A Randomized Study to Investigate Injection-Site Pain Following Subcutaneous Injections of 2 Ixekizumab Test Formulations Compared to the Commercial Formulation Using a Pre-filled Syringe in Healthy Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

I1F-MC-RHCS Protocol b 
 
A Randomized Study to Investigate Injection-Site Pain Following Subcutaneous Injections of 2 
Ixekizumab Test Formulations Compared to the Commercial Formulation using a Pre-filled 
Syringe in Healthy Subjects 
 
NCT03848403 
 
Approval Date: 30-May-2019 
 
 
 

I1F-MC-RHCS Clinical Pharmacology Protocol (b)
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Ixekizumab LY2439821
Protocol I1F-MC-RHCS (b)
A Randomized Study to Investigate Injection-Site Pain
Following Subcutaneous Injections of 2 Ixekizumab Test 
Formulations Compared to the Commercial Formulation 
using a Pre-filled Syringe 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: 29 October 
2018.
Amendment (a) Electronically Signed and Approved by Lilly:  03 December 2018
Amendment (b) Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 30-May-2019 GMT

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Table of Contents
A Randomized Study to Investigate Injection-Site Pain 
Following Subcutaneous Injections of 2 Ixekizumab Test 
Formulations Compared to the Commercial Formulation 
using a Pre-filled Syringe in Healthy Subjects
Section
Page
Protocol I1F-MC-RHCS (b) A Randomized Study to Investigate 
Injection-Site Pain Following Subcutaneous Injections of 2 
Ixekizumab Test Formulations Compared to the Commercial 
Formulation using a Pre-filled Syringe in Healthy Subjects.................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................17
3.1.
Study Rationale............................................................................................................17
3.2.
Background..................................................................................................................17
3.3.
Benefit/Risk Assessment..............................................................................................17
4.
Objectives and Endpoints..................................................................................................19
5.
Study Design.....................................................................................................................20
5.1.
Overall Design .............................................................................................................20
5.2.
Number of Participants.................................................................................................21
5.3.
End of Study Definition ...............................................................................................21
5.4.
Scientific Rationale for Study Design...........................................................................21
5.5.
Justification for Dose ...................................................................................................21
6.
Study Population...............................................................................................................23
6.1.
Inclusion Criteria..........................................................................................................23
6.2.
Exclusion Criteria ........................................................................................................25
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................28
6.3.
Lifestyle and/or Dietary Requirements .........................................................................28
6.3.1.
Meals and Dietary Restrictions.............................................................................28
6.3.2.
Alcohol and Tobacco ...........................................................................................29
6.3.3.
Activity................................................................................................................29
6.4.
Screen Failures.............................................................................................................29
7.
Treatment..........................................................................................................................30
7.1.
Treatment Administered...............................................................................................30
7.1.1.
Packaging and Labeling .......................................................................................31

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7.2.
Method of Treatment Assignment ................................................................................31
7.2.1.
Selection and Timing of Doses.............................................................................31
7.3.
Blinding .......................................................................................................................31
7.4.
Dose Modification........................................................................................................31
7.5.
Preparation/Handling/Storage/Accountability...............................................................31
7.6.
Treatment Compliance .................................................................................................32
7.7.
Concomitant Therapy...................................................................................................32
7.8.
Treatment after the End of the Study............................................................................32
8.
Discontinuation Criteria ....................................................................................................33
8.1.
Discontinuation from Study Treatment.........................................................................33
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................34
8.2.
Discontinuation from the Study....................................................................................34
8.3.
Subjects Lost to Follow-up...........................................................................................34
9.
Study Assessments and Procedures ...................................................................................36
9.1.
Efficacy Assessments...................................................................................................36
9.2.
Adverse Events ............................................................................................................36
9.2.1.
Serious Adverse Events........................................................................................37
9.2.1.1.
Adverse Events of Special Interest..................................................................37
9.2.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................38
9.2.2.
Complaint Handling.............................................................................................38
9.3.
Treatment of Overdose.................................................................................................39
9.4.
Safety...........................................................................................................................39
9.4.1.
Laboratory Tests ..................................................................................................39
9.4.2.
Vital Signs ...........................................................................................................39
9.4.3.
Electrocardiograms ..............................................................................................39
9.4.4.
Temperature.........................................................................................................40
9.4.5.
Other Tests...........................................................................................................40
9.4.5.1.
Injection-Site Assessments .............................................................................40
9.4.5.2.
Bleeding/Bruising Assessment........................................................................40
9.4.5.3.
Injection-Site Pain ..........................................................................................40
9.4.5.4.
Columbia Suicide Severity Rating Scale.........................................................41
9.4.5.5.
Hospital Anxiety Depression Scale.................................................................41
9.4.6.
Safety Monitoring ................................................................................................41
9.4.6.1.
Hepatic Safety................................................................................................41
9.5.
Pharmacokinetics .........................................................................................................42
9.6.
Pharmacodynamics ......................................................................................................42
9.6.1.
Immunogenicity Assessments ..............................................................................42
9.7.
Genetics .......................................................................................................................42

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9.8.
Biomarkers...................................................................................................................43
9.9.
Health Economics ........................................................................................................43
10.
Statistical Considerations and Data Analysis.....................................................................44
10.1. Sample Size Determination ..........................................................................................44
10.2. Populations for Analyses..............................................................................................44
10.2.1.
Study Participant Disposition ...............................................................................44
10.2.2.
Study Participant Characteristics ..........................................................................44
10.3. Statistical Analyses ......................................................................................................44
10.3.1.
Safety Analyses....................................................................................................45
10.3.1.1.
Clinical Evaluation of Safety..........................................................................45
10.3.1.2.
Statistical Evaluation of Safety.......................................................................45
10.3.1.2.1.
Injection-Site Pain ....................................................................................45
10.3.1.2.2.
Statistical Evaluation of Other Safety Parameters......................................45
10.3.2.
Data Review During the Study.............................................................................45
10.3.3.
Interim Analyses..................................................................................................46
11.
References ........................................................................................................................47

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List of Tables
Table
Page
Table RHCS.1.
Objectives and Endpoints .......................................................................19
Table RHCS.2.
Treatments Administered........................................................................30

