Clinical trial NCT04259346
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2020-02-05; Completion date: 2021-02-19
Enrollment: 245 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare two different formulations of ixekizumab. One formulation (Reference) is approved by the Food and Drug Administration (FDA) and one formulation (Test) is not approved. This study will compare how much of each formulation gets into the blood stream. Information about any side effects that may occur will also be collected. The study will last up to about four months for each participant.

Detailed description:

Arms: arm 1: Approved formulation of 80 milligram (mg) ixekizumab administered as a subcutaneous (SC) injection via autoinjector (AI). arm 2: Test formulation of 80 mg ixekizumab administered as a SC injection via AI.
Interventions: intervention 1: Ixekizumab
Intervention descriptions: intervention 1: Administered SC.

Protocol documents:
Prot_000.pdf: 
Protocol I1F-MC-RHCU(b) 
 
Bioequivalence of an Alternate Ixekizumab Formulation Compared to the Commercial Formulation 
in Healthy Subjects 
 
NCT04259346 
 
Approval Date: 29-Sep-2020 
 
 


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Protocol I1F-MC-RHCU(b)
Bioequivalence of an Alternate Ixekizumab Formulation
Compared to the Commercial Formulation in Healthy 
Subjects
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
ixekizumab (LY2439821), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
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 Approved by Lilly: 13 November 2019.
Amendment (a) Electronically Signed and Approved by Lilly:  21 February 2020
Amendment (b) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 29-Sep-2020 GMT


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Table of Contents
Bioequivalence of an Alternate Ixekizumab Formulation
Compared to the Commercial Formulation in Healthy 
Subjects
Section
Page
Protocol I1F-MC-RHCU(b) Bioequivalence of an Alternate Ixekizumab 
Formulation Compared to the Commercial Formulation in Healthy 
Subjects ..............................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................7
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................14
3.1.
Study Rationale............................................................................................................14
3.2.
Background..................................................................................................................14
3.3.
Benefit/Risk Assessment..............................................................................................14
4.
Objectives and Endpoints..................................................................................................17
5.
Study Design.....................................................................................................................18
5.1.
Overall Design .............................................................................................................18
5.2.
Number of Participants.................................................................................................19
5.3.
End of Study Definition ...............................................................................................19
5.4.
Scientific Rationale for Study Design...........................................................................19
5.5.
Justification for Dose ...................................................................................................20
6.
Study Population...............................................................................................................21
6.1.
Inclusion Criteria..........................................................................................................21
6.2.
Exclusion Criteria ........................................................................................................23
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................26
6.3.
Lifestyle and/or Dietary Requirements .........................................................................26
6.3.1.
Meals and Dietary Restrictions.............................................................................26
6.3.2.
Alcohol and Tobacco ...........................................................................................26
6.3.3.
Activity................................................................................................................27
6.4.
Screen Failures.............................................................................................................27
7.
Treatment..........................................................................................................................28
7.1.
Treatment Administered...............................................................................................28
7.1.1.
Packaging and Labeling .......................................................................................28
7.2.
Method of Treatment Assignment ................................................................................29
7.2.1.
Selection and Timing of Doses.............................................................................29


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7.3.
Blinding .......................................................................................................................29
7.4.
Dose Modification........................................................................................................29
7.4.1.
Special Treatment Considerations ........................................................................29
7.5.
Preparation/Handling/Storage/Accountability...............................................................30
7.6.
Treatment Compliance .................................................................................................30
7.7.
Concomitant Therapy...................................................................................................30
7.8.
Treatment after the End of the Study............................................................................31
8.
Discontinuation Criteria ....................................................................................................32
8.1.
Discontinuation from Study Treatment.........................................................................32
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................32
8.2.
Discontinuation from the Study....................................................................................32
8.3.
Subjects Lost to Follow-up...........................................................................................32
9.
Study Assessments and Procedures ...................................................................................33
9.1.
Efficacy Assessments...................................................................................................33
9.2.
Adverse Events ............................................................................................................33
9.2.1.
Serious Adverse Events........................................................................................34
9.2.1.1.
Adverse Events of Special Interest..................................................................34
9.2.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................35
9.2.1.3.
Systemic Hypersensitivity Reactions ..............................................................36
9.2.2.
Complaint Handling.............................................................................................36
9.3.
Treatment of Overdose.................................................................................................36
9.4.
Safety...........................................................................................................................36
9.4.1.
Laboratory Tests ..................................................................................................37
9.4.2.
Vital Signs ...........................................................................................................37
9.4.3.
Electrocardiograms ..............................................................................................37
9.4.4.
Temperature.........................................................................................................37
9.4.5.
Other Tests...........................................................................................................37
9.4.5.1.
Injection Site Assessments..............................................................................37
9.4.5.2.
Bleeding/Bruising Assessment........................................................................38
9.4.5.3.
Columbia Suicide Severity Rating Scale.........................................................38
9.4.5.3.1.
Hospital Anxiety Depression Scale ...........................................................38
9.4.6.
Safety Monitoring ................................................................................................39
9.4.6.1.
Hepatic Safety................................................................................................39
9.5.
Pharmacokinetics .........................................................................................................39
9.5.1.
Bioanalysis...........................................................................................................39
9.6.
Pharmacodynamics ......................................................................................................40
9.6.1.
Immunogenicity Assessments ..............................................................................40
9.7.
Genetics .......................................................................................................................40


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9.8.
Biomarkers...................................................................................................................41
9.9.
Health Economics ........................................................................................................41
10.
Statistical Considerations and Data Analysis.....................................................................42
10.1. Sample Size Determination ..........................................................................................42
10.2. Populations for Analyses..............................................................................................42
10.2.1.
Study Participant Disposition ...............................................................................42
10.2.2.
Study Participant Characteristics ..........................................................................42
10.3. Statistical Analyses ......................................................................................................42
10.3.1.
Safety Analyses....................................................................................................43
10.3.1.1.
Clinical Evaluation of Safety..........................................................................43
10.3.1.2.
Statistical Evaluation of Safety.......................................................................43
10.3.1.2.1.
Statistical Evaluation of Other Safety Parameters......................................43
10.3.2.
Pharmacokinetic Analyses....................................................................................43
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................43
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................43
10.3.3.
Evaluation of Immunogenicity .............................................................................44
10.3.4.
Interim Analyses..................................................................................................44
11.
References ........................................................................................................................45
12.
Appendices .......................................................................................................................46


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List of Tables
Table
Page
Table RHCU.1.
Objectives and Endpoints .......................................................................17
Table RHCU.2.
Study RHCU Stratification and Randomization Plan ..............................18
Table RHCU.3.
Treatments Administered........................................................................28


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................47
Appendix 2.
Clinical Laboratory Tests........................................................................52
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................53
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............56
Appendix 5.
Blood Sampling Summary......................................................................57
Appendix 6.
Recommended Laboratory Testing for Hypersensitivity Events..............58
Appendix 7.
Protocol Amendment I1F-MC-RHCU(b) Summary Bioequivalence 
of an Alternate Ixekizumab Formulation Compared to the 
Commercial Formulation in Healthy Subjects.........................................59


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1. Protocol Synopsis
Title of Study:
Bioequivalence of an Alternate Ixekizumab Formulation Compared to the Commercial 
Formulation in Healthy Subjects
Rationale:  
Two studies (I1F-MC-RHCS [RHCS] and I1F-MC-RHCT [RHCT]) in healthy volunteers have 
been conducted for the purpose of selecting an alternative formulation to the currently marketed 
formulation.  Study RHCS was conducted to investigate injection site pain following 
subcutaneous (SC) injections of 2 ixekizumab alternate formulations compared to the 
ixekizumab commercial formulation using a prefilled syringe (PFS).  Study RHCT was 
conducted to compare the relative bioavailability, safety, and tolerability of 2 alternate 
formulations of ixekizumab to the commercial product when administered subcutaneously via 
PFS.  The active ingredient concentration and the injection volume of the alternate formulations 
were the same as the commercial drug product.  
Based on the results of Studies RHCS and RHCT, a formulation was selected to take forward 
into the present Study I1F-MC-RHCU (RHCU) which is being conducted to evaluate the 
bioequivalence of the selected ixekizumab alternate formulation (test), compared to the 
ixekizumab commercial formulation (reference) when administered using an autoinjector (AI).  
Objective(s)/Endpoints:  
Objectives
Endpoints
Primary
To evaluate the bioequivalence of a single 80 mg SC 
dose of ixekizumab alternate formulation (test) 
compared to the ixekizumab commercial formulation 
(reference)

Cmax, AUC(0-∞), AUC(0-tlast)
Secondary
To describe the safety and tolerability of a single 80 mg 
SC dose of ixekizumab alternate formulation (test) 
compared to the commercial formulation (reference)
TEAEs, SAEs
Abbreviations:  AUC(0-∞) = area under the concentration versus time curve from time zero to infinity; AUC(0-tlast) = area under the 
concentration versus time curve from time zero to time t, where t is the last time point with a measurable concentration; Cmax = maximum 
observed drug concentration; SAE = serious adverse events; SC = subcutaneous; TEAE = treatment-emergent adverse event.
Summary of Study Design:  
Study RHCU is a Phase 1, subject-blind, 2-arm, randomized, parallel-design study in healthy 
subjects.  
Eligible subjects will be admitted to the clinical research unit (CRU) on Day -1 and stratified into 
weight, formulation, and injection site categories as described in the treatment arms and planned 


