3074828 solution formulation SC via 1-mL AI administered in the abdomen.

Interventions: intervention 1: LY3074828 intervention 2: Pre-filled syringe (PFS) intervention 3: Autoinjector (AI)
Intervention descriptions: intervention 1: Administered subcutaneously (SC) intervention 2: PFS used to administer LY3074828 intervention 3: AI used to administer LY3074828

Protocol document:
Prot_000.pdf: 
Protocol I6T-MC-AMBE 
 
A Safety, Tolerability, and Pharmacokinetic Study of Injections of LY3074828 Solution Using 
Investigational 1-mL Pre-filled Syringes and Investigational 1-mL Autoinjector in Healthy 
Subjects 
 
NCT03886948 
 
Approval Date: 17-Dec-2018 


I 6 T-M C -A M B E Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 1
L Y 3 0 7 4 8 2 8
Pr ot o c ol I 6 T-M C -A M B E
A S af et y , T ol er a bilit y, a n d P h ar m a c o ki n eti c St u d y of 
I nj e cti o ns of L Y 3 0 7 4 8 2 8 S ol uti o n U si n g I n v e sti g ati o n al 
1- m L P r e-fill ed S y ri n g es a n d I n v e sti g ati o n al 
1- m L
A u t oi nj e ct or i n H e alt h y S u bj e ct s
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s pr ot o c ol i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of 
cli ni c al i n v e sti g at or s.  It i s t h e pr o p ert y of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d 
s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al i n v e sti g ati o n of 
L Y 3 0 7 4 8 2 8 , u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y 
a n d C o m p a n y or it s s u b si di ari e s.
N ot e t o R e g ul at or y A ut h oriti e s:   T hi s d o c u m e nt m a y c o n t ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e.  Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e.  I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct to Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
A p pr o v al D at e: 1 7- D e c- 2 0 1 8 G M T
L Y 3 0 7 4 8 2 8
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Cli ni c al P h ar m a c ol o g y Pr ot o c ol El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n d at e 
pr o vi d e d b el o w.


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LY3074828
Table of Contents
A Safety, Tolerability, and Pharmacokinetic Study of 
Injections of LY3074828 Solution Using Investigational 
1-mL Pre-filled Syringes and Investigational 
1-mL Autoinjector in Healthy Subjects
Section
Page
Protocol I6T-MC-AMBE A Safety, Tolerability, and Pharmacokinetic 
Study of Injections of LY3074828 Solution Using Investigational 
1-mL Pre-filled Syringes and Investigational 1-mL Autoinjector in 
Healthy Subjects .................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................7
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................14
3.1.
Study Rationale............................................................................................................14
3.2.
Background..................................................................................................................14
3.3.
Benefit/Risk Assessment..............................................................................................16
4.
Objectives and Endpoints..................................................................................................17
5.
Study Design.....................................................................................................................18
5.1.
Overall Design .............................................................................................................18
5.2.
Number of Participants.................................................................................................19
5.3.
End of Study Definition ...............................................................................................19
5.4.
Scientific Rationale for Study Design...........................................................................19
5.5.
Justification for Dose ...................................................................................................19
6.
Study Population...............................................................................................................20
6.1.
Inclusion Criteria..........................................................................................................20
6.2.
Exclusion Criteria ........................................................................................................22
6.3.
Lifestyle and/or Dietary Requirements .........................................................................24
6.3.1.
Meals and Dietary Restrictions.............................................................................24
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................24
6.3.3.
Activity................................................................................................................24
6.3.4.
Blood and Plasma Donation .................................................................................24
6.4.
Screen Failures.............................................................................................................24
7.
Dosing Regimens..............................................................................................................25
7.1.
Dosing Regimens Administered ...................................................................................25
7.1.1.
Packaging and Labeling .......................................................................................26


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7.2.
Method of Treatment Assignment ................................................................................26
7.2.1.
Selection and Timing of Doses.............................................................................26
7.3.
Blinding .......................................................................................................................26
7.4.
Dose Modification........................................................................................................26
7.5.
Preparation/Handling/Storage/Accountability...............................................................27
7.6.
Treatment Compliance .................................................................................................27
7.7.
Concomitant Therapy...................................................................................................27
7.8.
Treatment after the End of the Study............................................................................27
8.
Discontinuation Criteria ....................................................................................................28
8.1.
Discontinuation from Study Treatment.........................................................................28
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................28
8.2.
Discontinuation from the Study....................................................................................28
8.3.
Subjects Lost to Follow-up...........................................................................................28
9.
Study Assessments and Procedures ...................................................................................29
9.1.
Efficacy Assessments...................................................................................................29
9.2.
Adverse Events ............................................................................................................29
9.2.1.
Serious Adverse Events........................................................................................30
9.2.1.1.
Adverse Device Effects ..................................................................................31
9.2.1.2.
Adverse Events of Special Interest..................................................................31
9.2.1.3.
Suspected Unexpected Serious Adverse Reactions..........................................31
9.2.2.
Complaint Handling.............................................................................................31
9.3.
Treatment of Overdose.................................................................................................32
9.4.
Safety...........................................................................................................................32
9.4.1.
Laboratory Tests ..................................................................................................32
9.4.2.
Vital Signs ...........................................................................................................32
9.4.3.
Electrocardiograms ..............................................................................................33
9.4.4.
Other Tests...........................................................................................................33
9.4.4.1.
Tuberculosis Testing.......................................................................................33
9.4.4.2.
Injection Duration Assessments......................................................................33
9.4.4.3.
Injection-Site Assessments .............................................................................34
9.4.4.4.
Bleeding Assessment......................................................................................34
9.4.4.5.
Injection-Site Pain ..........................................................................................34
9.4.5.
Safety Monitoring ................................................................................................34
9.4.5.1.
Hepatic Safety................................................................................................35
9.4.5.2.
Monitoring of Hypersensitivity Reactions.......................................................35
9.5.
Pharmacokinetics .........................................................................................................36
9.5.1.
Bioanalysis...........................................................................................................36
9.6.
Pharmacodynamics ......................................................................................................36


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9.6.1.
Immunogenicity Assessments ..............................................................................36
9.7.
Genetics .......................................................................................................................37
9.8.
Biomarkers...................................................................................................................37
9.9.
Health Economics ........................................................................................................37
10.
Statistical Considerations and Data Analysis.....................................................................38
10.1. Sample Size Determination ..........................................................................................38
10.2. Populations for Analyses..............................................................................................38
10.2.1.
Study Participant Disposition ...............................................................................38
10.2.2.
Study Participant Characteristics ..........................................................................38
10.3. Statistical Analyses ......................................................................................................38
10.3.1.
Safety Analyses....................................................................................................39
10.3.1.1.
Clinical Evaluation of Safety..........................................................................39
10.3.1.2.
Statistical Evaluation of Safety.......................................................................39
10.3.1.2.1.
Injection-Site Pain ....................................................................................39
10.3.1.2.2.
Duration of Injection.................................................................................39
10.3.1.2.3.
Injection-Site Assessments........................................................................40
10.3.1.2.4.
Statistical Evaluation of Other Safety Parameters......................................40
10.3.2.
Pharmacokinetic Analyses....................................................................................40
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................40
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................40
10.3.3.
Pharmacodynamic Analyses.................................................................................40
10.3.4.
Pharmacokinetic/Pharmacodynamic Analyses......................................................40
10.3.5.
Evaluation of Immunogenicity .............................................................................41
10.3.6.
Data Review During the Study.............................................................................41
10.3.7.
Interim Analyses..................................................................................................41
11.
References ........................................................................................................................42


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List of Tables
Table
Page
Table AMBE.1.
Objectives and Endpoints .......................................................................17
Table AMBE.2.
Dosing Regimens Administered .............................................................25


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................43
Appendix 2.
Clinical Laboratory Tests........................................................................47
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................48
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............51
Appendix 5.
Blood Sampling Summary......................................................................52


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1. Protocol Synopsis
Title of Study:
A Safety, Tolerability, and Pharmacokinetic Study of Injections of LY3074828 Solution Using Investigational 
1-mL Pre-filled Syringes and Investigational 1-mL Autoinjector in Healthy Subjects
Rationale: 
Study I6T-MC-AMBE (AMBE) will assess the pharmacokinetics (PK), safety and tolerability of, and pain 
associated with, a 125-mg subcutaneous (SC) dose of LY3074828 solution formulation administered using an 
investigational manual 1-mL pre-filled syringe (PFS) or an investigational 1-mL autoinjector (AI).  Both methods of 
administration will be evaluated at 3 different injection sites (arm, thigh, and abdomen) in order to expand the 
options for administration in patient use.  The study will provide data to bridge PFS administration of LY3074828, 
with the investigational AI device planned for use in subsequent studies and patient use.
Objectives/Endpoints:
Objectives
Endpoints
Primary

To evaluate the PK after SC administration of 
125-mg doses of LY3074828 solution 
formulation using a 1-mL PFS and a 1-mL AI 
injector in healthy subjects.

To assess pain associated with LY3074828 
PFS and AI SC administrations in healthy 
subjects at 3 different injection sites (arm, 
thigh, and abdomen).

The primary PK endpoints will be the Cmax, 
AUC(0-tlast), and AUC(0-∞) of LY3074828.

VAS pain score.
Secondary

To assess the safety and tolerability of 
LY3074828 in healthy subjects.

Incidence of TEAEs.
Abbreviations:  AI = autoinjector; AUC(0-∞) = area under the concentration versus time curve from time zero to 
infinity; AUC(0-tlast) = area under the concentration versus time curve from time zero to time t, where t is the 
last sample with a measurable concentration; Cmax = maximum observed drug concentration; PFS = pre-filled 
syringe; PK = pharmacokinetic; SC = subcutaneous; TEAE = treatment-emergent adverse event; VAS = visual 
analog scale.