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List of Figures
Figure
Page
Figure RHCS.1.
Illustration of study design for Protocol I1F-MC-RHCS. ........................21

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................48
Appendix 2.
Clinical Laboratory Tests........................................................................52
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................54
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............57
Appendix 5.
Blood Sampling Summary......................................................................58
Appendix 6.
Protocol Amendment I1F-MC-RHCS (b) Summary:  A 
Randomized Study to Investigate Injection-Site Pain Following 
Subcutaneous Injections of 2 Ixekizumab Test Formulations 
Compared to the Commercial Formulation using a Pre-filled 
Syringe in Healthy Subjects....................................................................59

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1. Protocol Synopsis
Title of Study:
A Randomized Study to Investigate Injection-Site Pain Following Subcutaneous Injections of 2 Ixekizumab Test 
Formulations Compared to the Commercial Formulation using a Pre-filled Syringe 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-RHCS is therefore being conducted to compare injection-site pain and tolerability of 
ixekizumab administered using 2 new formulations, compared to the commercial formulation.
Objective/Endpoint:  
Objective
Endpoint
Primary
Evaluate pain intensity on injection of ixekizumab with 
different formulations.
Visual analog scale (VAS) pain score immediately 
(within 1 minute) after injection
Summary of Study Design:
This will be a single-dose, subject-blind, 3-period, 3-treatment, randomized, crossover 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 treatment sequences.  
Subjects may be allowed to leave the CRU after completing the 4-hour safety assessments for Day 1, at the 
investigator’s discretion.  Subjects will be readmitted to the CRU on Days 7 and 14 to receive their second and third 
injections on Days 8 and 15, respectively, and may be allowed to leave the CRU after completing the 4-hour safety 
assessments at the investigators discretion on Days 8 and 15, respectively.  Subjects will return to the CRU as an 
outpatient on Days 21 (±1 day) and 43 (±3 days) for a safety check-up.  In addition, safety follow-up telephone calls
will be conducted in between outpatient visits, on Days 28 (± 1 day), 35 (± 3 days), 50 (± 3 days), 57 (± 3 days), and 
64 (± 3 days), with a final safety follow-up telephone call on Day 71 (± 3 days).  There will be a follow-up visit 
approximately 12 weeks after the last injection.
Safety and tolerability will be assessed by monitoring of adverse events (AEs), injection-site assessments, 
injection-site pain, bleeding/bruising assessments, Columbia Suicide Severity Rating Scale (C-SSRS), Hospital 
Anxiety Depression Scale (HADS), vital signs assessments, temperature, physical examination, 12-lead 
electrocardiograms (ECGs), and clinical laboratory tests.  Pain assessments will be made using an injection-site 
visual analog scale (VAS).
Treatment Arms and Planned Duration for an Individual Subject:  
All subjects will be screened within 28 days prior to enrollment.  On Days 1, 8, and 15, subjects will receive a single 
1-mL subcutaneous injection of 1 of the following treatments, according to the randomization schedule:

80 mg ixekizumab Commercial Formulation (Reference)

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
80 mg ixekizumab Test Formulation 1

80 mg ixekizumab Test Formulation 2
Subjects will participate in the study for approximately 18 weeks.  
Number of Subjects:
Up to 102 subjects may be enrolled to maximize the intent to have 78 subjects (26 in each treatment sequence) 
complete the study.  Attempts will be made to enroll a total of 3 Japanese completers.
Statistical Analysis:
Abnormal lab values will be listed.  Other safety parameters that will be assessed include injection-site assessments, 
including pain, induration, swelling, pruritus, bleeding/bruising, and erythema/redness.  The parameters will be 
listed, and summarized using standard 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.  Additional analyses may be performed if warranted 
upon review of the data.
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 be summarized by treatment and time 
point.

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2. Schedule of Activities

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Study Schedule Protocol I1F-MC-RHCS
Screening
Study Day
FU/
EDa
Comments
Procedure
-28 to -2 
days prior 
to Day 1
Day 
-1
Day 
1
Day 
7
Day 
8
Day 
14
Day 
15
Day 
21
(± 1 
day)
Days 
28 &  
35 
(± 3
days) 
Day 
43 
(± 3 
days)
Days 
50, 
57, & 
64
(± 3
days) 
Day 
71
(± 3 
days)
Informed 
Consent
X
Subject 
Admission to 
CRU
X
X
X
Subject 
Discharge from 
CRU
X
X
X
Safety 
Assessment 
(Telephone 
Call)
X
X
X
Every effort will be made to 
contact subjects as near to 
this time as possible but 
missed calls will not be 
recorded as protocol 
deviations.
Medical History 
and 
Demographics
X
Height
X
Weight
X
X
X
Serology
X
QuantiFERON®
-TB Gold or 
TST
X
Randomization
X

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Screening
Study Day
FU/
EDa
Comments
Procedure
-28 to -2 
days prior 
to Day 1
Day 
-1
Day 
1
Day 
7
Day 
8
Day 
14
Day 
15
Day 
21
(± 1 
day)
Days 
28 &  
35 
(± 3 
days)
Day 
43 
(± 3 
days)
Days 
50, 
57, & 
64
(± 3
days)
Day 
71
(± 3 
days)
Investigational 
Product 
Administration
X
X
X
Ethanol Testing 
and Urine Drug 
Screen
X
X
X
X
May be repeated at the 
discretion of the 
investigator.
Pregnancy Test 
(Females Only; 
as applicable)
X
X
X
X
X
Serum pregnancy test will 
be performed at screening.  
Urine pregnancy test will 
be performed at all 
subsequent time points.
FSH Test
X
Females only, if 
applicable.
Physical Exam
X
X
After baseline exam, 
medical assessment is 
performed only to include 
medical review and 
targeted examination, as 
appropriate.
12-lead ECG
X
X
Single readings will be 
taken after at least 
5 minutes in a supine 
position.