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duration section of this synopsis.  Subjects may be allowed to leave the CRU after completing 
the 4-hour safety assessments on Day 1, at the investigator’s discretion, and will return for 
pharmacokinetic (PK), immunogenicity sampling, and safety assessments at predefined times up 
to 12 weeks postdose.  Subjects will be monitored for safety between outpatient visits by way of 
telephone assessment.
Safety and tolerability will be assessed by clinical laboratory tests, vital sign measurements, 
temperature, recording of adverse events (AEs), physical examination (PE)/medical assessments, 
Columbia Suicide Severity Rating Scale (C-SSRS), and immunogenicity.  
Treatment Arms and Planned Duration for an Individual Subject:  
At screening, subjects will be stratified into 1 of 3 weight categories (<70.0 kg, 70.0 to 80.0 kg, 
>80.0 kg).  Within the 3 weight categories, subjects will be randomized 1:1 to either 80-mg 
ixekizumab commercial formulation (reference) or 80-mg ixekizumab alternate formulation 
(test) and subrandomized 1:1:1 to injection site (arm, thigh, or abdomen).  On Day 1, subjects 
will receive a single SC dose according to the randomization plan.  Subjects will participate for 
up to 16 weeks.
Number of Subjects:  
Up to approximately 240 subjects may be enrolled so that approximately 216 subjects complete 
the study (108 in the 80-mg ixekizumab commercial formulation [reference] group and 108 in 
the 80-mg ixekizumab alternate formulation [test] group).  
Statistical Analysis:
Pharmacokinetic parameters will be evaluated to determine the bioequivalence of ixekizumab 
alternate formulation (test) compared to the ixekizumab commercial formulation (reference).  
Log-transformed maximum observed drug concentration (Cmax) and area under the 
concentration versus time curve (AUC) parameters will be evaluated in a linear mixed-effects 
model with fixed effects for formulation and a random effect for subject.  The treatment 
differences will be back-transformed to present the ratios of geometric means and the 
corresponding 90% confidence interval (CI).  Bioequivalence will be concluded if the 90% CI is 
completely contained within the interval (0.80, 1.25).
The time to maximum drug concentration (tmax) will be analyzed using a Wilcoxon rank sum 
test.  Estimates of the median difference based on the observed medians, 90% CIs, and p-values 
from the Wilcoxon rank sum test will be calculated.
Safety laboratory parameters and vital signs data will be listed and summarized using standard 
descriptive statistics, where possible.  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 (i.e., if a subject’s answers are all ‘no’ for the C-SSRS, then that subject 
will not be displayed).  Hospital Anxiety Depression Scale (HADS) item scores will be listed for 
subjects with HADS depression subscale ≥11 at any time.  


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The frequency and percentage of subjects with preexisting antidrug antibodies (ADAs) and with 
treatment-emergent ADAs (TE-ADAs) to ixekizumab will be tabulated.  Treatment-emergent 
ADAs are defined as those with a titer 2-fold (1 dilution) greater than the minimum required 
dilution if no ADAs were detected at baseline (treatment-induced ADAs) or those with a 4-fold 
(2 dilutions) increase in titer compared to baseline if ADAs were detected at baseline (treatment-
boosted ADAs).  For the TE-ADA subjects, the distribution of maximum titers will be described.  
The frequency of neutralizing antibodies will also be tabulated in TE-ADA subjects.  
Additional analysis may be performed, if warranted, upon review of the data.


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2. Schedule of Activities


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


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Screening
Days
Comments
Procedure
-28 to -2 
days prior 
to Day 1
-1
1
3
5
±1d
8
±1d
11
±1d
15
±2d
22
±2d
29
±2d
36
±2d
43
±2d
50
±2d
57
±3d
64
±3d
71
±3d
85/ED
±3d
Physical Examination 
/Medical Assessment
X
X
Full physical 
examination/medical 
assessment at Day -1 and at 
Day 85/ED.  Symptom-directed 
examinations/assessments may 
be conducted at other visits, as 
deemed necessary by the 
investigator.  
Vital Signs (sitting)
(hours)
X
X
P, 
2-4
X
X
X
X
X
Vital signs can be taken at any 
time during the 2- to 4-hour 
window of Day 1.  Time points 
may be added if warranted and 
agreed upon between Lilly and
the investigator.
Clinical Laboratory 
Tests
X
X
X
X
X
See Appendix 2, Clinical 
Laboratory Tests, for details.
Serology
X
See Appendix 2, Clinical 
Laboratory Tests, for details.
QuantiFERON®-TB 
Gold Test/TST
X
Ethanol Test and 
Urine Drug Screen
X
X
May be repeated at the 
discretion of the investigator.  
FSH Test
X
Females only, if applicable (see 
Section 6.1, criterion 1b see 
3ii).
Pregnancy Test 
X
X
X
Females only.  Serum 
pregnancy test will be 
performed at screening.  Urine 
pregnancy test will be 
performed at other indicated 
times.


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Screening
Days
Comments
Procedure
-28 to -2 
days prior 
to Day 1
-1
1
3
5
±1d
8
±1d
11
±1d
15
±2d
22
±2d
29
±2d
36
±2d
43
±2d
50
±2d
57
±3d
64
±3d
71
±3d
85/ED
±3d
Single 12-lead ECG
X
X
Ixekizumab
Administration
X
Subjects will fast (water is 
permitted) from 1 hour before 
until 1 hour postdose.
Ixekizumab PK 
Sample
P
X
X
X
X
X
X
X
X
X
X
X
Immunogenicity 
Sample
P
X
X
X
A time-matched PK should be 
taken at each immunogenicity 
sample time point.
Pharmacogenetic 
Sample
P
AEs and Concomitant 
Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
If an AE of ISR is reported, the 
investigator or designee will 
complete a supplemental ISR 
AE form.
Abbreviations:  AE = adverse event; BMI = body mass index; CRU = clinical research unit; C-SSRS = Columbia Suicide Severity Rating Scale; d = days; ECG = 
electrocardiogram; ED = early discontinuation; FSH = follicle-stimulating hormone; HADS = Hospital Anxiety Depression Scale; ISR = injection site 
reaction; P = predose; PK = pharmacokinetics; TB = tuberculosis; TST = tuberculin skin test.


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3. Introduction
3.1.
Study Rationale
Ixekizumab is administered subcutaneously and is available commercially as an injectable 
solution in either a manual prefilled syringe (PFS) or an autoinjector (AI).  Each PFS or AI 
contains 80 mg ixekizumab in 1 mL.  Two studies (I1F-MC-RHCS [RHCS] and I1F-MC-RHCT 
[RHCT]) in healthy volunteers have been conducted for the purpose of selecting an alternative 
formulation to the currently marketed formulation.
Study RHCS was conducted to investigate injection site pain following subcutaneous (SC)
injections of 2 ixekizumab alternate formulations compared to the ixekizumab commercial 
formulation using a PFS.  Study RHCT was conducted to compare the relative bioavailability, 
safety, and tolerability of 2 alternate formulations of ixekizumab to the commercial product
when administered subcutaneously via PFS.  The active ingredient concentration and the 
injection volume of the alternate formulations were the same as the commercial drug product.
Based on the results of Studies RHCS and RHCT, a formulation was selected to take forward 
into the present Study I1F-MC-RHCU (RHCU) which is being conducted to evaluate the 
bioequivalence of the selected ixekizumab alternate formulation (test), compared to the 
ixekizumab commercial formulation (reference) when administered using an AI.  
3.2.
Background
Ixekizumab (LY2439821, Taltz®) is a humanized immunoglobulin G subclass 4 monoclonal 
antibody that binds with high affinity and specificity to interleukin 17A (IL-17A), a 
proinflammatory cytokine.  Ixekizumab is marketed in the US and EU for the treatment of 
moderate-to-severe plaque psoriasis (Ps) at a dose of 160 mg at Week 0, followed by 80 mg 
every 2 weeks up to Week 12, then maintenance dosing of 80 mg every 4 weeks, and for 
psoriatic arthritis (PsA) at a dose of 160 mg at Week 0 followed by 80 mg every 4 weeks.  
Ixekizumab is also marketed in the US for treatment of ankylosing spondylitis with a 
recommended dose of 160 mg (two 80-mg injections) at Week 0, followed by 80 mg every 
4 weeks.
In the ixekizumab clinical program, injection site pain was reported by 2.4% of patients with 
moderate-to-severe Ps and 1.5% of patients with PsA.  Most injection site pain occurred shortly 
after drug administration and the incidence rate declined with subsequent injections.  Post 
approval reports along with insights from customers have shown that pain is a clear concern and 
issue for patients, thus the rationale for evaluating an alternate formulation to help reduce 
injection site pain.  
3.3.
Benefit/Risk Assessment
As this study will enroll healthy subjects, there is no anticipated therapeutic benefit for the 
subjects.  
On the basis of the 21 Mar 2019 data cutoff dates for the current investigator’s brochure (IB)
(approved on 7 June 2019), approximately 9848 patients were treated with at least 1 dose of 


