Relative Bioavailability of 2 Ixekizumab Test Formulations Compared to the Commercial Formulation in Healthy Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

I1F-MC-RHCT (b) Clinical Pharmacology Protocol  
 
Relative Bioavailability of 2 Ixekizumab Test Formulations Compared to the Commercial 
Formulation in Healthy Subjects 
 
NCT03848416 
 
Approval Date: 09-May-2019 
 
 
 

I1F-MC-RHCT (b) Clinical Pharmacology Protocol
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Ixekizumab (LY2439821)
Protocol I1F-MC-RHCT (b)
Relative Bioavailability of 2 Ixekizumab Test Formulations 
Compared to the Commercial Formulation in Healthy 
Subjects
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
ixekizumab (LY2439821), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act Exemption 4 and 
may not be reproduced or otherwise disseminated without the written approval of Eli Lilly 
and Company or its subsidiaries.  
Ixekizumab (LY2439821)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly:  
19 September 2018
Amendment (a) Electronically Signed and Approved by Lilly:  15 November 2018
Amendment (b) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 09-May-2019 GMT

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Ixekizumab (LY2439821)
Table of Contents
Relative Bioavailability of 2 Ixekizumab Test Formulations 
Compared to the Commercial Formulation in Healthy 
Subjects
Section
Page
Protocol I1F-MC-RHCT (b) Relative Bioavailability of 2 Ixekizumab Test 
Formulations Compared to the Commercial Formulation in Healthy 
Subjects ..............................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................7
2.
Schedule of Activities .........................................................................................................9
3.
Introduction ......................................................................................................................14
3.1.
Study Rationale............................................................................................................14
3.2.
Background..................................................................................................................14
3.3.
Benefit/Risk Assessment..............................................................................................14
4.
Objectives and Endpoints..................................................................................................16
5.
Study Design.....................................................................................................................17
5.1.
Overall Design .............................................................................................................17
5.2.
Number of Participants.................................................................................................17
5.3.
End of Study Definition ...............................................................................................17
5.4.
Scientific Rationale for Study Design...........................................................................17
5.5.
Justification for Dose ...................................................................................................18
6.
Study Population...............................................................................................................19
6.1.
Inclusion Criteria..........................................................................................................19
6.2.
Exclusion Criteria ........................................................................................................21
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................24
6.3.
Lifestyle and/or Dietary Requirements .........................................................................24
6.3.1.
Meals and Dietary Restrictions.............................................................................24
6.3.2.
Alcohol and Tobacco ...........................................................................................25
6.3.3.
Activity................................................................................................................25
6.4.
Screen Failures.............................................................................................................25
7.
Treatment..........................................................................................................................26
7.1.
Treatment Administered...............................................................................................26
7.1.1.
Packaging and Labeling .......................................................................................26
7.2.
Method of Treatment Assignment ................................................................................27
7.2.1.
Selection and Timing of Doses.............................................................................27

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Ixekizumab (LY2439821)
7.3.
Blinding .......................................................................................................................27
7.4.
Dose Modification........................................................................................................27
7.4.1.
Special Treatment Considerations ........................................................................27
7.5.
Preparation/Handling/Storage/Accountability...............................................................27
7.6.
Treatment Compliance .................................................................................................28
7.7.
Concomitant Therapy...................................................................................................28
7.8.
Treatment After the End of the Study...........................................................................28
8.
Discontinuation Criteria ....................................................................................................29
8.1.
Discontinuation from Study Treatment.........................................................................29
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................29
8.2.
Discontinuation from the Study....................................................................................29
8.3.
Subjects Lost to Follow-up...........................................................................................29
9.
Study Assessments and Procedures ...................................................................................30
9.1.
Efficacy Assessments...................................................................................................30
9.2.
Adverse Events ............................................................................................................30
9.2.1.
Serious Adverse Events........................................................................................31
9.2.1.1.
Adverse Events of Special Interest..................................................................31
9.2.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................32
9.2.2.
Complaint Handling.............................................................................................32
9.3.
Treatment of Overdose.................................................................................................33
9.4.
Safety...........................................................................................................................33
9.4.1.
Laboratory Tests ..................................................................................................33
9.4.2.
Vital Signs ...........................................................................................................33
9.4.3.
Electrocardiograms ..............................................................................................34
9.4.4.
Temperature.........................................................................................................34
9.4.5.
Other Tests...........................................................................................................34
9.4.5.1.
Injection-Site Assessments .............................................................................34
9.4.5.2.
Bleeding/Bruising Assessment........................................................................34
9.4.5.3.
Injection-Site Pain ..........................................................................................34
9.4.5.4.
Columbia Suicide Severity Rating Scale.........................................................35
9.4.5.4.1.
Hospital Anxiety Depression Scale ...........................................................35
9.4.6.
Safety Monitoring ................................................................................................35
9.4.6.1.
Hepatic Safety................................................................................................35
9.5.
Pharmacokinetics .........................................................................................................36
9.5.1.
Bioanalysis...........................................................................................................36
9.6.
Pharmacodynamics ......................................................................................................36
9.6.1.
Immunogenicity Assessments ..............................................................................36
9.7.
Genetics .......................................................................................................................37

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Ixekizumab (LY2439821)
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....................................................................................................38
10.3.1.1.
Clinical Evaluation of Safety..........................................................................38
10.3.1.2.
Statistical Evaluation of Safety.......................................................................39
10.3.1.2.1.
Injection-Site Pain ....................................................................................39
10.3.1.2.2.
Statistical Evaluation of Other Safety Parameters......................................39
10.3.2.
Pharmacokinetic Analyses....................................................................................39
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................39
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................40
10.3.3.
Evaluation of Immunogenicity .............................................................................40
10.3.4.
Data Review During the Study.............................................................................40
10.3.5.
Interim Analyses..................................................................................................40
11.
References ........................................................................................................................41

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Ixekizumab (LY2439821)
List of Tables
Table
Page
Table RHCT.1.
Objectives and Endpoints .......................................................................16
Table RHCT.2.
Treatments Administered........................................................................26

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Ixekizumab (LY2439821)
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................42
Appendix 2.
Clinical Laboratory Tests........................................................................46
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................47
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............50
Appendix 5.
Blood Sampling Summary......................................................................51
Appendix 6.
Protocol Amendment I1F-MC-RHCT (b) Summary:  Relative 
Bioavailability of 2 Ixekizumab Test Formulations Compared to 
the Commercial Formulation in Healthy Subjects ...................................52

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Ixekizumab (LY2439821)
1. Protocol Synopsis
Title of Study:
Relative Bioavailability of 2 Ixekizumab Test Formulations Compared to the Commercial Formulation in Healthy 
Subjects
Rationale: 
Changes in buffer composition are being investigated as a potential way to address injection-site pain reported for 
ixekizumab.  Study I1F-MC-RHCT is therefore being conducted to compare the relative bioavailability and 
tolerability of ixekizumab administered using 2 new formulations compared to the marketed formulation.  
Objective(s)/Endpoints:  
Objectives
Endpoints
Primary
To evaluate the relative bioavailability of a single 
80 mg subcutaneous (SC) dose of ixekizumab Test 
Formulation 1 and Test Formulation 2 compared to the 
commercial formulation (Reference)
Maximum observed drug concentration (Cmax), area 
under the concentrations versus time curve from time 
zero to infinity (AUC[0-∞]), 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-tlast])
Secondary
To evaluate the safety and tolerability of a single 
80 mg SC dose of ixekizumab Test Formulation 1 and 
Test Formulation 2 compared to the commercial 
formulation (Reference)
Treatment-emergent adverse events (TEAEs), serious 
adverse events (SAEs), injection-site reactions (ISRs), 
and visual analog scale (VAS) pain score immediately 
after injection
Summary of Study Design:  
Study I1F-MC-RHCT is a Phase 1, subject-blind, 3-arm, randomized, parallel-design study in healthy subjects.  
Eligible subjects will be admitted to the clinical research unit (CRU) on Day -1 and randomized 1:1:1 to 1 of 
3 possible treatments.  Subjects may be allowed to leave the CRU after completing the 4-hour safety assessments on 
Day 1, at the investigator’s discretion, and will return for pharmacokinetic (PK) and immunogenicity sampling and 
safety assessments at predefined times up to 12 weeks postdose.  Subjects will be monitored for safety between 
outpatient visits by way of telephone assessment.
Safety and tolerability will be assessed by clinical laboratory tests, vital sign measurements, temperature, recording 
of adverse events (AEs), physical examination/medical assessments, Columbia Suicide Severity Rating Scale
(C-SSRS), Hospital Anxiety Depression Scale (HADS), immunogenicity, and injection-site assessments.  Pain 
assessments will be made using an injection-site VAS. 