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Screening
Study Day
FU/
EDa
Comments
Procedure
-28 to -2 
days prior 
to Day 1
Day 
-1
Day 
1
Day 
7
Day 
8
Day 
14
Day 
15
Day 
21
(± 1 
day)
Days 
28 &  
35 
(± 3
days)
Day 
43 
(± 3 
days)
Days 
50, 
57, & 
64
(± 3
days)
Day 
71
(± 3 
days)
HADS 
Depression 
sub-scale
X
X
X
X
X
X
X
C-SSRS and 
Lilly Self-Harm 
Supplement
X
X
X
X
X
X
X
At screening ‘Baseline -
Screening’ questionnaire 
to be used, all other 
timepoints use ‘Since Last 
Visit’ questionnaire.
Body 
Temperature
P
X
X
X
X
X
Clinical 
Chemistry, 
Hematology, 
and Urinalysis 
Tests
X
X
X
X
X
X
X
See Appendix 2, Clinical 
Laboratory Tests, for 
details.

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Screening
Study Day
FU/
EDa
Comments
Procedure
-28 to -2 
days prior 
to Day 1
Day 
-1
Day 
1
Day 
7
Day 
8
Day 
14
Day 
15
Day 
21
(± 1 
day)
Days 
28 &  
35 
(± 3 
days)
Day 
43
(± 3 
days)
Days 
50, 
57, & 
64
(± 3 
days)
Day 
71
(± 3 
days)
Injection-Site 
Assessments 
(Minutes)
0, 10, 
20, 
30, 
60, 
120, 
240
0, 
10, 
20, 
30, 
60, 
120, 
240
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.  Assessments 
will be conducted once 
during the 1-week follow-up 
on Day 21 (± 1 day) and on 
Day 43 (± 3 days). 
Injection-Site 
Pain
Assessment 
using VAS 
(Minutes)
0, 10, 
20, 
30, 60
0, 
10, 
20, 
30, 
60
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.
Screening
Study Day
FU/
EDa
Comments

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Procedure
-28 to -2 
days prior 
to Day 1
Day 
-1
Day 
1
Day 
7
Day 
8
Day 
14
Day 
15
Day 
21
(± 1 
day)
Days 
28 &  
35 
(± 3 
days)
Day 
43
(± 3 
days)
Days 
50, 
57, & 
64
(± 3 
days)
Day 
71
(± 3 
days)
Injection-Site 
Bleeding/Bruising 
Assessment
(Minutes)
0, 
10, 
20, 
30, 
60, 
120, 
240
0, 
10, 
20, 
30, 
60, 
120, 
240
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.
Pharmacokinetic 
Sample
X
X
Samples to be stored only.
Immunogenicity 
Sample
X
X
X
Samples to be stored only.
Vital Signs 
(Sitting)
X
X
P, 
2-4
X
P, 
2-4
X
P, 2-4
X
X
X
Day 1, 8, and 15: 2-4 hour 
assessment to be conducted 
at least 2 hours postdose 
and prior to discharge at 
approximately 4 hours 
postdose. Sitting blood 
pressure and pulse rate may 
be measured as clinically 
indicated.  Timepoints may 
be added if warranted.

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Screening
Study Day
FU/
EDa
Comments
Procedure
-28 to -2 
days prior 
to Day 1
Day 
-1
Day 
1
Day 
7
Day 
8
Day 
14
Day 
15
Day 
21
(± 1
day)
Days 
28 &  
35 
(± 3 
days)
Day 
43
(± 3 
days)
Days 
50, 
57, & 
64
(± 3 
days)
Day 
71
(± 3 
days)
Pharmacogenetic 
Sample
X
Adverse Events 
and Concomitant 
Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations:  CRU = clinical research unit; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; ED = early discontinuation; 
FSH = follicle-stimulating hormone; FU = follow-up; HADS = Hospital Anxiety and Depression Scale; P = predose; TB = tuberculosis; TST = tuberculin 
skin test; VAS = visual analog scale.
Note:  if multiple procedures take place at the same time point, the following order should be used: ECG, vital signs, and venipuncture.
a Follow-up / Early Discontinuation should be ~12 weeks post last injection (±1 week).

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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 a 1-mL autoinjector (AI). 
Study I1F-MC-RHCK was conducted to assess acute pain and injection site reactions 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 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.  Neither have been tested in humans or animals thus far.
One new formulation
 
 
 
Study RHCS is being conducted in parallel with Study I1F-MC-RHCT which will provide 
further assessment of the pharmacokinetics of ixekizumab and injection-site pain and ISRs 
associated with administration of the 3 ixekizumab formulations in a parallel-design study.
3.2.
Background
Ixekizumab (LY2439821, Taltz®) is a humanized immunoglobulin 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 
psoriasis (Ps) at a dose of 160 mg at Week 0, followed by 80 mg every 2 weeks (Q2W) up to 
Week 12, then maintenance dosing of 80 mg every 4 weeks (Q4W), and for active psoriatic 
arthritis at a dose of 160 mg at Week 0 followed by 80 mg Q4W. In Japan, ixekizumab is 
marketed for moderate-to-severe plaque Ps, erythrodermic Ps, pustular Ps, and psoriatic arthritis.  
3.3.
Benefit/Risk Assessment
As this study will enroll healthy subjects, there is no anticipated therapeutic benefit for the 
subjects.
As of the cut-off date for the current Investigator’s Brochure (IB; 22 March 2018), more than 
8755 clinical trial subjects have received at least 1 dose of ixekizumab (5934 patients with Ps, 

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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 adverse events (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 trials.  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 treatment-emergent AEs (TEAEs) were mild in severity and the most 
commonly reported TEAEs were ISRs, injection site pruritus, nausea, diarrhea, upper respiratory 
tract infection, and injection-site erythema.  Pharmacokinetic simulations (described further in 
Section 5.5) show that the 80 mg dose given every week for a total of 3 injections proposed for 
this study is projected to give exposures that are within the range of exposure to ixekizumab 
reported in previous studies, thus a similar TEAE profile is expected.  The excipients are 
expected to be safe and well tolerated.
More information about the known and expected benefits, risks, serious AEs (SAEs) and 
reasonably anticipated AEs of ixekizumab are to be found in the IB.  