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ixekizumab in clinical trials (6721 patients with Ps, 532 patients with rheumatoid arthritis, 
1413 patients with PsA, 253 healthy subjects, and an estimated 929 patients with axial 
spondyloarthritis (includes both radiographic and nonradiographic axial spondyloarthritis).  
Four previous studies have administered ixekizumab to healthy subjects.  These include Study 
I1F-MC-RHCA (RHCA) where 41 subjects were administered ixekizumab by PFS (160 mg 
[2 × 80 mg] followed by 80 mg 2 weeks later).  All treatment-emergent adverse events (TEAEs)
in Study RHCA were mild in severity.  The most commonly reported adverse events (AEs) were 
headache (4 events in 4 subjects), injection site erythema (4 events in 2 subjects), and fatigue (3 
events in 3 subjects).  With the exception of fatigue, this is consistent with commonly reported 
AEs reported in Phase 3 studies.  An additional 78 healthy subjects were administered 
ixekizumab by PFS, marketed AI, and modified AI (3 single 80 mg doses) in Study I1F-MC-
RHCK (RHCK).  In Study RHCK, all TEAEs were mild in severity and the most commonly 
reported Medical Dictionary for Regulatory Activities (MedDRA) preferred term was injection 
site reaction (ISR) (which represented solicited AEs) with injection site pruritus, nausea, 
diarrhea, upper respiratory tract infection, and injection site erythema (nonsolicited AEs) also 
reported by at least 2 subjects each.  
Study RHCS was a 3-period crossover design, hence each subject received three 80 mg
injections, each separated by 7 days (1 injection from each of the 2 alternate ixekizumab 
formulations [test] and 1 injection from the commercial ixekizumab formulation [reference]).  
Safety data collected during the study, including AEs, clinical laboratory tests, and vital signs,
indicated that all 3 treatments administered were consistent with previous studies with 
ixekizumab in healthy subjects.  The percentage of subjects reporting TEAEs (all causalities) 
was generally similar following administration of each treatment (17.5% to 26.2%).  The most 
commonly reported treatment-related TEAEs (all causalities) were in the General Disorders and 
Administration Site Conditions system organ class, with ISRs being the most frequently reported 
TEAE overall (18 events in 13 subjects).  Injection site rash, injection site hemorrhage, nasal 
congestion, productive cough, upper respiratory tract infection, headache, pain in extremity, and 
breast mass were each also reported by at least 2 subjects.  Infections and infestations that were 
considered to be treatment related were reported by 6 subjects overall. The majority of TEAEs 
were mild in severity.  
In Study RHCT, 99 healthy subjects received a single 80-mg SC ixekizumab injection (33 in 
each group of either the commercial or 2 test formulations). Safety data collected during the 
study, including AEs, clinical laboratory tests, and vital signs, indicated that all 3 treatments 
administered had similar safety profiles.  The percentage of subjects reporting treatment-related 
TEAEs was similar following administration of each treatment (30.3% to 45.5%).  The most 
commonly reported treatment-related TEAEs were in the General Disorders and Administration 
Site Conditions system organ class, with ISRs being the most frequently reported TEAE overall 
(5 events in 4 subjects).  Injection site erythema, abdominal pain, upper respiratory tract 
infection, and headache were each also reported by at least 2 subjects.  The majority of TEAEs 
were mild in severity. Antidrug antibody response observed in Study RHCT with healthy 
subjects was approximately 9.1% to 12.1% with a low incidence of neutralizing antibodies.  


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In Study RHCT, 2 subjects had a neutrophil count lower than the reference range at 1 postdose 
time point each during the study; neither of these decreases were clinically significant.  A 
decrease in neutrophil count is known to occur with IL-17 antagonism. One death was reported 
in Study RHCT in a hospitalized study participant who had 4 serious AEs (SAEs) (sinusitis, 
cerebral vein thrombophlebitis/cerebral vein thrombosis, periorbital abscess, and 
phaeohyphomycotic brain abscess).  These 4 SAEs were deemed unrelated to ixekizumab.
More information about the known and expected benefits, risks, SAEs and reasonably 
anticipated AEs of ixekizumab are to be found in the IB and the United States Product Insert 
(drug label).  


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4. Objectives and Endpoints
Table RHCU.1 shows the objectives and endpoints of the study.
Table RHCU.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the bioequivalence of a single 
80 mg SC dose of ixekizumab alternate 
formulation (test) compared to the ixekizumab 
commercial formulation (reference)

Cmax, AUC(0-∞), AUC(0-tlast)
Secondary
To describe the safety and tolerability of a 
single 80 mg SC dose of ixekizumab alternate 
formulation (test) compared to the commercial 
formulation (reference)

TEAEs, SAEs
Abbreviations:  AUC(0-∞) = area under the concentration versus time curve from time zero to infinity; 
AUC(0-tlast) = area under the concentration versus time curve from time zero to time t, where t is the last time point 
with a measurable concentration; Cmax = maximum observed drug concentration; SAE = serious adverse event; SC 
= subcutaneous; TEAE = treatment-emergent adverse event.  


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5. Study Design
5.1.
Overall Design  
Infection risk
Participants should follow local guidance and clinical research unit (CRU) precautions to 
minimize risk for COVID-19 infection.
Study RHCU is a Phase 1, subject-blind, 2-arm, randomized, parallel-design study in healthy 
subjects.  
All subjects will be screened within 28 days prior to enrollment.  Eligible subjects will be 
admitted to the CRU on Day -1.  At screening, subjects will be stratified into 1 of 3 weight 
categories (<70.0 kg, 70.0 to 80.0 kg, >80.0 kg).  Within the 3 weight categories, subjects will be 
randomized 1:1 to either 80-mg ixekizumab commercial formulation (reference) or 80-mg 
ixekizumab alternate formulation (test) and subrandomized 1:1:1 to injection site (arm, thigh, or 
abdomen) (Table RHCU.2). On Day 1, subjects will receive a single SC dose according to the 
randomization plan (Table RHCU.2 and Schedule of Activities, Section 2).  
The desire is to have approximately equal numbers of subjects in each weight category to avoid a 
large difference in mean weight between the test and reference formulation groups. A subject 
population of 72 per weight group is an approximate target with the recommended weight 
categories selected based on the distribution of weights in the prior studies, RHCS and RHCT. 
The number of subjects assigned to each formulation and the number of subjects assigned to 
each site of injection location is desired to be balanced.  
Table RHCU.2.
Study RHCU Stratification and Randomization Plan
Weight Category 
(Subjects)
Formulation 
(80-mg ixekizumab)
Subcutaneous 
Injection Locationa
Desired Number of 
Subjects
Low
<70.0 kg
(72 subjects)
Commercial (reference)
Arm
12
Alternate (test)
12
Commercial (reference)
Abdomen
12
Alternate (test)
12
Commercial (reference)
Thigh
12
Alternate (test)
12
Medium
70.0 kg – 80.0 kg
(72 subjects)
Commercial (reference)
Arm
12
Alternate (test)
12
Commercial (reference)
Abdomen
12
Alternate (test)
12
Commercial (reference)
Thigh
12
Alternate (test)
12
High
>80.0 kg
(72 subjects)
Commercial (reference)
Arm
12
Alternate (test)
12
Commercial (reference)
Abdomen
12
Alternate (test)
12
Commercial (reference)
Thigh
12
Alternate (test)
12


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Abbreviations:  RHCU = I1F-MC-RHCU; SC = subcutaneous.
a
A dose of investigational product will consist of 1 SC injection of 80-mg ixekizumab into the arm, thigh, or 
abdomen.  All doses will be administered by trained site staff.
Subjects may be allowed to leave the CRU after completing the 4-hour safety assessment on 
Day 1, at the investigator’s discretion, and will return for PK, immunogenicity sampling, and 
safety assessments at predefined times up to 12 weeks postdose.  Subjects will be monitored for 
safety between outpatient visits by way of telephone assessment.
Safety and tolerability will be assessed by clinical laboratory tests, vital sign measurements, 
temperature, recording of AEs, physical examination (PE)/medical assessments, Columbia 
Suicide Severity Rating Scale (C-SSRS), and immunogenicity.  
Study governance considerations are described in detail in Appendix 3.
5.2.
Number of Participants  
Up to approximately 240 subjects may be enrolled so that approximately 216 subjects complete 
the study (108 in the 80-mg ixekizumab commercial formulation [reference] group and 108 in 
the 80-mg ixekizumab alternate formulation [test] group).  
As described in Section 5.1, eligible subjects will be admitted to the CRU on Day -1.  At 
screening, subjects will be stratified and randomized as described in Section 5.1 and
Table RHCU.2.  On Day 1, subjects will receive a single SC dose (Schedule of Activities, 
Section 2) according to the randomization plan.  The number of subjects in each weight category
and assigned to each formulation is desired to be approximately equal.  The number of subjects 
assigned to each site of injection location is desired to be balanced.  
For purposes of this study, a subject completes the study when all scheduled procedures shown 
in the Schedule of Activities have been finished.
5.3.
End of Study Definition  
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
5.4.
Scientific Rationale for Study Design
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications in patients.  A population of healthy subjects is 
frequently used in the assessment of the bioequivalence of both small and large molecules.  
Single doses of ixekizumab and the PK sampling time points have been selected to generate PK 
profiles sufficient to fulfill the study objectives.  
A parallel-group design is chosen because a crossover design is impractical for ixekizumab, 
which has a half-life of approximately 13 days.  Additionally, a crossover study could confound 
PK data if subjects develop neutralizing antidrug antibodies (ADAs).  


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5.5.
Justification for Dose
The recommended dose for Ps patients is 160 mg by SC injection (two 80-mg injections) at 
Week 0, followed by an 80-mg injection at Weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 
4 weeks.  A dose of 80-mg ixekizumab was selected for Study RHCU to match the approved 
individual dose unit strength administered during treatment in clinical practice.


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6. Study Population
Eligibility of subjects for the study will be based on the results of screening medical history, PE, 
vital signs, clinical laboratory tests and electrocardiogram (ECG).  
The nature of any conditions present at the time of the PE and any preexisting conditions will be 
documented.  Screening and/or Day -1 laboratory testing may be repeated once at the discretion 
of the investigator for any out-of-range results.  
Screening may occur up to 28 days prior to enrollment.  Subjects who are not enrolled within 
28 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and/or Day -1:
[1]
are overtly healthy males or females, as determined by screening medical 
history and PE, or 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 ixekizumab dosing.
Examples of reliable methods of birth control,

for male subjects condoms with spermicide or male sterilization, 

for female partners of childbearing potential, a highly effective 
birth control method, 
o
oral or implanted contraceptives, 
o
intrauterine device or 
o
a combination of 2 effective methods (for example, female 
condom with spermicide).
Male 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.