I1F-MC-RHCT (b) Clinical Pharmacology Protocol
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Ixekizumab (LY2439821)
Treatment Arms and Planned Duration for an Individual subject:  
All subjects will be screened within 28 days prior to enrollment.  On Day 1, subjects will receive a single 
subcutaneous (SC) dose of 1 of the following treatments, according to the randomization schedule:  

80 mg ixekizumab Test Formulation 1

80 mg ixekizumab Test Formulation 2

80 mg ixekizumab Commercial Formulation (Reference).  
Subjects will participate in the study for up to 12 weeks postdose.  
Number of Subjects:
Up to 99 subjects may be enrolled so that 78 subjects (26 in each treatment arm) complete the study.  
Statistical Analysis:
Pharmacokinetic parameters will be evaluated to estimate relative bioavailability.  Log-transformed Cmax and AUC 
parameters will be evaluated in a linear mixed-effects model with fixed effects for formulation, and a random effect 
for subject.  The treatment differences will be back-transformed to present the ratios of geometric means and the 
corresponding 90% CI.  
The tmax will be analyzed using a Wilcoxon rank sum test.  Estimates of the median difference based on the 
observed medians, 90% CIs and p-values from the Wilcoxon rank sum test will be calculated.
Safety parameters will be listed and summarized using standard descriptive statistics, where possible.  Injection-site 
assessments, including induration, swelling, pruritis, bleeding/bruising, and erythema/redness, will also be assessed.  
The parameters will be listed and summarized using descriptive statistics.  Suicidal ideation and/or behavior and 
self-injurious behavior with no suicidal intent, based on the C-SSRS, will be listed by subject.  HADS item scores 
will be listed for subjects with HADS depression subscale ≥11 at any time.  VAS pain score will be summarized 
using standard descriptive statistics.  In addition, the severity of pain will be categorized by VAS pain score as: mild 
pain (≤ 30), moderate pain (> 30 and ≤ 70), and severe pain (> 70).  The number and percentage of the subjects in 
each pain severity category will summarized by formulation and time point.
The frequency and percentage of subjects with preexisting anti-drug antibodies (ADA) and with treatment-emergent 
ADA (TE ADA) to ixekizumab will be tabulated.  Treatment-emergent ADAs are defined as those with a titer 2-fold 
(1 dilution) greater than the minimum required dilution if no ADAs were detected at baseline (treatment-induced 
ADA) or those with a 4-fold (2 dilutions) increase in titer compared to baseline if ADAs were detected at baseline 
(treatment-boosted ADA).  For the TE ADA+ subjects the distribution of maximum titers will be described.  The 
frequency of neutralizing antibodies will also be tabulated in TE ADA+ subjects.
Additional analysis will be performed if warranted upon review of the data.  

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Ixekizumab (LY2439821)
2. Schedule of Activities

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Ixekizumab (LY2439821)
Study Schedule Protocol I1F-MC-RHCT
Screening
Days
Comments
Procedure
-28 to -2 
days prior 
to Day 1
-1
1
3
5
±1d
8
±1d
11
±1d
15
±2d
22
±2d
29
±2d
36
±2d
43
±2d
50 
±2d
57
±3d
64 
± 3d
71
±3d
85/ED
±3d
Informed Consent
X
Medical History and 
Demographics
X
Review/Confirm 
Inclusion/Exclusion 
Criteria
X
X
Subject Admission to 
CRU
X
Subject Discharge 
from CRU
X
Subjects may be discharged 
after completion of the 4-hour 
safety assessments on Day 1, at 
the investigator’s discretion.
Outpatient Visit
X
X
X
X
X
X
X
X
X
X
X
Safety Assessment 
(Telephone Call)
X
X
X
Randomization
X
C-SSRS Lilly 
Self-Harm 
Supplement 
X
X
X
X
X
At screening ‘Baseline -
Screening’ questionnaire to be 
used, all other timepoints use 
‘Since Last Visit’ questionnaire.
HADS Depression 
sub-scale
X
X
X
X
X
Height, Weight, and 
BMI
X
X
Weight only at Day 85/ED.
Body Temperature
(Oral)
P
X
X
X
X
X
X
X
X
X
X
X

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Ixekizumab (LY2439821)
Screening
Days
Comments
Procedure
-28 to -2 
days prior 
to Day 1
-1
1
3
5
±1d
8
±1d
11
±1d
15
±2d
22
±2d
29
±2d
36
±2d
43
±2d
50 
±2d
57
±3d
64 
± 3d
71
±3d
85/ED
±3d
Physical Examination 
/Medical Assessment
X
X
X
Full physical 
examination/medical 
assessment at Screening.  
Symptom-directed 
examinations/assessments at 
other times, and as deemed 
necessary by the investigator.  
Vital Signs (sitting)
(hours)
X
X
P, 
2-4
X
X
X
Day 1 2-4 hour assessment to 
be conducted at least 2 hours 
postdose and prior to discharge 
at approximately 4 hours 
postdose.  Time points may be 
added if warranted and agreed 
upon between Lilly and the 
investigator.
Clinical Laboratory 
Tests
X
X
X
X
X
See Appendix 2, Clinical 
Laboratory Tests, for details.
Serology
X
See Appendix 2, Clinical 
Laboratory Tests, for details.
QuantiFERON®-TB 
Gold Test/TST
X
Urine Ethanol Test 
and Drug Screen
X
X
May be repeated at the 
discretion of the investigator.  
FSH Test
X
Females only, if applicable.
Pregnancy Test 
X
X
X
Females only.  Serum 
pregnancy test will be 
performed at screening.  Urine 
pregnancy test will be 
performed at all other times.
Single 12-lead ECG
X
Single Screening ECG.
Ixekizumab
X
Subjects will fast (water only 

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Ixekizumab (LY2439821)
Screening
Days
Comments
Procedure
-28 to -2 
days prior 
to Day 1
-1
1
3
5
±1d
8
±1d
11
±1d
15
±2d
22
±2d
29
±2d
36
±2d
43
±2d
50 
±2d
57
±3d
64 
± 3d
71
±3d
85/ED
±3d
Administration
allowed) from 1 hour before 
until 1 hour after dosing. 
Injection-Site 
Assessments 
(minutes)
0, 
10, 
20, 
30, 
60, 
120
, 
240
X
X
Assessments of induration, 
swelling, pruritus, and 
erythema/redness (collected as 
described in Section 9.4.5.1).  
0-minute time point should be 
done within ± 1 minute 
following injection; within ± 2 
minutes of the 10, 20, and 
30-minute time points; within ± 
5 minutes of the 60, 120, and 
240-minute time points.
Injection-site 
Bleeding/Bruising 
Assessment
(minutes)
0, 
10, 
20, 
30, 
60, 
120
, 
240
X
X
Observational assessment of 
injection-site bleeding and 
bruising.  0-minute time point
should be done within ± 1 
minute following injection; 
within ± 2 minutes of the 10, 
20, and 30-minute time points; 
within ± 5 minutes of the 60, 
120, and 240-minute time 
points.
Injection-site Pain 
Assessments using 
VAS
(minutes)
0, 
10, 
20, 
30, 
60
Assessment of injection-site 
pain (VAS) at the 0-minute time 
point should be done
within ± 1 minute following 
injection; within ± 2 minutes of 
the 10, 20, and 30-minute time 
points; within ± 5 minutes of 
the 60-minute time point.