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4. Objectives and Endpoints
Table RHCS.1 shows the objectives and endpoints of the study.
Table RHCS.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
Evaluate pain intensity on injection of ixekizumab with 
different formulations.
Visual analog scale (VAS) pain score immediately 
(within 1 minute) after injection
Exploratory
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 scores

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5. Study Design
5.1.
Overall Design
This will be a single-dose, subject-blind, 3-period, 3-treatment, randomized, crossover 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 
treatment sequences (see Figure RHCS.1).  On Day 1, subjects will receive a single 1-mL SC
injection of 1 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 for 
Day 1, at the investigator’s discretion.  Subjects will be readmitted to the CRU on Days 7 and 14 
to receive their second and third injections on Days 8 and 15, respectively, and may be allowed 
to leave the CRU after completing the 4-hour safety assessments at the investigators discretion 
on Days 8 and 15, respectively.  Subjects will return to the CRU as an outpatient on Days 21
(± 1 day) and 43 (± 3 days) for a safety check-up.  In addition, safety follow-up telephone calls
will be conducted in between outpatient visits, on Days 28 (± 1 day), 35 (± 3 days), 50 (± 3 days), 
57 (± 3 days), and 64 (± 3 days), with a final safety follow-up telephone call on Day 71 (± 3 
days).  There will be a follow-up visit approximately 12 weeks after the last injection.
Site staff will administer all injections.  All injections will be administered in the abdomen while 
the subject is in a sitting or a reclining position.  Subsequent injections will be alternated 
between the abdominal quadrants.  The injection site will be documented.  Injections should not 
be made into an area that shows evidence of bruising, redness, or a rash from a previous injection.  
All study injection sites will be marked for size and with a surgical marker in order to identify 
study injection sites.  Every attempt will be made to have injections for individual subjects be 
performed by the same clinical staff member.
Injection-site assessments will be administered immediately after each injection and at 10, 20, 30, 
60, 120, and 240 minutes post injection.  The injection-site pain VAS will be administered 
immediately after each injection and at 10, 20, 30, and 60 minutes post-injection.
Safety and tolerability will be assessed by monitoring of AEs, injection-site assessments, 
injection-site pain, bleeding/bruising assessments, Columbia Suicide Severity Rating Scale 
(C-SSRS), Hospital Anxiety and Depression Scale (HADS), vital signs assessments, temperature, 
physical examination, 12-lead electrocardiograms (ECGs), and clinical laboratory tests.  
Study governance considerations are described in detail in Appendix 3.
Figure RHCS.1 illustrates the study design.

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Group 1
Group 2
Group 3
Subjects will be blinded to all treatments.
Figure RHCS.1.
Illustration of study design for Protocol I1F-MC-RHCS.
5.2.
Number of Participants
Up to 102 subjects may be enrolled to maximize the intent to have 78 subjects (26 subjects per 
treatment sequence) complete the study.  For purposes of this study, a subject completes the 
study when all procedures scheduled for Day 21 have been finished.  Attempts will be made to 
enroll a total of 3 Japanese completers.
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
Healthy subjects have been chosen for this exploratory study so that potential formulations may 
be explored prior to conducting trials in target patient populations.  
The study has a 3-period crossover design to allow each subject to act as their own control.  This 
design allows a comparison of the effects of ixekizumab administered using the commercial 
formulation to Test Formulation 1 and Test Formulation 2.  All injections will be administered in 
the abdomen for consistency, because the abdomen is one of the most commonly used sites for 
self-injection in clinical practice.
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 Q4W.  The 
Commercial 
Formulation
(Reference)
Test Formulation 
1
Test Formulation 
2
Test Formulation 
1
Test Formulation 
2
Commercial 
Formulation
(Reference)
Test Formulation 
2
Commercial 
Formulation
(Reference)
Test Formulation 
1

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dosing regimen in Study RHCS is not designed to mimic that used in clinical practice but to 
administer the commercial dose strength (80 mg/mL), since the primary objective is evaluation 
of the pain that occurs within 1 hour of the time of injection.  Subjects in Study RHCS will 
receive a total of 3 injections of 80 mg ixekizumab separated by 1-week intervals (total dose 
240 mg).
Across studies in Ps patients, doses of ixekizumab from 5 to 160 mg SC and 15 mg intravenously 
have been studied, given on a Q2W or Q4W basis. In addition, studies in rheumatoid arthritis 
patients evaluated doses up to 180 mg Q2W and 120 mg weekly. Pharmacokinetic simulations of 
the ixekizumab dose regimens proposed for Study RHCS were compared to pharmacokinetic 
data in healthy subjects in Study RHCA and in patients with Ps. These pharmacokinetic 
simulations show that the 80 mg dose given every week for a total of 3 injections proposed for 
this study is projected to give exposures that are within the range of exposure to ixekizumab 
reported in previous studies, thus a similar TEAE profile is expected (see Section 3.3).

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6. Study Population
Eligibility of subjects for the study will be based on the results of medical history, vital signs, 
clinical laboratory tests, electrocardiogram (ECG), and physical examination. 
The nature of any conditions present at the time of the physical examination 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 physical examination, or are males or females with chronic, stable
medical problems that, in the investigator’s 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) must be women of child-bearing potential who are abstinent (if this is complete 
abstinence, as their preferred and usual lifestyle) or in a same-sex relationship 
(as part of their preferred and usual lifestyle) must agree to either remain 
abstinent or stay in a same-sex relationship without sexual relationships with 
males.  Periodic abstinence (eg, calendar, ovulation, symptothermal, 

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post-ovulation methods), declaration of abstinence just for the duration of the 
trial, and withdrawal are not acceptable methods of contraception.
2) Otherwise, women of child-bearing 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 the last dose of ixekizumab.
i.
Women of child-bearing potential participating 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 within 24 hours prior to exposure to study drug at each 
entry to the CRU.
ii.
Either 1 highly-effective method of contraception (such as combination 
oral contraceptives, implanted contraceptives, or intrauterine device) or 
a combination of 2 effective methods (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 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.
3) Women not of child-bearing potential may participate and include those who 
are:
i.
infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, bilateral salpingectomy, tubal ligation, or permanent 
tubal occlusion such as Essure), a congenital anomaly such as mullerian 
agenesis; or
ii.
post-menopausal – defined as either:
a)
a woman at least 50 years of age with an intact uterus, not 
on hormone therapy, who has had either:

cessation of menses for at least 1 year; or

at least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone level >40 mIU/mL.
b)
a woman 55 years or older, not on hormone therapy, who 
has had at least 6 months of spontaneous amenorrhea;