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[1b] female subjects:
1) 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 (e.g., calendar, ovulation, symptothermal, 
postovulation 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 ixekizumab dosing.
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 on Day -1.
ii.
Either 1 highly effective method of contraception (e.g., 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.
postmenopausal, 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


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
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;
c)
a woman 55 years or older with a diagnosis of menopause 
prior to starting hormone replacement therapy
[2] are aged at least 18 to 75 years at the time of screening
[3] have a body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive 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
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or Day -1:
[7] are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling
[8]
are employees of Eli Lilly and Company (Lilly), Covance, or a third-party
organization involved in the study
[9]
are currently enrolled in a clinical study involving an investigational product
(IP) or any other type of medical research judged not to be scientifically or 
medically compatible with this study  
[10] have participated, within the last 30 days in a clinical study involving an IP.  
If the previous IP has a long half-life, 5 half-lives or 30 days (whichever is 
longer) should have passed
[11] have previously completed or withdrawn from this study or any other study 
investigating ixekizumab, and have previously received the IP or have been 
administered other anti-IL-17 agents
[12] have known allergies to ixekizumab, related compounds or any components of 
the formulation, or history of significant atopy
[13] have self-perceived dullness or loss of sensation on either side of their arm, 
thigh, or abdomen
[14] have uncontrolled arterial hypertension characterized by a systolic blood 
pressure >160 mmHg or diastolic blood pressure >100 mmHg


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Note:  if an initial blood pressure reading exceeds this limit, the reading may 
be repeated once after the subject has rested sitting for ≥10 minutes.  If the 
repeat value is less than the criterion limits, the second value may be accepted.
[15] have a significant history of, or current cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, endocrine, or hematologic disorders, that in the opinion 
of the investigator poses an unacceptable risk to the subject if participating in 
the study or of interfering with the interpretation of data
[16] have presence of significant uncontrolled neuropsychiatric disorder; have 
lifetime history of suicidal behavior (yes to any suicidal behavior question 
from the “Suicidal Behavior” portion of the C-SSRS from screening and 
between screening and baseline [Day -1]); have history of active suicidal 
ideation within the past year (yes to question 4 or 5 on the “Suicidal Ideation” 
portion of the C-SSRS from screening and between screening and baseline 
[Day -1]); and/or are clinically judged by the investigator to be at risk for 
suicide
[17] have recent history (past 30 days) of depression; have Hospital Anxiety 
Depression Scale (HADS) Depression subscale score of ≥11
[18] have current or history of inflammatory bowel disease (IBD) (Crohn’s disease or 
ulcerative colitis), signs or symptoms indicative of ulcerative colitis or Crohn’s 
disease (based on investigator determination), or knowledge of a family history of 
IBD in first degree relatives
[19] Infections:
[19a] have had a serious infection (e.g., pneumonia, cellulitis, and sepsis), 
have been hospitalized, or have received intravenous antibiotics for an 
infection within 12 weeks prior to Day 1; have had a serious bone or 
joint infection within 24 weeks prior to Day 1, or have ever had an 
infection of an artificial joint; or are immunocompromised to an extent 
such that participation in the study would pose an unacceptable risk to 
the subject
[19b] have or have had an infection typical of an immunocompromised host 
and/or that occurs with increased incidence in an immunocompromised 
host (including, but not limited to, pneumocystis jiroveci pneumonia, 
histoplasmosis, or coccidioidomycosis), or have a known 
immunodeficiency
[19c] have or have had a herpes zoster infection or any other clinically 
apparent varicella-zoster virus infection within 12 weeks of Day 1
[19d] have had any other active or recent infection within 4 weeks of Day 1 
that, in the opinion of the investigator, would pose an unacceptable risk 
to the subject if participating in the study; these subjects may be 
rescreened (once) ≥4 weeks after documented resolution of symptoms


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[20] have a history of uncompensated heart failure, fluid overload, or myocardial 
infarction, or evidence of new-onset ischemic heart disease or other serious 
cardiac disease, within 12 weeks prior to Day 1
[21] have clinical laboratory test results at screening that are outside the normal 
reference range for the population and are considered clinically significant, 
and/or have any of the following specific abnormalities:

neutrophil count <1500 cells/µL

lymphocyte count <800 cells/µL

platelet count <100,000 cells/µL

total white blood cell count <3000 cells/µL
Note:  Screening and/or Day -1 laboratory testing may be repeated 
(once) at the discretion of the investigator for any out of range 
results.  Thereafter, laboratory tests may not be repeated unless 
there is a documented technical error or clinical reason to believe a 
result may need to be retested within the screening period
[22] regularly use known drugs of abuse and/or show positive findings on drug 
screening
[23] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive HIV antibodies
[24] show evidence of hepatitis C or positive hepatitis C antibody
[25] show evidence of, or test positive for, hepatitis B and/or positive hepatitis B 
surface antigen and/or hepatitis B core antibody
[26] are women who are lactating
[27] have donated blood of more than 500 mL within the last month prior to dosing 
or intend to donate blood during the course of the study
[28] have an average weekly alcohol intake that exceeds 21 units per week (males
up to age 65) and 14 units per week (females up to and over 65, and males 
over 65), or are unwilling to stop alcohol consumption for 48 hours prior to 
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) during the outpatient period (1 unit = 12 oz or 
360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits)
[29] show evidence of active or latent tuberculosis (TB), as documented by 
medical history and examination, any recent chest x-rays (if obtained in the 
previous 6 months; x-rays will not be taken for the sole purpose of 
determining eligibility for this study), and TB testing


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[30] had a vaccination with Bacillus Calmette-Guérin (BCG), other live vaccines, 
or attenuated live vaccines within 12 months prior to 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
[31] have received treatment with biologic agents (such as monoclonal antibodies, 
including marketed drugs) within 3 months or 5 half-lives (whichever is 
longer) prior to dosing
[32] intend or are likely to use over-the-counter or prescription medication for pain 
or inflammation within 7 days prior to dose administration.  Subjects on stable 
doses of other medications (e.g., statins and antihypertensives) may be eligible 
for enrollment following discussion with the sponsor (Section 7.7)
[33] have a known allergy or hypersensitivity to any biologic therapy that would 
pose an unacceptable risk to the subject if participating in this study
[34] have had any malignancy within the past 5 years, except for basal cell or 
squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years
[35] have any condition that could affect pain perception from an injection
[36] have excessive tattoos or scars over the arm, thigh, or abdomen or other 
factors (e.g., rash, excessive folds of skin) that, in the investigator’s opinion, 
would interfere with injection site assessments
[37] in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
6.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion Criteria [7] and [8] prevent conflict of interest in study participants.  Exclusion 
Criteria [9] through [37] exclude items including, but not limited to, medical conditions, 
medication intolerance, and concomitant medication use that may confound the assessment of 
study endpoints.  
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
Subjects may receive a light meal (before dosing) on Day 1 but will be fasted (water is 
permitted) from 1 hour prior to dosing until 1 hour postdose.  Standard meals will be provided at 
all other times while subjects are resident at the CRU, per the CRU’s policy.
6.3.2. Alcohol and Tobacco
Alcohol consumption is not permitted while at the CRU and for 48 hours prior to each study visit.  
Alcohol intake during outpatient periods should not exceed 3 units per day (males up to age 65) 


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and 2 units per day (females up to and over 65, and males over 65).  In addition, subjects must 
abide by the CRU smoking restrictions during study visits and while resident in the CRU.  
6.3.3. Activity
Subjects will be encouraged to maintain their regular exercise; however, they should not 
undertake vigorous or prolonged exercise within 48 hours prior to each CRU visit.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be re-
screened (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 in a 1-mL volume into the arm, 
thigh, or abdomen.  All doses will be administered by trained site staff.
This study involves a comparison of:  

80-mg ixekizumab commercial formulation (reference) administered subcutaneously via 
AI

80-mg ixekizumab alternate formulation (test) administered subcutanenously via AI
Prior to the injection using the AI, the investigator or his/her designee will clean the subject’s 
skin. The injection will be administered by trained site staff, according to the instructions 
provided by the sponsor.
Table RHCU.3 shows the treatment regimens.
Table RHCU.3.
Treatments Administered
Treatment Name
Alternate Formulation (Test)
Commercial Formulation (Reference)
Formulation
solution for injection
solution for injection
Dose
80-mg ixekizumab
80-mg ixekizumab
Route of Administration
SC injection
SC injection
Delivery Method
AI
AI
Abbreviations:  AI = autoinjector; 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
where appropriate
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.  Retention samples must be kept as instructed by 
Lilly.  
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 ixekizumab AI is 


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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 an AI (80-
mg ixekizumab in a 1-mL volume)

ixekizumab alternate formulation (test; solution for injection) in an AI (80-mg 
ixekizumab in a 1-mL volume)
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.  Site personnel 
may create blinding processes and precautions as they deem necessary to maintain injection site 
assessor blinding.
The IP will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
The randomization table will be prepared by the statistician (or appropriate delegate) for the 
study and provided to the CRU pharmacists or pharmacy staff involved in dose preparation.
As described in Section 5.1, eligible subjects will be admitted to the CRU on Day -1.  At 
screening, subjects will be stratified into 1 of 3 weight categories (<70.0 kg, 70.0 to 80.0 kg, 
>80.0 kg).  Within the 3 weight categories, subjects will be randomized 1:1 to either 80-mg 
ixekizumab commercial formulation (reference) or 80-mg ixekizumab alternate formulation 
(test) and subrandomized 1:1:1 to injection site (arm, thigh, or abdomen) (Table RHCU.2).  
7.2.1. Selection and Timing of Doses
The actual time of dose administration will be recorded in the subject’s case report form (CRF).
7.3.
Blinding
Study RHCU is a subject-blind study.
7.4.
Dose Modification
Dose adjustments are not allowed in this study.
7.4.1. Special Treatment Considerations
All biological agents carry the risk of systemic allergic/hypersensitivity reactions.  Clinical 
manifestations of these reactions may include, but are not limited to skin rash, pruritus (itching), 
urticaria (hives), angioedema (e.g., swelling of the lips and/or tongue), and anaphylactic reaction.  
Sometimes these reactions can be life threatening.  Proteins may also cause redness, itching, 
swelling, or pain locally at the injection site.  Therefore, all subjects should be closely monitored 
for signs or symptoms that could result from such reactions, be educated on the signs or 
symptoms of these types of reactions, and be instructed to contact the study site immediately if 
any of the symptoms are experienced after discharge from the CRU.  