I1F-MC-RHCT (b) Clinical Pharmacology Protocol
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Ixekizumab (LY2439821)
Screening
Days
Comments
Procedure
-28 to -2 
days prior 
to Day 1
-1
1
3
5
±1d
8
±1d
11
±1d
15
±2d
22
±2d
29
±2d
36
±2d
43
±2d
50 
±2d
57
±3d
64 
± 3d
71
±3d
85/ED
±3d
Ixekizumab PK 
sample
P
X
X
X
X
X
X
X
X
X
X
X
Immunogenicity 
Sample
P
X
X
X
Pharmacogenetic 
Sample
X
Adverse Events and 
Concomitant 
Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations:  BMI = body mass index; CRU = clinical research unit; C-SSRS – Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; 
ED = early discontinuation; FSH = follicle-stimulating hormone; ISR = injection-site reaction; P = predose; PK = pharmacokinetics; TB = tuberculosis; 
TST = tuberculin skin test; VAS = visual analog scale.  

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Ixekizumab (LY2439821)
3. Introduction
3.1.
Study Rationale
Ixekizumab is administered subcutaneously (SC), and is available as an injectable solution in 
either a manual prefilled syringe (PFS) or an autoinjector (AI).  Each PFS or AI contains 80 mg 
ixekizumab in 1 mL.
Study I1F-MC-RHCK was conducted to assess acute pain and injection-site reactions (ISRs) 
following administration of ixekizumab via marketed AI (fast injection speed, visible needle), a 
modified AI (slow injection speed, hidden needle), the marketed PFS, and placebo administered 
using a device similar to the marketed AI (fast injection speed, visible needle).  The results 
showed no statistically significant difference in intensity of injection-site pain following single 
injections administered via any of the methods tested.  Safety profiles, including the frequency of 
injection-site reactions (ISRs) were also similar between treatments.  
Several solution-associated factors may contribute to pain perception associated with injectable 
therapeutics, including active pharmaceutical ingredient, pH, buffer composition, and tonicity 
(Laursen et al. 2006).
Two new formulations of ixekizumab have therefore been developed using alternative 
approaches for buffer and tonicity agent;
 
 
Study I1F-MC-RHCT (Study RHCT) is therefore being conducted to compare the relative 
bioavailability and tolerability of ixekizumab administered using the 2 new formulations, 
compared to the marketed formulation when administered using a PFS.  
Study RHCT is being conducted in parallel with Study I1F-MC-RHCS which will provide
further assessment of injection-site pain and ISRs associated with administration of the 
3 ixekizumab formulations in a crossover study design.  
3.2.
Background
Ixekizumab (LY2439821, Taltz®) is a humanized immunoglobulin (Ig)G subclass 4 monoclonal 
antibody that binds with high affinity and specificity to interleukin (IL)-17A, a proinflammatory 
cytokine.  Ixekizumab is marketed in the US and EU for the treatment of moderate-to-severe 
plaque psoriasis (Ps) at a dose of 160 mg at Week 0, followed by 80 mg every 2 weeks up to 
Week 12, then maintenance dosing of 80 mg every 4 weeks, and for psoriatic arthritis at a dose 
of 160 mg at Week 0 followed by 80 mg every 4 weeks. 
3.3.
Benefit/Risk Assessment
As this study will enrol healthy subjects, there is no anticipated therapeutic benefit for the 
subjects.  

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Ixekizumab (LY2439821)
As of the cut-off date for the current investigator’s brochure (IB; 22 March 2018), more than 
8755 subjects and patients have received at least 1 dose of ixekizumab (5934 patients with Ps, 
532 patients with rheumatoid arthritis, 1301 patients with psoriatic arthritis, 119 healthy subjects, 
and an estimated 869 patients with axial spondyloarthritis).  
Forty-one healthy subjects were administered ixekizumab by PFS (160 mg [2 × 80 mg] followed 
by 80 mg 2 weeks later) in Study I1F-MC-RHCA (Study RHCA).  All AEs in Study RHCA were 
mild in severity.  The most commonly reported AEs were headache, injection-site erythema, and 
fatigue.  With the exception of fatigue, this is consistent with commonly reported AEs reported 
in Phase 3 studies.  An additional 78 healthy subjects were administered ixekizumab by PFS, 
marketed AI, and modified AI (3 single 80 mg doses) in Study I1F-MC-RHCK.  All TEAEs 
were mild in severity and the most commonly reported TEAEs were ISR, injection-site pruritus, 
nausea, diarrhea, upper respiratory tract infection, and injection-site erythema.   
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated AEs of ixekizumab are to be found in the IB and the Package Insert.  

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Ixekizumab (LY2439821)
4. Objectives and Endpoints
Table RHCT.1 shows the objectives and endpoints of the study.
Table RHCT.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the relative bioavailability of a single 80 mg 
SC dose of ixekizumab Test Formulation 1 and Test 
Formulation 2 compared to the commercial formulation
(Reference)
Cmax, AUC(0-∞), AUC(0-tlast)
Secondary
To evaluate the safety and tolerability of a single 80 mg 
SC dose of ixekizumab Test Formulation 1 and Test
Formulation 2 formulations compared to the commercial 
formulation (Reference)
TEAEs, SAEs, ISRs, and VAS pain score immediately 
after injection
Exploratory
To evaluate the effect of ixekizumab on immunogenicity
TE ADAs
Abbreviations:  AUC(0-∞) = area under the concentrations 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; Cmax = maximum observed drug concentration; ISR = injection-site 
reaction; SAE = serious adverse events; TE ADA = treatment-emergent anti-drug antibodies; 
TEAE = treatment-emergent adverse event; VAS = visual analog scale.  

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Ixekizumab (LY2439821)
5. Study Design
5.1.
Overall Design
Study I1F-MC-RHCT is a Phase 1, subject-blind, 3-arm, randomized, parallel-design study in 
healthy subjects.  
All subjects will be screened within 28 days prior to enrollment.  Eligible subjects will be 
admitted to the clinical research unit (CRU) on Day -1 and randomized 1:1:1 to 1 of 3 possible 
treatments. On Day 1, subjects will receive a single SC dose of one of the following treatments, 
according to the randomization schedule:  

80 mg ixekizumab Commercial Formulation (Reference)

80 mg ixekizumab Test Formulation 1

80 mg ixekizumab Test Formulation 2
Subjects may be allowed to leave the CRU after completing the 4-hour safety assessments on 
Day 1, at the investigator’s discretion, and will return for pharmacokinetic (PK) and 
immunogenicity sampling and safety assessments at predefined times up to 12 weeks postdose.  
Subjects will be monitored for safety between outpatient visits by way of telephone assessment.
Safety and tolerability will be assessed by clinical laboratory tests, vital sign measurements, 
temperature, recording of AEs, physical examination (PE)/medical assessments, Columbia 
Suicide Severity Rating Scale (C-SSRS), immunogenicity, and injection-site assessments.  Pain 
assessments will be made using an injection-site visual analog scale (VAS).
Study governance considerations are described in detail in Appendix 3.
5.2.
Number of Participants
Up to 99 subjects may be enrolled so that 78 subjects (26 in each treatment arm) complete the 
study.  For the purposes of this study, a subject completes the study when all scheduled 
procedures shown in the Schedule of Activities (Section 2) have been completed.
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 the relative bioavailability of both small and large 
molecules.  
Single doses of ixekizumab and the PK sampling time points have been selected to generate PK
profiles sufficient to fulfill the study objectives.  