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Summary of Study Design:
Study I6T-MC-AMBE (AMBE) is a single-center, randomized, parallel-arm, open-label, Phase 1 single-dose study 
of LY3074828 solution formulation in healthy subjects.  Pharmacokinetics, safety and tolerability of, and pain 
associated with, 125-mg SC doses administered using a PFS or an investigational AI at 3 different injection sites 
will be evaluated.
Subjects will be randomized to a 1-mL PFS administration to the arm, thigh, or abdomen or a 1-mL AI
administration to the arm, thigh, or abdomen.  Subjects will report to the clinical research unit (CRU) on Day -1 and 
will remain at the CRU until the scheduled procedures have been completed on Day 2.  Study drug will be 
administered by investigative site staff by SC injection per the randomization scheme in the morning of Day 1 after 
an overnight fast.  Subjects will be followed for 12 weeks following dose administration.
Safety and tolerability will be assessed by clinical laboratory tests, vital sign measurements, 12-lead 
electrocardiograms, recording of adverse events and product complaints, physical examinations/medical 
assessments, immunogenicity, and injection-site assessments.  Pain assessments will be made using an injection-site 
pain visual analog scale (VAS).
Dosing Regimen Arms and Duration for an Individual Subject:  
Subjects will receive a 125-mg SC dose of LY3074828 and will be randomized to 1 of 6 dosing regimen arms:

Test 1:  1-mL AI injector containing 125 mg LY3074828 solution to be administered in the arm

Test 2:  1-mL AI injector containing 125 mg LY3074828 solution to be administered in the thigh

Test 3:  1-mL AI injector containing 125 mg LY3074828 solution to be administered in the abdomen

Reference 1:  1-mL PFS containing 125 mg LY3074828 solution to be administered in the arm

Reference 2:  1-mL PFS containing 125 mg LY3074828 solution to be administered in the thigh

Reference 3:  1-mL PFS containing 125 mg LY3074828 solution to be administered in the abdomen
Total duration of the study for each subject will be approximately 16 weeks (screening period ≤28 days, residential 
period of 2 days, and outpatient follow-up period of 12 weeks).
Number of Subjects:
A total of approximately 66 subjects who fulfill the eligibility criteria will be randomized to 1 of 6 dosing regimen 
arms, with 11 subjects randomized to each arm to ensure completion of 10 subjects in each (60 subjects completed 
in total).  A subject’s study participation is considered as complete if he/she receives the study drug as per the 
protocol requirements and completes all activities up to and including at least Day 57.  A maximum of 2 subjects per 
arm may be replaced if multiple subjects do not complete the study.
Statistical Analysis:
The area under the concentration versus time curve (AUC) from time zero to infinity (AUC[0-∞]), AUC from time 
zero to time t, where t is the last sample with a measurable concentration (AUC[0-tlast]), and maximum observed 
drug concentration (Cmax) will be log-transformed and analyzed using a linear fixed-effects model.  The model will 
include device and injection location as fixed effects.  The dosing regimen differences between AI and PFS 


I6T-MC-AMBE Clinical Pharmacology Protocol
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administrations will be back-transformed to present the ratios of geometric least squares (LS) means and the 
corresponding 90% confidence interval (CI).
The time to Cmax (tmax) of LY3074828 between AI and PFS administrations will be analyzed using a Wilcoxon rank 
sum test.  Estimates of the median difference, 90% CIs, and p-values from the Wilcoxon rank sum test will be 
calculated.
Additional PK analyses may be conducted if deemed appropriate.
A linear fixed-effects model will be used to analyze the post-injection pain VAS scores.  The model will include 
device and injection location as fixed effects.  The LS means and differences in LS means will be presented along 
with the corresponding 90% CI. 
Safety parameters will be listed and summarized using standard descriptive statistics, as appropriate.


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2. Schedule of Activities


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Study Schedule Protocol I6T-MC-AMBE
Screening
Days
Comments
Procedure
≤28 days
-1
1
2
4
±1d
8
±1d
11
±1d
15
±2d
22
±2d
29
±2d
43
±2d
57
±3d
71
±3d
85/ED
±3d
Informed consent
X
Review/confirm 
inclusion/exclusion 
criteria
X
X
Any time prior to dosing.
Subject admission to 
CRU
X
Subject discharge 
from CRU
X
Outpatient visit
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
Subjects randomized to 1 of 6 dosing regimen
arms.
LY3074828 injection
X
Doses administered by investigative site staff.
Stopwatch recording
X
Stopwatch is the source for injection duration
capture for PFS and AI.
Medical history
X
Weight, height, and 
BMI
X
Vital signs:  blood 
pressure, pulse rate, 
temperature (hour)
X
X
0, 6
24
X
X
X
X
X
X
X
X
Times with respect to start of dosing.  Single 
ECGs to be collected.  Zero-hour collection 
within 30 minutes before dosing.  Time 
allowance for 6- and 24-hour time points:  ±30 
and ±90 minutes, respectively.  For vital sign 
assessments, temperature need only be 
included at predose and when clinically 
indicated.
12-lead ECG (hour)
X
0
24
X
Physical examination/ 
medical assessment
X
X
X
X
X
Full physical examination/medical assessment 
at screening.  Symptom-directed physical 
examination/medical assessment at all other 
time points, and as deemed necessary by the 
investigator.


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Screening
Days
Comments
Procedure
≤28 days
-1
1
2
4
±1d
8
±1d
11
±1d
15
±2d
22
±2d
29
±2d
43
±2d
57
±3d
71
±3d
85/ED
±3d
AE review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE only after signing ICF.  Product complaints 
and device-related AEs collected as 
appropriate.
QuantiFERON®-TB 
Gold test 
X
Serology
X
See Appendix 2 for test details.
Ethanol test and urine 
drug screen
X
X
May be repeated at the discretion of the 
investigator.  Ethanol test may be measured in 
blood, urine, or expired air.  See Appendix 2
for test details.
FSH/serum 
pregnancy test
X
X
X
X
X
Serum pregnancy tests for all female subjects
at screening.  For all women who are 
considered to be peri-menopausal, FSH should 
be drawn at screening to confirm 
postmenopausal status as defined in inclusion 
criterion [1b].  Women with confirmed 
postmenopausal status at screening are 
exempted from further pregnancy tests during 
the study.  See Appendix 2 for test details.
Clinical chemistry, 
hematology, and 
urinalysis
X
X
X
X
X
X
See Appendix 2 for test details.
Creatine 
phosphokinase
X
X
X
Injection-site 
assessment for 
erythema, induration, 
pruritus, and edema
(hour)
0, 0.25 
X
X
X
Times with respect to start of dosing.  
Zero-hour assessments within 1 minute 
following injection.  Time allowance for 
0.25-hour assessment is ±5 minutes.  
Additional assessments performed if deemed 
necessary by the investigator.
Injection-site 
bleeding assessment 
(hour)
0
Time with respect to start of dosing.  
Zero-hour assessment within 1 minute 
following injection.  


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Screening
Days
Comments
Procedure
≤28 days
-1
1
2
4
±1d
8
±1d
11
±1d
15
±2d
22
±2d
29
±2d
43
±2d
57
±3d
71
±3d
85/ED
±3d
Pain assessment 
(VAS) (minutes)
1, 5, 15, 
30, 60, 
120
Time with respect to start of dosing.  Time
points are minutes post-injection as follows: 
within 1 minute of the end of injection, 5 
(±1.5), 15 (±2), 30 (±2), 60 (±5), 120 (±5)
minutes
LY3074828 
pharmacokinetic 
sampling (hour)
0, 2, 6
24
X
X
X
X
X
X
X
X
X
X
Times with respect to start of dosing.  
Zero-hour collection immediately (within 
15 minutes) before dosing.  Time allowance 
for 2-, 6-, and 24-hour time points:  ±15, ±30, 
and ±90 minutes, respectively.
For the 2-hour postdose timepoint, VAS pain 
assessment should be conducted prior to PK 
sample collection.
Immunogenicity 
sample
Predose
X
X
X
X
LY3074828 antibody sample.  In the event of 
an AE that could be immunologically 
mediated, additional samples may be taken 
(See Section 9.6.1).  Predose sample may be 
collected within 2 hours prior to planned 
dosing.
Pharmacogenetics 
sample
X
Abbreviations:  AE = adverse event; AI = autoinjector; BMI = body mass index; CRU = clinical research unit; d = day; ECG = electrocardiogram; ED = early 
discontinuation; FSH = follicle-stimulating hormone; ICF = informed consent form; PFS = pre-filled syringe; TB = tuberculosis; VAS = visual analog scale.
Site should schedule activities as appropriate. For the 2-hour postdose timepoint, VAS pain assessment should be conducted prior to pharmacokinetic sample 
collection. In other cases where several study procedures are scheduled at the same time, follow this order of priority for procedures:  pharmacokinetic 
samples, clinical laboratory tests, immunogenicity sample, stored sample, ECG, vital signs, pain assessment, injection-site assessment, such that 
pharmacokinetic sample collection occurs as close to the nominal collection time as possible.  


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3. Introduction
3.1.
Study Rationale
Study I6T-MC-AMBE (AMBE) will assess the pharmacokinetics (PK), safety and tolerability of, 
and pain associated with, a 125-mg subcutaneous (SC) dose of LY3074828 solution formulation 
administered using an investigational manual 1-mL pre-filled syringe (PFS) or an investigational 
1-mL autoinjector (AI).  Both devices will be evaluated at 3 different injection sites (arm, thigh, 
and abdomen) in order to expand the options for administration in patient use.  The study will 
provide data to bridge PFS administration of LY3074828, with the investigational AI device 
planned for use in subsequent studies and patient use.
3.2.
Background
LY3074828 is a humanized immunoglobulin G4-variant monoclonal antibody that is directed 
against the p19 subunit of interleukin (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.  Neutralization of IL-23 with an anti-mouse IL-23 surrogate 
antibody (directed against the p19 subunit) significantly reduced the development of arthritis and 
inhibited ileal inflammation in a mouse model of spondyloarthropathy with bowel inflammation 
(Ruutu et al. 2012).  Additionally, neutralization of IL-23 significantly reduced the disease score 
in the 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).  
Psoriasis is one of the most common immune-mediated chronic inflammatory skin diseases, 
affecting about 2% to 3% of the world's population (Nestle et al. 2009; Perera et al. 2012).  A 
typical organ-specific T-cell-driven inflammatory disease, psoriasis, had been considered a 
T helper (Th) 1-type skin disease for decades until a new Th population, Th17, was identified 
(Lew et al. 2004; Steinman 2007; Weaver et al. 2007).  However, substantial clinical and basic 
research observations now suggest that the IL-23/Th17 axis is essential in the pathogenesis of 
psoriasis (Di Cesare et al. 2009).  Treatment of psoriasis with biologic therapy, particularly with 
those agents targeting the IL-23/Th17 axis, has demonstrated clinical activity in patients with 
psoriasis (Crow 2012).
As of the Investigator’s Brochure (IB) cutoff date (02 February 2018 for Phase 1 studies), there 
have been approximately 819 participants in studies of LY3074828.  These include 245 patients 
with psoriasis, 248 patients with ulcerative colitis, 85 patients with Crohn’s disease, and 
241 healthy subjects who were exposed to either placebo or LY3074828 at single doses ranging 
from 5 to 1200 mg and multiple doses up to a maximum of 1000 mg intravenous (IV) and 
300 mg SC.
Data from the clinical pharmacology development program are available for 2 completed 
Phase 1 studies (Studies I6T-MC-AMAA [AMAA] and I6T-MC-AMAE [AMAE]) and 