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If a subject experiences an acute allergic/hypersensitivity reaction after an injection of IP, he or 
she should be managed appropriately and receive relevant supportive care.  The event should be 
recorded as an AE.  In case of systemic hypersensitivity reactions, defined as anaphylaxis or 
generalized urticaria, additional blood samples should be collected as close as possible to the 
onset of the event (Section 9.2.1.3). Follow-up samples should be obtained at the next regularly 
scheduled visit or 4 weeks after the event, whichever is later.  The lab results are provided to the 
sponsor via the central laboratory.  
7.5.
Preparation/Handling/Storage/Accountability
Investigational product will be stored refrigerated at 2°C to 8°C (36°F to 46°F) in its original 
carton to protect from light.  Investigational product should not be frozen or shaken.  
Sites will be required to monitor the temperature of the on-site storage conditions of the IP.  The 
investigator or designee must confirm appropriate temperature conditions have been maintained, 
as communicated by the sponsor, during transit for all IP received and ensure any discrepancies 
are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive IP or study materials, and only authorized 
site staff may supply IP.  All IP should be stored in an environmentally controlled and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff.
The investigator is responsible for study treatment accountability, reconciliation, and record 
maintenance (such as receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The IP will be administered at the clinical site, and documentation of treatment administration 
will occur at the site.
7.7.
Concomitant Therapy
Subjects on stable concomitant medication at the time of study entry should continue their 
regular, unchanged dose throughout the study.  Permitted concomitant medications, at the 
discretion of the investigator, include hormonal contraceptives, hormone replacement therapy, 
and thyroid replacement.  In addition, occasional acetaminophen is acceptable at the discretion of 
the investigator.  However, acetaminophen should not be administered on the dosing day within 
4 hours prior to the injection and until at least 4 hours after the injection.  No more than 3 g of 
acetaminophen will be permitted in any 24-hour period.  Inclusion of subjects on any other 
concomitant medication (e.g., statins and anti-hypertensives) is contingent upon approval 
following consultation with the sponsor.
Subjects will be restricted from applying any creams or lotions on the arm, thigh, or abdominal 
skin within 24 hours prior to or after the injection.
If the need for any additional concomitant medication arises, inclusion or continuation of the 
subject may be at the discretion of the investigator after consultation with a Lilly Clinical 


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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.
8.1.
Discontinuation from Study Treatment
Not applicable.
8.1.1. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CP/CRP and the investigator to 
determine if the subject may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CP/CRP to allow the 
inadvertently enrolled subject to continue in the study.  
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

enrollment in any other clinical study involving an IP or enrollment in any other type 
of medical research judged not to be scientifically or medically compatible with this 
study prior to receiving IP in this study.  If the subject has received IP, they will 
continue to be monitored for safety for the planned duration of the study.

participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

investigator decision
o
the investigator decides that the subject should be discontinued from the study

subject decision
o
the subject, or legal representative, requests to be withdrawn from the study
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the 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, or considered related to the IP or the 
study.  The subject should be followed until the event resolves, stabilizes with appropriate 
diagnostic evaluation, or is reasonably explained.  The frequency of follow-up evaluations of the 
AE is left to the discretion of the investigator.
The investigator will record all relevant AE and SAE information in the electronic CRF (eCRF).  
After the informed consent form is signed, study site personnel will record, via eCRF, the 
occurrence and nature of each subject’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  Additionally, site personnel will 
record any change in the condition(s) and the occurrence and nature of any AEs.  
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 the 
disease, 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.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.


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9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (i.e., 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 auto injector 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.
Although all AEs are recorded in the eCRF after signing informed consent, SAE reporting to the 
sponsor begins after the subject has signed informed consent and has received IP.  However, if 
an SAE occurs after signing informed consent, but prior to receiving IP, AND is considered 
reasonably possibly related to a study procedure then it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary CRF 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 administered by AI in this clinical study.
Adverse events of special interest for ixekizumab are:


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
cytopenias (leukopenia, neutropenia, and thrombocytopenia)

liver function test changes/enzyme elevations (alanine aminotransferase [ALT], 
aspartate aminotransferase [AST], total bilirubin level [TBL], and alkaline 
phosphatase [ALP]) that are considered to be clinically relevant by the principle 
investigator/investigator)

infection

ISRs (see Section 9.4.5.1)

allergic reactions/hypersensitivities

cerebrocardiovascular events

malignancies

depression

IBD (Crohn’s disease and ulcerative colitis)

interstitial lung disease
If infections, or allergic/hypersensitivity reactions are reported, these will be recorded as AEs.  
Investigators will also educate subjects about the symptoms of allergic/hypersensitivity reactions 
and will provide instructions on dealing with these reactions.  A blood sample will be collected 
when possible for any subject who experiences an AE of systemic 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 may be adjudicated by an external 
Clinical Events Committee (CEC) made up of a chair, 2 cardiologists, and a neurologist.  
Data on suspected IBD, as identified by events possibly indicative of ulcerative colitis and 
Crohn’s disease, will be collected.  The events may be adjudicated by an external CEC 
composed of gastroenterologists with expertise in IBD.  
The role of the CECs is to adjudicate defined clinical events, in a blinded, consistent, and 
unbiased manner throughout the course of a study.  The importance of the CECs is to ensure that 
all events that have been reported are evaluated uniformly by a single group.
9.2.1.2.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator reports as related to IP or procedure.  Lilly has procedures that 
will be followed for the recording and expedited reporting of SUSARs that are consistent with 
global regulations and the associated detailed guidances.


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9.2.1.3.
Systemic Hypersensitivity Reactions
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data describing each symptom should be provided
to the sponsor in the eCRF. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study drug.  It is recommended that participants
who experience a systemic hypersensitivity reaction be treated per the local standard of care.  
In case of systemic hypersensitivity reactions, defined as anaphylaxis or generalized urticaria,
additional blood samples should be collected as described in Appendix 6. Laboratory results are 
provided to the sponsor via the central laboratory.
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.
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.  Autoinjectors 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 (FDA resources page [WWW]).
9.4.
Safety
Safety will be assessed throughout the course of the study at site visits and via telephone calls in 
between site visits.  


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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).  
See Appendix 6 for further laboratory testing and instructions for hypersensitivity events.  
Lilly or its designee will provide the investigator with the results of laboratory tests analyzed by 
a central vendor, if a central vendor is used for the study.
9.4.2. Vital Signs
For each subject, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).  
Blood pressure and pulse rate should be measured after at least 5 minutes sitting.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  If orthostatic measurements are required, subjects should be supine 
for at least 5 minutes and stand for at least 2 minutes.  If the subject feels unable to stand, supine 
vital signs only will be recorded.  
Additional vital signs may be measured during each study period if warranted.
9.4.3. Electrocardiograms
For each subject, a single12-lead digital ECG will be collected according to the Schedule of 
Activities (Section 2).  
Electrocardiograms must be recorded before collecting any blood samples.  Subjects must be 
supine for 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 investigator (physician or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings be 
identified.  
9.4.4. Temperature
Body temperature 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 reactions will be captured on the ISR AE form and the eCRF as an AE. The 
findings of ISR (including induration, pain, edema, pruritus, and erythema) for a specific 
injection will be captured as a single AE, even if more than 1 of the findings is positive, and the 


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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 ≥3X upper limit of normal (ULN), ALP ≥2X ULN, 
or elevated total bilirubin ≥2X ULN, liver tests (Appendix 4) should be repeated within 3 to 5 
days including ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase (GGT), and 
creatinine kinase to confirm the abnormality and to determine if it is increasing or decreasing.  If 
the abnormality persists or worsens, clinical and laboratory monitoring should be initiated by the 
investigator based on consultation with the Lilly CP or CRP.  Monitoring should continue until 
levels normalize and/or are returning to approximate baseline levels. 
Additional safety data should be collected if 1 or more of the following conditions occur:  

elevation of serum ALT to ≥ 5X ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥ 2X ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥ 2X ULN on 2 or more consecutive blood tests 

subject discontinued from treatment due to a hepatic event or abnormality of liver 
tests

hepatic event considered to be an SAE
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), serum samples of 
approximately 3 mL each will be collected to determine the serum concentrations of ixekizumab.  
A maximum of 3 samples may be collected at additional time points during the study if 
warranted and agreed upon between both the investigator and sponsor.  Instructions for the 
collection and handling of blood samples will be provided by the sponsor.  The actual date and 
time (24-hour clock time) of each sampling will be recorded.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of ixekizumab will be assayed using a validated enzyme-linked immunosorbent 
assay (ELISA) method.  
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
1 year following last subject visit for the study.  During this time, samples remaining after the 


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bioanalyses may be used for exploratory metabolism studies or exploratory analyses such as 
bioanalytical assay validation or cross-validation exercises.
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 
will be collected to determine antibody production against ixekizumab.  Antibodies may be 
further characterized for their ability to neutralize the activity of ixekizumab.  To interpret the 
results of immunogenicity, a venous blood sample will be collected at the same time points to 
determine the serum concentrations of ixekizumab. All samples for immunogenicity should be 
taken predose when applicable and possible.
Treatment-emergent ADAs (TE-ADAs) are defined in Section 10.3.3.  If the immunogenicity 
titer at the last scheduled assessment or discontinuation visit is TE-ADA positive, additional 
samples may be taken until the signal returns to baseline (i.e., no longer TE-ADA positive) or for 
up to 1 year after dosing.
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and Ethical Review Boards (ERBs) allow, at a facility selected by the 
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to the 
IP.  Any samples remaining after 15 years will be destroyed.  
9.7.
Genetics
A blood sample (10 mL) 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 
ixekizumab and to investigate genetic variants thought to play a role in autoimmune disorders.  
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/IRBs 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.  