I1F-MC-RHCT (b) Clinical Pharmacology Protocol
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Ixekizumab (LY2439821)
A parallel-group design is chosen because a crossover design is impractical for ixekizumab, 
which has a half-life of approximately 13 days.  Additionally, a crossover study could confound 
PK data if subjects develop neutralizing antidrug antibodies (ADAs).  
5.5.
Justification for Dose
The recommended dose for Ps patients is 160 mg by SC injection (two 80-mg injections) at 
Week 0, followed by an 80-mg injection at Weeks 2, 4, 6, 8, 10, and 12, then 80 mg every
4 weeks.  A dose of 80 mg ixekizumab was selected for Study RHCT to match the approved
individual dose unit strength administered during treatment in clinical practice.

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Ixekizumab (LY2439821)
6. Study Population
Eligibility of subjects for the study will be based on the results of a screening medical history, 
PE, vital signs, clinical laboratory tests, and ECG.  
The nature of any conditions present at the time of the PE and any preexisting conditions will be 
documented.  Screening and/or Day -1 laboratory testing may be repeated once at the discretion 
of the investigator for any out of range results.  
Screening may occur up to 28 days prior to enrollment.  Subjects who are not enrolled within 
28 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and/or Day -1:
[1]
are overtly healthy males or females, as determined by screening medical 
history and PE, or males and females with chronic stable medical problems 
that, in the investigators opinion, will not place the subject at increased risk by 
participating in the study, and will not interfere with interpretation of the data.
[1a] male subjects:
agree to use a reliable method of birth control and to not donate sperm 
during the study and for 3 months following the last dose of ixekizumab.
Examples of reliable methods of birth control are condoms with spermicide, 
oral contraceptives or intrauterine device used by the female partner, and 
male sterilization.
Subjects 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 maintain abstinence or stay in a 
same-sex relationship without sexual relationships with females.  Periodic 
abstinence, declaration of abstinence just for the duration of the trial, and 
withdrawal are not acceptable methods of contraception.
[1b] female subjects:
1) Women of childbearing potential must test negative for pregnancy prior 
to initiation of treatment as indicated by a negative serum pregnancy test at 
the screening visit followed by a negative urine pregnancy test on Day -1.
2) 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 

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Ixekizumab (LY2439821)
either remain abstinent or stay in a same sex relationship without sexual 
relationships with males, and agree to use a condom with spermicide should 
the situation change.  Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence just for 
the duration of a study, and withdrawal are not acceptable methods of 
contraception.
3) Otherwise, women of childbearing potential must agree to use 1 highly 
effective method (less than 1% failure rate) of contraception, or a 
combination of 2 effective methods of contraception for the entirety of the 
study and for 3 months following dosing with ixekizumab.
Highly effective methods of contraception include 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 a reliable or acceptable method.  Thus, each 
barrier method must include the 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.
4) Women not of childbearing potential may participate and include those 
who are:
A.  Infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), a congenital anomaly such as 
mullerian agenesis, or
B.  Post-menopausal – defined as either
i.  A woman at least 50 years of age with an intact uterus, not 
on hormone therapy, who has had either
a) spontaneous amenorrhea for at least 1 year, or
b) at least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone level >40 mIU/mL, or
ii.  A woman 55 years or older, not on hormone therapy, who 
has had at least 6 months of spontaneous amenorrhea, or
iii.  A woman 55 years or older with a diagnosis of menopause 
prior to starting hormone replacement therapy.
[2]
are aged 18 to 75 years at the time of screening.  
[3]
have a body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive.
[4]
have venous access sufficient to allow for blood sampling as per the protocol.

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Ixekizumab (LY2439821)
[5]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[6]
are able and willing to give signed informed consent.
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or Day -1:
[7]
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.
[8]
are Lilly or Covance employees.
[9]
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.  
[10] have participated, within the last 30 days, in a clinical study involving an IP.  
If the previous IP has a long half-life, 5 half-lives or 30 days (whichever is 
longer) should have passed.
[11] have previously completed or withdrawn from this study or any other study 
investigating ixekizumab, and have previously received ixekizumab, or have 
ever been administered other IL-17 antagonists.  
[12] have known allergies to ixekizumab, related compounds, or any components 
of the formulation, or history of significant atopy.
[13] have self-perceived dullness or loss of sensation on either side of their 
abdomen.
[14] have uncontrolled arterial hypertension characterized by a systolic blood 
pressure >160 mmHg or diastolic blood pressure >100 mmHg.
Note:  if an initial blood pressure reading exceeds this limit, the reading may 
be repeated once after the subject has rested sitting for ≥10 minutes.  If the 
repeat value is less than the criterion limits, the second value may be accepted.
[15] have a significant history of, or current, cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrine, or hematologic disorders that in the opinion 
of the investigator poses an unacceptable risk to the subject if participating in 
the study or of interfering with the interpretation of data.

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[16] presence of significant uncontrolled neuropsychiatric disorder; have lifetime 
history of suicidal behavior (yes to any suicidal behavior question from the 
“Suicidal Behavior” portion of the C-SSRS from screening and between 
screening and baseline [Day -1]); have history of active suicidal ideation 
within the past year (yes to question 4 or 5 on the “Suicidal Ideation” portion 
of the C-SSRS from screening and between screening and baseline [Day -1]) 
and/or are clinically judged by the investigator to be at risk for suicide.
[17] have recent history (past 30 days) of depression; have HADS Depression 
subscale score of ≥11.
[18] have current or history of inflammatory bowel disease (IBD) (Crohn’s disease 
or ulcerative colitis), or signs or symptoms indicative of ulcerative colitis or 
Crohn’s disease (based on investigator determination), or knowledge of a 
family history of IBD in first degree relatives.
[19] Infections:
[19a] have had a serious infection (e.g., pneumonia, cellulitis, and sepsis), 
have been hospitalized, or have received intravenous antibiotics for an 
infection within 12 weeks prior to Day 1; have had a serious bone or joint 
infection within 24 weeks prior to Day 1, or have ever had an infection of an 
artificial joint; or are immunocompromised to an extent such that participation 
in the study would post an unacceptable risk to the subject.
[19b] have or have had an infection typical of an immunocompromised host 
and/or that occurs with increased incidence in an immunocompromised host 
(including, but not limited to, pneumocystis jiroveci pneumonia, 
histoplasmosis, or coccidioidomycosis), or have a known immunodeficiency.
[19c] have or have had a herpes zoster infection or any other clinically 
apparent varicella-zoster virus infection within 12 weeks of Day 1.
[19d] have had any other active or recent infection within 4 weeks of Day 1 
that, in the opinion of the investigator, would pose an unacceptable risk to the 
subject if participating in the study; these subjects may be re-screened (once) 
≥4 weeks after documented resolution of symptoms.
[20] have a history of uncompensated heart failure, fluid overload, or myocardial 
infarction, or evidence of new-onset ischemic heart disease or other serious 
cardiac disease, within 12 weeks prior to Day 1.
[21] have clinical laboratory test results at screening that are outside the normal 
reference range for the population and are considered clinically significant, 
and/or have any of the following specific abnormalities:

neutrophil count <1500 cells/μL

lymphocyte count <800 cells/μL

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Ixekizumab (LY2439821)

platelet count <100,000 cells/μL

total white blood cell count <3000 cells/μL
Note:  Laboratory tests may be repeated if there is a documented technical 
error, or once at the discretion of the investigator for any out of range results.
[22] regularly use known drugs of abuse and/or show positive findings on urinary 
drug screening.
[23] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive HIV antibodies.
[24] show evidence of hepatitis C and/or positive hepatitis C antibody.
[25] show evidence of hepatitis B and/or positive hepatitis B surface antigen and/or 
hepatitis B core antibody.  
[26] are women who are lactating.
[27] have donated blood of more than 500 mL within the last month prior to dosing 
or intend to donate blood during the course of the study.  
[28] have an average weekly alcohol intake that exceeds 21 units per week (males
up to age 65) and 14 units per week (females up to and over 65, and males 
over 65), or are unwilling to stop alcohol consumption for 48 hours prior to 
each study visit and while at the CRU, or are unwilling to restrict alcohol 
intake to 3 units per day (males) and 2 units per day (females) during 
outpatient periods (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).
[29] show evidence of active or latent tuberculosis (TB), as documented by 
medical history and examination, any recent chest x-rays (if obtained in the 
previous 6 months; x-rays will not be taken for the sole purpose of 
determining eligibility for this study), and TB testing:  either a positive 
tuberculin skin test (TST; defined as a skin induration >5 mm at 48 to 
72 hours, regardless of Bacillus Calmette-Guérin [BCG] or other vaccination 
history) or a positive (not indeterminate) QuantiFERON®-TB Gold test.  The 
choice to perform a TST or a QuantiFERON-TB Gold test will be made by the 
investigator according to local licensing and standard of care.  The 
QuantiFERON-TB Gold test can only be used in countries where it is 
licensed, and the use of this test is dependent on previous treatment(s).  This 
test may not be suitable if previous treatment(s) produce significant 
immunosuppression.