I6T-MC-AMBE Clinical Pharmacology Protocol
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LY3074828
4 ongoing Phase 1 studies (Studies I6T-JE-AMAD [AMAD], I6T-MC-AMAL [AMAL],
I9O-MC-AABA [AABA], and I6T-MC-AMAQ [AMAQ]).
No deaths, serious adverse events (SAEs), or discontinuations due to an adverse event (AE) have 
been reported in any of the Phase 1 studies.
In the completed Study AMAA, a total of 82 treatment-emergent AEs (TEAEs) were reported by 
37 subjects.  The most commonly reported TEAEs in this study were nasopharyngitis and 
headache.  There were no drug-related TEAEs of National Cancer Institute Common 
Terminology Criteria for Adverse Events Grade 2 or higher reported in Study AMAA.  
In the completed Study AMAE, the incidence of TEAEs was similar between the 125 mg
LY3074828 lyophilized formulation and the 125 mg LY3074828 PFS solution formulation, with 
a notably higher number of TEAEs reported by healthy subjects who received 500 mg 
LY3074828 solution formulation.  The most common TEAEs related to study treatment were 
events occurring at the site of injection, including injection-site reaction (ISR) and injection-site 
hemorrhage.  Across all formulations, the majority of TEAEs reported during the study were 
mild, with only 1 TEAE that was moderate in severity but not related to study drug.  
There were no obvious trends in the pattern of AEs across studies apart from ISRs.  Injection-site 
pain, of short duration (usually hours), has been reported in both the completed and ongoing 
clinical pharmacology studies.  Preliminary data from Studies AMAE and AMAL showed that 
most ISRs were mild or moderate in severity, with severe injection-site pain reported in 2% of 
ISRs in the 125-mg SC solution test formulation group.
Immunogenicity evaluations were performed in Study AMAA. Blood samples to evaluate 
anti-drug antibody (ADA) were collected at baseline and approximately 22, 43, and 85 days 
postdose. Anti-drug antibody 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 post-baseline. Only 1 subject who received LY3074828 was positive at baseline. Thirty-one
subjects who received LY3074828 (81.6%) were negative at all post-baseline time points
evaluated. Seven subjects who received LY3074828 had a post-baseline positive titer; however,
only 3 of those subjects (7.9% of LY3074828-treated individuals) developed treatment-emergent 
ADA (TE-ADA). Treatment-emergent positive ADA was defined as ADA that developed 
following study drug administration with an increase to ≥1:20 titer (2 dilutions/4-fold increase) 
after a negative baseline result OR preexisting ADA (ADA positive at baseline) that was 
increased at least 2 dilutions/4-fold over baseline following study drug administration. None of 
these cases of TE-ADA were associated with treatment-emergent adverse events (TEAEs) or 
changes in the clearance of LY3074828 in this study.
Study AMAE evaluated the relative bioavailability of LY3074828 solution formulation in PFSs 
and a lyophilized formulation.  A total of 8 subjects (14.8%) were ADA positive at predose 
(pre-existing reactivity); none of the pre-existing reactivity confirmed as positive for neutralizing 
antibodies. The incidence of TEADAs was similar across formulations, with 7 subjects (38.9%) 
administered 250 mg LY3074828 lyophilized formulation, 6 subjects (33.3%) administered 
250 mg LY3074828 PFS solution formulation, and 7 subjects (38.9%) administered 500 mg 


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LY3074828 PFS formulation testing positive for TEADAs. Most TEADAs were treatment-
induced (33.3% of subjects), with only 2 subjects having treatment-boosted TEADAs. Only 
1 subject had an ADA titer >1:1000 and there was no obvious trend towards a particular 
formulation having higher titers.
One subject had a TEADA titer greater than 1:1000 and met the protocol-defined requirement to 
have follow-up samples tested until titers were trending back to baseline. Multiple attempts were 
made to contact this subject for follow-up visits, but there was no response and the subject was 
considered lost to follow-up. The subject’s last recorded titer was 1:2560 at the final study visit
on Day 85.
3.3.
Benefit/Risk Assessment
Based on LY3074828 nonclinical and preliminary clinical data, there are no anticipated risks 
requiring monitoring beyond those for a typical humanized monoclonal antibody in human 
studies.  As with other immunomodulatory therapies, LY3074828 may increase the risk of 
developing an infection or may exacerbate an existing serious infection.  These may include 
opportunistic infections and reactivation of latent infections, such as tuberculosis (TB) and 
hepatitis B.  Subjects will therefore be screened for hepatitis B/C, human immunodeficiency 
virus (HIV), and TB.  Immunomodulatory therapies may increase the risk of malignancies; 
however, due to only single doses of LY3074828 being administered in this study, it is not 
considered necessary to monitor for such effects.  
Based on available data from Studies AMAA and AMAD, TE-ADAs have been observed in 2 of 
the 11 healthy subjects that received SC doses of LY3074828; however, titers were ≤1:160.  In 
the 33 patients with psoriasis who received single IV doses of LY3074828, TE-ADAs were 
detected in 3 subjects (Study AMAA).
No clinically significant safety or tolerability concerns have been identified in patients or healthy 
subjects to date for LY3074828 up to the highest doses given (single 2400-mg IV doses and 
2400-mg SC doses).  
Healthy subjects are not expected to derive any benefit from participating in studies with 
administration of LY3074828.  
As this study will use PFS and AIs, device-based risks will be evaluated.  Possible device-based 
risks include local effects such as pain at the injection sites from either the needle or the solution 
entry into the SC tissue, swelling, erythema, bleeding, and bruising.  These risks are mitigated by 
training of investigative site staff on proper injection techniques.  Systemic effects may include 
sweating, feeling faint, or fever, as a sign of infection.  
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of LY3074828 are found in the compound IB, and risks as well as reasonably 
anticipated adverse device effects of the AI are found in the device IB.


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4. Objectives and Endpoints
Table AMBE.1 shows the objectives and endpoints of the study.
Table AMBE.1.
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the PK after SC administration of 
125-mg doses of LY3074828 solution 
formulation using a 1-mL PFS and a 1-mL AI 
injector in healthy subjects.

To assess pain associated with LY3074828 
PFS and AI SC administrations in healthy 
subjects at 3 different injection sites (arm, 
thigh, and abdomen).

The primary PK endpoints will be the Cmax, 
AUC(0-tlast), and AUC(0-∞) of LY3074828.

VAS pain score.
Secondary

To assess the safety and tolerability of 
LY3074828 in healthy subjects.

Incidence of TEAEs.
Abbreviations:  AI = autoinjector; AUC(0-∞) = area under the concentration versus time curve from time zero to 
infinity; AUC(0-tlast) = area under the concentration versus time curve from time zero to time t, where t is the 
last sample with a measurable concentration; Cmax = maximum observed drug concentration; PFS = pre-filled 
syringe; PK = pharmacokinetic; SC = subcutaneous; TEAE = treatment-emergent adverse event; VAS = visual 
analog scale.


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5. Study Design
5.1.
Overall Design
Study I6T-MC-AMBE (AMBE) is a single-center, randomized, parallel-arm, open-label, Phase 1 
single-dose study of LY3074828 solution formulation in healthy subjects.  Pharmacokinetics, 
safety and tolerability of, and pain associated with, 125-mg SC doses administered using a PFS 
or AI at 3 different injection sites will be evaluated.
Screening Period (≤28 days):  Subjects will be evaluated for study eligibility ≤28 days prior to 
enrollment.
Residential Period (2 days):  A total of approximately 66 subjects who fulfill the eligibility 
criteria will be randomized to 1 of 6 dosing regimen arms, with 11 subjects randomized to each 
arm to ensure completion of 10 subjects in each:

Test 1:  1-mL AI injector containing 125 mg LY3074828 solution to be administered in 
the arm

Test 2:  1-mL AI injector containing 125 mg LY3074828 solution to be administered in 
the thigh

Test 3:  1-mL AI injector containing 125 mg LY3074828 solution to be administered in 
the abdomen

Reference 1:  1-mL PFS containing 125 mg LY3074828 solution to be administered in 
the arm

Reference 2:  1-mL PFS containing 125 mg LY3074828 solution to be administered in 
the thigh

Reference 3:  1-mL PFS containing 125 mg LY3074828 solution to be administered in 
the abdomen
Subjects will report to the clinical research unit (CRU) on Day -1 and will remain at the CRU 
until the scheduled procedures have been completed on Day 2.  Study drug will be administered 
by investigative site staff by SC injection per the randomization scheme in the morning of Day 1 
after an overnight fast.  
Safety and tolerability will be assessed by clinical laboratory tests, vital sign measurements, 
12-lead electrocardiograms (ECGs), recording of AEs and product complaints (PCs), physical 
examinations/medical assessments, immunogenicity, and injection-site assessments.  Pain 
assessments will be made using an injection-site pain visual analog scale (VAS).
Outpatient Follow-up Period (12 weeks):  The follow-up period will include outpatient visits 
for a total of 12 weeks (Days 4, 8, 11, 15, 22, 29, 43, 57, 71, and 85) following dose 
administration on Day 1 to assess the PK, safety and tolerability of, and pain associated with 
LY3074828 PFS and AI administrations.  Assessment of pain at the Follow-up visits does not 
include VAS score.


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5.2.
Number of Participants
A total of approximately 66 subjects who fulfill the eligibility criteria will be randomized to 1 of 
6 dosing regimen arms, with 11 subjects randomized to each arm to ensure completion of
10 subjects in each.  A subject’s study participation is considered as complete if he/she receives 
the study drug as per the protocol requirements and completes all activities up to and including at 
least Day 57.  A maximum of 2 subjects per arm may be replaced if multiple subjects do not 
complete the study.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
5.4.
Scientific Rationale for Study Design
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications in patients.  A population of healthy subjects is
frequently used in the assessment of bioavailability of both small and large molecules.
Single doses of LY3074828 and the PK sampling time points have been selected to generate PK 
profiles sufficient to fulfill the study objectives.  This study is not blinded due to the physical 
difference in devices being evaluated.  Subjects and site staff will be aware of the administration 
route and treatment.
A parallel-group design was chosen because a crossover design is impractical for compounds 
that have long half-lives, such as monoclonal antibodies.  Additionally, a crossover study design 
could confound PK data if subjects develop neutralizing ADAs.
Monoclonal antibody therapy has been associated with hypersensitivity reactions, including 
ISRs.  Follow-up details on ISRs will be collected by the investigative site regarding the severity, 
duration, type, and timing of the start of the event in relation to the start of study drug 
administration in order to further characterize these events.
Methods of administration will be evaluated at 3 different injection sites (arm, thigh, and 
abdomen) in order to expand the options for administration in patient use.  
5.5.
Justification for Dose
The doses for this study are based on the volume of solution that can be delivered by the PFS or 
AI (1 mL) and the solubility of LY3074828 (125 mg/mL), resulting in a dose of 125 mg
LY3074828.  
Intravenous doses up to 2400 mg and SC doses up to 2400 mg were found to be well tolerated in 
healthy subjects in the single-dose Studies AMAD and AABA.  Subcutaneous bioavailability 
was approximately 40% in Study AMAA.  In addition, 125 mg is one of the doses that are being 
evaluated in the Phase 3 development program.


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6. Study Population
Eligibility of subjects for study enrollment will be based on the results of medical history, 
physical examination, vital signs, clinical laboratory tests, and ECG.  
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening will occur up to 28 days prior to enrollment.  Subjects who are not enrolled within 
28 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrollment:
[1]
are overtly healthy male or female subjects, as determined by medical 
history and physical examination
[1a]
male subjects:

no male contraception required except in compliance with specific local 
government study requirement
[1b]
female subjects:

All female subjects must test negative for pregnancy prior to initiation of treatment 
as indicated by a negative serum pregnancy test at the screening visit. Women of 
childbearing potential must also have a negative serum pregnancy test within 
24 hours prior to initial exposure.  Women not of childbearing potential due to 
postmenopausal status must have follicle-stimulating hormone >40 mIU/mL at the 
screening visit

Women of childbearing potential who are abstinent (if this is complete abstinence, 
as their preferred and usual lifestyle) or in a same-sex relationship (as part of their 
preferred and usual lifestyle) must agree to either remain abstinent or stay in a 
same-sex relationship without sexual relationships with males.  Periodic abstinence 
(eg, calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence just for the duration of a trial, and withdrawal are not acceptable 
methods of contraception

Otherwise, women of childbearing potential participating must agree to use one 
highly effective method (less than 1% failure rate) of contraception, or a 
combination of 2 effective methods of contraception (for 12 weeks following 
dosing with the study drug)


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LY3074828
o
Either one highly effective method of contraception (such as combination 
oral contraceptives, implanted contraceptives, or intrauterine device) or a 
combination of 2 effective methods of contraception (such as male or 
female condoms with spermicide, diaphragms with spermicide, or cervical 
sponges) will be used.  The subject may choose to use a double-barrier
method of contraception.  Barrier protection methods without concomitant 
use of a spermicide are not reliable or acceptable methods.  Thus, each 
barrier method must include use of a spermicide.  It should be noted that the 
use of male and female condoms as a double-barrier method is not 
considered acceptable due to the high failure rate when these methods are 
combined