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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 approximately 240 subjects may be enrolled so that approximately 216 subjects (108 in the 
80-mg ixekizumab commercial formulation [reference] group and 108 in the 80-mg ixekizumab 
alternate formulation [test] group) complete the study.  
A sample size of 108 subjects per treatment group will provide approximately 90% power that 
the 90% confidence interval (CI) of the geometric mean ratio of maximum observed drug 
concentration (Cmax) and area under the concentration versus time curve (AUC) between groups
will fall within equivalence range of 0.8 to 1.25.  This sample size calculation was based on the 
assumptions that the PK parameters have log-normal distribution, the percent coefficients of 
variation (%CV) of Cmax and AUC are less or equal to 48% (from study RHCT), the expected 
ratio of geometric means is between 0.997 to 1.04, and the %CV are the same for subjects from 
each treatment group.
Subjects who are randomized but not administered treatment and subjects who do not complete 
PK sampling (including day 85) may be replaced so that approximately 216 subjects (108 for 
each treatment) complete the study.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study.  
10.2.2. Study Participant Characteristics
The subjects’ age, sex, weight, height, BMI, race, site of injection, 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 Lilly or its designee.
Pharmacokinetic (PK) analyses will be conducted on data from all subjects who receive the
complete single dose of ixekizumab and have sufficient evaluable PK.  Only subjects who 
complete the PK sampling schedule to Day 85 will be included in the statistical analysis of PK 
parameters.  
Additional exploratory analyses of the data will be conducted as deemed appropriate, and study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post hoc analyses and incomplete disclosures of analyses.  


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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 using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with IP as perceived by the investigator.  Symptoms reported to occur prior to study entry will be 
distinguished from those reported as new or increased in severity during the study.  Each 
symptom will be classified by the most suitable term from MedDRA.
The number of IP-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters and vital signs 
parameters.  The parameters will be listed and summarized using standard descriptive statistics.  
Additional analysis will be performed if warranted upon review of the data.
10.3.1.2.1.Statistical Evaluation of Other Safety Parameters
Safety laboratory parameters and vital signs data will be listed and summarized using standard 
descriptive statistics, where possible.  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 (i.e., if a subject’s answers are all ‘no’ for the C-SSRS, then that subject 
will not be displayed).  Hospital Anxiety Depression Scale item scores will be listed for subjects 
with HADS depression subscale ≥11 at any time.  Additional analysis may be performed if 
warranted upon review of the data.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for ixekizumab will be calculated by standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be Cmax, AUC(0-tlast) and AUC(0-∞) of ixekizumab.  
Other noncompartmental parameters, such as time to maximum drug concentration (tmax),
half-life associated with the terminal rate constant in noncompartmental analysis (t1/2), apparent 
clearance, and apparent volume of distribution may be reported.  
Pharmacokinetic parameters may also be normalized by body weight for summarizing the data 
and may be summarized by site of injection location using descriptive statistics.  
10.3.2.2. Pharmacokinetic Statistical Inference
Pharmacokinetic parameters will be evaluated to determine the bioequivalence of ixekizumab 
alternate formulation (test) compared to the ixekizumab commercial formulation (reference).  
Log-transformed Cmax and AUC parameters will be evaluated in a linear mixed-effects model 


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with fixed effects for formulation and a random effect for subject.  The treatment differences will 
be back-transformed to present the ratios of geometric means and the corresponding 90% CI.  
The tmax will be analyzed using a Wilcoxon rank sum test.  Estimates of the median difference 
based on the observed medians, 90% CIs and p-values from the Wilcoxon rank sum test will be 
calculated.
Bioequivalence will be concluded if the 90% CI is completely contained within the interval 
(0.80, 1.25).
10.3.3. Evaluation of Immunogenicity
The frequency and percentage of subjects with preexisting ADAs and with TE-ADAs to 
ixekizumab will be tabulated. Treatment-emergent ADAs are defined as those with a titer 2-fold 
(1 dilution) greater than the minimum required dilution if no ADAs were detected at baseline 
(treatment-induced ADA) or those with a 4-fold (2 dilutions) increase in titer compared to 
baseline if ADAs were detected at baseline (treatment-boosted ADA). For the TE-ADA 
subjects, the distribution of maximum titers will be described.  The frequency of neutralizing 
antibodies will also be tabulated in TE-ADA subjects.
The relationship between the presence of antibodies and the safety and PK parameters to 
ixekizumab may be assessed.
10.3.4. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly CP, CRP/investigator, or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol.


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11.
References
Snaith RP. The Hospital Anxiety and Depression Scale. Health Qual Life Outcomes. 2003;1:29.
Taltz (ixekizumab) Injection Label. Food and Drug Administration web site. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125521s016lbl.pdf. Accessed 
October, 22 2019.
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;175:452-454.
Williamson A, 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(6):361-370.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
%CV
percent coefficients of variation
ADA
antidrug antibody
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
AI
autoinjector
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
BCG
Bacillus Calmette-Guérin
blinding
A procedure in which one or more parties to the study are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his/her staff are aware of the 
treatment but the subject is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/or his/her staff and the subject are not.  A double-blind study is one 
in which neither the subject nor any of the investigators or sponsor staff who are involved 
in the treatment or clinical evaluation of the subjects are aware of the treatment received
BMI
body mass index
CEC
Clinical Events Committee
CI
confidence interval
Cmax
maximum observed drug concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.


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CP
Clinical Pharmacologist
CRF
case report form
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
ELISA
enzyme-linked immunosorbent assay
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
IL
interleukin
IL-17A
interleukin 17A
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.  
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.
IP
investigational product:  A pharmaceutical form of an active ingredient or placebo being 
tested or used as a reference in a clinical study, including products already on the market 
when used or assembled (formulated or packaged) in a way different from the authorized 
form, or marketed products used for an unauthorized indication, or marketed products used 
to gain further information about the authorized form.


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ISR
injection site reaction
Legal 
Representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective subject, to the subject’s participation in the clinical study.
Lilly
Eli Lilly and Company
MedDRA
Medical Dictionary for Regulatory Activities
randomize
The process of assigning subjects/patients to an experimental group on a random basis.
PE
physical examination
PFS
prefilled syringe
PK
pharmacokinetic
Ps
plaque psoriasis
PsA
psoriatic arthritis
RHCA
Study I1F-MC-RHCA
RHCK
Study I1F-MC-RHCK
RHCS
Study I1F-MC-RHCS
RHCT
Study I1F-MC-RHCT
RHCU
Study I1F-MC-RHCU
SAE
serious adverse event
SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SUSARs
suspected unexpected serious adverse reactions
TBL
total bilirubin level
TE-ADA
treatment-emergent antidrug antibody
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment.
t1/2
half-life associated with the terminal rate constant in noncompartmental analysis
tmax
time to maximum drug concentration


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ULN
upper limit of normal
VAS
visual analog scale


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


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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
Eli Lilly and Company (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 
Harmonization (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative sites.  Lilly or its representatives must approve the ICF 
before it is used at the investigative sites.  All ICFs must be compliant with the ICH guideline on 
good clinical practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current IB and 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 (CIOMS) 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 that, to the best of his or her knowledge, the report accurately describes the conduct 
and results of the study.
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 CRFs, and study 
procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate case report form (CRF) data and/or use standard computer edits 
to detect errors in data collection

conduct a quality review of the database


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


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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 Eli Lilly and Company or its designee
clinical research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis 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-RHCU Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
28
1
28
Clinical laboratory testsa
15.2
4
60.8
Pharmacokinetics 
3
15b
45
Immunogenicity
10
4
40
Pharmacogenetics
10
1
10
Total
183.8
Total for clinical purposes [rounded up to nearest 10 mL]
190
a
Additional samples may be drawn if needed for safety purposes.
b
Includes an additional 3 samples, if required.  


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Appendix 6.
Recommended Laboratory Testing for 
Hypersensitivity Events
Lab testing should be performed at the time of a Systemic Hypersensitivity Event. Important 
information about why, when, and what to test for is provided below. The management of the 
adverse event may warrant lab testing beyond that described below and should be performed as 
clinically indicated.
When should labs be obtained?
In the presence of generalized urticaria or if anaphylaxis is suspected, after the subject has been 
stabilized:

obtain a sample within 1-2 hours of the event; however, samples may be obtained as late 
as 12 hours after the event as analytes can remain altered for an extended period of time.  
Record the time at which the sample was collected.

obtain a follow up sample at the next regularly scheduled visit or after 4 weeks, 
whichever is later.
Selected tests may be obtained in the events of anaphylaxis or generalized urticaria.
Hypersensitivity Testsa
Anti-LY2439821 antibodies (immunogenicity)
Tryptaseb
LY2439821 concentration (PK)
N-methylhistamine
Drug-specific IgEc
Basophil activation Testc
Complementsd
Cytokine panele
Abbreviations:  Ig= immunoglobulin; LY2439821 = ixekizumab; PK = pharmacokinetics.
a
Assayed by Lilly-designated laboratory.  These labs are bundled in the Clinical Laboratory Operations 
Hypersensitivity Lab Testing Kit.  
b
If a tryptase sample is obtained more than 2 hours after the event (i.e., within 2 to 12 hours), or is not obtained 
because more than 12 hours have lapsed since the event, obtain urine for N- methylhistamine (NMH) testing. 
Note that for tryptase serum samples obtained within 2-12 hours of the event, urine NMH testing is performed in 
addition to tryptase testing. Collect the first void urine following the event. Obtain a follow up urine for NMH 
testing at the next regularly scheduled visit or after 4 weeks, whichever is later.
c
Basophil activation test will be performed if a drug-specific IgE assay is unavailable.  
d
C3a and C5a. 
e
IL-6, IL-1β, IL-10 (or any cytokine panel that includes these 3 cytokines).  


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Appendix 7.
Protocol Amendment I1F-MC-RHCU(b) 
Summary Bioequivalence of an Alternate Ixekizumab 
Formulation Compared to the Commercial Formulation 
in Healthy Subjects
Protocol I1F-MC-RHCU, Bioequivalence of an Alternate Ixekizumab Formulation Compared to 
the Commercial Formulation in Healthy Subjects, has been amended.  The new protocol is 
indicated by Amendment (b) and will be used to conduct the study in place of any preceding 
version of the protocol.
The overall changes made to this protocol are as follows:

Modified Exclusion Criterion [8] in Section 6.2 to consider employees of third-party 
organizations, in addition to employees of Lilly and Covance who are involved in the 
study.