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Ixekizumab (LY2439821)
[30] had a vaccination with BCG, other live vaccines, or attenuated live vaccines
within 12 months prior to first admission to the CRU, or intend to have a 
vaccination with BCG during the course of the study, or within 12 months of 
completing treatment in this study.
Note:  killed/inactive or subunit vaccines are expected to be safe; however, 
their efficacy with concomitant ixekizumab is unknown.
[31]  have received treatment with biologic agents (such as monoclonal antibodies, 
including marketed drugs) within 3 months or 5 half-lives (whichever is 
longer) prior to dosing.
[32] intend or are likely to use over-the-counter or prescription medication for pain 
or inflammation within 7 days prior to Day 1.  Subjects on stable doses of 
other medications (for example, statins and anti-hypertensives) may be 
eligible for enrollment following discussion with the Sponsor (Section 7.7).
[33] have a known allergy or hypersensitivity to any biologic therapy that would 
pose an unacceptable risk to the subject if participating in this study.
[34] have had 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.  
[35] have any condition that could affect pain perception from an injection.
[36] have excessive tattoos or scars over the abdomen, or other factors (eg, rash, 
excessive folds of skin) that, in the investigator's opinion, would interfere with 
injection-site assessments.
[37] in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study.
6.2.1.
Rationale for Exclusion of Certain Study Candidates
Exclusion Criteria [7] and [8] prevent conflict of interest in study participants.  Exclusion 
Criteria [9] through [37] exclude items including, but not limited to medical conditions, 
medication intolerance, and concomitant medication use that may confound the assessment of 
study endpoints.  
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 receive a light breakfast on the morning of Day 1 but will be fasted (water is 
permitted) from 1 hour prior to dosing until 1 hour postdose.  Standard meals will be provided at 
all other times while subjects are resident at the CRU, per the CRU’s policy.  

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Ixekizumab (LY2439821)
6.3.2. Alcohol and Tobacco
Alcohol consumption is not permitted while at the CRU, and for 48 hours prior to each study 
visit.  Alcohol intake during outpatient periods should not exceed 3 units per day (males) and 
2 units per day (females).  In addition, subjects must abide by the CRU smoking restrictions 
during study visits and while resident in the CRU.
6.3.3.
Activity
Subjects will be encouraged to maintain their regular exercise; however, they should not 
undertake vigorous or prolonged exercise within 48 hours prior to each CRU visit.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once at the investigator’s discretion (see Section 6).

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Ixekizumab (LY2439821)
7. Treatment
7.1.
Treatment Administered
A dose of IP will consist of 1 injection of 80 mg ixekizumab into the abdomen.  All doses will be 
administered by trained site staff.
This study involves a comparison of:  

80 mg ixekizumab Commercial Formulation administered SC via PFS (Reference)

80 mg ixekizumab Test Formulation 1 administered SC via PFS (Test Formulation 1)

80 mg ixekizumab Test Formulation 2 administered SC via PFS (Test Formulation 2)
Table RHCT.2 shows the treatment regimens.
Table RHCT.2.
Treatments Administered
Treatment Name
Reference
Test Formulation 1
Test Formulation 2
Formulation
solution for injection
solution for injection
solution for injection
Dose
80 mg ixekizumab
80 mg ixekizumab
80 mg ixekizumab
Route of Administration
SC injection
SC injection
SC injection
Delivery Method
PFS
PFS
PFS
Abbreviations:  PFS = prefilled syringe; SC = subcutaneous.  
The investigator or designee is responsible for:

explaining the correct use of the IPs to the site personnel

verifying that instructions are followed properly

maintaining accurate records of IP dispensing and collection

and returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials.  
7.1.1. Packaging and Labeling
Ixekizumab will be supplied by the sponsor or its designee in accordance with current good 
manufacturing practice (GMP), labeled according to the country’s regulatory requirements, and 
supplied with lot numbers, expiry dates, and certificates of analysis, as applicable.  Each syringe 
of ixekizumab is designed to deliver 80 mg of ixekizumab.  The following products will be 
supplied by Lilly, with study-specific labels, for use in the study:

ixekizumab commercial formulation (Reference; solution for injection) in 1-mL 
single-dose, prefilled, disposable manual syringes

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Ixekizumab (LY2439821)

ixekizumab Test Formulation 1 (solution for injection) in 1-mL single-dose, prefilled, 
disposable manual syringes

ixekizumab Test Formulation 2 (solution for injection) in 1-mL single-dose, prefilled, 
disposable manual syringes
Unblinded Site Personnel will be responsible for handling and administering IP.  Unblinded Site 
Personnel are also responsible to make sure subjects remain blinded to treatment (i.e., subjects 
must not see the syringe before, during or after the drug administration).
7.2.
Method of Treatment Assignment
Subjects will be randomly assigned to 1 of 3 treatments using a computer-generated allocation 
code.
7.2.1. Selection and Timing of Doses
The actual time of all injections will be recorded in the subject’s electronic case report form 
(eCRF).
7.3.
Blinding
Blinding will be in place for subjects and for site staff conducting injection-site assessments and 
injection-site bleeding/bruising assessments.
7.4.
Dose Modification
Dose modification is not permitted in this study.
7.4.1. Special Treatment Considerations 
All biological agents carry the risk of systemic allergic/hypersensitivity reactions.  Clinical 
manifestations of these reactions may include, but are not limited to skin rash, pruritus (itching), 
urticaria (hives), angioedema (eg, swelling of the lips and/or tongue), and anaphylactic reaction.  
Sometimes these reactions can be life-threatening.  Proteins may also cause redness, itching, 
swelling, or pain locally at the injection site.  Therefore, all subjects should be closely monitored 
for signs or symptoms that could result from such reactions, be educated on the signs or 
symptoms of these types of reactions, and be instructed to contact the study site immediately if 
any of the symptoms are experienced after discharge from the CRU.  If a subject experiences an 
acute allergic/hypersensitivity reaction after an injection of IP, he or she should be managed 
appropriately and receive relevant supportive care.  The event should be recorded as an AE.  
7.5.
Preparation/Handling/Storage/Accountability
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 the temperature of the on-site storage conditions of the IP.  The 
investigator or designee must confirm appropriate temperature conditions have been maintained, 