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c)
a woman 55 years or older with a diagnosis of menopause 
prior to starting hormone replacement therapy.
[2]
are aged at least 18 (20 for Japanese subjects) to 75 years at the time of screening.
[3]
have a body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive at screening.
[4]
have venous access sufficient to allow for blood sampling as per the protocol.
[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 informed consent.
[7]
For Japanese subjects, the subject, the subject’s biological parents, and all 
of the subject’s biological grandparents must be of exclusive Japanese 
descent and born in Japan.
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:
[8] are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling.
[9] are Lilly,
 or Covance employees.
[10] are currently enrolled in a clinical study involving an investigational product 
(IP) or any other type of medical research judged not to be scientifically or 
medically compatible with this study.
[11] have participated, 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.
[12]
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.
[13]
have known allergies to ixekizumab, related compounds or any components of 
the formulations, or history of significant atopy.
[14]
have self-perceived dullness or loss of sensation on either side of their 
abdomen.
[15]
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.

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[16]
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.
[17]
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.
[18]
Have recent history (past 30 days) of depression; have HADS Depression 
subscale score of ≥11.
[19]
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.
[20]
Infections:
[20a] 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.
[20b] 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.
[20c] Have or have had a herpes zoster infection or any other clinically 
apparent varicella-zoster virus infection within 12 weeks of Day 1.
[20d] 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.
[21]
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.
[22]
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:

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
neutrophil count <1500 cells/µL

lymphocyte count <800 cells/µL

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.
[23]
regularly use known drugs of abuse and/or show positive findings on drug 
screening.
[24]
show evidence of human immunodeficiency virus (HIV) infection and/or 
positive HIV antibodies.
[25]
show evidence of hepatitis C and/or positive hepatitis C antibody.
[26]
show evidence of, or test positive for hepatitis B and/or positive hepatitis B 
surface antigen and/or hepatitis B core antibody.
[27]
are women who are lactating.
[28]
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.
[29]
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 admission to the CRU until CRU discharge, plus 48 hours prior to 
admission to the CRU for the 12-week follow-up visit until final discharge 
from the CRU, or are unwilling to restrict alcohol intake to 3 units per day 
(males) and 2 units per day (females) between CRU admission 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).
[30]
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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[31] 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.
[32] 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.
[33] intend or are likely to use over-the-counter or prescription medication for pain 
or inflammation within 7 days prior to each dose administration.  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).
[34] have a known allergy or hypersensitivity to any biologic therapy that would 
pose an unacceptable risk to the subject if participating in this study.
[35] 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.
[36] have any condition that could affect pain perception from an injection.
[37] 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.
[38] 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 [8] and [9] prevent conflict of interest in study participants.  Exclusion criteria 
[10] through [38] 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.  Subjects will also be required to adhere to 
contraceptive requirements, as outlined in the inclusion criteria (Section 6.1).
6.3.1. Meals and Dietary Restrictions
Subjects will receive a light breakfast on the morning of Days 1, 8, and 15, 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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6.3.2. Alcohol and Tobacco
Subjects should not drink alcohol for 48 hours prior to each admission to the CRU until CRU 
discharge, plus 48 hours prior to admission to the CRU for the 12-week follow-up visit until final 
discharge from the CRU.  Alcohol intake between CRU admission 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 whilst 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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7. Treatment
7.1.
Treatment Administered
A dose of IP will consist of 1 SC injection of 80 mg ixekizumab into the abdomen.  All doses 
will be administered by clinical site staff.
The 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)
Prior to the PFS injection, the investigator or his/her designee will clean the subject’s skin.  The 
injection will be administered by clinical site staff, according to the instructions provided by the 
sponsor.
Table RHCS.2 shows the treatment regimens.
Table RHCS.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.

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7.1.1. Packaging and Labeling
Ixekizumab will be supplied by the sponsor or its designee in accordance with current good 
manufacturing practice, 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, pre-filled, disposable manual syringes

ixekizumab Test Formulation 1 (solution for injection) in 1-mL single-dose, pre-filled, 
disposable manual syringes

ixekizumab Test Formulation 2 (solution for injection) in 1-mL single-dose, pre-filled, 
disposable manual syringes
7.2.
Method of Treatment Assignment
Subjects will be randomly assigned to 1 of 3 possible treatment sequences 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.
7.5.
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 temperature of the on-site storage conditions of the IP.  The 
investigator or designee must confirm appropriate temperature conditions have been maintained, 
as communicated by the sponsor, during transit for all IP received and ensure any discrepancies 
are reported and resolved before use of the study treatment.
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 (ie, subjects
must not see the syringe before, during or after the drug administration).  Blinded assessors of 
injection site assessments and bleeding/bruising will not have access to the IP.

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Only participants enrolled in the study may receive IP or study materials, and only authorized 
site staff may supply IP or administer investigational product.  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 dosing days until at least 
4 hours after the injection or 4 hours before the next injection.  No more than 3 g of 
acetaminophen will be permitted in any 24-hour period.  Inclusion of subjects on any other 
concomitant medication 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, 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
Not applicable.

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8. Discontinuation Criteria
Subjects discontinuing from the treatment prematurely for any reason should complete AE and 
other follow-up procedures per Section 2 of this protocol.
Subjects discontinuing from the study prematurely for any reason must complete AE and 
follow-up/ED procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Discontinuation of the IP for abnormal liver tests should be considered by the investigator when 
a subject meets 1 of the following conditions after consultation with the Lilly designated medical 
monitor:

alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × upper limit of 
normal (ULN)

ALT or AST >3 × ULN sustained for more than 2 weeks

ALT or AST >3 × ULN and total bilirubin level (TBL) >2 × ULN or International 
Normalized Ratio >1.5

ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

alkaline phosphatase (ALP) >3 × ULN;

ALP >2.5 × ULN and TBL >2 × ULN;

ALP >2.5 × ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%)
In addition, subjects will be discontinued from the study drug in the following circumstances:

Neutrophil (segmented) counts:
o
<500 cells/µL
o
≥500 and <1000 cells/µL (based on 2 test results; the second test performed 
within 1 week from knowledge of the initial result)
o
≥1000 and <1500 cells/µL (based on 3 test results) and an infection that is not 
fully resolved

Total white blood cell count <2000 cells/µL

Lymphocyte count <200 cells/µL

Platelet count <50,000 cells/µL
Subjects will also be evaluated for discontinuation from study treatment if a suicide-related
thought or behavior is identified at any time during the study, or if during the study a subject 
gives:

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
a “yes” answer to Question 4 (Active Suicidal Ideation with Some Intent to Act, Without 
Specific Plan) on the “Suicidal Ideation” portion of the C-SSRS

a “yes” answer to Question 5 (Active Suicidal Ideation with Specific Plan and Intent) on 
the “Suicidal Ideation” portion of the C-SSRS

a “yes” answer to any of the suicide-related behaviors (actual attempt, interrupted 
attempt, aborted attempt, preparatory act, or behavior) on the “Suicidal Behavior” portion 
of the C-SSRS
In addition, subjects will also be evaluated for discontinuation from study treatment if they have 
self-injurious behavior that would be classified as non-suicidal self-injurious behavior, or if they 
had a HADS depression sub-scale ≥11 at any predose visit.  It is recommended that a subject be 
assessed by a psychiatrist or appropriately trained professional to assist the investigator in 
deciding whether the subject should be discontinued from the study treatment.
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 with or without continued treatment with 
IP.  
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

Enrollment in any other clinical study involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study.

Subject Decision
o
the subject requests to be withdrawn from the study.
Subjects discontinuing from the study prematurely for any reason must complete AE and 
follow-up/ED procedures per Section 2 of this protocol.
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 

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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 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.
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 the IP 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 is signed, study site personnel will record, via eCRF, the 
occurrence and nature of each subject’s preexisting conditions.  Additionally, site personnel will 
record any change in the condition(s) and the occurrence and nature of any AEs.  
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 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 1 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
When a condition related to the investigational device necessitates medical or surgical 
intervention to preclude either permanent impairment of a body function or permanent damage to 
a body structure, the serious outcome of “required intervention” will be assigned.  Study site 
personnel must alert the Lilly CRP/CP, or its designee, of any SAE as soon as practically 
possible.
Additionally, study site personnel must alert Lilly Global Patient Safety, 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 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 in this clinical study.
Adverse events of special interest for ixekizumab are:

cytopenias (leukopenia, neutropenia, and thrombocytopenia)

liver function test changes/enzyme elevations (ALT, AST, TBL, and 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, ISRs, or allergic/hypersensitivity reactions are reported, sites will provide details on 
these events as instructed on the eCRF.  Investigators will also educate subjects about the 
symptoms of allergic/hypersensitivity reactions and will provide instructions on dealing with 
those reactions.  A blood sample will be collected when possible for any subject who experiences 
an AE of allergic/hypersensitivity reaction during the study.
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 will 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.  Suspected IBD cases will be 
adjudicated by an external CEC composed of gastroenterologists with expertise in inflammatory 
bowel disease.
The role of the CEC is to adjudicate defined clinical events, in a blinded, consistent, and 
unbiased manner throughout the course of the 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 trials in order 
to ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements.
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the IP or drug delivery system so that the situation can be assessed.

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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, 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.  Additional 
vital signs may be assessed as clinically indicated as well as at the scheduled times.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted.
9.4.3. Electrocardiograms
For each subject, ECGs should be collected according to the Schedule of Activities (Section 2).  
Any clinically significant findings from unscheduled ECGs that result in a diagnosis and that 
occur after the subject receives the first dose of the IP, should be reported to Lilly, or its 
designee, as an AE via eCRF.

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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.  
If a clinically significant finding is identified after enrollment, the investigator will determine if 
the subject can continue in the study.  The investigator, or qualified designee, is responsible for 
determining if any change in subject management is needed, and must document his/her review 
of the ECG printed at the time of collection.  Any new clinically relevant finding should be 
reported as an AE.
9.4.4. Temperature
Body temperature 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 any 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 blinded assessor.
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 blinded assessor, 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 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:  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 as 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.
9.4.5.5.
Hospital Anxiety Depression Scale 
The HADS depression subscale is a 7-item self-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 × ULN, ALP ≥2 × ULN, or elevated TBL
≥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 creatinine 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 2 or more consecutive blood tests

elevated serum TBL to ≥2 × ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2 × ULN on 2 or more consecutive blood tests 

subject discontinued from treatment due to a hepatic event or abnormality of liver 
tests

hepatic event considered to be an SAE
9.5.
Pharmacokinetics
At the times specified in the Schedule of Activities (Section 2), venous blood samples of 
approximately 3 mL each will be collected.  PK samples will not be analyzed for ixekizumab
serum concentration unless ADA samples are also analyzed due to hypersensitivity or other 
adverse events, as described in Section 9.6.1.
Samples will be retained for a maximum of 1 year after the last subject visit.  
9.6.
Pharmacodynamics
Not applicable.
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.  Due to the crossover design ADA samples will be collected and not analyzed 
unless clinically suggested by hypersensitivity or other AEs.
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 
at least 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.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and 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, 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 

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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
Not applicable.
9.9.
Health Economics
Not applicable.

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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Up to 102 subjects may be enrolled to maximize the intent to have 78 subjects (26 subjects per 
treatment sequence) complete the study.  
The objective of this study is to evaluate the injection pain immediately following dosing.  
Because of the crossover study design, each subject will have the opportunity to receive each 
treatment.  
 
 
 
Subjects who are randomized but not administered treatment may be replaced to ensure that 
approximately 78 subjects may complete the study.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study. 
10.2.2. Study Participant Characteristics
The 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.
Safety analyses will be conducted for all enrolled subjects who receive at least 1 dose of study 
drug, whether or not they completed all protocol requirements.
Continuous data will be summarized in terms of the mean, standard deviation, minimum, 
maximum, median, and number of observations.  Categorical data will be summarized as 
frequency counts and percentages.
Any change to the data analysis methods described in the protocol, and the justification for 
making the change, will be described in the clinical study report.  Additional exploratory 
analyses of the data will be conducted as deemed appropriate.  Complete details of the planned 
analyses will be documented in the Statistical Analysis Plan.