Women not of childbearing potential may participate and include those who are: 
o
infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, 
or tubal ligation) or congenital anomaly such as Müllerian agenesis; or 
o
postmenopausal – defined as either:

A woman at least 50 years of age with an intact uterus, not on 
hormone therapy, who has had either:

cessation of menses for at least 1 year; or 

at least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone >40 mIU/mL; or 

A woman 55 years of age or older not on hormone therapy, who has 
had at least 6 months of spontaneous amenorrhea; or 

A woman at least 55 years of age with a diagnosis of menopause 
prior to starting hormone-replacement therapy
[2]
are between 18 and 65 years of age, inclusive, at time of screening
[3]
have a body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, at time of 
screening
[4]
have clinical laboratory test results within normal reference ranges for the 
investigative site, or results with acceptable deviations that are judged to be 
not clinically significant by the investigator
[5]
have venous access sufficient to allow for blood sampling as per the 
protocol
[6]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[7]
are able and willing to give signed informed consent


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6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[8]
are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling
[9]
are Lilly employees or employees of Covance
[10]
are currently enrolled in a clinical study involving an investigational 
product (IP) or any other type of medical research judged not to be 
scientifically or medically compatible with this study
[11]
have participated in a clinical trial involving an IP within 30 days or 
5 half-lives (whichever is longer) prior to screening.  If the clinical trial 
involved treatment with biologic agents (such as monoclonal antibodies, 
including marketed drugs), at least 3 months or 5 half-lives (whichever is 
longer) should have elapsed prior to Day 1
[12]
have previously completed or withdrawn from this study or any other study 
investigating LY3074828, and have previously received the IP
[13]
have ever received anti-IL-12p40 antibodies (for example, ustekinumab 
[Stelara®]) or anti-IL-23p19 antibodies (for example, risankizumab 
[BI-655066], brazikumab [MEDI2070], guselkumab [CNTO 1959], or 
tildrakizumab [MK-3222]) for any indication, including investigational use
[14]
have known allergies to LY3074828, related compounds, or any 
components of the formulation, or history of significant atopy
[15]
have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study
[16]
have an abnormal blood pressure as determined by the investigator
[17]
have a history or presence of 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 IP; or of interfering with the 
interpretation of data
[18]
have known or ongoing psychiatric disorders deemed clinically significant 
by the investigator
[19]
regularly use known drugs of abuse and/or show positive findings on drug 
screening
[20]
show evidence of HIV infection and/or positive HIV antibodies
[21]
show evidence of hepatitis C and/or positive hepatitis C antibody


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LY3074828
[22]
show evidence of hepatitis B and/or positive hepatitis B surface antigen
[23]
are women who are lactating
[24]
have used or intend to use over-the-counter or prescription medications, 
including herbal medications, within 14 days prior to dosing and for the 
duration of the study.  Stable doses of oral contraceptive or 
hormone-replacement therapy are permitted, at the discretion of the 
investigator
[25]
have donated blood of more than 500 mL within 1 month prior to screening 
[26]
have an average weekly alcohol intake that exceeds 21 units per week 
(males) and 14 units per week (females), have a positive test for ethanol, or 
are unwilling to abide by the alcohol restrictions described in Section 6.3.2
(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)
[27]
have a tobacco consumption of more than 10 cigarettes per day (or 
equivalent), or who are unwilling to abide by the CRU smoking guidelines 
described in Section 6.3.2
[28]
have had symptomatic herpes zoster within 3 months of screening
[29]
show evidence of active or latent TB, as documented by medical history, 
examination, and TB testing (negative [not indeterminate] 
QuantiFERON® -TB Gold test); or have had household contact with a 
person with active TB, unless appropriate and documented prophylaxis 
treatment has been given.  Subjects with any history of active TB are 
excluded from the study, regardless of previous or current TB treatments
[30]
have received live vaccine(s), including attenuated live vaccines and those 
administered intranasally, within 8 weeks of screening, or intend to during 
the study
[31]
have been treated with oral steroids within 1 month of screening, or intend 
to during the study (mild topical steroid creams/ointments are permitted)
[32]
are immunocompromised
[33]
have significant allergies to humanized monoclonal antibodies 
[34]
have clinically significant multiple or severe drug allergies, or intolerance 
to topical corticosteroids, or severe posttreatment hypersensitivity reactions 
(including, but not limited to, erythema multiforme major, linear 
immunoglobulin A dermatosis, toxic epidermal necrolysis, or exfoliative 
dermatitis)
[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


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[37]
have excessive tattoos over the arm, thigh, or abdomen that would interfere 
with injection-site assessments
[38]
in the opinion of the investigator, are unsuitable for inclusion in the study
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
Subjects will fast overnight for at least 8 hours before dosing (water is permitted).  Standard 
meals will be provided at all other times while subjects are resident at the CRU, as per the 
CRU’s policy. Fasting is not required prior to routine safety laboratory tests.
6.3.2. Caffeine, Alcohol, and Tobacco
Subjects will not consume caffeinated beverages (decaffeinated beverages are permitted) while 
at the CRU, and for 12 hours prior to admission to the CRU.  At other times during the outpatient 
period, subjects will be allowed to maintain their regular caffeine consumption.
Alcohol consumption is not permitted while at the CRU, and for 12 hours prior to each study 
visit.  At other times, alcohol consumption should be limited to 2 units per day (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).
Subjects who smoke will be advised to not increase their consumption of tobacco products 
during the study.  Subjects will be expected to refrain from smoking while residing in the CRU, 
and to abide by the CRU smoking guidelines.
6.3.3. Activity
Subjects will be advised to maintain their regular levels of physical activity/exercise during the 
study, but to refrain from strenuous activity from 24 hours prior to each visit and 48 hours prior 
to any visit where creatine phosphokinase testing will occur (Day -1, Day 8, and Day 29).  While 
certain study procedures are in progress at the site, subjects may be required to remain recumbent 
or sitting.
6.3.4. Blood and Plasma Donation
Subjects will not donate blood or plasma for 12 weeks following dosing with the study drug.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened.


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7. Dosing Regimens
7.1.
Dosing Regimens Administered
This study will evaluate the PK, safety and tolerability of, and pain associated with 125-mg SC 
doses administered using 1-mL PFS or an investigational 1-mL AI at 3 different injection sites.
Using the investigational 1-mL AI, the targeted injection duration will be approximately 5 to 
10 seconds.  Manual injection using the PFS should target an injection duration of about 5 to 
10 seconds to approximate the injection time range for the AI.  Approximate injection durations 
for AIs and PFSs will be obtained using a calibrated stopwatch and recorded in the electronic 
case report form (eCRF).  
Drug and device accountability records will be maintained by the site pharmacy.
Table AMBE.2 shows the dosing regimens for the study.
Table AMBE.2.
Dosing Regimens Administered
Dosing 
Regimen
PFS
AI
Reference/test
Reference
1
Reference
2
Reference
3
Test
1
Test
2
Test
3
Injection site
Arm
Thigh
Abdomen
Arm
Thigh
Abdomen
Product
LY3074828
LY3074828
Dose
125 mg
125 mg
Concentration
125 mg/mL
125 mg/mL
Injection 
volumes
1 mL
1 mL
Number of 
injections
1
1
Injection 
duration
5 to 10 seconds per injection
5 to 10 seconds per injection
Formulation 
and 
presentation
Solution in a PFS
Solution in an AI
Abbreviations:  AI = autoinjector; PFS = pre-filled syringe.
The PFSs and investigational AIs containing LY3074828 will be supplied fully assembled to the 
clinical site by Lilly.
Injections, whether administered by PFS or AI, will be given into the arm, thigh, or lower 
quadrant of the abdomen. Investigational product will be administered to subjects on-site by 
designated trained clinical site personnel.  


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Prior to the PFS or AI injection, the investigator or his/her designee will prepare the subject’s 
skin per Instructions for Use (IFU).  Injections into the arm, thigh, or abdomen will be 
administered by investigative site staff according to the instructions provided by the sponsor.  All 
study injection sites will be marked using a template for size and with a surgical marker in order 
to identify study injection sites for later assessments.  Further information regarding SC 
administration will be included in the device IFU for the PFS and in the device IB (which 
contains IFU) for the AI.
In some cases, the site may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical trial materials. 
7.1.1. Packaging and Labeling
LY3074828 will be supplied by the sponsor or its designee in accordance with current good 
manufacturing process, and labeled according to the country’s regulatory requirements.  All IPs
will be stored, inventoried, reconciled, and returned or destroyed according to applicable 
regulations. The following products will be supplied by Lilly:

pre-assembled LY3074828 PFSs, 1 mL

pre-assembled investigational LY3074828 AIs, 1 mL
Each investigational device will be individually identified and labeled according to US 
regulatory requirements for investigational devices.
7.2.
Method of Treatment Assignment
Subjects will be randomized to a 1-mL PFS administration to the arm, thigh, or abdomen or a 
1-mL AI administration to the arm, thigh, or abdomen (Table AMBE.2).
Randomization will be performed using a computer-generated randomization schedule.
7.2.1. Selection and Timing of Doses
The actual time of all dose administrations will be recorded in the subject’s eCRF.
7.3.
Blinding
This is an open-label study.
7.4.
Dose Modification
Dose adjustments are not permitted in this study.


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7.5.
Preparation/Handling/Storage/Accountability
The IPs for this study will be:

LY3074828 in PFSs

LY3074828 in investigational AIs
Investigational product will be stored refrigerated at 2°C to 8°C (36°F to 46°F) in its original 
carton to protect from light.  Investigational product should not be frozen or shaken.  Sites will 
be required to monitor temperature of the on-site storage conditions of the IP.  The investigator 
or designee must confirm appropriate temperature conditions have been maintained, as 
communicated by sponsor, during transit for all IP received and any discrepancies are reported 
and resolved before use of the study treatment.
The AIs and PFSs containing LY3074828 should be allowed to warm to room temperature 
before use.  
Only participants enrolled in the study may receive IP or study materials, and only authorized 
site staff may supply or administer IP.  All IP should be stored in an environmentally controlled 
and monitored (manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff.
The investigator is responsible for study treatment accountability, reconciliation, and record 
maintenance (such as receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The IP will be administered at the clinical site, and documentation of treatment administration 
will occur at the site.
7.7.
Concomitant Therapy
Over-the-counter or prescription medications, including herbal medication, are not permitted 
within 14 days prior to dosing and throughout the study.  However, stable doses of oral 
contraceptive or hormone-replacement therapy are permitted at the discretion of the investigator.
Paracetamol/acetaminophen (up to 2 g/day) is permitted at the discretion of the investigator, but 
should be avoided during the 4-hour postdose period when pain assessments are made.  
Additional drugs are to be avoided during the study, unless required to treat an AE.
If the need for concomitant medication arises per Investigator discretion, continuation of the 
subject may be at the discretion of the investigator in consultation with a Lilly clinical 
pharmacologist (CP) or clinical research physician (CRP).  Any additional medication used 
during the course of the study must be documented.
7.8.
Treatment after the End of the Study
This section is not applicable for this study.