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Ixekizumab (LY2439821)
as communicated by the sponsor, during transit for all IP received and ensure any discrepancies 
are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive IP or study materials, and only authorized 
site staff may supply 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
Subjects on stable concomitant medication at the time of study entry should continue their 
regular, unchanged dose throughout the study.  Permitted concomitant medications include oral 
contraceptives, hormone replacement therapy, and thyroid replacement at the discretion of the 
investigator.  In addition, occasional acetaminophen is acceptable at the discretion of the 
investigator. However, acetaminophen should not be administered on the dosing day within 
4 hours prior to the injection and until at least 4 hours after the injection.  No more than 3 g of 
acetaminophen will be permitted in any 24-hour period.  Inclusion of subjects on any other 
concomitant medication (for example, statins and anti-hypertensives) is contingent upon 
approval following consultation with the Sponsor.
Subjects will be restricted from applying any creams or lotions on the abdominal skin the 
morning prior to injection and for 24 hours after injection.
If the need for any additional concomitant medication arises, inclusion or continuation of the 
subject may be at the discretion of the investigator after consultation with a Lilly Clinical 
Pharmacologist (CP) or Clinical Research Physician (CRP).  Any 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
Subjects discontinuing from the study prematurely for any reason should complete AE and other 
Day 85/ED procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Not applicable in this single-dose study.
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/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/CRP to allow the 
inadvertently enrolled subject to continue in the study.  
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
prior to receiving IP in this study.  If the subject has received IP, they will continue to be 
monitored for safety for the planned duration of the 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

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study

Subject Decision
o
the subject, or legal representative, requests to be withdrawn from the study.
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he 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.
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
Not applicable for this study.  
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
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, 
or that caused the subject to discontinue before completing the study.  The subject should be 
followed until the event resolves, stabilizes with appropriate diagnostic evaluation, or is 
reasonably explained.  The frequency of follow-up evaluations of the AE is left to the discretion 
of the investigator.
After the informed consent form (ICF) is signed, study site personnel will record, initially via 
source documents and then 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.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account the disease, 
concomitant treatment or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the IP and/or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.

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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 subject or may require intervention to prevent 
one of the other outcomes listed in the definition above.
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, 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.
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 electronic case report form 
[eCRF] has been completed).  However, if the investigator learns of any SAE, including a death, 
at any time after a subject has been discharged from the study, and he/she considers the event 
reasonably possibly related to the study treatment or study participation, the investigator must 
promptly notify Lilly.  
Pregnancy (maternal or paternal exposure to 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 Events of Special Interest
The following AEs of special interest will be used to determine the safety and tolerability of 
ixekizumab injections administered by PFS in this clinical study.
Adverse events of special interest for ixekizumab are:

cytopenias (leukopenia, neutropenia, and thrombocytopenia)

liver function test changes/enzyme elevations (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], total bilirubin level [TBL], and alkaline phosphatase [ALP])

infection

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
ISRs

allergic reactions/hypersensitivities

cerebrocardiovascular events

malignancies

depression

inflammatory bowel disease (Crohn’s disease and ulcerative colitis)

interstitial lung disease
If infections, or allergic/hypersensitivity reactions are reported, these will be recorded as AEs.  
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.
Injection-site reactions will be recorded as described in Section 9.4.5.1
Data on cerebrocardiovascular events (defined as death, myocardial infarction, stroke, 
hospitalization for unstable angina, hospitalization for heart failure, coronary revascularization 
procedure, peripheral revascularization procedure, cardiogenic shock due to myocardial 
infarction, resuscitated sudden death, serious arrhythmia, hospitalization for hypertension, and 
peripheral arterial event) will be collected and the events may be adjudicated by an external 
Clinical Events Committee (CEC) made up of a chair, 2 cardiologists, and a neurologist.  
Data on suspected inflammatory bowel disease, as identified by events possibly indicative of 
ulcerative colitis and Crohn’s disease, will be collected.  The events may be adjudicated by an 
external CEC composed of gastroenterologists with expertise in inflammatory bowel disease.  
The role of the CECs is to adjudicate defined clinical events, in a blinded, consistent, and 
unbiased manner throughout the course of a study.  The importance of the CECs is to ensure that 
all events that have been reported are evaluated uniformly by a single group.
9.2.1.2.
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 product complaints on IPs and drug delivery systems used in clinical studies 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.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed Product Complaint Form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
Product Complaint Form with the product.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of ixekizumab is considered any dose higher than the 
dose assigned through randomization.  Syringes used in this study can deliver only 1 mL volume 
of ixekizumab.
There is no specific antidote for ixekizumab.  In the event of an overdose, the subject should 
receive appropriate supportive care and any AEs should be documented.
Refer to the Taltz Product Label.
9.4.
Safety
Safety will be assessed throughout the course of the study at site visits and via telephone calls in 
between site visits. 
9.4.1. Laboratory Tests
For each subject, clinical laboratory tests detailed in Appendix 2 should be conducted according 
to the Schedule of Activities (Section 2).  
9.4.2. Vital Signs
For each subject, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).  
Blood pressure and pulse rate should be measured after at least 5 minutes sitting.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  If orthostatic measurements are required, subjects should be supine 
for at least 5 minutes and stand for at least 2 minutes.  If the subject feels unable to stand, supine 
vital signs only will be recorded.  
Additional vital signs may be measured during each study period if warranted.

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9.4.3. Electrocardiograms
For each subject, a single 12-lead ECG should be collected according to the Schedule of 
Activities (Section 2).  
Electrocardiograms must be recorded before collecting any blood samples.  Subjects must be 
supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake 
during ECG collection.  Electrocardiograms may be obtained at additional times, when deemed 
clinically necessary.  All ECGs recorded should be stored at the investigational site.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
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.  
9.4.4. Temperature
Body temperature (oral) will be assessed at the times indicated in the Schedule of Activities 
(Section 2).
9.4.5. Other Tests
9.4.5.1.
Injection-Site Assessments
Injection-site assessments will be performed at the times indicated in the Schedule of Activities 
(Section 2).
If the investigator determines that the ISR is clinically significant, or if a subject indicates 
symptoms are indicative of an ISR (unsolicited event; volunteered by subject), the event will be 
captured as an AE.  
Induration, swelling, pruritus, and erythema/redness associated with study injection sites will be 
evaluated by the investigator or designee.
9.4.5.2.
Bleeding/Bruising 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/bruising will be recorded on 
the eCRF.  A bandage may be placed on the injection site after assessment.
9.4.5.3.
Injection-Site Pain
Pain measurements will be quantified using the 100-mm VAS pain score for all subjects.  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 
imaginable pain.”  The subject will be asked to relate any pain at the injection site on a scale of 
1 to 100 mm on the line immediately (within 1 minute) following injection and at the additional
time points listed in the Schedule of Activities (Section 2).  

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9.4.5.4.
Columbia Suicide Severity Rating Scale
Columbia Suicide Severity Rating Scale (C-SSRS):  A scale that captures the occurrence, 
severity, and frequency of suicidal ideation and/or behavior during the assessment period.  The 
scale includes suggested questions to solicit the type of information needed to determine if 
suicidal ideation and/or behavior occurred.  Any occurrence of suicide-related thoughts and 
behaviors will be assessed at the times indicated in the Schedule of Activities (Section 2) using 
the C-SSRS.  The C-SSRS is administered by an appropriately trained healthcare professional 
with at least 1 year of patient care/clinical experience.
The nonleading AE collection should occur prior to the collection of the C-SSRS.  If a 
suicide-related event is discovered during the C-SSRS but was not captured during the 
nonleading AE collection, sites should not change the AE form.  If an event is serious or leads to 
discontinuation, this is an exception where the SAE and/or AE leading to discontinuation should 
be included on the AE form and the process for reporting SAEs should be followed.  The first 
time the scale is administered in this study, the C-SSRS ‘Baseline – Screening’ version will be 
used, and the findings will constitute the baseline assessment.  The C-SSRS ‘Since Last Visit’ 
scale will be used for all subsequent assessments.  The Lilly Self-Harm Supplement should be 
completed every time the C-SSRS is administered.  If there are positive findings on the 
Self-Harm Supplement, then the Lilly Self-Harm Follow-Up form will be used to collect 
additional information to allow for a more complete assessment of these behaviors.
9.4.5.4.1. Hospital Anxiety Depression Scale
The HADS depression subscale is a 7-item assessment scale that determines the levels of 
depression that a subject is experiencing over the past week.  The HADS depression subscale 
utilizes a 4-point Likert scale (e.g., 0 to 3) for each question and is intended for ages 12 to 
65 years (Zigmond and Snaith, 1983; White et al.  1999).  The score can range from 0 to 21, with 
higher scores indicating greater depression (Zigmond and Snaith 1983; Snaith 2003).
9.4.6. 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 trends in safety data, laboratory analytes, and AEs.  
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
9.4.6.1.
Hepatic Safety
If a study subject experiences elevated ALT ≥3 × upper limit of normal (ULN), ALP ≥2 × ULN, 
or elevated total bilirubin ≥2 × ULN, liver tests (Appendix 4) should be repeated within 3 to
5 days including ALT, AST, ALP, TBL, conjugated 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.  