Minor editorial changes and formatting corrections were made but are not necessarily 
documented in the revision below.

Added in verbiage to Section 5.1 for COVID 19 related precautions to be taken by the 
CRU.

Removed verbiage in Section 10.3.1 on safety analyses in enrolled patients


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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.
6.2. Exclusion Criteria
[8] are Eli Lilly and Company (Lilly) or Covance employees are employees of Eli Lilly 
and Company (Lilly), Covance, or a third-party organization involved in the study.
5. Study Design
5.1 Overall Design
Participants should follow local guidance and CRU precautions to minimize risk for COVID-19 
infection.
10.3. Statistical Analysis
10.3.1 Safety Analysis
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.


Leo Document ID = 9aad3972-e07b-49ac-a25e-2746a4b9c4f9
Approver: 
Approval Date & Time: 28-Sep-2020 20:02:30 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 29-Sep-2020 00:58:37 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
I1F-MC-RHCU Statistical Analysis Plan Final Version 2 
 
Bioequivalence of an Alternate Ixekizumab Formulation Compared to the Commercial Formulation 
in Healthy Subjects 
 
NCT04259346 
 
Approval Date: 18-Dec-2020 
 
 
 


Final V2, 17 Dec 2020
             Page 1 of 17
STATISTICAL ANALYSIS PLAN
Bioequivalence of an Alternate Ixekizumab Formulation
Compared to the Commercial Formulation in Healthy
Subjects
Statistical Analysis Plan Status:  Final V2
Statistical Analysis Plan Date: 17-December-2020
Study Drug: Ixekizumab (LY2439821)
Sponsor Reference: I1F-MC-RHCU
Covance CRU Study: 1000071-8414464
Clinical Phase I
Approval Date: 18-Dec-2020 GMT


Final V2, 17 Dec 2020
             Page 2 of 17
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8414464
Sponsor Reference I1F-MC-RHCU
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 4
3.
INTRODUCTION ......................................................................................................... 6
4.
STUDY OBJECTIVES.................................................................................................. 6
4.1
Primary Objective.................................................................................................... 6
4.2
Secondary Objective................................................................................................ 6
4.3
Exploratory Objective.............................................................................................. 6
5.
STUDY DESIGN........................................................................................................... 7
6.
TREATMENTS............................................................................................................. 7
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 8
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 8
9.
STATISTICAL METHODOLOGY ............................................................................... 8
9.1
General.................................................................................................................... 8
9.2
Demographics and Subject Disposition.................................................................... 9
9.3
Pharmacokinetic Assessment................................................................................... 9
9.3.1
Pharmacokinetic Analysis............................................................................... 9
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 13
9.4
Safety and Tolerability Assessments...................................................................... 14
9.4.1
Adverse events ............................................................................................. 14
9.4.2
Concomitant medication............................................................................... 14
9.4.3
Clinical laboratory parameters...................................................................... 14
9.4.4
Vital signs .................................................................................................... 15
9.4.5
Electrocardiogram (ECG)............................................................................. 15
9.4.6
Hepatic Monitoring ...................................................................................... 15
9.4.7
Immunogenicity Assessments....................................................................... 15
9.4.8
Hypersensitivity reactions............................................................................. 15
9.4.9
Injection-Site Assessments ........................................................................... 16
9.4.10
Visual analog scale (VAS) pain .................................................................... 16
9.4.11
Columbia-Suicide Severity Rating Scale (C-SSRS), Self-Harm Supplement and 
Hospital Anxiety Depression Scale (HADS)................................................. 16
9.4.12
Other assessments......................................................................................... 16
9.4.13
Safety and Tolerability Statistical Methodology............................................ 16


Final V2, 17 Dec 2020
             Page 3 of 17
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8414464
Sponsor Reference I1F-MC-RHCU
10. INTERIM ANALYSES ............................................................................................... 16
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 16
12. REFERENCES ............................................................................................................ 17
13. DATA PRESENTATION ............................................................................................ 17
13.1 Derived Parameters ............................................................................................... 17
13.2 Missing Data ......................................................................................................... 17
13.3 Insufficient Data for Presentation .......................................................................... 17


Final V2, 17 Dec 2020
             Page 4 of 17
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8414464
Sponsor Reference I1F-MC-RHCU
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
ADA
Antidrug antibody
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
BQL
Below the lower limit of quantification
CI
Confidence interval
Clast
Last observed concentration
CL/F
Apparent total body clearance of drug calculated after extra-vascular 
administration
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale
CV%
Coefficient of variation
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
HADS
Hospital Anxiety Depression Scale
ICH
International Conference on Harmonisation
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MRE
Magnetic resonance elastography
PK
Pharmacokinetic
SAP
Statistical Analysis Plan
SD
Standard deviation 


Final V2, 17 Dec 2020
             Page 5 of 17
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8414464
Sponsor Reference I1F-MC-RHCU
SC
Subcutaneous
TBL
Total bilirubin
TE ADA
Treatment-emergent antidrug antibody
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
tmax
Time of maximum observed drug concentration
tlast
Time of last observed drug concentration
ULN
Upper limit of normal
VAS
Visual analog scale
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


Final V2, 17 Dec 2020
             Page 6 of 17
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8414464
Sponsor Reference I1F-MC-RHCU
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
13 November 2019), Protocol Amendment (a) (final version dated 21 February 2020) and 
Protocol Amendment (b) (final version dated 29 September 2020).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) data 
from this study. A detailed description of the planned TFLs to be presented in the clinical study 
report (CSR) is provided in the accompanying TFL shell document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement with Eli Lilly and Company. A limited amount of information concerning this 
study (e.g. objectives, study design) is given to help the reader’s interpretation. When the SAP 
and TFL shells are agreed upon and finalized, they will serve as the template for this study’s 
CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon with
Eli Lilly and Company and identified in the CSR. Any minor deviations from the TFLs may not 
be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
4.1
Primary Objective
To evaluate the bioequivalence of a single 80-mg subcutaneous (SC) dose of ixekizumab 
alternate formulation (test) compared to the ixekizumab commercial formulation (reference).
4.2
Secondary Objective
To describe the safety and tolerability of a single 80-mg SC dose of ixekizumab alternate
formulation (test) compared to the commercial formulation (reference).
4.3
Exploratory Objective
To evaluate the immunogenicity of ixekizumab in the alternate formulation (test) and the 
commercial formulation (reference).


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8414464
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5. STUDY DESIGN
Participants should follow local guidance and clinical research unit (CRU) precautions to 
minimize risk for Coronavirus Disease 2019 infection.
Study RHCU is a Phase 1, subject-blind, 2-arm, randomized, parallel-design study in healthy
subjects.
All subjects will be screened within 28 days prior to enrollment. Eligible subjects will be
admitted to the CRU on Day -1. At screening, subjects will be stratified
into 1 of 3 weight categories (<70.0 kg, 70.0 to 80.0 kg, >80.0 kg). Within the 3 weight
categories, subjects will be randomized 1:1 to either 80-mg ixekizumab commercial formulation
(reference) or 80-mg ixekizumab alternate formulation (test) and subrandomized 1:1:1 to
injection site (arm, thigh, or abdomen) (Table RHCU.1). On Day 1, subjects will receive a
single SC dose according to the randomization plan (Table RHCU.1).
Table RHCU.1. Study RHCU Stratification and Randomization Plan
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Study Treatment Name
Abbreviation
Treatment order in TFL
80-mg ixekizumab commercial formulation 
Reference
1


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Covance Clinical Study No. 1000071-8414464
Sponsor Reference I1F-MC-RHCU
80-mg ixekizumab alternate formulation 
Test
2
7. SAMPLE SIZE JUSTIFICATION
Up to approximately 240 subjects may be enrolled so that approximately 216 subjects (108 in the 
80-mg ixekizumab commercial formulation [reference] group and 108 in the 80-mg ixekizumab 
alternate formulation [test] group) complete the study.
A sample size of 108 subjects per treatment group will provide approximately 90% power that 
the 90% confidence interval (CI) of the geometric mean ratio of maximum observed drug 
concentration (Cmax) and area under the concentration versus time curve (AUC) between groups 
will fall within equivalence range of 0.8 to 1.25. This sample size calculation was based on the 
assumptions that the PK parameters have log-normal distribution, the percent coefficients of 
variation (CV%) of Cmax and AUC are less or equal to 48% (from study RHCT), the expected 
ratio of geometric means is between 0.997 to 1.04, and the CV% are the same for subjects from 
each treatment group.
Subjects who are randomized but not administered treatment and subjects who do not complete 
PK sampling (including Day 85) may be replaced so that approximately 216 subjects (108 for 
each treatment) complete the study.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled subjects, whether or not they completed all
protocol requirements.
The “Pharmacokinetic” population will consist of all subjects who received at least one complete 
dose of ixekizumab and have evaluable PK data. Only subjects who had all PK samples collected 
up to Day 85 or subjects who had one missing PK sample after Day 15 but with at least 3 data 
points and Rsq adj>0.7 to calculate half-life parameter could be included in the statistical 
analysis of the PK parameters.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: AUCs and Cmax) the geometric 
mean and geometric CV% will also be presented. For categorical data, frequency count and 
percentages will be presented. Data listings will be provided for all subjects up to the point of 
withdrawal, with any subjects excluded from the relevant population highlighted. Summary 


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8414464
Sponsor Reference I1F-MC-RHCU
statistics and statistical analyses will generally only be performed for subjects included in the 
relevant analysis population. For the calculation of summary statistics and statistical analysis, 
unrounded data will be used. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, body 
weight, height and body mass index will be summarized and listed. All other demographic
variables will be listed only.
9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
Non-compartmental methods applied with a validated software program (Phoenix WinNonlin 
Version 8.1 or later) to the serum concentrations of ixekizumab will be used to determine the 
following PK parameters, when possible:


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8414464
Sponsor Reference I1F-MC-RHCU
Parameter
Units
Definition
AUC(0-tlast)
µg.day/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
AUC(0-∞)
µg.day/mL
area under the concentration versus time curve from time zero to 
infinity
Cmax
µg/mL
maximum observed drug concentration
tmax
day
time of maximum observed drug concentration
tlast
day
time of last observed drug concentration
t1/2
h
half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vss/F
L
apparent volume of distribution at steady state after extra-vascular
administration
Additional PK parameters may be calculated, as appropriate. The software and version used for 
the final analyses will be specified in the CSR. Any exceptions or special handling of data will 
be clearly documented within the final study report.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus predose sampling times which will be set to zero.