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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Randomized subjects who discontinue the study prematurely for any reason should complete the 
early discontinuation (ED) procedures as shown in the Schedule of Activities (Section 2).  The 
reason for and the date of discontinuation will be collected for all subjects.
8.1.1. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CP or CRP and the investigator 
to determine if the subject may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CP or CRP to allow 
the inadvertently enrolled subject to continue in the study.  Any subjects that are inadvertently 
enrolled will be followed for safety.
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

Enrollment in any other clinical study involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice

The investigator decides that the subject should be discontinued from the study

The subject requests to be withdrawn from the study
Subjects who discontinue the study early will have ED procedures performed as shown in the 
Schedule of Activities (Section 2).
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the clinical laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.
The specifications in this protocol for the timings of safety and sample collection are given as 
targets to be achieved within reasonable limits.  Modifications may be made to the time points 
based upon emerging clinical information.  The scheduled time points may be subject to minor 
alterations; however, the actual time must be correctly recorded in the eCRF.  Late collection 
outside the stipulated time allowances or failure to obtain samples due to clinical issues, such as 
problems with equipment, venous access, or subject defaulting on a scheduled procedure, will 
not be considered as protocol deviations but the site will still be required to notify the sponsor in 
writing via a file-note.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
This section is not applicable to this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the IP or the study.  
The subject should be followed until the event resolves, stabilizes with appropriate diagnostic 
evaluation, or is reasonably explained.  The frequency of follow-up evaluations of the AE is left 
to the discretion of the investigator.
After the informed consent form is signed, study site personnel will record, via eCRF, the 
occurrence and nature of each subject’s preexisting conditions.  Additionally, site personnel will 
record any change in the condition(s) and the occurrence and nature of any AEs.  


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The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account 
concomitant treatment or pathologies.  
A “reasonable possibility” means that there is a cause and effect relationship between the IP, 
study device, and/or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above

when a condition related to the investigational device (PFS or AI) necessitates medical or 
surgical intervention to preclude either permanent impairment of a body function or 
permanent damage to a body structure, the serious outcome of “required intervention” 
will be assigned.
Study site personnel must alert the Lilly CRP/CP, or its designee, of any SAE as soon as 
practically possible.
Additionally, study site personnel must alert Lilly Global Patient Safety (GPS), or its designee, 
of any SAE within 24 hours of investigator awareness of the event via a sponsor-approved 
method.  If alerts are issued via telephone, they are to be immediately followed with official 
notification on study-specific SAE forms.  This 24-hour notification requirement refers to the 
initial SAE information and all follow-up SAE information.
Although all AEs are recorded in the eCRF after signing informed consent, SAE reporting to the 
sponsor begins after the subject has signed informed consent and has received IP.  However, if 
an SAE occurs after signing informed consent, but prior to receiving IP, AND is considered 
Reasonably Possibly Related to a study procedure then it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 


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been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly. 
Pregnancy (maternal or paternal exposure to IP) does not meet the definition of an AE.  
However, to fulfill regulatory requirements any pregnancy should be reported following the SAE 
process to collect data on the outcome for both mother and fetus.
9.2.1.1.
Adverse Device Effects
Any AE believed to have a reasonable possibility of being related or associated to an issue with 
the AI or PFS, such as a malfunction or a deficiency, is considered an adverse device event.  
These events must be clearly indicated as such in the eCRF, and reported to the sponsor. A 
Product Complaint should also be reported.
For the purpose of this protocol, “unanticipated” serious adverse device effect means any SAE
alleged to have a reasonable possibility to be associated or related to the device, which was not 
previously defined as anticipated in study documents, such as the device IB or IFU.  The SAE 
relatedness must be clearly indicated as such in the eCRF, and reported to the sponsor within 
24 hours of site knowledge of the event.  A Product Complaint should also be reported.
9.2.1.2.
Adverse Events of Special Interest
The following AEs of special interest will be used to determine the safety and tolerability of 
LY3074828 injections administered by either PFS or investigational AI in this clinical study.
Adverse events of special interest for LY3074828 are:

infection

ISRs

allergic/hypersensitivity reactions
If infections, ISRs, or allergic/hypersensitivity reactions are reported, sites will provide details on 
these events as instructed on the eCRF.  Investigators will also educate subjects about the 
symptoms of allergic/hypersensitivity reactions and will provide instructions on dealing with 
these reactions.  A blood sample will be collected when possible for any subject who experiences 
an AE of allergic/hypersensitivity reaction during the study.
9.2.1.3.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator reports as related to IP or procedure.  Lilly has procedures that 
will be followed for the recording and expedited reporting of SUSARs that are consistent with 
global regulations and the associated detailed guidances.
9.2.2. Complaint Handling
Lilly collects PCs 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.


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Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the IP or drug delivery system so that the situation can be assessed.  
A PFS or AI that is associated with a product quality issue or complaint must be returned to 
Lilly.
The investigator or his/her designee is responsible for reporting and handling the following 
aspects of the Product Complaints (PC) process in accordance with instructions on the Product 
Complaints form, and the instructions provided for this study:

recording a complete description of the PC reported and any associated AEs using the 
study-specific complaint forms provided for this purpose

forwarding via email or fax the completed Product Complaint form within 24 hours to 
Lilly or its designee if associated to an SAE, otherwise within 1 business day.
If the investigator is asked to return the product for investigation, he/she will return a copy of the
completed Product Complaint form with the product.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY3074828 is considered any dose higher than the 
dose assigned through randomization.
There is no specific antidote for LY3074828.  In the event of an overdose, the subject should 
receive appropriate supportive care and any AEs should be documented.
Refer to the study drug IB for further details.
9.4.
Safety
9.4.1. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).
Lilly or its designee will provide the investigator with the results of laboratory tests analyzed by 
a central vendor, if a central vendor is used for the study.
9.4.2. Vital Signs
For each subject, vital sign measurements (blood pressure, pulse rate, and temperature) should be 
conducted according to the Schedule of Activities (Section 2).  Additional vital signs may be 
measured during the study if warranted.
Blood pressure and pulse rate should be measured after at least 5 minutes supine.
If orthostatic measurements are required, subjects should be supine for at least 5 minutes and 
stand for at least 2 minutes.


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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.  
9.4.3. Electrocardiograms
For each subject, a single 12-lead digital ECG will be collected according to the Schedule of 
Activities (Section 2).  Electrocardiograms must be recorded before collecting any blood 
samples.  Subjects must be supine for at least 5 minutes before ECG collection and remain 
supine but awake during ECG collection.  Electrocardiograms may be obtained at additional 
times, when deemed clinically necessary.  All ECGs recorded should be stored at the 
investigational site.
Electrocardiograms will be interpreted by 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 finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the subject can 
continue in the study.  The investigator, or qualified designee, is responsible for determining if 
any change in subject management is needed, and must document his/her review of the ECG 
printed at the time of collection.  
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the IP should be reported to Lilly, or its designee, as an AE via 
eCRF.
9.4.4. Other Tests
9.4.4.1.
Tuberculosis Testing
Subjects will be tested as indicated in the Schedule of Activities (Section 2) for evidence of 
active or latent TB using the QuantiFERON-TB Gold test.  If the test is indeterminate, 1 retest is 
allowed.  If the retest is indeterminate, the subject will be excluded from the study.
Subjects who have had household contact with a person with active TB must be excluded unless 
appropriate and documented prophylaxis treatment for TB has been completed.
Subjects with any history of active TB are excluded from the study, regardless of previous or 
current TB treatments.
9.4.4.2.
Injection Duration Assessments
Injection duration will be measured by a calibrated stopwatch by qualified trained study staff.  
The duration of injection for the PFS will be defined as the time between when the plunger rod is 
pressed down and when all of the LY3074828 solution is injected.  The duration of injection for 
the AI will be defined as the time between the first audible click after the injection button is 


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pressed and the last audible click, which indicates that the needle has retracted and the injection 
is complete.  
9.4.4.3.
Injection-Site Assessments
Injection site findings (including erythema, induration, pruritus, and edema) will be captured on 
a separate ISR form, as indicated in the Schedule of Activities (Section 2).
Data from injection site evaluations (including pain) which are recorded as a result of specific 
questionnaire/s will not be reported as AEs. If the investigator determines that the ISR is
clinically significant or if it is an unsolicited event (volunteered by subject), the event will be 
captured in the subject’s eCRF as an AE.  
If an ISR is deemed to be an AE, the ISR form will be used to capture specific information about 
this reaction (eg, degree and area of erythema).
Injection-site tenderness on contact reported by subjects may be recorded as an AE, but is not 
required to be captured in ISR form.
9.4.4.4.
Bleeding Assessment
All injection sites will be observed at the times indicated in the Schedule of Activities (Section 2) 
by the investigator or designee, and the presence of visible bleeding will be recorded on the 
eCRF.  A bandage may be placed on the injection site after assessment.
9.4.4.5.
Injection-Site Pain
Pain measurements will be quantified using the 100-mm validated VAS pain score for all 
subjects, whether or not they report injection pain.  The VAS is a well-validated tool 
(Williamson and Hoggart 2005) to assess injection-site pain; it is presented as a 100-mm line 
anchored by verbal descriptors, usually “no pain” and “worst possible pain.”  The subject will be 
asked to rate any pain at the injection site on a scale of 0 to 100 mm on the line immediately 
(within 1 minute) following the injection and at the time points listed in the Schedule of 
Activities (Section 2).
9.4.5. Safety Monitoring
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CP or 
CRP will periodically review the following data:

trends in safety data

laboratory analytes

AEs, including monitoring of incidence of any nature of any infections, and ISRs

PCs


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When appropriate, the Lilly CP or CRP will consult with the functionally independent GPS 
therapeutic area physician, GPS device physician, or GPS clinical research scientist.
9.4.5.1.
Hepatic Safety
If a study subject experiences elevated alanine aminotransferase (ALT) ≥3× upper limit of 
normal (ULN), alkaline phosphatase (ALP) ≥2× ULN, or elevated total bilirubin (TBL) 
≥2× ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, 
aspartate aminotransferase, ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and 
creatine phosphokinase to confirm the abnormality and to determine if it is increasing or 
decreasing.  If the abnormality persists or worsens, clinical and laboratory monitoring should be 
initiated by the investigator based on consultation with the Lilly CP or CRP.  Monitoring should 
continue until levels normalize and/or are returning to approximate baseline levels. 
Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥5× ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2× ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests 

hepatic event considered to be an SAE
9.4.5.2.
Monitoring of Hypersensitivity Reactions
There is a risk of systemic hypersensitivity reactions with any biological agent, including acute 
anaphylaxis and delayed hypersensitivities to LY3074828.  Symptoms and signs that may occur 
as part of these hypersensitivity reactions include, but are not limited to: fever, chills, joint and 
muscle pain, rash, itching, urticaria, dizziness, headache, throat irritation, and shortness of 
breath.  Less commonly, life-threatening anaphylactic reactions may occur, which may include 
vascular collapse and/or respiratory compromise.
All subjects will be closely monitored for signs and symptoms of hypersensitivity reactions 
following administration of the study drug, and appropriate medical care should be provided.  
Hypersensitivity reactions will be evaluated by examination of TEAEs and SAEs, and through 
the use of a follow-up form which will be completed by the investigator.  Potential 
hypersensitivity events will be evaluated by a Lilly CRP based on accepted criteria (Sampson et 
al. 2006).
In the event of drug hypersensitivity reactions (immediate or non-immediate), additional samples 
will be collected as close to the onset of the event as possible, at the resolution of the event, and
approximately 30 days following the event to evaluate ADA, PK, and additional exploratory 
biomarkers of hypersensitivity which could include tryptase, complement levels and cytokine 
measurements. 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.