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Additional safety data should be collected if 1 or more of the following conditions occur:  

elevation of serum ALT to ≥ 5 × ULN on two 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 

subject discontinued from treatment due to a hepatic event or abnormality of liver 
tests

hepatic event considered to be a SAE.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 3 mL each will be collected to determine the serum concentrations of 
ixekizumab.  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 ixekizumab will be assayed using a validated 
enzyme-linked immunosorbent assay method.
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
1 year following last subject visit for the study.  
9.6.
Pharmacodynamics
This section is not applicable for this study.  
9.6.1.
Immunogenicity Assessments 
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 10 mL each will be collected to determine antibody production against 
ixekizumab.  To interpret the results of immunogenicity, venous blood samples will be collected 
at the same time points to determine the serum concentrations of ixekizumab. 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 30 days 
following the event.  Instructions for the collection and handling of blood samples will be 
provided by the sponsor.  The actual date and time (24-hour clock time) of each sampling will be 
recorded.  
Treatment-emergent ADAs (TE ADAs) are defined in Section 10.3.3.  

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Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of ixekizumab at a laboratory approved by the sponsor.  Antibodies may be further characterized
and/or evaluated for their ability to neutralize the activity of ixekizumab and/or their ability to 
cross-react with endogenous counterparts.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and ethical review boards (ERBs) allow, at a facility selected by the 
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to 
ixekizumab.  Any samples remaining after 15 years will be destroyed.  
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 
ixekizumab and to investigate genetic variants thought to play a role in Ps.  Assessment of 
variable response may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or ERBs 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 ixekizumab.  
Molecular technologies are expected to improve during the 15 year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section.  
9.8.
Biomarkers
This section is not applicable for this study.  
9.9.
Health Economics
This section is not applicable for this study.

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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Up to 99 subjects may be enrolled to ensure that 78 subjects (26 for each treatment) complete the 
study.  
 
 
Subjects who are randomized but not administered treatment may be replaced to ensure that 
78 subjects (26 for each treatment) 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 subjects’ age, sex, weight, height, BMI, race, and other demographic characteristics will be 
recorded and summarized using descriptive statistics.
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 data from all subjects who receive 1 dose of 
ixekizumab and have evaluable PK.  
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses.  
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All IP and protocol procedure AEs will be listed, and if the frequency of events allows, safety 
data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with IP as perceived by the investigator.  Symptoms reported to occur prior to study entry will be 

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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-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
10.3.1.2.1.Injection-Site Pain
VAS pain score will be summarized using standard descriptive statistics.  In addition, the 
severity of pain will be categorized by VAS pain score as: mild pain (≤30), moderate pain 
(>30 and ≤70), and severe pain (>70).  The number and percentage of the subjects in each pain 
severity category will summarized by formulation and time point.
A mixed model for the repeating measures analysis model will be used to analyze the continuous 
injection-site pain VAS score.  The model will include formulation and time post injection 
(0, 10, 20, 30, and 60 minutes) and formulation by time as fixed factors.  The covariance 
structure of the model will be unstructured.  Other covariance matrices may be explored if 
needed.  The Kenward-Roger method will be used to estimate the denominator degrees of 
freedom.  Type III sums of squares for the least squares means will be used for the statistical 
comparison; the treatment differences along with their corresponding 95% CIs will also be 
reported.
Additional analyses may be performed as deemed necessary.
10.3.1.2.2.Statistical Evaluation of Other Safety Parameters
Safety laboratory parameters and vital signs data will be listed and summarized using standard 
descriptive statistics, where possible.  Injection-site assessments, including induration, swelling, 
pruritis, bleeding/bruising, and erythema/redness, will also be assessed.  The parameters will be 
listed and summarized using descriptive statistics.  Suicidal ideation and/or behavior and 
self-injurious behavior with no suicidal intent, based on the C-SSRS, will be listed by subject.  
Only subjects that show suicidal ideation/behavior or self-injurious behavior without suicidal 
intent will be included in the listing (ie, if a subject’s answers are all ‘no’ for the C-SSRS, then 
that subject will not be displayed).  HADS item scores will be listed for subjects with HADS 
depression subscale ≥11 at any time.  Additional analysis may 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 ixekizumab will be calculated by standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be Cmax, AUC(0-∞), AUC(0-tlast) of ixekizumab.  
Other noncompartmental parameters, such as time to maximum drug concentration (tmax), 
half-life associated with the terminal rate constant in noncompartmental analysis (t1/2), apparent 
clearance, and apparent volume of distribution may be reported.  PK parameters may also be 

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normalized by body weight in the event there are differences in body weight between the 
treatment groups.
10.3.2.2. Pharmacokinetic Statistical Inference
Pharmacokinetic parameters will be evaluated to estimate the relative bioavailability of Test 
Formulation 1 and Test Formulation 2 compared to the commercial formulation (Reference).  
Log-transformed Cmax and AUC parameters will be evaluated in a linear mixed-effects model 
with a fixed effect for formulation and a random effect for subject.  The treatment differences 
will be back-transformed to present the ratios of geometric means and the corresponding 
90% CI.  
The tmax will be analyzed using a Wilcoxon rank sum test.  Estimates of the median difference 
based on the observed medians, 90% CIs and p-values from the Wilcoxon rank sum test will be 
calculated.
10.3.3. Evaluation of Immunogenicity 
The frequency and percentage of subjects with preexisting ADA and with TE ADA+ to 
ixekizumab will be tabulated. Treatment-emergent ADAs are defined as those with a titer 2-fold 
(1 dilution) greater than the minimum required dilution if no ADAs were detected at baseline 
(treatment-induced ADA) or those with a 4-fold (2 dilutions) increase in titer compared to 
baseline, if ADAs were detected at baseline (treatment-boosted ADA). For the TE ADA+
subjects the distribution of maximum titers will be described.  The frequency of neutralizing 
antibodies will also be tabulated in TE ADA+ subjects.
The relationship between the presence of antibodies and the PK parameters and of ixekizumab
may be assessed.
10.3.4. Data Review During the Study
Review of the PK and safety data may be conducted during the conduct of this study to inform 
internal Chemistry, Manufacturing, and Control processes with respect to the new ixekizumab
formulation development. 
10.3.5. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly CP/CRP/investigator, or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol.

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11.
References
Laursen T, Hansen B, Fisker S. Pain perception after subcutaneous injections of media 
containing different buffers. Basic Clin Pharmacol Toxicol. 2006;98(2):218-221.  
Medicines.org.uk.  (2018) Taltz 80 mg solution for injection – Summary of Product 
Characteristics (SPC).  [online] available at
https://www.medicines.org.uk/emc/product/7233/smpc [Accessed 05 September 2018]
Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin 
Nurs. 2005;14(7):798-804.