Cmax and tmax will be reported from observed values. If Cmax occurs at more than one time
point, tmax will be assigned to the first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule). The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive serum concentrations above the lower limit of quantification (LLOQ), with at 
least one of these concentrations following Cmax.

AUC(0-∞) values where the percentage of the total area extrapolated is more than 20% 
will be flagged.  Any AUC(0-∞) value excluded from summary statistics will be noted in 
the footnote of the summary table.  If AUC(0-∞) cannot be determined for all subjects an 
alternative AUC measure, such as AUC to a fixed time point, may be used in the 
assessment exposure between dose groups.


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Covance Clinical Study No. 1000071-8414464
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
Half-life (t½) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 
phase for each subject will be defined by visual inspection and generally will be the first 
point at which there is no systematic deviation from the log-linear decline in serum
concentrations. Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points. If t½ is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t½ value excluded from summary statistics will be documented in the footnote of the 
summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal log-
linear portion of the concentration-time curve.

The parameters based on last observed concentration (Clast) will be reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantification (BQL). Serum concentrations reported as BQL will be set to a value of 
zero when all of the following conditions are met:
o
The compound is non-endogenous.
o
The samples are from the initial dose period for a subject.
o
The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing.

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times.


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Covance Clinical Study No. 1000071-8414464
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
The average concentration profiles will be graphed using arithmetic average 
concentrations.

The predose average concentration for single-dose data from non-endogenous 
compounds will be set to zero. Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations.

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the final study 
report.

A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements that are within the 
sampling time window specified in the protocol or ± 10%. An average concentration 
estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all PK analyses is not a requirement. Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate. This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis. The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:

For PK profiles during single dosing of non-endogenous compounds, the concentration in 
a predose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results may be reported with and without the suspected datum.
Data between Individual Profiles
1.
If n<6, then the dataset is too small to conduct a reliable range test. Data will be analyzed 
with and without the atypical value, and both sets of results will be reported.  
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.


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Covance Clinical Study No. 1000071-8414464
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b. Find the most extreme value from the arithmetic mean of the log-transformed
values and exclude that value from the dataset.
c.
Calculate the lower and upper bounds of the range defined by the arithmetic 
mean ±3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is 
not an outlier and will be retained in the dataset.
e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is 
an outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values.
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final report. Approval of the 
final report will connote approval of the exclusion.
9.3.2
Pharmacokinetic Statistical Methodology
PK parameters will be evaluated to determine the bioequivalence of ixekizumab alternate 
formulation (test) compared to the ixekizumab commercial formulation (reference). Log-
transformed Cmax, AUC(0-∞) and AUC(0-tlast) will be evaluated in a linear mixed-effects model
with fixed effects for formulation and a random effect for subject. The treatment differences will
be back-transformed to present the ratios of geometric means and the corresponding 90% CI.
Example SAS code:   
proc mixed data=pk;
   by parameter;
   class formulation subject;
   model log_pk= formulation / residual ddfm=kr; 
   random intercept / subject=subject;
   estimate ‘Test - Ref’ trtmnt -1 1 / cl alpha=0.1;
run;
The tmax will be analyzed using a Wilcoxon rank sum test. Estimates of the median difference
based on the observed medians, 90% CIs and p-values from the Wilcoxon rank sum test will be
calculated.
Bioequivalence will be concluded if the 90% CI is completely contained within the interval
(0.80, 1.25).


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8414464
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PK parameters may be normalized by body weight for summarizing the data and may be 
summarized by site of injection location using descriptive statistics. Additional comparisons may 
also be conducted as necessary.
A sensitivity analysis will be performed to complete the statistical comparison above using the 
subjects who completed the PK sampling schedule to Day 85 only (subjects with no missing PK 
samples).
9.4
Safety and Tolerability Assessments
9.4.1
Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (AE) will be reported in the listings, only the most severe will be used in the 
summary tables. A pre-existing condition is defined as an AE that starts before the subject has 
provided written informed consent and is ongoing at consent. A non-treatment emergent AE is 
defined as an AE which starts after informed consent but prior to dosing. A treatment-emergent 
AE is defined as an AE which occurs postdose or which is present prior to dosing and becomes 
more severe postdose. 
If the investigator determines an injection-site reaction (ISR) is clinically significant or it is an 
unsolicited reporting, the event will be recorded as an AE and findings of the ISR (including 
induration, pain, edema, pruritus, and erythema) will be captured on the ISR AE form. Any ISRs 
that are present (besides induration, pain, edema, pruritus, and erythema) will be recorded as AEs 
at the discretion of the investigator only.
All AEs will be listed. Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug. The frequency (the number of AEs, the number of subjects 
experiencing an AE and the percentage of subjects experiencing an AE) of treatment-emergent 
AEs will be summarized by treatment, Medical Dictionary for Regulatory Activities (MedDRA) 
version 22.0 system organ class and preferred term. The summary and frequency AE tables will 
be presented for all causalities and those considered related to the study drug by the investigator. 
Any serious AEs will be listed. 
Discontinuations due to AEs will be listed.
9.4.2
Concomitant medication
Concomitant medication will be coded using the World Health Organization (WHO) drug 
dictionary (Version September 2019 B3). Concomitant medication will be listed.
9.4.3
Clinical laboratory parameters
All clinical chemistry and hematology data, with changes from baseline, will be summarized by 
parameter and treatment, and listed. Urinalysis data will be listed. Additionally clinical 
chemistry, hematology and urinalysis data outside the reference ranges will be listed and flagged 
on individual subject data listings.


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8414464
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9.4.4
Vital signs
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as the Day 1 predose assessment. Figures of mean vital signs and mean 
changes from baseline profiles will be presented by treatment. 
Values for individual subjects will be listed.
9.4.5
Electrocardiogram (ECG)
ECGs will be performed for safety monitoring purposes only and will not be presented. Any 
clinically significant findings from ECGs will be reported as an AE.
9.4.6
Hepatic Monitoring
If a subject experiences elevated alanine aminotransferase (ALT) ≥3× upper limit of normal 
(ULN), alkaline phosphatase (ALP) ≥2× ULN, or elevated total bilirubin (TBL) ≥2× ULN, liver 
tests will be performed to confirm the abnormality. Additional safety data may be collected if 
required, as defined in the protocol. Where applicable, the following will be presented.
The subjects’ liver disease history and associated person liver disease history data will be listed. 
Any concomitant that have potential for hepatotoxicity, including acetaminophen will be listed.
Results from any hepatic monitoring procedures, such as a magnetic resonance elastography 
(MRE) scan, and biopsy assessments will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual subject data listings.
9.4.7
Immunogenicity Assessments
The frequency and percentage of subjects with pre-existing antidrug antibody (ADA) and with 
treatment-emergent ADAs (TE ADA) to ixekizumab will be tabulated. 
For subjects who are ADA negative at baseline, TE ADAs are defined as those with a titer 2-fold 
(1 dilution) greater than the minimum required dilution of the assay (1:5). For subjects who are 
ADA positive at baseline, TE ADAs are defined as those with a 4-fold (2 dilution) increase in 
titer compared to baseline. The frequency and percentage of subjects with cross-reactive and 
neutralizing antibodies, if measured, may also be tabulated for subjects with TE ADA.
9.4.8
Hypersensitivity reactions
For all drug hypersensitivity reactions that occur, additional follow-up data will be collected to
assess the subject’s medical history, alternative causes, and symptoms.
These data will be listed.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8414464
Sponsor Reference I1F-MC-RHCU
9.4.9
Injection-Site Assessments
Injection sites will be assessed for reactions including bleeding, induration, pain, edema, 
pruritus, and erythema. Any available injection-site assessment data will be listed.
9.4.10
Visual analog scale (VAS) pain
Intensity of pain data will be quantified using a 100-mm validated visual analog scale (VAS) for 
any subject that answers “Yes” to the question “How much pain have you had at the injection 
site?”. The data will be listed and summarized by treatment and time point.
In addition, the severity of pain will be categorized by VAS pain score as no pain (0), mild pain 
(> 0 and ≤ 30), moderate pain (> 30 and ≤ 70), and severe pain (> 70). The number and 
percentage of subjects in each pain severity category will be summarized by treatment and time 
point. The percentage of subjects in each pain severity category will also be presented in a 
frequency figure. Figures of the continuous injection-site pain VAS score will also be presented, 
by treatment and measuring time point.
9.4.11
Columbia-Suicide Severity Rating Scale (C-SSRS), Self-Harm Supplement and 
Hospital Anxiety Depression Scale (HADS)
Given that few or no suicidal ideation or behaviors are anticipated, a listing of C-SSRS data will 
be produced by subject and visit. Only subjects that show suicidal ideation/behavior or self-
injurious behavior without suicidal intent will be included in the listing (i.e., if a subject’s 
answers are all ‘no’ for the C-SSRS, then that subject will not be displayed). However, if a 
subject reported any suicidal ideation/behavior or self-injurious behavior without suicidal intent 
at any time point then all their ideation and behavior will be included, even if not positive.
HADS item scores will be listed for subjects with HADS depression subscale ≥ 11 at any time.
9.4.12
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.4.13
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.


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Covance Clinical Study No. 1000071-8414464
Sponsor Reference I1F-MC-RHCU
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the center of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = cb424143-78fc-424a-88cf-d051825c0579
Approver: 
Approval Date & Time: 18-Dec-2020 09:07:49 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 18-Dec-2020 13:57:25 GMT
Signature meaning: Approved
PPD
PPD