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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.
The incidence of symptoms for each treatment will be presented by severity and by association 
with IP as perceived by the investigator.  Symptoms reported to occur prior to study entry will be 
distinguished from those reported as new or increased in severity during the study.  Each 
symptom will be classified by the most suitable term from the medical regulatory dictionary.
The number of 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 be summarized by treatment and time point.
A mixed-effects repeated measures analysis model will be used to analyze the continuous 
injection-site pain VAS score by each time post-injection (0, 10, 20, 30, and 60 minutes). For 
measures at each time post-injection, the model will include treatment, period (Day 1, Day 8, or 
Day 15), treatment sequence, and treatment by treatment sequence as fixed effects. The 
covariance structure of the model will be unstructured.  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; treatment differences on every time point will 
be reported, along with the corresponding 95% confidence intervals for the differences. All 
pair-wise treatment comparisons by measuring time point will be evaluated and presented.
10.3.1.2.2.Statistical Evaluation of Other Safety Parameters
Abnormal lab values will be listed. Other safety parameters that will be assessed include 
injection-site assessments, including pain, induration, swelling, pruritus, bleeding/bruising, and 
erythema/redness.  The parameters will be listed and summarized using standard 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 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 sub-scale ≥11 at any time.  
Additional analyses may be performed if warranted upon review of the data.
10.3.2. Data Review During the Study
Data will be reviewed by the investigator and Sponsor throughout the course of the study to 
ensure subject safety.

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10.3.3. Interim Analyses
One formal interim analysis is planned for this study.  The interim analysis will include review 
of all available subjects’ safety data (AEs, VAS, and ISR data) collected up to and including Day 
21.

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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.  
Snaith RP. The Hospital Anxiety and Depression Scale. Health and Quality of Life Outcomes.
2003;1:29. Available at: http://www.hqlo.com/content/1/1/29. Accessed October, 2018.
White D, Leach C, Sims R, Atkinson M, Cottrell D. Validation of the Hospital Anxiety and
Depression Scale for use with adolescents. Br J Psychiatry. 1999;175(5):452-454.
Williamson A and Hoggart B.  Pain:  A review of three commonly used pain rating scales.  
J Clin Nurs.  2005;14(7):798-804.
Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand.  
1983;67:361-370.

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Appendix 1.
Abbreviations and Definitions

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Term
Definition
AE
adverse event:  Any untoward medical occurrence in a subject 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.
ADA
antidrug antibodies
AI
autoinjector
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BCG
Bacillus Calmette-Guérin
BMI
body mass index
CEC
Clinical Events Committee
CIOMS
Council for International Organizations of Medical Sciences
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 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
C-SSRS
Columbia Suicide Severity Rating Scale
ECG
electrocardiogram
eCRF
electronic case report form

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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
HADS
Hospital Anxiety and Depression Scale
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
ICF
informed consent form
ICH
International Council for Harmonisation
Ig
immunoglobulin
IL
interleukin
IND
Investigational New Drug:  An application to the FDA to allow testing of a new drug in 
humans.
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
IV
intravenous
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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MTD
maximum tolerated dose
PFS
prefilled syringe
Ps
psoriasis
Q2W
every 2 weeks
Q4W
every 4 weeks
randomize
the process of assigning subjects to an experimental group on a random basis
RBC
red blood cell
SAE
serious adverse event
SC
Subcutaneous(ly)
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SUSARs
suspected unexpected serious adverse reactions 
TB
tuberculosis
TBL
total bilirubin level
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 
TST
tuberculosis skin test
ULN
upper limit of normal
VAS
visual analogue 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) 
Blood urea nitrogen (BUN)
Platelets
Uric acid
Total cholesterol
Differential WBC absolute counts of:
Total protein
Neutrophils
Albumin
Lymphocytes
Total bilirubin
Monocytes
Direct bilirubin
Eosinophils
Triglycerides
Basophils
Alkaline phosphatase (ALP)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Creatinine
Urinalysis
Specific gravity
Phosphorus
pH
Protein
Other tests
Glucose
Pregnancy test (females only, if applicable)b
Ketones
FSH (females only, if applicable)a, c
Bilirubin
QuantiFERON®-TB Gold or TSTa
Urobilinogen
Ethanol testingd
Blood
Urine drug screend
Nitrite
Microscopy (if dipstick abnormal)
Serology
Hepatitis B surface antigena
Hepatitis B core antibodya
Hepatitis C antibodya
HIVa
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
TST = tuberculin skin test; WBC = white blood cells.
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 had spontaneous amenhorrhea for ≥6 months 
but <1 year to confirm non-childbearing potential (>40 mIU/mL).

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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 informed consent form 
(ICF) prior to the performance of any protocol procedures and prior to the administration 
of investigational product.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for subjects.  Individual 
investigators may have additional local requirements or processes.  Study specific recruitment 
material should be approved by Lilly.
Ethical Review
The investigator or appropriate local representative must give assurance that the ethical review 
board (ERB) was properly constituted and convened as required by International Council for 
Harmonisation (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.
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 lead investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the eCRFs, and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

review and evaluate eCRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.

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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 good clinical 
practice.

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Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with 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
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; RBC = red blood 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, safety laboratories, and bioanalytical assays) during the study.  
Protocol I1F-MC-RHCS Sampling Summary
Purpose
Blood Volume per 
Sample (mL)b
Number of Blood 
Samples
Total Volume 
(mL)b
Screening testsa
45 / 27.7
1
45 / 27.7
Clinical laboratory testsa
12.5 / 11.7
6
75 / 70.2
Pharmacokinetics
3
2
6
Immunogenicity
10
3
30
Pharmacogenetics
10
1
10
Total
166 / 143.9
Total for clinical purposes
170 / 150
a
Additional samples may be drawn if needed for safety purposes.
b    Differing blood sample volumes pertain to different study sites.