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Appendix 1.
Abbreviations and Definitions

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Term
Definition
ADA
antidrug antibodies
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
AST
aspartate aminotransferase
AUC(0-∞)
area under the concentration versus time curve from zero to infinity
AUC(0-tlast)
area under the concentration versus time curve from time zero to time t, where t is last the 
time point with a measurable concentration
BCG
Bacillus Calmette-Guérin
BMI
body mass index
CEC
Clinical Events Committee
CI
confidence interval
Cmax
maximum drug concentration 
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the 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:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician or other medical officer.
CRU
clinical research unit

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C-SSRS
Columbia Suicide Severity Rating Scale
ECG
electrocardiogram
eCRF
electronic case report form
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.
ERB
ethical review board
GCP
Good Clinical Practice
GMP
good manufacturing practice
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonization
Ig
immunoglobulin
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.
Investigational 
product (IP)
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.
ISR
injection-site reaction
Legal 
Representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective subject, to the subject’s participation in the clinical study.

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Non-
investigational 
product (non-IP)
A product that is not being tested or used as a reference in the clinical study, but is provided 
to subjects and used in accordance with the protocol, such as:  concomitant or rescue/escape 
medication for preventative, diagnostic, or therapeutic reasons, medication to ensure 
adequate medical care, and/or products used to induce a physiological response.
PE
physical examination
PFS
prefilled syringe
PK
pharmacokinetic
Ps
psoriasis
randomize
the process of assigning subjects to an experimental group on a random basis
RBC
red blood cell
SAE
serious adverse event
SC
subcutaneous
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 
t1/2
terminal rate constant in noncompartmental analysis
TB
tuberculosis
TBL
total bilirubin level
TE ADA
treatment-emergent antidrug antibodies
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment 
tmax
time of maximum drug concentration
TST
tuberculin skin test
ULN
upper limit of normal
VAS
visual analog scale
WBC
white blood cell

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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Glucose (random)
Leukocytes (WBC) 
Platelets
Blood urea nitrogen (BUN)
Uric acid
Total cholesterol
Differential WBC absolute counts of:
Total protein
Neutrophils
Albumin
Lymphocytes
Total bilirubin level (TBL)
Monocytes
Direct bilirubin
Eosinophils
Triglycerides
Basophils
Alkaline phosphatase (ALP)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Creatinine
Urinalysis
Specific gravity
Phosphorus
pH
Protein
Glucose
Other tests
Ketones
Pregnancy test (females only)b
Bilirubin
FSH (females only, if applicable)a,c
Urobilinogen
QuantiFERON®-TB Golda or TST
Blood
Ethanol testingd
Nitrite
Urine drug screend
Microscopy (if dipstick abnormal)
Serology
Hepatitis B surface antigena
Hepatitis B core antibodya
Hepatitis C antibodya
HIV antibodiesa
Abbreviations:  FSH = follicle-stimulating hormone; RBC = red blood cell; TB = tuberculosis; TST = tuberculin 
skin test; WBC = white blood cell.
a
Performed at screening only.
b Serum pregnancy test to be performed at screening.  Urine pregnancy test to be performed at all other times.  
c
FSH test performed for women ≥50 and <55 years of age who have an intact uterus and are not on hormone 
therapy, and have had spontaneous amenorrhea for ≥6 months but <1 year to confirm non-childbearing potential 
(>40 mIU/mL).
d    Urine drug screen and ethanol level will be performed locally at screening and at admission to the clinical 
research unit.  Test may be repeated at additional time points at the discretion of the investigator.  

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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 ICF prior to the 
performance of any protocol procedures and prior to the administration of IP.

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 or appropriate local representative must give assurance that the ERB was 
properly constituted and convened as required by International Council for Harmonization (ICH)
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current IB and Summary of Product Characteristics 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 case report forms (CRFs), and 
study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.

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Ixekizumab (LY2439821)
In addition, Lilly or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site.  The study may be audited by Lilly and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.  
The purpose and use of subject personal information collected will be provided in a written 
document to the subject by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.

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Ixekizumab (LY2439821)
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 CRP.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin level (TBL)
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALP = alkaline phosphatase; 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.

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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, clinical laboratory, pharmacokinetics, immunogenicity, and 
bioanalytical assays) during the study.  
Protocol I1F-MC-RHCT Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
26
1
26
Clinical laboratory testsa
15.2
4
60.8
Pharmacokinetics 
3
15b
45
Immunogenicity
10
4
40
Pharmacogenetics
10
1
10
Total
181.8
Total for clinical purposes 
190
a
Additional samples may be drawn if needed for safety purposes.
b
Includes an additional 3 samples, if required.  

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Ixekizumab (LY2439821)
Appendix 6.
Protocol Amendment I1F-MC-RHCT (b) 
Summary: Relative Bioavailability of 2 Ixekizumab Test 
Formulations Compared to the Commercial Formulation 
in Healthy Subjects
Overview
Protocol I1F-MC-RHCT, Relative Bioavailability of 2 Ixekizumab Test Formulations Compared 
to the Commercial Formulation in Healthy Subjects, has been amended.  The new protocol is 
indicated by Amendment (b) and will be used to conduct the study in place of any preceding 
version of the protocol.
A temperature assessment was added to each site visit.  In addition, safety telephone calls were 
added in between outpatient visits as appropriate.
The additional study activities are being implemented to further monitor the health of subjects 
due to emerging data in response to a reporting of an SAE in this study.

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Ixekizumab (LY2439821)
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
1. Protocol Synopsis
Eligible subjects will be admitted to the clinical research unit (CRU) on Day -1 and randomized 1:1:1 to 1 of 
3 possible treatments.  Subjects may be allowed to leave the CRU after completing the 4-hour safety assessments on 
Day 1, at the investigator’s discretion, and will return for pharmacokinetic (PK) and immunogenicity sampling and 
safety assessments at predefined times up to 12 weeks postdose.  Subjects will be monitored for safety between 
outpatient visits by way of telephone assessment.
Safety and tolerability will be assessed by clinical laboratory tests, vital sign measurements, temperature, recording 
of adverse events (AEs), physical examination/medical assessments, Columbia Suicide Severity Rating Scale
(C-SSRS), Hospital Anxiety Depression Scale (HADS), immunogenicity, and injection-site assessments.  Pain 
assessments will be made using an injection-site VAS. 

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Ixekizumab (LY2439821) 
2. Schedule of Activities 
 
Screening 
Study Day 
 
Procedure 
-28 to -2 
days prior to 
Day 1 
-1 
1 
3 
5 
±1d 
8 
±1d 
11 
±1d 
15 
±2d 
22 
±2d 
29 
±2d 
36±2d 
43 
±2d 
50 
±2d 
57 
±3d 
64  
± 3d 
71 
±3d 
85/ED 
±3d 
Safety 
Assessment 
(Telephone Call) 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
Body 
Temperature 
(Oral) 
 
P 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Adverse Events 
and Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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3.3 Benefit/Risk Assessment
As of the cut-off date for the current investigator’s brochure (IB; 22 March 2018), more than 
8755 subjects and patients have received at least 1 dose of ixekizumab (5934 patients with Ps, 
532 patients with rheumatoid arthritis, 1301 patients with psoriatic arthritis, 119 healthy subjects, 
and an estimated 869 patients with axial spondyloarthritis).  
5. Study Design
5.1 Overall Design
Subjects may be allowed to leave the CRU after completing the 4-hour safety assessments on 
Day 1, at the investigator’s discretion, and will return for pharmacokinetic (PK) and 
immunogenicity sampling and safety assessments at predefined times up to 12 weeks postdose.  
Subjects will be monitored for safety between outpatient visits by way of telephone assessment.
Safety and tolerability will be assessed by clinical laboratory tests, vital sign measurements, 
temperature, recording of AEs, physical examination (PE)/medical assessments, Columbia 
Suicide Severity Rating Scale (C-SSRS), immunogenicity, and injection-site assessments.  Pain 
assessments will be made using an injection-site visual analog scale (VAS). 
9.4 Safety
Safety will be assessed throughout the course of the study at site visits and via telephone calls in 
between site visits. 
9.4.4. Temperature
Body temperature (oral) will be assessed at the times indicated in the Schedule of Activities 
(Section 2).