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9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 2 mL each will be collected to determine the 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.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.  Concentrations of LY3074828 will be assayed using a validated 
enzyme-linked immunosorbent assay.  
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
1 year following last subject visit for the study.  During this time, samples remaining after the 
bioanalysis may be used for exploratory metabolism or exploratory analyses such as 
bioanalytical assay validation or cross-validation exercises.
9.6.
Pharmacodynamics
9.6.1. Immunogenicity Assessments
Blood samples for immunogenicity testing will be collected to determine antibody production 
against LY3074828, as specified in the Schedule of Activities (Section 2).  Additional samples 
may be collected if there is a possibility that an AE is immunologically mediated.  If additional 
immunogenicity testing samples are taken, matching PK sample collections will also be required.  
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of the IP.  Antibodies may be further characterized and/or evaluated for their ability to neutralize 
the activity of the IP.  
A risk-based approach will be used to monitor subjects who develop TE-ADAs during and 
following treatment with LY3074828.
Subjects will have ADA sampling at the visits specified in the Schedule of Activities (Section 2).
Subjects who have clinical sequelae that are considered potentially related to the presence of 
TE-ADA may be asked to return for additional follow-up testing.
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and institutional review boards (IRBs) allow, at a facility selected by 
the sponsor.  The duration allows the sponsor to respond to future regulatory requests related to 
the IP.  Any samples remaining after 15 years will be destroyed.


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9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2), where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
LY3074828 and to investigate genetic variants thought to play a role in autoimmune and 
inflammatory diseases.  Assessment of variable response may include evaluation of AEs or 
differences in efficacy.  
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or IRB impose shorter time limits, for the study at a facility 
selected by Lilly or its designee.  This retention period enables use of new technologies, response 
to regulatory questions, and investigation of variable response that may not be observed until 
later in the development of LY3074828 or after LY3074828 is commercially available.  
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section.
9.8.
Biomarkers
This section is not applicable for this study.
9.9.
Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Approximately 66 subjects will be enrolled with a target of 60 subjects completing the study 
(10 completers per treatment). 
Data from AMAL (2 x 1-mL doses of 125 mg LY3074828) and AMAE (2 x 1-mL PFS doses of 
125 mg LY3074828) studies showed that the geometric coefficient of variation ranged from 55% 
to 40% for the PK measurements (ie, area under the concentration versus time curve [AUC] from 
time zero to infinity [AUC(0-∞)], AUC from time zero to time t, where t is the last sample with a 
measurable concentration [AUC(0-tlast)], and maximum observed drug concentration [Cmax]).
Thus, the geometric coefficient of variation was assumed to be 55% when calculating precision.
A sample size of 60 subjects will provide a precision (ie, half-width of 90% of confidence 
interval [CI] with a coverage probability of 90%), in log scale, of approximately 0.48 for 
the geometric means ratio of reference versus test for AUC(0-∞), AUC(0-tlast), and Cmax. 
Equivalently, there is a 90% probability that the distance between the lower limit of the 90% CI 
and the point estimate of the geometric means ratio is not larger than 38%.
Subjects who are randomized but not administered treatment, or subjects (maximum of
2 subjects per dose regimen arm) that are administered treatment but do not have PK and ADA 
samples collected up to and including Day 57, may be replaced to ensure that approximately 
10 subjects from each treatment arm may complete the study.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study. 
10.2.2. Study Participant Characteristics
The subject’s age, sex, weight, BMI, height, race/subrace, and other demographic data will be 
summarized by dosing regimen and overall.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetic analyses will be conducted on the full analysis set.  This set includes all data 
from all randomized subjects receiving the dose of LY3074828 with evaluable PK data.  Safety 
analyses will be conducted for all subjects receiving a dose of LY3074828, whether or not they 
completed all protocol requirements.


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Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses.  
No adjustments for multiple comparisons will be made.
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All IP and protocol procedure AEs and PCs 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 study entry 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.
The number of IP- and device-related SAEs and any related PCs will be reported.
10.3.1.2. Statistical Evaluation of Safety
10.3.1.2.1.Injection-Site Pain
The intensity of pain at the injection site within 1 minute of the end of injection and 5 minutes 
after the end of the injection will be evaluated, as reported by the subject and measured 
according to the 0- to 100-mm VAS.  VAS scores will be categorized into mild (0- to 30-mm), 
moderate (31- to 70-mm), and severe (71- to 100-mm).  Assessments will also be performed at 
15, 30, 60, and 120 minutes post-injection; however, the primary endpoints will be the 1- and 
5-minute assessments. 
Descriptive statistics will be used to summarize the intensity of pain at each time point.
A linear fixed-effects model will be used to analyze the 1- and 5-minute post-injection pain VAS 
scores separately.  The model will include device and injection location as fixed effects.  The 
least squares (LS) means and differences in LS means will be presented along with the 
corresponding 90% CI overall and by location as subgroups.  The distribution of the data will be 
explored prior to analysis to determine whether data transformation is required.  It is possible 
that the pain scores will be 0, so if the distribution of the data implies that a log-transformation is 
required then the score may be updated to log(VAS+1) to allow for the inclusion of the 0 values 
in the analysis.  If the assumptions of this model appear violated, a non-parametric method may 
be used.
10.3.1.2.2.Duration of Injection
The duration of the injection (measured in seconds) will be summarized for each drug delivery 
device for each injection site.


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10.3.1.2.3.Injection-Site Assessments
The incidence of the following AEs will be listed and summarized for each drug delivery device 
for each injection site: erythema, induration, pruritus, and edema.  Occurrence of bleeding will 
be listed.  
10.3.1.2.4.Statistical Evaluation of Other Safety Parameters
Other safety parameters that will be assessed include clinical laboratory parameters and vital 
signs.  The parameters and changes from baseline (predose), where appropriate, will be listed 
and summarized using standard descriptive statistics.  Additional analyses will be performed if
warranted upon review of the data.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for LY3074828 will be calculated by standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be AUC(0-∞), AUC(0-tlast), and Cmax for LY3074828.  
The secondary parameter for analysis will be the time to maximum observed drug concentration 
(tmax) of LY3074828.  Other noncompartmental parameters, such as half-life associated with the 
terminal rate constant (t1/2), apparent total body clearance of drug calculated after extra-vascular 
administration (CL/F), and apparent volume of distribution during the terminal phase after 
extra-vascular administration (Vz/F), may be reported.
10.3.2.2. Pharmacokinetic Statistical Inference
The AUC(0-∞), AUC(0-tlast), and Cmax will be log-transformed and analyzed using a linear 
fixed-effects model.  The model will include device and injection location as fixed effects.  The 
dosing regimen differences between AI and PFS administrations will be back-transformed to 
present the ratios of geometric LS means and the corresponding 90% CI.  Comparisons will be 
made between the 2 devices and then between the 3 injection locations.
The tmax of LY3074828 between AI and PFS administrations will be analyzed using a Wilcoxon 
rank sum test.  Estimates of the median difference, 90% CIs, and p-values from the Wilcoxon 
rank sum test will be calculated.
Additional PK analyses may be conducted if deemed appropriate.
10.3.3. Pharmacodynamic Analyses
This section is not applicable for this study.
10.3.4. Pharmacokinetic/Pharmacodynamic Analyses
This section is not applicable for this study.


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10.3.5. Evaluation of Immunogenicity
The frequency of formation of antibodies to LY3074828 will be determined.  
Treatment-emergent ADAs are those that are induced or boosted by exposure to study drug, with 
a 4-fold or greater increase in titer compared to baseline if ADAs were detected at baseline, or a 
titer 2-fold greater than the minimum required dilution (1:10) if no ADAs were detected at 
baseline.
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) will be assessed.  Likewise, the relationship between the presence of 
antibodies and the PK parameters or concentrations of LY3074828 may be assessed if deemed 
appropriate.
10.3.6. Data Review During the Study
Data may be accessed and analyzed while the trial is ongoing, but no changes to the study design 
are planned.  An assessment committee will not be formed.
Available safety data will be reviewed at approximately Day 30 of the last cohort dosed in order 
to review emerging safety and tolerability data.
10.3.7. Interim Analyses
No formal interim analysis will be conducted. Data may be accessed as described in 
Section 10.3.6.


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11.
References
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.
Crow JM. Therapeutics: silencing psoriasis. Nature. 2012;492(7429):S58-S59.
Di Cesare A, Di Meglio P, Nestle FO. The IL-23/Th17 axis in the immunopathogenesis of 
psoriasis. J Invest Dermatol. 2009;129(6):1339-1350.
Lew W, Bowcock AM, Krueger JG. Psoriasis vulgaris: cutaneous lymphoid tissue supports 
T-cell activation and “Type 1” inflammatory gene expression. Trends Immunol. 
2004;25(6):295-305.
Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361(5):496-509.
Perera GK, Di Meglio P, Nestle FO. Psoriasis. Annu Rev Pathol. 2012;7:385-422.
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.
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, Brown 
SG, Camargo CA Jr, Cydulka R, Galli SJ, Gidudu J, Gruchalla RS, Harlor AD Jr, Hepner DL, 
Lewis LM, Lieberman PL, Metcalfe DD, O'Connor R, Muraro A, Rudman A, Schmitt C, 
Scherrer D, Simons FE, Thomas S, Wood JP, Decker WW. Second symposium on the 
definition and management of anaphylaxis: summary report - Second National Institute of 
Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy 
Clin Immunol. 2006;117(2):391-397.
Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of 
T cell-mediated tissue damage. Nat Med. 2007;13(2):139-145.
Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding 
diversity of effector T cell lineages. Annu Rev Immunol. 2007;25:821-852.
Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin 
Nurs. 2005;14(7):798-804.


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
ADA
anti-drug 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.
AI
autoinjector
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AUC
area under the concentration versus time curve
AUC(0-∞)
area under the concentration versus time curve from time zero to infinity
AUC(0-tlast)
area under the concentration versus time curve from time zero to time t, where t is the last 
sample with a measurable concentration
BMI
body mass index
CI
confidence interval
Cmax
maximum observed drug concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CP
clinical pharmacologist
CRP
clinical research physician
CRU
clinical research unit
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation


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LY3074828
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Subjects entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
GCP
good clinical practice
GPS
Global Patient Safety
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IFU
Instructions for Use
IL
interleukin
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the 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 study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
IP
investigational product:  A pharmaceutical form of an active ingredient or placebo being 
tested or used as a reference in a clinical study, including products already on the market 
when used or assembled (formulated or packaged) in a way different from the authorized 
form, or marketed products used for an unauthorized indication, or marketed products used 
to gain further information about the authorized form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
IRB
institutional review board
ISR
injection-site reaction
IV
intravenous(ly)
LS
least squares
open-label
A study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study participant are aware of the drug therapy received during the 
study.
PC
product complaint


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PFS
pre-filled syringe
PK
pharmacokinetic(s)
randomize
The process of assigning subjects/patients to an experimental group on a random basis.
SAE
serious adverse event
SC
subcutaneous(ly)
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SUSARs
suspected unexpected serious adverse reactions 
TB
tuberculosis
TBL
total bilirubin
TE-ADA
treatment-emergent anti-drug antibody
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment.
Th
T helper
tmax
time to maximum observed drug concentration
ULN
upper limit of normal
VAS
visual analog scale