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Appendix 6.
Protocol Amendment I1F-MC-RHCS (b) 
Summary:  A Randomized Study to Investigate 
Injection-Site Pain Following Subcutaneous Injections of 
2 Ixekizumab Test Formulations Compared to the 
Commercial Formulation using a Pre-filled Syringe in 
Healthy Subjects
Overview
Protocol I1F-MC-RHCS, A Randomized Study to Investigate Injection-Site Pain Following 
Subcutaneous Injections of 2 Ixekizumab Test Formulations Compared to the Commercial 
Formulation using a Pre-filled Syringe 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.
Temperature assessments were added to each site visit.  In addition, weekly safety telephone 
calls were added in between outpatient visits as appropriate.
The additional study activities were implemented to further monitor the health of subjects due to 
emerging data in response to a reporting of an SAE in the I1F-MC-RHCT study.
Enrollment into this study was paused in April 2019 to evaluate a potential safety concern 
observed in the I1F-MC-RHCT (PK Study). Approximately 80% of the VAS data had been 
collected; the team decided to conduct the protocol specified interim analysis based on all the 
available data, and stop enrolling new subjects.

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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
1. Protocol Synopsis
Subjects may be allowed to leave the CRU after completing the 4-hour safety assessments for Day 1, at the 
investigator’s discretion.  Subjects will be readmitted to the CRU on Days 7 and 14 to receive their second and third 
injections on Days 8 and 15, respectively, and may be allowed to leave the CRU after completing the 4-hour safety 
assessments at the investigators discretion on Days 8 and 15, respectively.  Subjects will return to the CRU as an 
outpatient on Days 21 (±1 day) and 43 (±3 days) for a safety check-up.  In addition, A safety follow-up telephone 
calls will be conducted in between outpatient visits, on Days 28 (± 1 day), 35 (± 3 days), 50 (± 3 days), 
57 (± 3 days), and 64 (± 3 days), with a final safety follow-up telephone call on Day 71 (± 3 days).  There will be a 
follow-up visit approximately 12 weeks after the last injection.
Safety and tolerability will be assessed by monitoring of adverse events (AEs), injection-site assessments, 
injection-site pain, bleeding/bruising assessments, Columbia Suicide Severity Rating Scale (C-SSRS), Hospital 
Anxiety Depression Scale (HADS), vital signs assessments, temperature, physical examination, 12-lead 
electrocardiograms (ECGs), and clinical laboratory tests.  Pain assessments will be made using an injection-site 
visual analog scale (VAS).

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2. Schedule of Activities

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Screening
Study Day
Comments
Procedure
-28 to -2 days 
prior to Day 
1
Day 
-1
Day 
1
Day 
7
Day 
8
Day 
14
Day 
15
Day 
21
(± 1 
day)
Days 
28 &  
35 
(± 3
days)
Day 43 
(± 3 
days)
Days 
50, 57, 
& 64
(± 3
days)
Day 71
(± 3 
days)
Follow-up
FU/
EDa
~12 weeks 
post 
injection 
(±1 week)
Safety 
Assessment 
(Telephone 
Call)
X
X
X
Every effort 
will be made 
to contact 
subjects as 
near to this 
time as 
possible but 
missed calls 
will not be 
recorded as 
protocol 
deviations.
Subjects will 
be asked 
about the 
occurrence 
of AEs, 
injection-site 
reactions, 
and 
concomitant 
medication 
use.
Body 
Temperature
P
X
X
X
X
X

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Adverse Events 
and 
Concomitant 
Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
a Follow-up / Early Discontinuation should be ~12 weeks post last injection (±1 week).

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5. Study Design
5.1 Overall Design
Subjects may be allowed to leave the CRU after completing the 4-hour safety assessments for 
Day 1, at the investigator’s discretion.  Subjects will be readmitted to the CRU on Days 7 and 14 
to receive their second and third injections on Days 8 and 15, respectively, and may be allowed 
to leave the CRU after completing the 4-hour safety assessments at the investigators discretion 
on Days 8 and 15, respectively.  Subjects will return to the CRU as an outpatient on Days 21 (±1 
day) and 43 (±3 days) for a safety check-up.  In addition, A safety follow-up telephone calls will 
be conducted in between outpatient visits, on Days 28 (± 1 day), 35 (± 3 days), 50 (± 3 days), 
57 (± 3 days), and 64 (± 3 days), with a final safety follow-up telephone call on Day 71 
(± 3 days).  There will be a follow-up visit approximately 12 weeks after the last injection.
Safety and tolerability will be assessed by monitoring of AEs, injection-site assessments, 
injection-site pain, bleeding/bruising assessments, Columbia Suicide Severity Rating Scale 
(C-SSRS), Hospital Anxiety and Depression Scale (HADS), vital signs assessments, temperature, 
physical examination, 12-lead electrocardiograms (ECGs), and clinical laboratory tests.  
5.4 Scientific Rationale for Study Design
All doses will be administered by clinical site staff to reflect safety and tolerability of the device 
during its intended usage.
7.1.2. Medical Device
The investigator or his/her designee will ensure that the instructions have been followed 
properly; maintaining accurate records of study devices, dispensing, and collection.  The used or 
unused PFS may be destroyed by a qualified vendor.  However, a used PFS with a product 
complaint will need to be returned to Lilly.
9.2. Adverse Events
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account 
concomitant treatment or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the IP, study device and/or study procedure and the AE.
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 Devices used in this study can deliver only 1 mL 
volume of ixekizumab.
9.4. Safety

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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 will be assessed at the times indicated in the Schedule of Activities (Section 2).
10.2.3. Treatment Compliance
Every attempt will be made to select subjects who have the ability to understand and comply 
with instructions.  Noncompliant subjects may be discontinued from the study.  The time and day 
of administration of ixekizumab injections will be recorded.  Device accountability records will 
be maintained by the study site.
The specifications in this protocol for the timings of safety assessments are given as targets, to be 
achieved within reasonable limits.  Modifications may be made to the time points based upon the 
safety information obtained.  The scheduled time points may be subject to minor alterations; 
however, the actual time must be correctly recorded in the eCRF.
10.3.2. Data Review During the Study
Data will be reviewed by the investigator and Sponsor throughout the course of the study to 
ensure subject safety.
10.3.3. Interim Analyses 
One formal interim analysis is planned for this study.  The interim analysis will include review 
of all available subjects’ safety data (AEs, VAS, and ISR data) collected up to and including 
Day 21.