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematologya
Clinical Chemistrya
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Calcium
Mean cell volume 
Phosphorus
Mean cell hemoglobin 
Glucose (random)
Mean cell hemoglobin concentration 
Blood urea nitrogen (BUN)
Leukocytes (WBC)
Uric acid
Cell morphology
Total cholesterol
Absolute counts of:
Total protein
Neutrophils
Albumin
Lymphocytes
Total bilirubinc
Monocytes
Alkaline phosphatase (ALP)
Eosinophils
Aspartate aminotransferase (AST)
Basophils
Alanine aminotransferase (ALT)
Platelets
Creatinine
Creatine phosphokinase (CPK)d
Urinalysisa
Ethanol testinge
Specific gravity
Urine drug screene
pH
QuantiFERON-TB Gold testa,f
Protein
Glucose
Serologyf
Ketones
Hepatitis B surface antigen
Bilirubin
Hepatitis C antibody
Urobilinogen
HIV antibodies
Blood
Nitrite
Serum pregnancy testg,h
Microscopic examination of sedimentb
Hormone panel
Follicle-stimulating hormone f,i
Abbreviations:  HIV = human immunodeficiency virus; RBC = red blood cells; TB = tuberculosis; WBC = white 
blood cells.
a
Results will be validated by the local laboratory at the time of initial testing.
b
If clinically indicated, per investigator’s discretion.
c
If total bilirubin is elevated, direct bilirubin and indirect bilirubin may be measured.
d
Not collected routinely as part of clinical chemistry panel. Only collected when specified in Schedule of 
Activities (Section 2).
e
Urine drug screen and ethanol level (determined via breath, blood, or urine testing) will be performed locally at 
screening and on Day -1 during admission to the clinical research unit.  May be repeated at the discretion of the 
investigator. 
f
Performed at screening only.
g
For all females at screening, and only for women of childbearing potential at sampling time points thereafter.
h
Refer to Section 2 for specific sampling timing.
i
To confirm postmenopausal status (see Section 6.1, inclusion criterion 1b) 


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


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Regulatory Considerations
This study will be conducted in accordance with the protocol and with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences International Ethical Guidelines 
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations.
Some of the obligations of the sponsor will be assigned to a third-party organization.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the electronic case report forms 
(eCRFs), and study procedures

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate eCRF data and/or use standard computer edits to detect errors in data 
collection

conduct a quality review of the database.


I6T-MC-AMBE Clinical Pharmacology Protocol
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LY3074828
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 IRBs with direct access to the original source 
documents.
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.  
The purpose and use of subject personal information collected will be provided in a written 
document to the subject by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the IRB
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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LY3074828
Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with subjects in consultation with Lilly or its designee clinical research 
physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis C antibody
Hepatic Chemistrya
Hepatitis E antibody, IgG
Total bilirubin
Hepatitis E antibody, IgM
Conjugated bilirubin
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
Alkaline phosphatase isoenzymesa
GGT
CPK 
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


I6T-MC-AMBE Clinical Pharmacology Protocol
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LY3074828
Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol I6T-MC-AMBE Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
22.5
1
22.5
Clinical laboratory testsa
12.5
5
62.5
Pharmacokineticsb
2
17
34
Immunogenicitya
10
5
50
Pregnancy tests
3.5
4
14
Pharmacogenetics
10
1
10
Total
193
Total for clinical purposes [rounded up to nearest 10 mL]
200
a
Additional samples may be drawn if needed for safety purposes.
b
Includes a potential 3 additional samples to be matched to additional immunogenicity samples (see 
Section 9.6.1).


P P D
L e o  D o c u m e n t  I D  =  6 a 6 9 f 3 1 c - 0 b 0 3 - 4 1 1 5 - 8 f 9 e - f 4 b b 1 e d e 4 f 5 5
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 3 - D e c - 2 0 1 8  2 1 : 1 0 : 2 7  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 7 - D e c - 2 0 1 8  1 6 : 0 7 : 2 6  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D

SAP_001.pdf: 
Statistical Analysis Plan I6T-MC-AMBE 
 
A Safety, Tolerability, and Pharmacokinetic Study of Injections of LY3074828 Solution Using 
Investigational 1-mL Pre-filled Syringes and Investigational 1-mL Autoinjector in Healthy 
Subjects 
 
NCT03886948 
 
Approval Date: 04-Mar-2019 


Final, 28 February 2019 
Page 1 of 16
STATISTICAL ANALYSIS PLAN
A Safety, Tolerability, and Pharmacokinetic Study of Injections of LY3074828 Solution 
Using Investigational 1-mL Pre-filled Syringes and Investigational 1-mL Autoinjector in 
Healthy Subjects
Statistical Analysis Plan Status: Final
Statistical Analysis Plan Date: 28-February-2019
Study Drug: LY3074828
Sponsor Reference: I6T-MC-AMBE
Covance CRU Study: 1000071-8379029
Clinical Phase I
Approval Date: 04-Mar-2019 GMT


Final, 28 February 2019 
Page 2 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1000071-8379029
Sponsor Reference: I6T-MC-AMBE
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS .....................................................................................................2
2.
ABBREVIATIONS..............................................................................................................3
3.
INTRODUCTION ...............................................................................................................5
4.
STUDY OBJECTIVES........................................................................................................5
4.1
Primary Objectives ........................................................................................................5
4.2
Secondary Objective......................................................................................................5
5.
STUDY DESIGN.................................................................................................................5
6.
TREATMENTS...................................................................................................................6
7.
SAMPLE SIZE JUSTIFICATION .......................................................................................7
8.
DEFINITION OF ANALYSIS POPULATIONS..................................................................7
9.
STATISTICAL METHODOLOGY .....................................................................................8
9.1
General..........................................................................................................................8
9.2
Demographics and Subject Disposition..........................................................................8
9.3
Pharmacokinetic Assessment.........................................................................................8
9.3.1
Pharmacokinetic Analysis.....................................................................................8
9.3.2
Pharmacokinetic Statistical Methodology ...........................................................12
9.4
Safety and Tolerability Assessments............................................................................13
9.4.1
Adverse events ...................................................................................................13
9.4.2
Concomitant medication.....................................................................................13
9.4.3
Clinical laboratory parameters............................................................................13
9.4.4
Vital signs ..........................................................................................................13
9.4.5
Electrocardiogram (ECG)...................................................................................14
9.4.6
Injection-Site Pain ..............................................................................................14
9.4.7
Injection-Site Reactions......................................................................................14
9.4.8
Injection Duration...............................................................................................15
9.4.9
Immunogenicity .................................................................................................15
9.4.10
Hepatic Monitoring ............................................................................................15
9.4.11
Other assessments...............................................................................................15
10. INTERIM ANALYSES .....................................................................................................16
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............16
12. REFERENCES ..................................................................................................................16
13. DATA PRESENTATION ..................................................................................................16
13.1 Derived Parameters .....................................................................................................16
13.2 Missing Data ...............................................................................................................16
13.3 Insufficient Data for Presentation ................................................................................16


Final, 28 February 2019 
Page 3 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1000071-8379029
Sponsor Reference: I6T-MC-AMBE
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
ADA
Anti-drug antibody
AI
Autoinjector
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
%AUC(tlast-)
Percentage of AUC(0-∞) extrapolated
BQL
Below the lower limit of quantitation
Cmax
Maximum observed drug concentration
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
ICH
International Conference on Harmonisation
LLOQ
Lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
PC
Product complaint
PFS
Pre-filled syringe
PK
Pharmacokinetic


Final, 28 February 2019 
Page 4 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1000071-8379029
Sponsor Reference: I6T-MC-AMBE
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard deviation 
SOP
Standard Operating Procedure
TBL
Total bilirubin
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
VAS
Visual analog scale
Vss/F
apparent volume of distribution at steady state after extra-vascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


Final, 28 February 2019 
Page 5 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1000071-8379029
Sponsor Reference: I6T-MC-AMBE
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
17 December 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
4.1
Primary Objectives

To evaluate the PK after subcutaneous (SC) administration of 125-mg doses of 
LY3074828 solution formulation using a 1-mL pre-filled syringe (PFS) and a 1-mL 
autoinjector (AI) injector in healthy subjects.

To assess pain associated with LY3074828 PFS and AI SC administrations in healthy 
subjects at 3 different injection sites (arm, thigh, and abdomen).
4.2
Secondary Objective

To assess the safety and tolerability of LY3074828 in healthy subjects.
5. STUDY DESIGN
Study I6T-MC-AMBE (AMBE) is a single-center, randomized, parallel-arm, open-label, Phase 1 
single-dose study of LY3074828 solution formulation in healthy subjects. Pharmacokinetics, 


Final, 28 February 2019 
Page 6 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1000071-8379029
Sponsor Reference: I6T-MC-AMBE
safety and tolerability of, and pain associated with, 125-mg SC doses administered using a PFS 
or AI at 3 different injection sites will be evaluated.
Screening Period (≤28 days): Subjects will be evaluated for study eligibility ≤28 days prior to
enrollment.
Residential Period (2 days): A total of approximately 66 subjects who fulfill the eligibility 
criteria will be randomized to 1 of 6 dosing regimen arms, with 11 subjects randomized to each 
arm to ensure completion of 10 subjects in each:

Test 1: 1-mL AI injector containing 125 mg LY3074828 solution to be administered in 
the arm

Test 2: 1-mL AI injector containing 125 mg LY3074828 solution to be administered in 
the thigh

Test 3: 1-mL AI injector containing 125 mg LY3074828 solution to be administered in 
the abdomen

Reference 1: 1-mL PFS containing 125 mg LY3074828 solution to be administered in the 
arm

Reference 2: 1-mL PFS containing 125 mg LY3074828 solution to be administered in the 
thigh

Reference 3: 1-mL PFS containing 125 mg LY3074828 solution to be administered in the 
abdomen
Subjects will report to the clinical research unit (CRU) on Day -1 and will remain at the CRU 
until the scheduled procedures have been completed on Day 2. Study drug will be administered 
by investigative site staff by SC injection per the randomization scheme in the morning of Day 1 
after an overnight fast.
Safety and tolerability will be assessed by clinical laboratory tests, vital sign measurements, 
12-lead electrocardiograms (ECGs), recording of AEs and product complaints (PCs), physical 
examinations/medical assessments, immunogenicity, and injection-site assessments. Pain 
assessments will be made using an injection-site pain visual analog scale (VAS).
Outpatient Follow-up Period (12 weeks): The follow-up period will include outpatient visits 
for a total of 12 weeks (Days 4, 8, 11, 15, 22, 29, 43, 57, 71, and 85) following dose 
administration on Day 1 to assess the PK, safety and tolerability of, and pain associated with 
LY3074828 PFS and AI administrations. Assessment of pain at the Follow-up visits does not 
include VAS score.
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.


Final, 28 February 2019 
Page 7 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1000071-8379029
Sponsor Reference: I6T-MC-AMBE
Study Treatment Name
Abbreviation
Treatment order in TFL
125 mg LY3074828 PFS (Arm)
Reference 1
1
125 mg LY3074828 PFS (Thigh)
Reference 2
2  
125 mg LY3074828 PFS (Abdomen)
Reference 3
3
125 mg LY3074828 AI (Arm)
Test 1
4
125 mg LY3074828 AI (Thigh)
Test 2
5
125 mg LY3074828 AI (Abdomen)
Test 3
6
Abbreviations: AI = Autoinjector; PFS = pre-filled syringe.
7. SAMPLE SIZE JUSTIFICATION
Approximately 66 subjects will be enrolled with a target of 60 subjects completing the study (10 
completers per treatment).
Data from AMAL (2 x 1-mL doses of 125 mg LY3074828) and AMAE (2 x 1-mL PFS doses of
125 mg LY3074828) studies showed that the geometric coefficient of variation (CV) ranged 
from 55% to 40% for the PK measurements (ie, area under the concentration versus time curve 
[AUC] from time zero to infinity [AUC(0-∞)], AUC from time zero to time t, where t is the last 
sample with a measurable concentration [AUC(0-tlast)], and maximum observed drug 
concentration [Cmax]). Thus, the geometric coefficient of variation was assumed to be 55% when 
calculating precision.
A sample size of 60 subjects will provide a precision (ie, half-width of 90% of confidence 
interval [CI] with a coverage probability of 90%), in log scale, of approximately 0.48 for the 
geometric means ratio of reference versus test for AUC(0-∞), AUC(0-tlast), and Cmax. 
Equivalently, there is a 90% probability that the distance between the lower limit of the 90% CI 
and the point estimate of the geometric means ratio is not larger than 38%.
Subjects who are randomized but not administered treatment, or subjects (maximum of 2 
subjects per dose regimen arm) that are administered treatment but do not have PK and anti-drug 
antibody (ADA) samples collected up to and including Day 57, may be replaced to ensure that 
approximately 10 subjects from each treatment arm may complete the study.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all subjects who received at least one dose of 
LY3074828 and have at least one postdose safety assessment.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
LY3074828 and have evaluable PK data.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1000071-8379029
Sponsor Reference: I6T-MC-AMBE
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: AUCs and Cmax) the geometric 
mean and geometric CV% will also be presented. For categorical data, frequency count and 
percentages will be presented. Data listings will be provided for all subjects up to the point of 
withdrawal, with any subjects excluded from the relevant population highlighted. Summary 
statistics and statistical analyses will generally only be performed for subjects included in the 
relevant analysis population. For the calculation of summary statistics and statistical analysis, 
unrounded data will be used. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, country of 
enrolment, site ID, body weight, height and body mass index will be summarized and listed.
All other demographic variables will be listed only.
9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
The PK parameter estimates will be determined using non-compartmental procedures in 
validated software program (Phoenix WinNonlin Version 8.1 or later).
Serum concentrations of LY3074828 will be used to determine the following PK parameters, 
when possible: 


Final, 28 February 2019 
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1000071-8379029
Sponsor Reference: I6T-MC-AMBE
Parameter
Units
Definition
AUC(0-tlast)
day*µg/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
AUC(0-∞)
day*µg/mL
area under the concentration versus time curve from time zero to 
infinity
%AUC(tlast-)
%
percentage of AUC(0-∞) extrapolated
Cmax
µg/mL
maximum observed drug concentration
tmax
day
time of maximum observed drug concentration
t1/2
day
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/day
apparent total body clearance of drug calculated after 
extra-vascular administration
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vss/F
L
apparent volume of distribution at steady state after extra-vascular
administration
Additional PK parameters may be calculated, as appropriate. The software and version used for 
the final analyses will be specified in the clinical study report. Any exceptions or special 
handling of data will be clearly documented within the final study report.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero.

Cmax and tmax will be reported from observed values. If Cmax occurs at more than one time 
point, tmax will be assigned to the first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule). The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive concentrations above the lower limit of quantitation (LLOQ), with at least 
one of these concentrations following Cmax.

AUC(0-) values where the percentage of the total area extrapolated is more than 20% 
will be flagged. Any AUC(0-) value excluded from summary statistics will be noted in 
the footnote of the summary table.


Final, 28 February 2019 
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1000071-8379029
Sponsor Reference: I6T-MC-AMBE

Half-life (t½) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 
phase for each subject will be defined by visual inspection and generally will be the first 
point at which there is no systematic deviation from the log-linear decline in serum 
concentrations. Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points. If t½ is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t½ value excluded from summary statistics will be documented in the footnote of the 
summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal 
log-linear portion of the concentration-time curve.

The parameters based on observed Clast will be reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL). Serum concentrations reported as BQL will be set to a value of zero
when all of the following conditions are met:
o
The compound is non-endogenous.
o
The samples are from the initial dose period for a subject or from a subsequent 
dose period following a suitable wash-out period.
o
The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing.

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times.


Final, 28 February 2019 
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1000071-8379029
Sponsor Reference: I6T-MC-AMBE

The average concentration profiles will be graphed using arithmetic average 
concentrations.

The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero. Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations.

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the final study 
report.

A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements that are within the 
sampling time window specified in the protocol or ± 10%. An average concentration 
estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all PK analyses is not a requirement. Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate. This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis. The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:

For PK profiles during single dosing of non-endogenous compounds, the concentration in 
a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum.
Data between Individual Profiles
1.
If n<6, then the dataset is too small to conduct a reliable range test. Data will be analyzed 
with and without the atypical value, and both sets of results will be reported. 
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.


Final, 28 February 2019 
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1000071-8379029
Sponsor Reference: I6T-MC-AMBE
b. Find the most extreme value from the arithmetic mean of the log transformed
values and exclude that value from the dataset.
c.
Calculate the lower and upper bounds of the range defined by the arithmetic 
mean ±3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is 
not an outlier and will be retained in the dataset.
e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is 
an outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values.
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final report. Approval of the 
final report will connote approval of the exclusion.
9.3.2
Pharmacokinetic Statistical Methodology
The AUC(0-∞), AUC(0-tlast), and Cmax will be log-transformed and analyzed using a linear 
fixed-effects model. The model will include device and injection site as fixed effects. The 
differences between the AI (Test) and PFS (Reference) will be back-transformed to present the 
ratios of geometric least squares means and the corresponding 90% CI.
Example SAS code:
proc mixed data=datain alpha=0.1;
   class device inj_site;
   model log_pk = device inj_site / ddfm=kr alpha=0.1;
   lsmeans device / pdiff cl alpha=0.1;
   ods output lsmeans=lsmeans;
   ods output diffs=diffs;
run;
The tmax of LY3074828 between AI and PFS administrations will be analyzed using a Wilcoxon 
rank sum test. Estimates of the median difference, 90% CIs, and p-values from the Wilcoxon 
rank sum test will be calculated. 
In addition, the following comparisons will also be made:

AI versus PFS separately at each injection site (injection site will be removed from the 
model above)


Final, 28 February 2019 
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1000071-8379029
Sponsor Reference: I6T-MC-AMBE

Arm versus abdomen and thigh versus abdomen separately for each device (device will 
be removed from the model above)
Additional PK analyses may 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 and PCs will be listed. Treatment-emergent AEs will be summarized by 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 treatment, Medical Dictionary for Regulatory 
Activities (MedDRA) version 21.1 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 listed. 
9.4.2
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2018). 
Concomitant medication will be listed.
9.4.3
Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by parameter and treatment, and 
listed. Urinalysis data will be listed. Changes from baseline, Day -1, will also be presented. 
Additionally clinical chemistry, hematology and urinalysis data outside the reference ranges will 
be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.
9.4.4
Vital signs
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as Day 1 predose. Figures of mean vital signs and mean changes from 
baseline will be presented by treatment. 
Furthermore, values for individual subjects will be listed.


Final, 28 February 2019 
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1000071-8379029
Sponsor Reference: I6T-MC-AMBE
9.4.5
Electrocardiogram (ECG)
ECGs will be performed for safety monitoring purposes and will not be presented. Any clinically 
relevant findings will be reported as an AE.
9.4.6
Injection-Site Pain
Intensity of pain data will be quantified using a 100-mm validated VAS. The data will be listed 
and summarized by treatment and time point. In addition, the scores will be categorized into mild 
(0- to 30-mm), moderate (31- to 70-mm), and severe (71- to 100-mm), and presented in 
frequency tables by treatment and timepoint. Furthermore, scatter plots of the 1 minute, 5 
minute, and 15-minute VAS scores will be presented by treatment and time point.
A linear fixed-effects model will be used to analyze the 1- and 5-minute post-injection pain VAS
scores separately. The model will include device and injection site as fixed effects. The least 
squares means and differences between the AI (Test) and PFS (Reference) will be presented 
along with the corresponding 90% CI for the difference.
If the assumptions of this model appear to be violated, a non-parametric method may be used.
The distribution of the data will be explored prior to analysis to determine whether data 
transformation is required. It is possible that the pain scores will be 0, so if the distribution of the 
data implies that a log-transformation is required then the score may be updated to log(VAS+1) 
to allow for the inclusion of the 0 values in the analysis. If the assumptions of this model appear 
violated, a non-parametric method may be used.
The above analyses will also be repeated for each injection site separately.
SAS code similar to Section 9.3.2 will be used for this model.
9.4.7
Injection-Site Reactions
Injection-site reactions will be evaluated through the collection of pain assessments and specific 
site assessments for local tolerability, which will evaluate erythema, induration, pruritus, and 
edema. Data from injection-site evaluations (including pain), which are recorded as a result of 
specific questionnaires, will not be reported as AEs. However, injection site reactions may be 
reported as AEs if:
a) Spontaneously reported by a subject.
b) At the discretion of the principal investigator.
Injection-site reaction data will be listed and reactions reported as AEs will be summarized by 
treatment in frequency tables.
Any bruising or bleeding from the injection site will also be listed.


Final, 28 February 2019 
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1000071-8379029
Sponsor Reference: I6T-MC-AMBE
9.4.8
Injection Duration
The duration of the injection (measured in seconds) will be summarized by treatment and listed.
9.4.9
Immunogenicity
Immunogenicity data will be listed and frequency tables will be presented. The frequency of 
treatment-emergent ADAs will also be calculated. Treatment-emergent ADAs are those that are 
induced or boosted by exposure to study drug, with a 4-fold increase in titer compared to 
baseline if ADAs were detected at baseline or a titer 2-fold greater than the minimum required 
dilution (1:10) if no ADAs were detected at baseline.
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) will be assessed. Likewise, the relationship between the presence of antibodies 
and the PK parameters or concentrations of LY3074828 may be assessed if deemed appropriate.
9.4.10
Hepatic Monitoring
If a study subject experiences elevated alanine aminotransferase (ALT) ≥3× upper limit of 
normal (ULN), alkaline phosphatase (ALP) ≥2× ULN, or elevated total bilirubin 
(TBL) ≥2× ULN, liver tests should be repeated within 3 to 5 days including ALT, aspartate 
aminotransferase, ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine 
phosphokinase to confirm the abnormality and to determine if it is increasing or decreasing. 
Monitoring should continue until levels normalize and/or are returning to approximate baseline 
levels.
Additional safety data may be collected if required, as defined in the protocol. Where applicable, 
the following will be presented.
The subjects’ liver disease history and associated person liver disease history data will be listed. 
Any concomitant medication of acetaminophen/paracetamol will be listed. Results from a 
magnetic resonance elastography scan and biopsy assessment will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual subject data listings.
9.4.11
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analysed.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1000071-8379029
Sponsor Reference: I6T-MC-AMBE
10.
INTERIM ANALYSES
No formal interim analysis will be conducted. However, data may be accessed and analyzed 
while the trial is ongoing, but no changes to the study design are planned. An assessment 
committee will not be formed.
Available safety data will be reviewed at approximately Day 30 of the last cohort dosed in order
to review emerging safety and tolerability data.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = 3e3784ea-070a-42f6-aaa2-02560cd023fe
Approver: 
Approval Date & Time: 01-Mar-2019 09:32:04 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 01-Mar-2019 09:52:34 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 01-Mar-2019 13:30:37 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 04-Mar-2019 21:02:20 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD