A 24-Week Multicenter, Randomized, Blinded, Parallel-Group Study Comparing the Efficacy and Safety of Ixekizumab to Guselkumab in Patients With Moderate-to-Severe Plaque Psoriasis
Phase: PHASE4
Conditions: Plaque Psoriasis
Sponsor: Eli Lilly and Company

Protocol I1F-MC-RHCR (b) 
A 24-Week Multicenter, Randomized, Double-Blind, Parallel-Group Study Comparing the 
Efficacy and Safety of Ixekizumab to Guselkumab in Patients with Moderate-to-Severe Plaque 
Psoriasis  
 
NCT03573323 
 
Approval Date: 07-Dec-2018 
 
 
 

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Protocol I1F-MC-RHCR(b)
A 24-Week Multicenter, Randomized, Double-Blind, 
Parallel-Group Study Comparing the Efficacy and Safety of 
Ixekizumab to Guselkumab in Patients with 
Moderate-to-Severe Plaque Psoriasis
Confidential Information
The information contained in this document 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
Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 07-Dec-2018 GMT

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Table of Contents
Section
Page
Protocol I1F-MC-RHCR(b) A 24-Week Multicenter, Randomized, 
Double-Blind, Parallel-Group Study Comparing the Efficacy and 
Safety of Ixekizumab to Guselkumab in Patients with 
Moderate-to-Severe Plaque Psoriasis...................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................17
3.1.
Study Rationale............................................................................................................17
3.2.
Background..................................................................................................................17
3.3.
Benefit/Risk Assessment..............................................................................................19
4.
Objectives and Endpoints..................................................................................................21
5.
Study Design.....................................................................................................................23
5.1.
Overall Design .............................................................................................................23
5.1.1.
Screening Period (Period 1)..................................................................................24
5.1.2.
Induction Dosing Period (Period 2) ......................................................................25
5.1.3.
Extension Period (Period 3)..................................................................................25
5.1.4.
Post-Treatment Follow-Up Period (Period 4) .......................................................25
5.2.
Number of Participants.................................................................................................26
5.3.
End of Study Definition ...............................................................................................26
5.4.
Scientific Rationale for Study Design...........................................................................26
5.5.
Justification for Dose ...................................................................................................27
6.
Study Population...............................................................................................................28
6.1.
Inclusion Criteria..........................................................................................................28
6.2.
Exclusion Criteria ........................................................................................................29
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................33
6.3.
Lifestyle Restrictions....................................................................................................34
7.
Treatments........................................................................................................................35
7.1.
Treatments Administered .............................................................................................35
7.1.1.
Administration of Ixekizumab, Guselkumab and Placebo.....................................36
7.1.2.
Observations after Study Drug Administration.....................................................37
7.1.3.
Packaging and Labelling ......................................................................................37
7.2.
Method of Treatment Assignment ................................................................................37
7.3.
Screen Failures.............................................................................................................38

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7.3.1.
Selection and Timing of Doses.............................................................................38
7.4.
Blinding .......................................................................................................................38
7.5.
Dosage Modification....................................................................................................39
7.6.
Preparation/Handling/Storage/Accountability...............................................................39
7.7.
Treatment Compliance .................................................................................................39
7.8.
Concomitant Therapy...................................................................................................40
7.9.
Treatment after the End of the Study............................................................................43
7.9.1.
Treatment after Study Completion........................................................................43
7.9.2.
Special Treatment Considerations ........................................................................43
8.
Discontinuation Criteria ....................................................................................................45
8.1.
Discontinuation from Study drug..................................................................................45
8.1.1.
Permanent Discontinuation from Study drug ........................................................45
8.1.2.
Discontinuation of Inadvertently Enrolled Patients...............................................46
8.2.
Discontinuation from the Study....................................................................................46
8.3.
Lost to Follow-Up........................................................................................................47
9.
Study Assessments and Procedures ...................................................................................48
9.1.
Efficacy Assessments...................................................................................................48
9.1.1.
Primary Efficacy Assessments .............................................................................48
9.1.1.1.
Psoriasis Area and Severity Index...................................................................48
9.1.2.
Major Secondary Efficacy Assessments ...............................................................48
9.1.2.1.
Static Physician Global Assessment................................................................48
9.1.3.
Other Efficacy Assessments .................................................................................48
9.1.3.1.
Percentage of Body Surface Area ...................................................................48
9.1.3.2.
Physician’s Global Assessment of Disease Activity 
Visual Analog Scale (for Patients with PsA)...................................................49
9.1.3.3.
PGA-F Physician’s Global Assessment of Fingernail 
Psoriasis .........................................................................................................49
9.1.4.
Health Outcome Endpoints...................................................................................49
9.1.4.1.
Itch Numeric Rating Scale..............................................................................49
9.1.4.2.
Skin Pain Visual Analog Scale .......................................................................49
9.1.4.3.
Patient’s Global Assessment of Disease Severity............................................49
9.1.4.4.
Dermatology Life Quality Index.....................................................................49
9.1.4.5.
Patient’s Assessment of Pain Visual Analog Scale (for 
Patients with PsA) ..........................................................................................50
9.1.4.6.
Patient’s Global Assessment of Disease Activity Visual 
Analog Scale (for Patients with PsA)..............................................................50
9.1.5.
Appropriateness of Assessments ..........................................................................50
9.2.
Adverse Events ............................................................................................................50
9.2.1.
Serious Adverse Events........................................................................................51

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9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................52
9.2.1.2.
Adverse Events of Special Interest..................................................................52
9.2.2.
Complaint Handling.............................................................................................53
9.3.
Treatment of Overdose.................................................................................................53
9.4.
Safety...........................................................................................................................54
9.4.1.
Laboratory Tests ..................................................................................................54
9.4.2.
Immunogenicity Assessments ..............................................................................54
9.4.2.1.
Ixekizumab Serum Concentration...................................................................54
9.4.3.
Physical Examination...........................................................................................55
9.4.4.
Chest X-Ray and Tuberculosis Testing.................................................................55
9.4.5.
Columbia-Suicide Severity Rating Scale ..............................................................56
9.4.6.
Safety Monitoring ................................................................................................56
9.4.6.1.
Neutropenia....................................................................................................56
9.4.6.2.
Hepatic...........................................................................................................58
9.4.6.2.1.
Hepatic Safety Data Collection .................................................................58
9.4.6.3.
Hepatitis B Monitoring...................................................................................59
9.5.
Pharmacokinetics .........................................................................................................59
9.6.
Pharmacodynamics ......................................................................................................59
9.7.
Pharmacogenomics or Genetics....................................................................................59
9.8.
Biomarkers...................................................................................................................59
9.9.
Health Economics or Medical Resource Utilization and Health 
Economics ...................................................................................................................59
10.
Statistical Considerations ..................................................................................................60
10.1. Sample Size Determination ..........................................................................................60
10.2. Populations for Analyses..............................................................................................60
10.3. Statistical Analyses ......................................................................................................60
10.3.1.
General Statistical Considerations ........................................................................60
10.3.2.
Treatment Group Comparability...........................................................................61
10.3.2.1.
Patient Disposition..........................................................................................61
10.3.2.2.
Patient Characteristics ....................................................................................62
10.3.2.3.
Concomitant Therapy .....................................................................................62
10.3.2.4.
Treatment Compliance....................................................................................62
10.3.3.
Efficacy Analyses ................................................................................................62
10.3.3.1.
Primary Analyses ...........................................................................................62
10.3.3.2.
Major Secondary Analyses .............................................................................62
10.3.3.3.
Exploratory Efficacy Analyses........................................................................63
10.3.4.
Safety Analyses....................................................................................................63
10.3.4.1.
Adverse Events...............................................................................................63

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10.3.4.2.
Clinical Laboratory Tests................................................................................64
10.3.4.3.
Other Safety Evaluations ................................................................................64
10.3.5.
Evaluation of Immunogenicity .............................................................................65
10.3.6.
Other Analyses.....................................................................................................65
10.3.6.1.
Subgroup Analyses.........................................................................................65
10.3.7.
Interim Analyses..................................................................................................65
11.
References ........................................................................................................................66
12.
Appendices .......................................................................................................................70

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List of Tables
Table
Page
Table RHCR.2.1.Schedule of Activities....................................................................................13
Table RHCR.4.1.Objectives and Endpoints...............................................................................21
Table RHCR.7.1.Treatment Regimens......................................................................................35
Table RHCR.7.2.Ixekizumab and Guselkumab Treatment Group Dosing Summary for 
the Induction and Extension Periods ..............................................................36
Table RHCR.7.3.Concomitant Medications Permitted/Not Permitted in the Study and 
Conditions for Use.........................................................................................41
Table RHCR.10.1.
Primary and Major Secondary Outcome Analyses...............................63

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List of Figures
Figure
Page
Figure RHCR.1. Illustration of study design for clinical protocol RHCR..................................23

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................71
Appendix 2.
Clinical Laboratory Tests...............................................................................76
Appendix 3.
Study Governance Considerations..................................................................78
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................83
Appendix 5.
Protocol Amendment I1F-MC-RHCR(b) Summary: A 24 Week 
Multicenter, Randomized, Double Blind, Parallel Group Study 
Comparing the Efficacy and Safety of Ixekizumab to Guselkumab in 
Patients with Moderate to Severe Plaque Psoriasis.........................................84

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1. Synopsis
Title of Study:
A 24-week multicenter, randomized, double-blind, parallel-group study comparing the efficacy 
and safety of ixekizumab to guselkumab in patients with moderate-to-severe plaque psoriasis.
Rationale:
In early studies of biologics targeting the tumor necrosis factor (TNF) pathway to treat patients 
with chronic plaque psoriasis (hereafter, Ps), significant clinical improvement was obtained at a 
75% clearance of skin from baseline (Psoriasis Activity and Severity Index; PASI 75).  Newer 
biologics targeting the interleukin (IL)-17 or IL-23 immune pathway have raised the level of 
expected improvement to almost clear (at least a 90% improvement from baseline in PASI score;
PASI 90) or completely clear (a 100% improvement from baseline in PASI score; PASI 100) 
skin, and studies suggest that this improvement is attainable in a high proportion of patients 
(Papp et al. 2005; Reich et al. 2005; Leonardi et al. 2008; Menter et al. 2008; Papp et al. 2008; 
Langley et al. 2014; Griffiths et al. 2015; Krueger et al. 2015; Lebwohl et al. 2015; Papp et al. 
2015; Blauvelt et al. 2017; Reich et al. 2017).
As new drugs targeting these pathways come to the market, there is a need to directly compare
the efficacy and safety, as well as rapidness of efficacy, between products to better inform 
dermatologists and patients regarding drug selection.
Study I1F-MC-RHCR (RHCR) is a 24-week study to compare the efficacy and safety, as well as 
rapidness of efficacy, between ixekizumab and guselkumab in patients with moderate-to-severe 
Ps.  The primary efficacy endpoint of this trial is the percentage of patients reaching 100% 
improvement from baseline (complete clearance) in PASI score, as demonstrated by PASI 100 at 
Week 12.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary
To assess whether ixekizumab is superior to 
guselkumab at Week 12 in the treatment of patients 
with moderate-to-severe Ps, as measured by PASI 100

The proportion of patients achieving PASI 100 
at Week 12
Major Secondary
To assess whether ixekizumab is superior to 
guselkumab in the treatment of patients with 
moderate-to-severe Ps at different time points, as 
measured by:

PASI 75

The proportion of patients achieving PASI 75 at 
Week 2

PASI 90

The proportion of patients achieving PASI 90 at 
Weeks 4 and 8

PASI 100 

The proportion of patients achieving PASI 100 
at Weeks 4, 8 and 24

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Objectives
Endpoints

Static Physician Global Assessment score of 0 
(sPGA [0])

The proportion of patients achieving sPGA (0) at 
Week 12

PASI 50

The proportion of patients achieving PASI 50 at 
Week 1
Abbreviations: PASI = Psoriasis Area and Severity Index; Ps = plaque psoriasis; sPGA = Static Physician Global 
Assessment.
Summary of Study Design:
Study RHCR is a multicenter, randomized, double-blind, parallel-group Phase 4 study with 
4 study periods in patients with chronic moderate-to-severe Ps.
Treatment Groups and Duration:
There are 2 treatment groups in this study.  Patients will be randomized at Week 0 to receive 
either:
(i)
Ixekizumab:  80 mg subcutaneous (SC) injection.  At Week 0, 160 mg starting dose 
(two 80 mg injections), followed by 80 mg every 2 weeks (Q2W) from Weeks 2 
through 12, and then followed by 80 mg every 4 weeks (Q4W) thereafter (i.e., at 
Weeks 16 and 20).
or
(ii)
Guselkumab: 100 mg SC injection.  At Weeks 0 and 4, 100 mg injection, followed 
by 100 mg every 8 weeks (Q8W) thereafter (i.e., at Weeks 12 and 20).
The study duration for the 4 study periods are: Screening Period (Period 1; up to 28 days); 
Induction Dosing Period (Period 2; 12 weeks); Extension Period (Period 3; 12 weeks); 
Post-Treatment Follow-Up Period (Period 4; at least 12 weeks after the date of patients’ early 
termination visit [ETV] or last regularly scheduled visit).
Number of Patients:
Approximately 960 patients are planned to be randomized.
Statistical Analysis:
The total sample size for this study will be 960 patients randomized at a 1:1 ratio, stratified by 
site, into the double-blind Induction Dosing Period (Period 2) to ixekizumab or guselkumab.
With 480 patients per treatment group, the study will have approximately 98% power to test the 
superiority of ixekizumab to guselkumab for PASI 100 at Week 12. The power calculation is 
based on the assumption of 35.3% and 23.0% response rate at Week 12 for the ixekizumab and 
guselkumab treatment groups, respectively. A 2-sided Fisher’s exact test at significance level 
0.05 is assumed.
For the Induction Dosing Period (Period 2), unless otherwise specified, analyses of efficacy and 
health outcomes will be conducted on the intent-to-treat (ITT) population and safety analyses 

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will be conducted on the safety population. The primary analysis method for treatment 
comparisons of categorical efficacy and health outcome variables will be a 
Cochran-Mantel-Haenszel (CMH) test stratified by pooled site, using the nonresponder 
imputation (NRI) method.
The primary analyses for the continuous efficacy and health outcome variables will be performed 
using mixed effects model for repeated measures (MMRM) analysis.  The model will include 
treatment, pooled site, baseline value, visit, treatment-by-visit interaction and baseline 
value-by-visit as fixed factors.  A secondary analysis for continuous efficacy and health 
outcomes variables will be made using analysis of covariance (ANCOVA) adjusting for pooled 
site and baseline value.
Fisher’s exact test will be used for all adverse events (AE), baseline, discontinuation, and other 
categorical safety data.  Continuous laboratory values will be analyzed by an analysis of 
covariance (ANCOVA) with treatment and baseline value in the model.

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2. Schedule of Activities

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= human immunodeficiency virus; LV = last visit; NRS = numeric rating scale; Patient Assmt of Pain = Patient’s Assessment of Pain; Patient Global Assmt 
Disease Activity = Patient’s Global Assessment of Disease Activity; PASI = Psoriasis Area and Severity Index; PatGA = Patient’s global assessment of 
disease severity; PGA-F = Physician’s Global Assessment of Fingernail Psoriasis; PK = pharmacokinetics; sPGA = static Physician’s Global Assessment; TB 
= tuberculosis; V = visit; VAS = visual analog scale; W = week.
a
Includes year of birth, gender, and ethnicity.
b
Complete physical at screening (excluding pelvic, rectal, and breast examinations).  Physicals should include symptom-directed physical, as well as an 
examination of heart, lungs, and abdomen, and visual examination of the skin.
c
To be performed if not done in the prior 6 months.
d
Patients who test positive for latent TB at screening may be re screened following appropriate treatment.  Additionally, patients who do not qualify at baseline 
under Exclusion Criterion [34] (active or recent infection) may be re-screened (1 time).
e
See Table RHCR.7.1. All patients should remain under observation for at least 1 hour after study drug administration to monitor safety at Week 0.
f
Designated Unblinded Site Personnel will be responsible for handling and dispensing of all study drugs (ixekizumab, guselkumab, and placebo).
g
Administered only to patients with PsA at the baseline (W0) visit.
h
To be completed only by patients with PsA at the baseline (W0) visit.
i
Patients who test positive for latent TB at screening may be re-screened.  QuantiFERON® may be performed by a Lilly-designated or local laboratory.  See 
Section 9.4.4 for detailed description of QuantiFERON®-TB Gold .
j
FSH test performed for women ≥40 and <60 years of age who have had a cessation of menses for at least 12 months to confirm non-childbearing potential 
(≥40 mIU/mL).
k
All patients will be tested for HBV at screening.  Patient who meet criteria for HBV monitoring (see Section 9.4.6.3) will be identified by the central 
laboratory at baseline and monitored according to the study schedule.
l
To be performed for females of childbearing potential only.  Additional urine pregnancy testing can be performed at the investigator’s decision.  Patients 
determined to be pregnant will be discontinued from treatment and will no longer be administered study drug.
m To be performed for females of childbearing potential only.  Patients determined to be pregnant will be discontinued from treatment and will no longer be 
administered study drug.
n
To analyze change from baseline, the immunogenicity sample collected at baseline (W0) will be used.  For any patient who experiences a potential systemic 
allergic/hypersensitivity reaction during the study as judged by the investigator, a sample will also be collected when possible to be tested for immunogenicity 
and PK.  Samples from patients treated with guselkumab will not be analyzed for anti guselkumab antibodies.  These samples will be discarded at the end of 
the study.

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3. Introduction
3.1.
Study Rationale
In early studies of biologics targeting the tumor necrosis factor (TNF) pathway to treat patients 
with chronic plaque psoriasis (Ps), significant clinical improvement was obtained at a 75% 
clearance of skin from baseline (Psoriasis Activity and Severity Index; PASI 75).  Newer 
biologics targeting the interleukin (IL)-17 or IL-23 immune pathway have raised the level of 
expected improvement to almost clear (at least a 90% improvement from baseline in PASI score; 
PASI 90) or completely clear (a 100% improvement from baseline in PASI score; PASI 100)
skin, and studies suggest this improvement is attainable in a high proportion of patients (Papp et 
al. 2005; Reich et al. 2005; Leonardi et al. 2008; Menter et al. 2008; Papp et al. 2008; Langley et 
al. 2014; Griffiths et al. 2015; Krueger et al. 2015; Lebwohl et al. 2015; Papp et al. 2015; 
Blauvelt et al. 2017; Reich et al. 2017).
As new drugs targeting these pathways come to the market, there is a need to directly compare 
the efficacy and safety, as well as rapidness of efficacy, between products to better inform 
dermatologists and patients regarding drug selection.
Study I1F-MC-RHCR (RHCR) is a 24-week study to compare the efficacy and safety, as well as 
rapidness of efficacy, between ixekizumab and guselkumab in patients with moderate-to-severe 
Ps.  The primary efficacy endpoint of this study is the percentage of patients reaching 100% 
improvement from baseline (complete clearance) in PASI score, as demonstrated by PASI 100 at 
Week 12.
3.2.
Background
Psoriasis is a common, lifelong and life-shortening, chronic inflammatory skin disease 
manifested by prototypic red, thick, and scaly plaques.  Plaque psoriasis is the most common 
form and has been shown to have a significant impact on the overall health of patients.  Along 
with an association with inflammatory arthritis in the form of psoriatic arthritis (PsA), Ps is 
associated with increased risk for multiple comorbid conditions, including myocardial infarction 
(MI) and stroke, metabolic syndrome, diabetes mellitus, chronic renal insufficiency, and liver 
abnormalities (Yeung et al. 2013).  The life span of patients with moderate-to-severe Ps may be 
shortened by as many as 5 years, partly due to association with comorbidities (Gelfand et al. 
2006; Ryan and Kirby 2015).
The worldwide prevalence of Ps is 2% to 3% (Christophers 2001; International Federation of 
Psoriasis Associations [IFPA] 2017; National Psoriasis Foundation [NPF] 2018). Almost
one-third of patients with Ps in the United States (US) suffer from moderate-to-severe disease 
(Dubin et al. 2003).  Certain symptoms, such as itching, can especially impact the quality of life 
and is detrimental to work productivity and sleep (Zimolag et al. 2009; Gowda et al. 2010; 
Janowski et al. 2014; Lebwohl et al. 2014).
Early treatments for Ps obtained 50% to 75% improvement in skin clearance; however,
expectations for treatment goals of efficacy are expected to be higher as new and more 
efficacious therapies have emerged. Recent studies of biologics which block the IL-17 or IL-23

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pathways, both central to Pspathogenesis(Leonardi et al.2012; Langley et al.2014; Sofen et al.
2014; Gordon et al.2015; Griffiths et al.2015; Krueger et al.2015; Lebwohl et al.2015; Papp et 
al.2015),have demonstrated substantial efficacy.Complete skin clearance and improved 
long-term efficacy have increasingly become the desired treatment outcomes (Gniadecki et al.
2015; Bartoset al.2016).Some studies have suggested that increasedlevels of clearance 
resulted in greater improvement in quality of life (Takeshita et al. 2014; Vishwanathan et al. 
2015; Feldman et al. 2016; Fairchild et al. 2017).
Ixekizumab (LY2439821) is a humanized immunoglobulin G(IgG)subclass4monoclonal 
antibody(MAb)designed and engineered to selectively inhibit IL-17A.  It binds with high 
affinity (<3pM) and specificity to IL-17A, a proinflammatory cytokine.  Neutralization of 
IL-17A by ixekizumab has been shown to reduce excess keratinocyte proliferation and activation 
(Kruegeret al. 2012).  Ixekizumabdoes not bind the other members of the IL-17 family (IL-17B, 
IL-17C, IL-17D, IL-17E, orIL-17F).
Ixekizumab has demonstrated efficacy at both short-and long-term time points, with a favorable 
safety profile(Griffiths et al. 2015, Gordon et al. 2016, Strober et al. 2017).  In all 3pivotal 
Phase 3 studies (the UNCOVER studies), ixekizumab was superior to placebo with respect to all 
primary and major secondary endpoints. IntheUNCOVER studies, 32% to 42% of patients who 
received treatment with ixekizumab had complete resolution (PASI 100 or static Physician 
Global Assessment [sPGA]score of 0; versus [vs.]none in the placebo group) of their Psat 
Week 12; high levels of clinical response were maintainedwith continued exposure to 
ixekizumab 80 mg Q4Wthrough Week 60 with at least 50% of patients maintaining or attaining 
PASI 100(Gordon et al. 2016). In the UNCOVER-2 and UNCOVER-3 studies,ixekizumab had
greater efficacy than etanercept,a TNF inhibitor (TNFi);40.5% of patients treated with 
ixekizumab 80 mg Q2W, compared with 5.3% of etanercept-treated patients,achieved PASI 100
after 12 weeks(Griffiths et al. 2015, Gordon et al. 2016).In aPhase 3 head-to-head study
(IXORA-S), ixekizumabdemonstrated superiority overthe IL-12/23 antagonist ustekinumab in 
patients with moderate-to-severe Psat Week 12;this trendwasmaintained through Week 52. 
The majority (76.5%) of ixekizumab-treated patients sustained a PASI 90 response through 1
year, and over halfof ixekizumab-treated patients (52.2%) had completely clear skin at Week 52.  
The corresponding rates for the ustekinumab-treated patients were 59.0% and 35.5%, 
respectively.
Guselkumabis a fully human IgGsubclass1 lambda monoclonal antibody that binds to the p19 
subunit of IL-23; itinhibits the intracellular and downstream signaling of IL-23, which is 
required for terminal differentiation and survival of T helper (Th)17 cells.
In 2recent Phase 3studies, VOYAGE 1(Blauvelt et al. 2017)and VOYAGE 2(Reich et al. 
2017),guselkumab treatment (administered as a single 100-mg injection initially, 4 weeks later 
and subsequently every 8 weeks [Q8W]) resulted in statistically significant improvements in
efficacy compared with placeboand superiority to adalimumab,a TNFi,in the treatment of 
moderate-to-severe Ps(Gordon et al. 2018).  In the VOYAGE 1 study, compared with placebo, 
significantly higher proportions of patients taking guselkumab achieved Investigator Global 
Assessment(IGA; co-primary endpoint)0/1 (6.9% vs.85.1%) and PASI 90 (co-primary 

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endpoint; 2.9% vs. 73.3%) at Week 16. In addition, the proportions achieving IGA 0 (1.1% vs.
47.7%) and PASI 100 (0.6% vs. 37.4%) were significantly higher for guselkumab vs. placebo at 
Week 16. Compared with adalimumab, a higher proportion of patients in the guselkumab group 
achieved IGA 0/1 (85.1% vs. 65.9%) and PASI 90 (73.3% vs. 49.7%) at Week 16. Significantly 
better responses to guselkumab compared with adalimumab were maintained at Week 24 and at 
Week 48; PASI 100 responses in the guselkumab group were also significantly better than those 
in the adalimumab group at Weeks 24 and 48. The results of VOYAGE 2 study confirmed the 
results of VOYAGE 1.  Guselkumab was superior to placebo at the Week 16 co-primary 
endpoints (IGA 0/1 and PASI 90). Guselkumab was also superior to adalimumab at the Week 16
endpoints (IGA 0/1, PASI 75/90) and at Week 24 (IGA 0, PASI 90, and PASI 100).
Adalimumab is one of the earliest biologics approved for Ps and targets the TNF pathway. 
Guselkumab, being one of the most recent biologics, targets the IL-23 pathway.  As the IL-17/23 
pathway has been shown to be selectively important in the pathogenesis of Ps (Leonardi et al.
2012; Langley et al. 2014; Sofen et al. 2014; Gordon et al. 2015; Griffiths et al. 2015; Krueger et 
al. 2015; Lebwohl et al. 2015; Papp et al. 2015), the results of the VOYAGE studies 
(guselkumab [IL-23p19 antagonist]) are not surprising, nor are the results of the UNCOVER-2 
and -3 studies that demonstrated superior efficacy of ixekizumab (IL-17A antagonist) compared 
to the TNFi etanercept.  These studies help inform dermatologists that newer biologics have
superior efficacy compared to older biologics targeting the TNF pathway and, thus, are a good 
choice for treating patients who desire nearly clear or completely clear skin.
To date, there is no publication comparing biologics for the treatment of Ps that inhibit IL-23
(specifically IL-23p19) vs. those that inhibit IL-17; thus expectations of efficacy between these 2
types of new biologics are not well delineated. Studies of ixekizumab suggest equal, if not 
superior ability compared to guselkumab to achieve PASI 90 (as shown in the VOYAGE 
studies). Ixekizumab also demonstrated a high percentage of patients achieving PASI 100, and a 
rapid onset of skin improvement after administration of ixekizumab (UNCOVER).  Comparing 
these 2 classes of biologics in a study, in which both are tested with the same endpoints and
measured at the same time, will provide important information to clinicians trying to determine 
which drug class is the best for a given patient.  The purpose of this study is to compare efficacy 
and safety, as well as rapidness of efficacy, of ixekizumab and guselkumab.
3.3.
Benefit/Risk Assessment
Ixekizumab has been demonstrated to be safe and effective for the treatment of patients with 
moderate-to-severe chronic Ps and active PsA.  The risk profile for patients within this study is 
anticipated to be consistent with the known safety experience for ixekizumab described in the 
currently approved labeling of Taltz® (Taltz package insert, 2018).
More information about the known and expected benefits, risks, serious adverse events (SAEs),
and reasonably anticipated adverse events (AEs) of ixekizumab are found in the Investigator’s 
Brochure (IB). Information on AEs expected to be related to the study drug may be found in 
Section 6.2 (Development Core Safety Information) of the IB.  Information on SAEs that are 
expected in the study population independent of drug exposure and that will be assessed by the 

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sponsor in aggregate periodically during the course of the study, may be found in Section 5
(Effects in Humans) of the IB.
The known and expected benefits, risks, and SAEs for guselkumab are outlined in the United 
States Package Insert (USPI) for Tremfya® (Tremfya USPI package insert, 2017; Canada 
Product Monograph, 2017).

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4. Objectives and Endpoints
Table RHCR.4.1 shows the objectives and endpoints of the study.
Table RHCR.4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess whether ixekizumab is superior to 
guselkumab at Week 12 in the treatment of patients 
with moderate-to-severe Ps, as measured by PASI 100

The proportion of patients achieving PASI 100
at Week 12
Major Secondary
To assess whether ixekizumab is superior to 
guselkumab in the treatment of patients with 
moderate-to-severe Ps at different time points, as 
measured by:

PASI 75

The proportion of patients achieving PASI 75 at 
Week 2

PASI 90

The proportion of patients achieving PASI 90 at 
Weeks 4 and 8

PASI 100

The proportion of patients achieving PASI 100 
at Weeks 4, 8 and 24

sPGA [0]

The proportion of patients achieving sPGA (0) at 
Week 12

PASI 50

The proportion of patients achieving PASI 50 at 
Week 1
Exploratory
To assess whether ixekizumab is superior to 
guselkumab in the treatment of patients with 
moderate-to-severe Ps at different time points, as 
measured by:

sPGA score of 0 and 1 (sPGA [0, 1])

The proportion of patients with a static sPGA 
(0,1) with at least a 2-point improvement from 
baseline at Weeks 4, 8, 12, 24

Itch NRS:
o
Responder
o
The proportion of patients achieving the Itch 
NRS Responder definition at Weeks 4, 8, 12, 
and 24 (restricted to those patients with Itch 
NRS score ≥4 points at baseline)
o
Change from baseline
o
Change from baseline in Itch NRS score at 
Weeks 4, 8, 12, and 24
o
Score of 0 (Itch NRS [0])
o
The proportion of patients achieving Itch NRS 
(0) at Weeks 4, 8, 12, and 24 (restricted to 
those patients with Itch NRS score >0 at 
baseline)

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Objectives
Endpoints

Skin Pain VAS
o
Skin Pain VAS (0)
o
The proportion of patients achieving Skin Pain 
VAS (0) at Weeks 4, 8, 12, and 24 (restricted 
to those patients with Skin Pain VAS score >0 
at baseline)
o
Change from baseline
o
Change from baseline in Skin Pain VAS score
at Weeks 4, 8, 12, and 24

DLQI (0,1)

The proportion of patients achieving DLQI (0,1) 
at Weeks 2, 4, 8, 12, and 24 (restricted to those 
patients with DLQI score >1 at baseline)
Abbreviations: DLQI = Dermatology Life Quality Index; NRS = Numeric Rating Scale; PASI = Psoriasis Area and 
Severity Index; Ps = plaque psoriasis; sPGA = static Physician Global Assessment; VAS = visual analog scale.

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5. Study Design
5.1.
Overall Design
Study RHCR is a multicenter, randomized, double-blind, parallel-group Phase 4 study with 
4 study periods in patients with chronic moderate-to-severe Ps.
Study governance considerations are described in detail in Appendix 3.
Abbreviations:  GUS = guselkumab; IXE = ixekizumab; LV = last visit; Q2W = every 2 weeks; Q4W = every 4 
weeks; Q8W = every 8 weeks; SC = subcutaneous; R = randomization; V = study visit; W = week.
Figure RHCR.1.
Illustration of study design for clinical protocol RHCR.
The following treatment groups will be assessed in this study:

Ixekizumab:  80 mg SC injection.  At Week 0, 160 mg starting dose (two 80 mg 
injections), followed by 80 mg Q2W from Weeks 2 through 12, and then followed by 
80 mg Q4W thereafter (i.e., at Weeks 16 and 20).

Guselkumab: 100 mg SC injection.  At Weeks 0 and 4, 100 mg injection, followed by 
100 mg Q8W thereafter (i.e., at Weeks 12 and 20).
The study will consist of 4 periods:

Period 1 (Section 5.1.1):  Screening Period (Visit 1) will assess patient eligibility and 
occurs approximately 5 to 28 days prior to Period 2 (baseline; Week 0 [Visit 2]).

Period 2 (Section 5.1.2): Induction Dosing Period occurring from Week 0 (baseline; 
Visit 2) to Week 12 (Visit 9).

Period 3 (Section 5.1.3):  Extension Period occurring after Week 12 (Visit 9) to 
Week 24 (Visit 12).

Period 4 (Section 5.1.4): Post-Treatment Follow-Up Period occurring from last 
treatment period Visit 12 (Week 24) or ETV, for a minimum of 12 weeks following that 
visit.

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All procedures to be conducted during the study, including timing and sequence (as necessary), 
are indicated in the Schedule of Activities (Section 2).  Appendix 2 lists the specific laboratory 
tests that will be performed for this study.
Patients discontinuing from the study drug who have received at least 1 dose of study drug will 
continue to the ETV before proceeding to the Post-Treatment Follow-Up Period (Period 4).  For 
the management of patient safety, all patients should be monitored through Period 4 at least as 
frequently as indicated on the Schedule of Activities (Section 2).
Treatment assignments will remain blinded to investigators, study site personnel directly 
involved in patient efficacy and safety assessments, and patients.
Designated Unblinded Site Personnel are responsible for receipt of study drug shipments, 
dispensing study drug, administering study drug, recording information in the Study Drug 
Administration Log, and confirming treatment assignments.
Unblinded Site Personnel are also responsible for maintaining the blind of the patient (e.g., by 
means of a blindfold or other appropriate physical barrier means communicated to the sponsor 
for final approval). Designated Unblinded Site Personnel will not be involved in any clinical 
aspects of the study, including clinical evaluations and AE assessments. It is critical that the 
blind is maintained throughout the study (24 weeks).
All treatment groups are described in Section 7.1, Table RHCR.7.1, and administration of the 
study drug is described in Section 7.1, Table RHCR.7.2.
Excluded and restricted therapies are detailed in Section 7.8.
Section 10.3.7 outlines the information regarding interim analyses, including the primary 
database lock at Week 12.
5.1.1. Screening Period (Period 1)
The duration of the Screening Period will be 5 to 28 days before the Induction Dosing Period 
(Period 2) and consists of 1 screening visit (Visit 1) to assess patient eligibility.  The patient will 
sign the informed consent form (ICF) before any study assessments, examinations, or procedures 
are performed.
All inclusion and exclusion criteria are provided in Sections 6.1 and 6.2, respectively.  Screening 
procedures (including complete medical history and demographics) will be performed according 
to the Schedule of Activities (Section 2).  At Visit 1, a QuantiFERON®-TB Gold test assay may
be performed by a Lilly-designated or local laboratory (Section 9.4.4).
Patients who test positive for latent tuberculosis (TB) at screening may be re-screened one time
following appropriate treatment as described in Section 9.4.4.
Additionally, patients who do not qualify at screening under Exclusion Criteria [34] may be 
re-screened (1 time), as described in Section 7.3 with approval of Lilly Medical Team (clinical 
research scientist[CRS]/ clinical research physician [CRP]).

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5.1.2. Induction Dosing Period (Period 2)
The Induction Dosing Period (Period 2) will be a double-blind treatment period that will occur 
from Week 0 (baseline; Visit 2) to Week 12 (Visit 9).
At Week 0 (baseline, Visit 2), routine safety assessments, laboratory tests, and clinical efficacy 
assessments will be performed on eligible patients, according to the Schedule of Activities
(Section 2).
Patients will be randomized at a 1:1 ratio, to 1 of 2 treatment groups according to commercially 
prescribed dosing.  
Please refer to Section 7.1, Table RHCR.7.1, and Table RHCR.7.2 for a full description of 
treatment groups and dosing during Period 2.
Training of administration of study drug is outlined in Sections 7.1.1.
Patients who discontinue from study drug for any reason during this period will continue to the 
ETV before entering the Post-Treatment Follow-Up Period (Period 4; Section 5.1.4).
5.1.3. Extension Period (Period 3)
The Extension Period (Period 3) will be a double-blind treatment period that will occur from 
Week 12 (Visit 9) up to Week 24 (Visit 12).
During Period 3, safety and efficacy parameters in participating patients will continue to be 
evaluated according to the Schedule of Activities (Section 2).
Please refer to Section 7.1, Table RHCR.7.1, and Table RHCR.7.2 for a full description of 
treatment groups and dosing during Period 3.
Patients who discontinue from study drug for any reason during Period 3 will continue to the 
ETV before entering the Post-Treatment Follow-Up Period (Period 4; Section 5.1.4).
5.1.4. Post-Treatment Follow-Up Period (Period 4)
All patients receiving at least 1 dose of study drug will enter the Post-Treatment Follow-Up 
Period (Period 4) for a minimum of 12 weeks, beginning after their last regularly scheduled visit 
(or the date of their ETV).  
Required study visits should occur at 4 weeks (Visit 801) and at 12 weeks (Visit 802) after the 
last regularly scheduled visit (or the date of the patient’s ETV), except for patients with a 
concurrent infection that requires systemic anti-infective therapy (described in Section 9.4.6.1).
If, at Visit 802, a patient’s neutrophil count is ≥1500 cells/L or greater than or equal to the 
patient’s baseline neutrophil count, the patient’s participation in the study will be considered 
complete unless the investigator determines additional follow-up may be necessary.  An 
additional study visit (Visit 803) 12 weeks after Visit 802 may be required.  Additional visits 
before Visit 803 may be required for appropriate patient management (described in 
Section 9.4.6.1).

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For patients who have entered Period 4, Ps therapy is allowed, as determined appropriate by the 
investigator. These allowed Ps therapies include the treatment patients received during the 
double-blind trial.
5.2.
Number of Participants
Approximately 1300 participants will be screened to achieve 960 randomized participants 
(480 randomized participants per treatment group).  Based on experience from the previous 
UNCOVER-1, -2, -3, and IXORA-S trials, a 5% dropout rate is anticipated.
Patients with previous biologic use can be included in the study provided all inclusion/exclusion 
criteria, including the washout period(s), as specified in Sections 6.1 and 6.2 of this protocol are 
respected.  Patients with previous exposure to another IL-17 antagonist(s) will be limited to 
approximately 15% of the total patient population.
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 patient.
5.4.
Scientific Rationale for Study Design
This study will examine the effect of ixekizumab vs. that of the active comparator (guselkumab) 
on patients with moderate-to-severe Ps.
Guselkumab was chosen as the active comparator, as it:

demonstrates a good safety profile (Blauvelt et al. 2017; Reich et al. 2017),

is given as SC injection, and

represents an important class of drugs for Ps treatment.
During the Induction Dosing Period (Period 2), patients randomized to ixekizumab 
(80 mg Q2W) will be compared with patients randomized to guselkumab (100 mg at Week 0 and 
4).  During the Extension Period (Period 3), guselkumab 100 mg Q8W (starting at Week 12) and 
ixekizumab 80 mg Q4W will be studied.
Traditionally PASI 75 has been considered the gold standard to measure drug efficacy in Ps.  
However, data suggested that only higher levels of clinical response (>90% improvement) are 
associated with normalization of patients’ health-related quality of life.  While these levels of 
clearance are rarely provided by conventional drugs and TNFi, they are more consistently 
obtained with IL-23 antagonists and IL-17 antagonists.  Therefore, in this trial, the efficacy of 
ixekizumab and guselkumab in treating patients with Ps will be measured by the PASI 100 
response at Week 12.  This measurement and the Week 12 endpoint are in alignment with 
efficacy endpoints for currently approved Ps therapies, as well as regulatory guidance (EMA 
2004).
The Extension Period (Period 3) will permit collection of data for the assessment of longer-term 
safety and efficacy data of ixekizumab compared to guselkumab.

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The Post-Treatment Follow-Up Period (Period 4) is for safety monitoring following the last 
treatment period and study visit.
5.5.
Justification for Dose
The general approach to dosing ixekizumab in this study is to use the commercially approved 
dosing regimen for treatment of adults with moderate-to-severe Ps (Taltz USPI [WWW]; Canada 
Product Monograph [WWW]).
The guselkumab dosing regimen used in this study (100 mg at Weeks 0, 4, 12, and 20) is the
approved dose for the treatment of adults with moderate-to-severe Ps (Tremfya USPI package 
insert, 2017; Canada Product Monograph [WWW]).

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6. Study Population
This study will include patients with moderate-to-severe chronic Ps who have given written 
informed consent approved by Eli Lilly and Company (Lilly), or its designee, and the ethics 
review board (ERB) governing the site.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened in the following circumstances:  patients who test positive for latent TB at screening 
may be re-screened following appropriate treatment, as described in Section 9.4.4.  Additionally, 
patients who do not qualify at screening under Exclusion Criteria [34] may be re-screened once, 
≥4 weeks after documented resolution of symptoms.  When re-screening is performed, the 
individual must sign a new ICF and will be assigned a new identification number.
Study investigator(s) will review patient records and/or patient history and screening test 
results/measurements to determine if the patient meets all inclusion and exclusion criteria to 
qualify for participation in the study.  All screening activities must be completed and reviewed 
before the patient is randomized.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
Patient with chronic plaque psoriasis based on a diagnosis for at least 
6 months before baseline (Week 0; Visit 2), as determined by the 
investigator.
[2]
Are a candidate for phototherapy and/or systemic therapy.
[3]
Have both an sPGA score of ≥3 and a PASI score ≥12 at screening (Visit 1)
and at baseline (Week 0, Visit 2).
[4]
Have ≥10% body surface area (BSA) involvement at screening (Visit 1) and 
baseline (Week 0, Visit 2).
[5]
Are patients 18 years or older.
[6]
If a male patient, agree to use a reliable method of birth control during the
study.
[7]
Female patients:
Participants of child-bearing age or child-bearing potential who are sexually 
active who test negative for pregnancy must be counseled and agree to use either 
1 highly effective method of contraception or 2 acceptable methods of 
contraception combined for the duration of the study and for at least 12 weeks 
following the last dose of study drug, or remain abstinent during the study and for 
at least 12 weeks following the last dose of study drug.

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If the highly effective contraceptive methods are contraindicated or strictly 
declined by patient, acceptable birth control methods may be considered. These 
may include combination of both of the following methods:

Male or female condom with spermicide

Cap, diaphragm, or sponge with spermicide
1. Highly effective methods of contraception (use 1 form):
a.
combined oral contraceptive pill and mini-pill
b. NuvaRing®
c.
implantable contraceptives
d. injectable contraceptives (such as Depo-Provera®)
e.
intrauterine device (such as Mirena® and ParaGard®)
f.
contraceptive patch—ONLY women <198 pounds or 90 kg
g. abstinence from sex
h. vasectomy—for men in clinical studies
2. Effective methods of contraception (use 2 forms combined)

male condom with spermicide

female condom with spermicide

diaphragm with spermicide

cervical sponge

cervical cap with spermicide
Females who are not of childbearing potential include those who have undergone or who 
have:

female sterilization

hysterectomy

menopause- as confirmed by diagnostically elevated follicle-stimulating hormone 
(FSH) at baseline.

Müllerian agenesis (Mayer–Rokitansky–Küster–Hauser syndrome [also referred 
to as congenital absence of the uterus and vagina])
[8]
Have given written informed consent approved by Lilly, or its designee, and 
the Institutional Review Board (IRB)/ERB governing the site.
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria:
[9]
Have predominant pattern of pustular, erythrodermic, and/or guttate forms 
of psoriasis.
[10] Have a history of drug-induced psoriasis.
[11] Had a clinically significant flare of psoriasis during the 12 weeks before
baseline (Week 0, Visit 2).

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Medications/Therapies
[12] Use of tanning booths for at least 4 weeks before baseline (Week 0, Visit 2) 
and during the study, per investigator assessment.
[13] Concurrent or recent use of any biologic agent within the following periods 
prior to baseline (Week 0, Visit 2):  etanercept <28 days; infliximab, 
adalimumab, certolizumab pegol, or alefacept <60 days; golimumab 
<90 days; rituximab <12 months; secukinumab <5 months; or any other 
biologic agent (e.g., ustekinumab) <5 half-lives.
[14] Have prior use of IL-23p19 antagonists (e.g., guselkumab, tildrakizumab, 
risankizumab), or have any condition or contraindication as addressed in the 
local labeling for guselkumab that would preclude the patient from 
participating in this protocol.
[15] Have previously completed or withdrawn from this study, participated in 
any other study with ixekizumab or guselkumab, have participated in any 
study investigating IL-23p19 antagonists, or have received treatment with 
ixekizumab.
[16] Have previously failed to respond to an IL-17 antagonist, per investigator 
assessment.
Vaccinations
[17] Have had a live vaccination within 12 weeks of baseline (Week 0, Visit 2), 
or intend to have a live vaccination during the course of the study or within 
15 weeks of completing treatment in this study, or have participated in a 
vaccine clinical study within 12 weeks of baseline.  Investigators should 
review the vaccination status of their patients and follow the local guidelines 
for adult vaccination with nonlive vaccines intended to prevent infectious 
disease before therapy.
(Note:  killed/inactive or subunit vaccines are expected to be safe; however, 
their efficacy with concomitant ixekizumab and guselkumab treatment is 
unknown).
[18] Have had a vaccination with Bacillus Calmette-Guérin (BCG) within 
12 months of baseline (Week 0, Visit 2) or intend to have vaccination with 
BCG during the course of the study or within 5 half-life of completing 
treatment in this study.
Medical Status and Medical History
[19] Have a known allergy or hypersensitivity to any biologic therapy that 
would, in the opinion of the investigator, pose an unacceptable risk to the 
patient if participating in this study.
[20] Are currently enrolled in any other clinical study involving a study drug or 
any other type of medical research judged not to be scientifically or 
medically compatible with this study.

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[21] Have had any major surgery within 8 weeks of baseline (Week 0, Visit 2) or 
will require major surgery during the study that, in the opinion of the 
investigator in consultation with Lilly, would pose an unacceptable risk to 
the patient.
[22] Have current or a history of lymphoproliferative disease, or signs or 
symptoms of lymphoproliferative disease within 5 years of baseline 
(Week 0, Visit 2); or have active or history of malignant disease within 
5 years of baseline (Week 0, Visit 2), except for basal cell carcinoma, 
squamous cell carcinoma, skin Bowen’s disease or actinic keratoses that 
have been treated with no evidence of recurrence in the past 12 weeks or 
carcinoma in situ of the cervix or non-invasive malignant colon polyps that 
have been removed.
(Note:  patients with history of malignancy with no evidence of recurrence 
or active disease within 5 years of baseline may participate in the study).
[23] Presence of significant uncontrolled cerebro-cardiovascular (e.g., MI,
arrhythmias, unstable angina, unstable arterial hypertension, 
moderate-to-severe [New York Heart Association class III/IV] heart failure, 
or cerebrovascular accident), respiratory, hepatic, renal, gastrointestinal, 
endocrine, hematologic, neurologic or neuropsychiatric disorders or 
abnormal laboratory values at screening (Visit 1) that, in the opinion of the 
investigator, pose an unacceptable risk to the patient if participating in the 
study or of interfering with the interpretation of data.
[24] Have had fluid overload, MI, or new onset ischemic heart disease (e.g., 
unstable angina), uncompensated heart failure, or in the opinion of the 
investigator other serious cardiac disease within 12 weeks of baseline 
(Week 0; Visit 2).
[25] Presence of significant uncontrolled neuropsychiatric disorder, have recent 
history (within 30 days prior to screening [Visit 1] and any time between 
screening [Visit 1] and baseline randomization [Visit 2]) of a suicide 
attempt; or have active suicidal ideation with some intent to act with or 
without a specific plan (yes to question 4 or 5 on the “Suicidal Ideation” 
portion of the Columbia-Suicide Severity Rating Scale [C-SSRS]); or are 
clinically judged by the investigator to be at risk for suicide.
[26] Have evidence of active or non-treated latent TB (refer to Section 9.4.4 for 
details on determining full TB exclusion criteria).
[27] Are positive for human immunodeficiency virus (HIV) serology (positive 
for HIV antibody).
[28] Have evidence of or test positive for hepatitis B virus (HBV) by testing 
positive for:  1) HBV surface antigen (HBsAg+); OR 2) anti-hepatitis B core 
antibody (HBcAb+) and are HBV deoxyribonucleic acid (DNA) positive.

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Note:  Patients who are HBsAg-, and HBcAb+ and HBV DNA negative may be 
enrolled in the study.  Patients who meet these criteria at screening will be 
identified by the central laboratory and monitored during the study as detailed in 
Section 9.4.6.3.
[29] Have evidence of or test positive for hepatitis C virus (HCV).  A positive 
test for HCV is defined as:  1) positive for hepatitis C antibody and 
2) positive via a confirmatory test for HCV (e.g., HCV polymerase chain 
reaction).
[30] Has any current unstable and/or clinically significant medical condition at 
Visit 1 that in the investigator’s opinion could interfere with participation in 
the study.
Infections
[31] 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 of baseline (Week 0, Visit 2); have had a serious bone or 
joint infection within 24 weeks of baseline (Week 0, Visit 2); 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 patient.
[32] 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.
[33] Have or have had a herpes zoster infection or any other clinically apparent 
varicella-zoster virus infection within 12 weeks of baseline (Week 0, 
Visit 2).
[34] Have had any other active or recent infection within 4 weeks of baseline 
(Week 0, Visit 2) that, in the opinion of the investigator, would pose an 
unacceptable risk to the patient if participating in the study; these patients 
may be re-screened (1 time) ≥4 weeks after documented resolution of 
symptoms.
Clinical Laboratory Results
[35] At screening (Visit 1), have a neutrophil count <1500 cells/μL 
(<1.50x103/L or <1.50 GI/L).
[36] At screening (Visit 1), have a lymphocyte count <800 cells/μL 
(<0.80x103/L or <0.80 GI/L).
[37] At screening (Visit 1), have a platelet count <100 000 cells/μL 
(<100x103/L or <100 GI/L).

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[38] At screening (Visit 1), have aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) >2.5 times (x) the upper limit of normal (ULN).
(Note:  The AST and ALT may be repeated once within a week if the initial 
response exceeds this limit, and the repeat value may be accepted if it meets 
this criterion.)
[39] At screening (Visit 1), have alkaline phosphatase (ALP) >3xULN or 
alkaline phosphatase >2.5xULN and total bilirubin >2xULN.
[40] At screening (Visit 1), have a total white blood cell (WBC) count 
<3000 cells/μL (<3.00x103/L or <3.00 GI/L).
[41] At screening (Visit 1), have hemoglobin <8.5 g/dL (85.0 g/L) for male 
patients and <8.0 g/dL (80 g/L) for female patients.
[42] At screening (Visit 1), have clinical laboratory test results that are outside 
the normal reference range for the population and are considered clinically 
significant, per investigator assessment.
[43] At screening (Visit 1), have serum creatinine level >2.0 mg/dL.
(Note:  Laboratory tests should not be repeated unless there is a technical error or clinical reasons 
to believe a result may be erroneous.)
Other
[44] Are women who are pregnant, or who are lactating (breast-feeding).
[45] Have any other condition that precludes the patient from following and 
completing the protocol, in the opinion of the investigator.
[46] Are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, 
or sibling, whether biological or legally adopted.
[47] Are Lilly employees or are employees of third-party organizations (TPOs) 
involved in the study.
[48] Are unwilling or unable to comply with the use of a data collection device to 
directly record data from the subject.
6.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion Criteria [12] through [16] exclude patients who have prior exposure to guselkumab, or 
any other IL-23p19 antagonist, or ixekizumab (note: see details in Sections 6.2 and 5.2), or any 
patients who are receiving treatment or concomitant medications that could have a negative 
impact on the safety of patients enrolled or confound the results of the study.  Exclusion Criteria 
[17] through [43] exclude patients who would be at a greater safety risk, including patients at 
increased risk of infective complications or immunosuppression, if administered ixekizumab or 
guselkumab or whose data could confound the results of the study in the analysis of ixekizumab 

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and/or patients.  Exclusion Criterion [44] provides protection to offspring.  Exclusion Criteria 
[45], [46], and [47] reduce the potential bias that may be introduced at the study site.
The majority of the exclusion criteria are applied to reduce risks to patients by enrolling 
medically stable, relatively healthy (aside from the disease being studied) patients who are not 
receiving concomitant therapies that may impact their safety and/or confound effects when 
combined with the study drug being studied.
6.3.
Lifestyle Restrictions
See inclusion criteria [6] and [7] in Section 6.1 for birth control requirements.

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Syringes should be at room temperature before injection (refer to the Unblinded Site Personnel 
Dispensing and Dosing Instructions).
Unblinded Site Personnel will record information in a Study Drug Administration Log, including 
the date, time, and anatomical location of administration of study drug (for treatment 
compliance), package number, who administered the study drug, and if applicable, the reason for 
which study drug was not administered or was not fully administered.  Unblinded Site Personnel 
are also responsible to make sure patients remain blinded to treatment (i.e., patients must not see 
the syringe before, during or after the drug administration).
7.1.2. Observations after Study Drug Administration
All patients should remain under observation for at least 1 hour after study drug administration to 
monitor safety at Week 0.
7.1.3. Packaging and Labelling
The ixekizumab, guselkumab, and placebo solution for injection will be supplied by the sponsor 
or its designee in accordance with current Good Manufacturing Practice and will be supplied 
with lot numbers, expiry dates, and certificates of analysis, as applicable.
Ixekizumab and placebo will be supplied as an injectable solution in 1-mL, single-dose, 
disposable manual syringe.  Each syringe of ixekizumab is designed to deliver 80 mg of 
ixekizumab.  The syringes (and contents) containing either ixekizumab or placebo will be visibly 
indistinguishable from each other.  Guselkumab will be supplied as a single-dose 100 mg/mL 
disposable manual prefilled syringe.
Syringes will be supplied in cartons, with the appropriate quantity of syringes specific to the 
planned dispensing schedule of the study drug.
Unblinded Site Personnel will be responsible for handling and administering guselkumab, 
ixekizumab, and placebo to avoid unblinding.
Clinical trial materials will be labeled according to the country’s regulatory requirements.  All 
study drugs will be stored, inventoried, reconciled, and destroyed according to applicable 
regulations.
7.2.
Method of Treatment Assignment
At Week 0 (Visit 2), patients who meet all criteria for enrollment at Visits 1 and 2 will be 
randomized at a 1:1 ratio to double-blind treatment groups (i.e., 80 mg ixekizumab or 100 mg 
guselkumab) as determined by a computer-generated random sequence using an interactive 
web-response system (IWRS).  The IWRS will be used to assign blinded study drug to each 
patient.  The Unblinded Site Personnel at the site will confirm that they have located the correct 
assigned study drug package by entering a confirmation number found on the package into the 
IWRS as described for Unblinded Site Personnel in the Unblinded Site Personnel Dispensing and 
Dosing Instructions.
Randomization will be stratified by site for this study.

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7.3.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened. Individuals may be re-screened up to 1 time.  Each time a re-screening is 
performed, the individual must sign a new ICF and will be assigned a new identification number.
Individuals may be re-screened in the following circumstances:

Patients who test positive for latent TB at screening and have undergone documented 
subsequent treatment for at least 4 weeks (more details in Section 9.4.4).

Patients who do not qualify at screening under exclusion criteria [34] may be re-screened 
once, 4 or more weeks after documented resolution of symptoms.

Other reasons for re-screening must be discussed, approved and documented by the Lilly 
Medical Team (CRS/CRP).
7.3.1. Selection and Timing of Doses
Patients will be assigned to treatment and will receive their assigned treatment as outlined in 
Sections 7.1.1.
Study drug should be administered on the same day of the week, at approximately the same time 
each day, as much as possible.  The actual time of all dose administrations will be recorded in the 
subject’s case report form (CRF).  For injections not administered on the scheduled day of the 
week from Weeks 0 to 12, the missed dose should be administered within 3 days of the 
scheduled day; after Week 12, the missed dose should be administered within 5 days of the 
scheduled day. Dates of subsequent study visits should not be modified according to the delay of 
the injection of the missed scheduled dose.  The doses at Weeks 0 to 12 should not be 
administered until after all assessments per the Schedule of Activities (Section 2) are completed.
Throughout their participation in the study, site personnel will record information in a Study 
Drug Administration Log, including the date, time, and anatomical location of administration of 
study drug (for treatment compliance), syringe number, who administered the study drug, and the 
reason if study drug was not administered or not fully administered.
7.4.
Blinding
This is a double-blind study; patients and study site personnel performing assessments of 
outcomes will be blinded to study drug until all patients have completed the study.  To preserve 
the blinding of the study, sponsor personnel will not see the randomization table and treatment 
assignments before the study is unblinded.  Section 7.1 provides the dosing details pertinent to 
maintenance of the study blind.  Emergency unblinding for AEs may be performed through an 
IWRS which may supplement or take the place of emergency codes generated by a computer 
drug-labeling system. This option may be used ONLY if the patient’s well-being requires 
knowledge of the patient’s treatment assignment.  All actions resulting in an unblinding event 
will be recorded and reported by the IWRS.
If an investigator, site personnel performing assessments, or patient is prematurely unblinded, the 
patient must be discontinued from the study drug and should continue in the Post-Treatment 

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Follow-Up Period (Period 4).  In cases for which there are ethical reasons to have the patient 
remain on the study drug, the investigator must obtain specific, documented approval from a
Lilly CRS/CRP or representative for the patient to continue in the study.
Processes to maintain blinding during the interim analyses are described in Section 10.3.7.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event. The 
patient safety must always be the first consideration in making such a determination.  If a 
patient’s treatment assignment is unblinded, Lilly must be notified immediately. If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
7.5.
Dosage Modification
Not applicable.
7.6.
Preparation/Handling/Storage/Accountability
The investigator or his/her designee is responsible for the following:

confirming appropriate temperature conditions have been maintained during 
transit for all study drug received and any discrepancies are reported and resolved 
before use of the study drug.

ensuring that only participants enrolled in the study may receive study drug and 
only authorized site staff may supply and administer study drug.  All study drugs 
must be stored in a secure, 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, institution, or the head of the medical institution (where 
applicable) is responsible for study drug accountability, reconciliation, and record 
maintenance (such as receipt, reconciliation and final disposition records).

the study drug should be stored at 2°C to 8°C (36°F to 46°F) in its original carton to 
protect from light.  Study drug should not be frozen.  Sites will be required to monitor 
temperature of the on-site storage conditions of the study drug.
Details for the requirements for dispensing ixekizumab, guselkumab, and placebo syringes will 
be provided to the Unblinded Site Personnel in the Unblinded Site Personnel Dispensing and 
Dosing Instructions.
7.7.
Treatment Compliance
Every attempt will be made to select patients who have the ability to understand and comply with 
instructions.  To ensure high treatment compliance, the investigator is responsible for discussing 
requirements of the trial with the patient before randomization.
Throughout their participation in the treatment periods (Induction Dosing and Extension
Periods), trained unblinded site personnel will record information in a Study Drug 

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Administration Log, including the date, time, and anatomical location of administration of study 
drug, syringe number, who administered the study drug, the reason if the study drug was not 
administered or not fully administered, and the count of empty study drug packaging.  The time 
and day of each study drug administration (and other items included in the above paragraph) 
must be recorded into the electronic case report form (eCRF) by site personnel.
7.8.
Concomitant Therapy
All concomitant medication taken during the study must be recorded on the Concomitant 
Medication CRF at the study visits indicated in the Schedule of Activities (Section 2).  Treatment 
with concomitant Ps therapies during the study will be permitted only as outlined in the inclusion 
and exclusion criteria (Sections 6.1 and 6.2, respectively) and as described in the paragraphs 
below.  Patients taking permitted medications need to be documented to be in stable control.  
After trial enrollment, significant dose escalation of a concomitant medication should be 
discussed with Lilly medical before allowing patient to receive study drug.
Table RHCR.7.3 summarizes concomitant medications that are and are not permitted and their 
conditions for use during the study.

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Table RHCR.7.3.
Concomitant Medications Permitted/Not Permitted in the Study and Conditions for Use
Drug Class
Permitted/Not 
Permitted
During the 
Trial
Conditions for Use
Bath oils and oatmeal bath preparations
Permitted
Not to be used within 12 hours of a study visit.
NSAIDs, acetaminophen, or aspirin
Permitted
Allowed as needed.
Shampoos
Permitted
May not contain >3% salicylic acid, corticosteroids, coal tar, or vitamin D3 
analogues.
Not to be used within 12 hours of a study visit.
Topical moisturizers/emollients and other 
non-prescription topical products
Permitted
Do not contain urea, >3% salicylic acid, alpha- or beta-hydroxyl acids, 
corticosteroids, or vitamin D3 analogues.  Not to be used within 12 hours of a study 
visit.
Topical steroids
mild (such as hydrocortisone) are permitted
Permitted
Permitted for use limited to the face, axilla, groin, and/or genitalia, as needed.  These 
topical medications should not be used within approximately 24 hours before study 
visits requiring sPGA and PASI measures.  More widespread use on large surfaces is 
not permitted.
strong (such as mometasone), very strong 
(Betamethasone)a, and Halogenated steroids
(clobetesone) are not permitted
Not permitted
Biologic agents other than study drug as part of this 
protocol 
Not Permitted
Washout periods before baseline (Week 0, Visit 2); at least 5 half-lives
IL-17, IL-23p19 antagonists, other than the 2 products 
used as part of this protocol.
Not permitted
Must have never received ixekizumab or IL-23p19 antagonists; or participated in any 
study investigating IL-23p19 antagonists.  Patient with previous exposure to another 
IL-17 antagonist(s) will be limited to approximately15% of the total patient 
population.
Natalizumab or other agents targeting α 4 integrin
Not permitted
Must have never received.
Phototherapy (including either oral and topical PUVA 
light therapy, UVB, or self-treatment with tanning 
beds or therapeutic sunbathing)
Not permitted
Must not have received within 4 weeks of baseline (Week 0, Visit 2).

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Concomitant Medications Permitted/Not Permitted in the Study and Conditions for Use
Abbreviations:  CRS/CRP = clinical research scientist/clinical research physician; IL = interleukin; MTX = methotrexate; NSAID = nonsteroidal 
anti-inflammatory drug; PASI = Psoriasis Area and Severity Index; PUVA = psoralen and ultraviolet A; sPGA = static Physician Global Assessment; 
UVB = ultraviolet B.
a
Mason et al. 2002.
Drug Class
Permitted/Not 
Permitted
Conditions for Use
Systemic nonbiologic psoriasis therapy (e.g., oral 
psoralens and ultraviolet A light therapy, cyclosporine, 
corticosteroids, MTX, oral retinoids, mycophenolate 
mofetil, thioguanine, hydroxyurea, sirolimus, 
azathioprine, fumaric acid derivatives, apremilast, and
1, 25 dihydroxy vitamin D3 and analogues)
Not permitted
Must not have received within 4 weeks of baseline (Week 0, Visit 2).
Vaccine, Bacillus Calmette-Guérin
Not permitted
Must not have received within 12 months of baseline (Week 0, Visit 2).
Should not receive within 12 months of completed treatment in this study.
Vaccines, live 
Not permitted
Must not have received within 12 weeks of baseline (Week 0, Visit 2).
Should not receive within 15 weeks of completed treatment in this study.
Vaccines, nonlive seasonal and/or emergency
Permitted with 
conditions
Killed/inactive or subunit vaccines are expected to be safe; however, their efficacy 
with concomitant ixekizumab and guselkumab treatments is unknown. Check with
Lilly Medical Team (CRS/CRP) before administration.

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Additional drugs are to be avoided during the study unless required to treat an AE or for the 
treatment of an ongoing medical problem.  If the need for concomitant medication arises, the 
investigator should base decisions on the patient and clinical factors.  Any additional medication
(including the limited use of therapeutic agents which, if used under treatment regimens other 
than for treating an AE or for appropriate medical management, might be considered Ps 
therapies) whether prescription or over-the-counter, used at baseline (Week 0, Visit 2) and/or 
during the course of the study, must be documented with the start and stop dates on the 
Concomitant Medications CRF.
Patients will maintain their usual medication regimen for other concomitant diseases throughout 
the study unless those medications are specifically excluded in the protocol.  Patients taking 
concomitant medications should be on stable doses at the time of baseline (Week 0, Visit 2) and 
should remain at a stable dose throughout the study, unless changes need to be made for an AE 
or for appropriate medical management.  Other medications may be allowed if approved by the 
sponsor or its designee.
Patients should be instructed to consult the investigator or other appropriate study personnel at 
the site before taking any new medications or supplements.  Any changes in medications not 
addressed above should be discussed by the investigator with the sponsor.
7.9.
Treatment after the End of the Study
7.9.1. Treatment after Study Completion
Study drug will not be made available after conclusion of the study to patients.
7.9.2. Special Treatment Considerations
Patients will be screened for eligibility in the study as described in Sections 6.1 and 6.2 and will 
be informed of the study-specific restrictions and requirements of the study.  Patients who are not 
willing to comply with the study restrictions and requirements of the study will not be eligible 
for enrollment.
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)

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 patients 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 following an injection.  If a patient experiences an acute 

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allergic/hypersensitivity reaction after an injection of study drug, he or she should be managed 
appropriately and given instruction to receive relevant supportive care.
Additionally, for an event judged by the investigator to be a potential systemic 
allergic/hypersensitivity reaction, a blood sample should be drawn as soon as possible.  These 
samples may be tested for anti-drug antibodies (ADAs), other laboratory tests needed to 
elucidate the cause of the allergic/hypersensitivity reaction, and/or ixekizumab serum 
concentration.  These results will not be provided to the investigator for patient care decisions 
but are intended to assist the sponsor in accurately characterizing the reaction.
For patients who experience a potential allergic/hypersensitivity reaction, consideration for any 
premedication for future injections will be agreed upon between the investigator and sponsor 
and/or its designee.  Examples of potential allergic/hypersensitivity reactions that might merit 
premedication include mild-to-moderate skin rashes, mild-to-moderate generalized pruritus 
and/or urticaria, and mild-to-moderate injection site reactions (e.g., injection-site erythema, 
injection-site pruritus).  Patients who develop clinically significant systemic 
allergic/hypersensitivity reactions following administration of study drug who do not respond to 
symptomatic medication, or have a reaction that results in clinical sequelae (e.g., 
hospitalization), should be discontinued from study drug and not receive further doses of study 
drug, with or without premedication (Section 8.1).  Medications considered appropriate for 
premedication include (but are not restricted to) acetaminophen/paracetamol up to 1000 mg and 
antihistamines (e.g., oral diphenhydramine, 50 mg) given 30 to 60 minutes before study drug
injection.  Patients may self-premedicate at home before administration of study drug, as directed 
by the investigator.  All such premedications will be recorded as concomitant therapy.  
Corticosteroids are not permitted as agents for premedication.

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8. Discontinuation Criteria
8.1.
Discontinuation from Study drug
8.1.1. Permanent Discontinuation from Study drug
Possible reasons leading to permanent discontinuation of study drug:

Subject Decision
o
the patient requests to discontinue study drug.

Discontinuation due to a hepatic event or liver test abnormality.
o
Patients who are discontinued from study drug due to a hepatic event or liver test 
abnormality should have additional hepatic safety data collected via CRF.
Discontinuation of the study drug for abnormal liver tests should be considered by the 
investigator when a patient meets one of the following conditions after consultation 
with the Lilly designated medical monitor:

ALT or AST >8x ULN

ALT or AST >5xULN for more than 2 weeks

ALT or AST >3xULN and total bilirubin level (TBL) >2xULN or 
international normalized ratio (INR) >1.5

ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)

ALP >3xULN

ALP >2.5xULN and TBL >2xULN

ALP >2.5xULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
In addition, patients will be discontinued from the study drug in the following circumstances:

Neutrophil (segmented) counts (see safety monitoring for neutropenia Section 9.4.6.1):

<500 cells/L

≥500 and <1000 cells/L (based on 2 test results; the second test performed 
within 1 week from knowledge of the initial result)

≥1000 and <1500 cells/L (based on 3 test results as specified in Section 9.4.6.1) 
AND an infection that is not fully resolved

Total WBC count <2000 cells/L

Lymphocyte count <200 cells/μL

Platelet count <50,000 cells/μL

The patient experiences a severe AE, an SAE, or a clinically significant change in a 
laboratory value occurs that in the opinion of the investigator, merits the discontinuation 

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of the study drug and appropriate measures being taken.  In this case, Lilly or its designee 
is to be notified immediately via email and the event is to be documented.

Clinically significant systemic hypersensitivity reaction following SC administration of 
study drug that does not respond to symptomatic medication or results in clinical 
sequelae

The patient becomes pregnant

The patient develops a malignancy (Note:  patients may be allowed to continue if they 
develop no more than 2 non-melanoma skin cancers during the study)

if the patient develops active suicidal ideation with some intent to act with or without a 
specific plan (yes to question 4 or 5 on the “Suicidal Ideation” portion of the C-SSRS),
-OR-
if the patient develops suicide-related behaviors as recorded on the C-SSRS,
then it is recommended that the patient be assessed by a psychiatrist or appropriately 
trained professional to assist in deciding whether the patient is to be discontinued from 
the study.
Patients discontinuing from the study drug prematurely for any reason should complete AE and 
other follow-up procedures per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events),
and Section 9.4 (Safety) of this protocol.
8.1.2. Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly.
If the sponsor or investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the patient to continue on 
study drug.  If the investigator and the sponsor CRP agree it is medically appropriate to continue, 
the investigator must obtain documented approval from the sponsor CRP to allow the 
inadvertently enrolled patient to continue in the study with or without treatment with study drug. 
Safety follow-up is as outlined in Section 2 (Schedule of Activities), Section 9.2 (Adverse 
Events), and Section 9.4 (Safety) of the protocol.
8.2.
Discontinuation from the Study
Patients will be discontinued in the following circumstances:

enrollment in any other clinical study involving an study drug or enrollment in 
any other type of medical research judged not to be scientifically or medically 
compatible with this study

participation in the study needs to be stopped for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and good clinical 
practice 

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
investigator decision

the investigator decides that the patient should be discontinued from the 
study

if the patient for any reason, requires treatment with another therapeutic 
agent that has been demonstrated to be effective for the treatment of the 
study indication, discontinuation from the study occurs before introduction 
of the new agent

subject decision

the patient requests to be withdrawn from the study
Patients discontinuing from the study prematurely for any reason should complete AE
and other safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse 
Events), and Section 9.4 (Safety) of this protocol.
8.3.
Lost to Follow-Up
A patient 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 patients or their families/relatives who fail to return for a scheduled 
visit or were otherwise unable to be followed up by the site.
Lilly personnel will not be involved in any attempts to collect vital status information.

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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).  All study assessments except for the C-SSRS, Self-Harm, and 
Self-Harm Follow-Up will be completed electronically.
Appendix 2 lists the laboratory tests that will be performed for this study.
Unless otherwise stated in the 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
9.1.1. Primary Efficacy Assessments
The primary efficacy endpoint is PASI 100 response at Week 12 (Visit 9).
9.1.1.1.
Psoriasis Area and Severity Index
The PASI is an accepted primary efficacy measurement for this phase of development of Ps
treatments (EMA 2004).  The PASI combines assessments of the extent of body-surface 
involvement in 4 anatomical regions (head, trunk, arms, and legs) and the severity of 
desquamation (scaling), erythema, and plaque induration/infiltration (thickness) in each region, 
yielding an overall score from 0 for no Ps up to 72 for the most severe disease (Fredriksson and 
Pettersson 1978).  The PASI has been the most frequently used endpoint and measure of Ps
severity in clinical trials (EMA 2004; Menter et al. 2008).  A clinically meaningful response is a 
PASI 75, which represents at least a 75% decrease (improvement) from the baseline PASI score.  
Higher levels of clearance (PASI 90), as well as complete resolution of Ps (PASI 100), have 
become additional endpoints because of the increasing recognition of the association of higher 
clearance with greater health-related quality of life (Puig 2015).
9.1.2. Major Secondary Efficacy Assessments
9.1.2.1.
Static Physician Global Assessment
The sPGA is the physician’s determination of the patient’s Ps lesions overall at a given time 
point.  The sPGA is recommended as an endpoint to assess efficacy in the treatment of Ps (EMA 
2004).  Overall, lesions are categorized by descriptions for induration, erythema, and scaling.  
For the analysis of responses, the patient’s Ps is assessed as clear (0), minimal (1), mild (2), 
moderate (3), severe (4), or very severe (5).
9.1.3. Other Efficacy Assessments
9.1.3.1.
Percentage of Body Surface Area
The investigator will evaluate the percentage involvement of Ps on each patient’s BSA on a 
continuous scale from 0% (no involvement) to 100% (full involvement), in which 

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1% corresponds to the size of the patient’s hand (including the palm, fingers, and thumb) 
(Thomas and Finlay 2007).
9.1.3.2.
Physician’s Global Assessment of Disease Activity Visual Analog Scale
(for Patients with PsA)
The investigator will be asked to give an overall assessment of the severity of the patient’s 
current PsA activity using a 100-mm horizontal visual analog scale (VAS), where 0 represents 
no disease activity and 100 represents extremely active disease. The investigator making the 
assessment must be a rheumatologist or medically qualified physician. The same assessor should 
preferably perform the Physician’s Global Assessment of Disease Activity VAS for a given 
patient to minimize inter-observer variation.
9.1.3.3.
PGA-F Physician’s Global Assessment of Fingernail Psoriasis
The Physician’s Global Assessment of Fingernail Psoriasis (PGA-F), was developed for 
clinicians to evaluate the severity of fingernail abnormalities in patients with nail psoriasis.  The 
scale assesses the nail bed and nail matrix signs of disease on a 0 to 4 scale (0 - clear, 
1 - minimal, 2 - mild, 3 - moderate, 4 - severe).
9.1.4. Health Outcome Endpoints
9.1.4.1.
Itch Numeric Rating Scale
The Itch NRS is a patient-administered single-item 11-point horizontal scale anchored at 0 and 
10, with 0 representing “no itch” and 10 representing “worst itch imaginable.”  Patients indicate 
their overall severity of itching from Ps by circling the number that best describes the worst level 
of itching in the past 24 hours.
9.1.4.2.
Skin Pain Visual Analog Scale
The Skin Pain VAS is a patient-administered scale designed to measure skin pain from Ps using 
a 100-mm horizontal VAS.  Overall severity of a patient’s skin pain from Ps at the present time 
is indicated by placing a single mark on the horizontal scale (0 = no skin pain; 100 = severe skin 
pain).
9.1.4.3.
Patient’s Global Assessment of Disease Severity
The Patient’s Global Assessment of Disease Severity is a patient-administered, single-item scale 
on which patients are asked to rank, by circling a number on a 0 to 5 NRS, the severity of their
Ps “today” from 0 (clear), no Ps; to 5 (severe).
9.1.4.4.
Dermatology Life Quality Index
The Dermatology Life Quality Index (DLQI) is a simple, patient-administered, 10-question, 
validated, quality-of-life questionnaire that covers 6 domains:  symptoms and feelings, daily 
activities, leisure, work and school, personal relationships, and treatment.  Response categories 
include “not at all,” “a little,” “a lot,” and “very much,” with corresponding scores of 0, 1, 2, and 
3, respectively, and “not relevant” responses scored as “0.”  Totals range from 0 to 30 (less to 
more impairment), a DLQI score of 0 or 1 suggests no impact on patients’ life.

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9.1.4.5.
Patient’s Assessment of Pain Visual Analog Scale (for Patients with PsA)
The patient will be asked to assess his or her current level of joint pain by marking a vertical tick 
on a 100-mm horizontal VAS where the left end represents no joint pain and the right end 
represents worst possible joint pain. Results will be expressed in millimeters measured between 
the left end of the scale and the crossing point of the vertical line of the tick; this procedure is 
applicable for all VAS used in the trial.
9.1.4.6.
Patient’s Global Assessment of Disease Activity Visual Analog Scale (for 
Patients with PsA)
The patient’s overall assessment of his or her PsA activity will be recorded using the 100-mm 
horizontal VAS where the left end represents no disease activity and the right end represents 
extremely active disease activity.
9.1.5. Appropriateness of Assessments
All of the clinical and safety assessments/measures included in the primary and major secondary 
objectives in this study are standard, widely used, and generally recognized as reliable, accurate, 
and relevant.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients 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 patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the study drug or the 
study, or that caused the patient to discontinue the study drug before completing the study.  The 
patient should be followed until the event resolves, stabilizes with appropriate diagnostic 
evaluation, or is reasonably explained.  The frequency of follow-up evaluations of the AE is left 
to the discretion of the investigator.
After the ICF is signed, study site personnel will record via eCRF the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs. Investigators should record their assessment of the 
potential relatedness of each AE to protocol procedure, study drug, via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study drug, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the study 
drug, study device, and/or study procedure and the AE.

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The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s study drug is discontinued as a result of an AE, study site personnel must report this 
to Lilly or its designee via eCRF, clarifying if possible, the circumstances leading to 
discontinuations of treatment.
Study site personnel must alert Lilly or its designee within 24 hours of the investigator 
unblinding a patient’s treatment group assignment for any reason.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  The SAE reporting to the sponsor begins after the patient has signed the ICF and has 
received study drug.  However, if an SAE occurs after signing the ICF, but prior to receiving 
study drug, the SAE should be reported to the sponsor per SAE reporting requirements and 
timelines (see Section 9.2) if it is considered reasonably possibly related to study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.  Patients with a serious hepatic AE should have additional data collected using the 
eCRF.
Pregnancy (during maternal or paternal exposure to study drug) 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.

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Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient disposition 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 drug or study participation, the investigator must promptly notify Lilly.
Data on occurrence of SAEs up to and including the patient’s last study visit will be collected, 
regardless of the investigator’s opinion of causation, in the clinical data collection database and 
the pharmacovigilance system at the sponsor.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to study drug or procedure.  United States
21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the associated 
detailed guidances or national regulatory requirements in participating countries require the 
reporting of SUSARs.  Lilly has procedures that will be followed for the identification, recording 
and expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidances.
9.2.1.2.
Adverse Events of Special Interest
The following adverse events of special interest (AESIs) will be used to determine the safety and 
tolerability of ixekizumab over the range of doses selected for this clinical study.
Adverse events of special interests for ixekizumab are the following:

cytopenias (leukopenia, neutropenia, and thrombocytopenia)

liver function test changes/enzyme elevations (ALT, AST, bilirubin, and ALP)

infections

injection-site reactions

allergic reactions/hypersensitivities

cerebro-cardiovascular events

malignancies

inflammatory bowel disease (IBD)

depression 
Sites will provide details on AEs as instructed on the eCRF.  Investigators will also educate 
patients and/or caregivers about the symptoms of systemic allergic/hypersensitivity reactions and 
will provide instructions on the management and reporting of these reactions.  Blood samples 
will be collected as soon as possible for any patient who experiences an AE of a potential 

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systemic allergic/hypersensitivity reaction during the study as judged by the investigator.  These 
samples may be tested for ADAs, other laboratory tests needed to elucidate the cause of the 
allergic/hypersensitivity reaction, and/or ixekizumab serum concentration.
Data on preferred terms associated with cerebro-cardiovascular events (defined as death, cardiac 
ischemic event including MI and hospitalization for unstable angina, hospitalization for heart 
failure, serious arrhythmia, resuscitated sudden death, cardiogenic shock, coronary 
revascularization procedure, stroke/transient ischemic attack, peripheral revascularization 
procedure, peripheral arterial event, and hospitalization for hypertension) will be collected, and 
these events and any deaths will be adjudicated by an external Clinical Events Committee (CEC) 
made up of a chairperson, 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 and the events will be adjudicated by an external CEC with
expertise in IBD.
The role of the external CECs is to adjudicate defined clinical events in a blinded, consistent, and 
unbiased manner throughout the course of a study.  The purpose of the CEC for adjudication of 
cerebro-cardiovascular events and the CEC for adjudication of suspected IBD events is to ensure 
that all reported events are evaluated uniformly by a single group.
9.2.2. Complaint Handling
Lilly collects product complaints on study drugs and drug delivery systems used in clinical 
studies in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
For blinded studies, all product complaints associated with material packaged, labeled, and 
released by Lilly or delegate will be reported.
The designated Unblinded Site Personnel must be 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

filing the product complaint and associated records in a secure location, separate from 
blinded site staff
If the investigative site is asked to return the product for investigation, the designated Unblinded 
Site Personnel will return a copy of the product complaint form with the product.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
Refer to the IB.

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9.4.
Safety
9.4.1. Laboratory Tests
For each patient, laboratory tests detailed in (Appendix 2) should be conducted according to the 
Schedule of Activities (Section 2).
With the exception of laboratory test results that may unblind the study, Lilly or its designee will 
provide the investigator with the results of laboratory tests analyzed by the central vendor, if a 
central vendor is used for the clinical trial.
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of study drug should be reported to Lilly or its designee as 
an AE via eCRF.
9.4.2. Immunogenicity Assessments
Samples for immunogenicity testing including a pharmacokinetic sample will be collected at 
Visit 2, and at later time points in case of event judged by the investigator to be a potential 
systemic allergic/hypersensitivity reaction, when possible.  Venous blood samples 
(approximately 10 mL) will be collected in tubes and used to determine antibody production 
against ixekizumab.  The actual date of each sampling will be recorded on the laboratory 
requisition.  To analyze change from baseline, the exploratory sample collected at Visit 2 will be 
used.  If analyzed, the samples will be evaluated in validated immunogenicity assays at an 
external vendor in a screening assay and if positive a neutralizing ADA assay. Assay validation 
details are available upon request.
Samples from patients treated with guselkumab will not be analyzed for anti-guselkumab 
antibodies.  These samples will be discarded at the end of the study.  Immunogenicity will be 
assessed by a validated assay designed to perform in the presence of ixekizumab.  Antibodies 
may be further characterized and/or evaluated for their ability to neutralize the activity of 
ixekizumab.  Samples will be retained for a maximum of 15 years after the last patient visit or 
for a shorter period if local regulations and ERBs allow, at a facility selected by the sponsor, to 
enable further analysis of immune responses to ixekizumab.  This duration will allow the sponsor 
to respond to regulatory requests related to the study drug. Any samples remaining after 15 
years will be destroyed.
9.4.2.1.
Ixekizumab Serum Concentration
Immunogenicity samples may also be analyzed for ixekizumab serum concentrations to facilitate 
the interpretation of the immunogenicity data if needed.  Analysis of samples collected from 
guselkumab-treated patients is not planned.  Samples sent for ixekizumab serum concentration 
analysis will be tested at a laboratory approved by Lilly or its designee.  Concentrations of 
immunoreactive ixekizumab in human serum will be determined by a validated method.
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following last patient visit for the study.

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9.4.3. Physical Examination
One complete physical examination (excluding pelvic, rectal, and breast examinations) will be 
performed at screening.  This examination will determine whether the patient meets the criteria 
required to participate in the study and will also serve as a monitor for preexisting conditions and 
as a baseline for treatment-emergent AE (TEAE) assessment.  All physical examinations should 
include a symptom-directed physical evaluation as well as an examination of the heart, lungs, 
and abdomen and a visual examination of the skin.
Any clinically significant findings from a complete physical examination that result in a 
diagnosis are to be reported to Lilly or its designee as AEs via eCRF.
9.4.4. Chest X-Ray and Tuberculosis Testing
An anterior-posterior view chest x-ray will be obtained, unless the x-ray or results from a chest 
x-ray obtained within 6 months before the study are available.  The chest x-ray or results will be 
reviewed by the investigator or designee to exclude patients with active TB infection prior to 
randomization.
In addition, patients will be tested at screening as indicated in Section 2 for evidence of active or 
latent TB using the QuantiFERON®-TB Gold test (according to “Guidelines for Using the 
QuantiFERON®-TB Gold Test for Detecting Mycobacterium tuberculosis Infection, United 
States” [CDC (WWW)], or other published regional recommendations as applicable).  This may 
be performed by a Lilly-designated or local laboratory.  If the QuantiFERON®-TB Gold test is 
indeterminate, 1 retest is allowed and must be done by QuantiFERON®-TB Gold.  If the retest is 
indeterminate, then the patient will be excluded from the study.
Patients with documentation of a negative test result within 3 months before baseline (Week 0, 
Visit 2) do not need a TB screen at Visit 1.
However, patients with a positive QuantiFERON®-TB Gold test at screening but with no other 
evidence of active TB may be re-screened 1 time and may be enrolled without repeating a 
QuantiFERON®-TB GOLD test if the following conditions are met:

after receiving at least 4 weeks of appropriate latent TB infection therapy,

with no evidence of hepatotoxicity (ALT/AST must remain ≤2xULN) upon retesting of 
serum ALT/AST prior to randomization.  Such patients must complete appropriate latent 
TB infection therapy during the course of the study to remain eligible, and 

meet all other inclusion and exclusion criteria for participation.
If re-screening occurs within 6 months of the date of the screening chest x-ray, there is no need 
for repeat of chest x-ray for considering enrollment.  Patients who have a documented history of 
completing an appropriate TB treatment regimen with no history of re-exposure to TB since 
their treatment was completed and no evidence of active TB will be eligible to participate in the 
study.  Patients who have had household contact with a person with active TB will be excluded, 
unless appropriate and documented prophylaxis for TB was given.

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9.4.5. Columbia-Suicide Severity Rating Scale
The C-SSRS is a scale that captures the occurrence, severity, and frequency of suicidal ideation 
and/or behavior during the assessment period.  The scale includes suggested questions to solicit 
the type of information needed to determine if suicidal ideation and/or behavior occurred.  The 
C-SSRS is administered by an appropriately trained healthcare professional with at least 1 year 
of patient care/clinical experience or some or all of the patients may have this data solicited 
through electronic patient-reported outcomes (ePRO) technology.  The tool was developed by 
the National Institute of Mental Health trial group (TASA) for the purpose of being a counterpart 
to the Columbia Classification Algorithm of Suicide Assessment categorization of suicidal 
events. Patients will be assessed according to the Schedule of Activities (Section 2). The 
Self-Harm Supplement Form is a 1-question form that asks for the number of suicidal or
nonsuicidal self-injurious behaviors the patient has experienced since the last assessment. For
each unique event identified, a questionnaire (Self-Harm Follow-Up Form) which collects
supplemental information on the self-injurious behavior is to be completed. The Self-Harm
Supplement Form will be completed according to the Schedule of Activities (Section 2).
The non-leading AE collection should occur prior to the collection of the C-SSRS.  If a 
suicide-related event is discovered during the C-SSRS, but was not captured during the 
non-leading AE collection, sites should not change the AE form.  If an event is serious or leads 
to discontinuation, this is an exception where the SAE and/or AE leading to discontinuation 
should be included on the AE form and the process for reporting SAEs should be followed.
9.4.6. Safety Monitoring 
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
9.4.6.1.
Neutropenia
During treatment with study drug, patients with neutrophil counts <1500 cells/L should be 
managed for neutropenia as follows:

<500 cells/L (<0.50x103/L or <0.50 GI/L), see discontinuation criteria (Section 8.1.1)

≥500 cells/L and <1000 cells/L (≥0.50x103/L and <1.00x103/L or ≥0.50 GI/L and 
<1.00 GI/L), see discontinuation criteria (Section 8.1.1)

≥1000 cells/L and <1500 cells/L (≥1.00x103/L and <1.50x103/L or ≥1.00 GI/L and 
<1.50 GI/L), and the patient has a concurrent infection that requires systemic 
anti-infective therapy (e.g., antibiotic, antifungal agent, and antiviral agent):
o
The dose of study drug should be withheld, the patient should receive appropriate 
medical care, and a repeat test for neutrophil count should be performed within 
4 weeks from knowledge of the initial report.  If the repeat neutrophil count has 
returned to ≥1500 cells/L (≥1.50x103/L or ≥1.50x103/L) and the infection has 
resolved or is resolving, the patient may resume dosing of study drug and 
evaluation at scheduled visits.  If the neutrophil count remains ≥1000 cells/L and 
<1500 cells/L (≥1.00x103/L and <1.50x103/L or ≥1.00 GI/L and <1.50 GI/L), 
study drug should continue to be withheld and a repeat neutrophil count should 

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again be performed within another 4 weeks.  If, after 2 repeat tests, the neutrophil 
count still remains ≥1000 cells/L and <1500 cells/L (≥1.00x103/L and 
<1.50x103/L or ≥1.00 GI/L and <1.50 GI/L), and:
a.
the infection has not fully resolved, the patient will be discontinued from 
the study.
b. the infection has resolved, the patient may resume dosing and evaluation 
at scheduled visits.  However, if resumption of dosing is not deemed 
appropriate by the investigator, the patient will be discontinued from the 
study.

≥1000 cells/L and <1500 cells/L (≥1.00x103/L and <1.50x103/L or ≥1.00 GI/L and 
<1.50 GI/L), and the patient has no concurrent infection that requires systemic 
anti-infective therapy (e.g., antibiotic, antifungal agent, and antiviral agent):
o
Dosing may continue, and a repeat neutrophil count should be performed 4 to 
8 weeks from knowledge of the initial report.  Testing may be at a regularly 
scheduled visit or at an unscheduled visit, as necessary.
o
Repeat testing should be performed at 4- to 8-week intervals until the neutrophil 
count has returned to ≥1500 cells/L (≥1.50x103/L or ≥1.50 GI/L).  If the patient 
has 3 or more postbaseline neutrophil counts of ≥1000 cells/L (≥1.00x103/L or 
≥1.00 GI/L) and <1500 cells/L (<1.50x103/L or <1.50 GI/L), no value of 
<1000 cells/L (<1.00 x103/L or <1.00 GI/L), and no postbaseline infection 
requiring systemic anti-infective therapy, the patient may continue or resume 
further evaluation at scheduled visits, as deemed appropriate by the investigator.
If a patient without initial concurrent infection develops an infection that requires systemic 
anti-infective therapy, then the patient should be managed as indicated above for patients with 
concurrent infection.  Management of neutropenia during the Post-Treatment Follow-Up Period 
(Period 4) is described below.
If, at the last scheduled visit or ETV, the patient’s neutrophil count is <1500 cells/L 
(<1.50x103/L or <1.50 GI/L) and less than the patient’s baseline neutrophil count, the 
following measures should be taken:
[1]
Patients with concurrent infection:  if there is a concurrent infection that requires 
systemic anti-infective therapy, the patient should receive appropriate medical care and a 
repeat test for neutrophil count should be performed at least Q4W (or sooner as 
appropriate) until resolution of infection.  Upon resolution of infection, the neutrophil 
count should be monitored using the required study visits in Period 4 design at Visits 801 
(4 weeks post resolution of infection), 802 (8 weeks after Visit 801), and 803 (if 
necessary; 12 weeks after Visit 802).  Additional visits may be required depending on the 
degree of neutropenia.
[2]
Patients without concurrent infection:  if there is no concurrent infection that requires 
systemic anti-infective therapy, the neutrophil count should be monitored using the 
required study visits in Period 4 design at Visits 801 (4 weeks post ETV or last regularly 

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scheduled visit), 802, and 803 (if necessary).  Additional visits may be required 
depending on the degree of neutropenia.
[3]
For Visit 801 and subsequent visits, the following monitoring applies:

As long as a patient’s neutrophil count is <1000 cells/L (<1.00x103/L or 
<1.00 GI/L) at any follow-up visit, the patient should return for visits at least 
Q4W (may require unscheduled visits).

As long as a patient’s neutrophil count is ≥1000 cells/L and <1500 cells/L 
(≥1.00x103/L and <1.50x103/L or ≥1.00 GI/L and <1.50 GI/L) at any 
follow-up visit, the patient should return for additional visit(s) at least every 4 to 
8 weeks (may require unscheduled visits).

If, at Visit 802 or Visit 803, the patient’s neutrophil count is ≥1500 cells/L 
(≥1.50x103/L or ≥1.50 GI/L) or greater than or equal to the patient’s baseline 
neutrophil count (whichever is lower), the patient’s participation in the study will 
be considered complete unless the investigator determines additional follow-up 
may be necessary.
If, at Visit 803, the patient’s neutrophil count remains <1500 cells/L (<1.50x103/L or 
<1.50 GI/L) and is less than the patient’s baseline neutrophil count, or if the investigator 
determines additional follow-up may be necessary, the investigator in consultation with Lilly, or 
qualified designee, will determine the appropriate management of the patient and the appropriate 
timing of additional contact(s) or visit(s).
9.4.6.2.
Hepatic
If a study patient experiences elevated ALT ≥3xULN, ALP ≥2xULN, or elevated TBL ≥2xULN, 
liver testing (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, ALP, 
TBL, direct bilirubin, gamma-glutamyl transferase, and creatine 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 and in 
consultation with the study medical monitor. Monitoring of ALT, AST, TBL, and ALP should 
continue until levels normalize or return to approximate baseline levels.
9.4.6.2.1. Hepatic Safety Data Collection
Additional safety data should be collected via the eCRF if 1 or more of the following conditions 
occur:

elevation of serum ALT to ≥5xULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2xULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥2xULN on 2 or more consecutive blood tests

patient discontinued from treatment due to a hepatic event or abnormality of 
liver tests

hepatic event considered to be a SAE

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9.4.6.3.
Hepatitis B Monitoring
Patients who are negative for hepatitis B surface antigen (HBsAg-) and positive for anti-hepatitis 
B core antibody (HBcAb+) at screening, regardless of other hepatitis B testing results, will have 
a serum HBV DNA obtained to be analyzed by the central laboratory.  Patients who are 
determined to be HBV DNA negative (undetectable) may be enrolled into the study with 
required HBV DNA monitoring every 3 to 4 months during treatment and 12 weeks after the last 
dose of ixekizumab.  Patients who are found to be HBV DNA positive (detectable) at screening 
will be excluded from the trial (see “Interpretation of Hepatitis B Serologic Test Results” [CDC 
resources page (WWW)], or other published regional recommendations as applicable).
Any enrolled patient with a positive HBV DNA test results at any time must be discontinued 
from the study and should receive appropriate follow-up medical care, including consideration 
for antiviral therapy.
Study investigators should consult with a specialist physician in the care of patients with 
hepatitis (e.g., infectious disease or hepatologist subspecialists) on whether to continue any 
immunosuppressant therapy including study drug for a period of time while antiviral therapy is 
being initiated.  Timing of withdrawal from study drug should be based on recommendation of 
the consulting specialist physician in conjunction with the investigator and local or regional 
medical guidelines or standards of care.
Upon discontinuation from study drug, the patient should be discontinued from the study.  Any 
patient who discontinued the study for any reason will complete the ETV before entering the 
Post-Treatment Follow-Up Period (Period 4).
9.5.
Pharmacokinetics
See Section 9.4.2.1.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Pharmacogenomics or Genetics
Not applicable.
9.8.
Biomarkers
Not applicable.
9.9.
Health Economics or Medical Resource Utilization and Health 
Economics
Not applicable.

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10.
Statistical Considerations
10.1. Sample Size Determination
Approximately 960 patients will be randomized at a 1:1 ratio to ixekizumab 80 mg Q2W and 
guselkumab 100 mg Q8W. With 480 patients per treatment group, this study will have 
98% power to test the superiority of ixekizumab 80 mg Q2W to guselkumab 100 mg Q8W for 
PASI 100 at Week 12. The following assumptions were used for the power calculation response 
rate at Week 12: 35.3% and 23.0% for ixekizumab and guselkumab group, respectively. A 
2-sided Fisher’s exact test at significance level 0.05 is assumed.  These assumptions are based on 
the ixekizumab and guselkumab clinical studies in Ps (Griffiths et al. 2015; Gordon et al. 2016;
Blauvelt et al. 2017; Reich et al. 2017).
This study is also powered at 95% to test the superiority of ixekizumab for PASI 100 at Week 24 
assuming the response rate of ixekizumab and guselkumab at 56% and 44%, respectively.
10.2. Populations for Analyses
Unless otherwise specified, efficacy and health outcome analyses will be conducted on the 
intent-to-treat (ITT) population; whereas, safety analyses will be conducted on the safety 
population defined below:
Population
Description
Intent-to-Treat Population
All randomized patients, even if the patient does not take the assigned treatment, 
does not receive the correct treatment, or otherwise does not follow the protocol. 
Patients will be analyzed according to the treatment to which they were 
assigned.
Safety
All randomized participants who take at least 1 dose of study drug. Participants 
will be included in the treatment group to which they were randomized. In the 
event of a treatment error, participants will be analyzed according to the 
treatment they actually received.
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly.
Continuous data will be summarized in terms of the mean, standard deviation, minimum,
maximum, median, and number of observations. Categorical data will be summarized as
frequency counts and percentages.
Unless otherwise specified, efficacy, and health outcome analyses will be conducted on the ITT
population.  This set includes all data from all randomized patients according to the treatment the
patients were assigned, regardless of whether they received the treatment or not.
The randomization to treatment groups is stratified by site as described in Section 7.2. Study 
sites with fewer than 5 randomized patients per treatment group will be pooled for statistical 
analysis purposes. All efficacy and health outcomes analyses will use pooled sites.

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All tests of treatment effects will be 2-sided, unless otherwise stated.
The Induction Dosing Period (Period 2) starts at the first injection of study drug at Week 0 
(Visit 2) and ends prior to the first injection of study drug at Week 12 or the ETV (between 
Weeks 0 and 12).
Baseline will be defined as the last available value before the first injection for efficacy, health
outcomes, and safety analyses. In most cases, this will be the measure recorded at Week 0 
(Visit 2). For efficacy measures, if the patient does not take any injection, the last available 
value on or prior to the randomization date will be used. Change from baseline will be 
calculated as the visit value of interest minus the baseline value. For safety analyses using a 
baseline period, the baseline period is defined as the time from Visit 1 to the date/time of the first 
injection.
The primary analysis method for treatment comparisons of categorical efficacy, health outcomes
variables at specific time points will be made using a Cochran-Mantel-Haenszel (CMH) test 
stratified by pooled site. Missing data will be imputed using the nonresponder imputation (NRI)
method.  The 95% confidence interval (CI) associated with the treatment response rate, and 
treatment difference will be provided.  Secondary analysis will be conducted using a Fisher’s 
exact test.
The primary analyses for the continuous efficacy and health outcome variables will be performed 
using mixed effects model for repeated measures (MMRM) analysis.  The model will include 
treatment, pooled site, baseline value, visit, treatment-by-visit interaction and baseline 
value-by-visit as fixed factors.  A secondary analysis for continuous efficacy and health 
outcomes variables will be made using analysis of covariance (ANCOVA) adjusting for pooled 
site and baseline value.
Fisher’s exact test will be used for all AE, baseline, discontinuation, and other categorical safety
data.  Continuous laboratory values will be analyzed by an ANCOVA with treatment and 
baseline value in the model.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report (CSR).  Additional exploratory analyses of the data will be conducted 
as deemed appropriate.
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
All patients who discontinue from the study will be identified, and the extent of their
participation in the study will be reported.  If known, a reason for their discontinuation will be
given.

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Patient disposition will be summarized for each treatment period.  Reasons for discontinuation
from the study will be tabulated by treatment randomized. A detailed description of patient 
disposition will be provided at the end of the study. 
10.3.2.2. Patient Characteristics
Patient characteristics and baseline clinical measures will be recorded and summarized by 
treatment group. Baseline characteristics will include gender, age, height, weight, race, duration 
of disease, previous nonbiologic systemic therapy, and previous biologic therapy. Baseline 
clinical and health outcome measurements will include sPGA, PASI, BSA, Itch NRS, DLQI, 
skin pain and patient global assessment, PGA-F, physician’s global assessment of disease 
activity VAS, patient’s assessment of pain VAS, patient’s global assessment of disease activity 
VAS, and C-SSRS.
Comparisons between treatment groups will be conducted using Fisher’s exact test and analysis 
of variance (ANOVA) for categorical data and continuous data, respectively.
10.3.2.3. Concomitant Therapy
Previous and concomitant medications will be summarized for patients who enter each treatment 
period and presented by World Health Organization Anatomic Therapeutic Class (WHOATC) 
Level 4 and generic name.
10.3.2.4. Treatment Compliance
Treatment compliance with study drug will be summarized for each treatment period separately. 
Overall compliance with therapy is defined to be missing no more than 20% of the expected 
doses and not missing 2 consecutive doses. A patient will be considered compliant overall for 
each study period if he/she is missing no more than 20% of the expected doses and not missing 
2 consecutive doses. Proportions of patients compliant by visit and overall will be compared 
between treatment groups.  Detailed analytical method for comparison will be defined in the 
statistical analysis plan (SAP).
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary analysis, that is, the proportion of patients who achieve PASI 100 at Week 12, will 
be based on the ITT population.
Treatment comparisons between ixekizumab treatment group and guselkumab in the proportion
of patients achieving a PASI 100 response at Week 12 will be made using the CMH test 
stratified by pooled site. Missing data will be imputed using the NRI method. The 95% CI 
associated with the treatment response rate, and treatment difference will be provided.
Secondary analyses for PASI 100 at Week 12 will be conducted using Fisher’s exact test.
10.3.3.2. Major Secondary Analyses
Table RHCR.10.1 summarizes the primary and major secondary outcomes and analysis methods.
All analyses listed will be performed based on the ITT Population unless otherwise specified.

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baseline and on or prior to the date of the last visit within the treatment period. Both the 
date/time of the event onset and the date/time of the first study drug injection are considered 
when determining TEAEs. Treatment-emergent adverse events will be assigned to the treatment 
period in which they first occurred or worsened. A follow-up emergent AE (FEAE) is defined as 
an event that first occurred or worsened in severity after the date of Week 24 or the ETV. For 
events that are gender specific, the denominator and computation of the percentage will include 
only patients from the given gender.
An overall summary of AEs will be provided for each of the treatment periods, including the 
number and percentage of patients who experienced TEAEs, TEAEs by maximum severity, 
deaths, SAEs, TEAEs related to study drug, discontinuations from the treatment due to an AE,
and treatment-emergent AESIs. Treatment-emergent AEs (all, by maximum severity, and 
TEAEs possibly related to study drug by the investigator), SAEs including deaths, and AEs that 
lead to treatment discontinuation will be summarized and analyzed by MedDRA System Organ 
Class, and Preferred Term.
In addition to general safety parameters, safety information on specific topics of AESIs will also 
be presented. Potential AESIs will be identified by a standardized MedDRA query or a Lilly 
defined MedDRA preferred term listing.
Follow-up emergent adverse events, SAEs including deaths, and AEs that lead to study
discontinuation will be summarized for Post-Treatment Follow-Up Period (Period 4).
10.3.4.2. Clinical Laboratory Tests
Laboratory assessments will be presented as mean changes from baseline, and as incidence of 
treatment-emergent abnormal, high, or low laboratory values (see below). Shift tables will be 
presented for selected parameters.

For categorical lab tests:
o
Treatment-emergent abnormal value = a change from normal at all baseline visits
to abnormal at any time post baseline.

For continuous lab tests:
o
Treatment-emergent high value = a change from a value less than or equal to the
high limit at all baseline visits to a value greater than the high limit at any time
post baseline.
o
Treatment-emergent low value = a change from a value greater than or equal to
the low limit at all baseline visits to a value less than the low limit at any time
post baseline.
10.3.4.3. Other Safety Evaluations
Suicide-related thoughts and behaviors and self-injurious behavior with no suicidal intent, based 
on the C-SSRS, will be listed by patient.
Further details for these analyses will be provided in the SAP.

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10.3.5. Evaluation of Immunogenicity
For patients randomized to ixekizumab who experience a potential systemic 
allergic/hypersensitivity event during the study, an immunogenicity sample will be collected and 
evaluated for ADA compared to a stored baseline sample if possible. Immunogenicity samples 
will not be evaluated for anti-guselkumab antibodies.
10.3.6. Other Analyses
10.3.6.1. Subgroup Analyses
The effect of the following baseline characteristics on the primary efficacy endpoint, PASI 100 
at Week 12, will be assessed:

Demographics (e.g., gender, age, weight, and race)

Disease characteristics (e.g., disease severity, duration of disease, and age of onset)

Previous treatment for Ps (e.g., previous use of nonbiologic systemic therapy, and 
previous use of biologic therapy)
Detailed description of the subgroup variables will be provided in the SAP. Additional subgroup
analyses on efficacy or subgroup analyses on safety may be performed as deemed appropriate
and necessary.
10.3.7. Interim Analyses
One interim analysis is planned when all patients have completed their Week 12 visit or ETV. 
The interim analysis will include all data collected by the cutoff date, including the data from the 
Extension Period (Period 3) and the Post Treatment Follow-Up Period (Period 4). The analyses 
from the Week 12 lock will be treated as a primary analysis because all primary and major 
secondary objectives, except for PASI 100 at Week 24, will be assessed at this time.
Prior to a Week 12 database lock, all members of the study team will be blinded to the treatment 
allocations.  At the time of the Week 12 database lock, study team members that do not have 
direct access to study sites will have access to the unblinded treatment allocation and unblinded 
data.  Study team members that have direct access to study sites and data collection will remain 
blinded to the treatment allocations until all patients have completed the study (or discontinued 
on or prior to Week 24) and final database lock has occurred.  Site staff, clinical monitors, and 
patients will remain blinded to the patient treatment allocation until after final database lock.
Information that may unblind the study during the analyses will not be reported to study sites or 
blinded study team until the study has been unblinded. All investigators, patients and personnel 
in contact with study sites will be kept blinded to treatment assignments until final CSR is 
complete.
Additional analyses and snapshots of study data may be performed after all patients complete 
Period 3 (Week 24 or ETV) to fulfill the need for regulatory interactions or publication purposes.
Unblinding details are specified in the unblinding plan section of the SAP or a separate 
unblinding plan document.

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12.
Appendices

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Appendix 1.
Abbreviations and Definitions
Term
Definition
ADA
anti-drug antibody
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event 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.
AESI
adverse events of special interest
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BCG
Bacillus Calmette-Guérin
Blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are
aware of the treatment received.
BSA
body surface area
CEC
Clinical Events Committee
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CMH
Cochran-Mantel-Haenszel
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 study-related, good clinical practice (GCP), and applicable regulatory 
requirements.

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consent
The act of obtaining informed consent for participation in a clinical trial from patients 
deemed eligible or potentially eligible to participate in the clinical trial.  Patients 
entered into a trial are those who sign the informed consent form directly or through 
their legally acceptable representatives.
CRF/eCRF
Case report form/electronic case report form:  Sometimes referred to as clinical report 
form:  A printed or electronic form for recording study participants’ data during a 
clinical study, as required by the protocol.
CRP/CRS
clinical research physician/clinical research scientist: Individual responsible for the 
medical conduct of the study.  Responsibilities of the CRP may be performed by a 
physician, CRS, global safety physician or other medical officer.
CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
DLQI
dermatology life quality index
DNA
deoxyribonucleic acid
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition
EDC
electronic data capture
EMA
European Medicines Agency
ERB/IRB
Ethical review board/institutional review board:  A board or committee (institutional, 
regional, or national) composed of medical and nonmedical members whose 
responsibility is to verify that the safety, welfare, and human rights of the patients 
participating in a clinical study are protected.
end of study (trial)
End of study (trial) is the date of the last visit or last scheduled procedure shown in the 
Schedule of Events for the last patient.  
enroll
The act of assigning a patient to a treatment.  Patient who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patient entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ETV
Early Termination Visit
FSH
Follicle-stimulating hormone
GCP
good clinical practice
HBcAb
anti-hepatitis B virus core antibody
HBsAg
hepatitis B virus surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus

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HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
ICF
informed consent form
ICH
International Council for Harmonisation
IGA
Investigator Global Assessment
IgG
immunoglobulin G
IL
interleukin
Informed consent
A process by which a patient 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 patient’s decision to participate.  Informed consent is documented by 
means of a written, signed and dated informed consent form.
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
INR
international normalized ratio
ITT
intention to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IWRS
interactive voice-response system/interactive web-response system
LS
least-squares 
MAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infaraction
MMRM
mixed model for repeated measures
MTX
methotrexate
NRI
nonresponder imputation

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NRS
numeric rating scale
PASI
Psoriasis Area and Severity Index
PASI 50/75/90
at least a (≥)50%/75%/90% improvement in PASI score from baseline
PASI 100
a 100% improvement in PASI score from baseline
PatGA
Patient’s global assessment of disease severity
PGA-F
Physician’s Global Assessment of Fingernail Psoriasis
PK
pharmacokinetics
PPS
per-protocol set:  The set of data generated by the subset of patients who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the 
effects of treatment, according to the underlying scientific model.
PRO/ePRO
patient-reported outcomes/electronic patient-reported outcomes
Ps
plaque psoriasis
PsA
psoriatic arthritis
Q2W
every 2 weeks
Q4W
every 4 weeks
Q8W
every 8 weeks
randomize
The process of assigning patients to an experimental group on a random basis.
re-screen
To screen a patient who was previously declared a screen failure for the same study.
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
sPGA
static Physician Global Assessment
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. 
study drug
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
SUSARs
suspected unexpected serious adverse reactions
TB
tuberculosis

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TBL
total bilirubin level
TEAE
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
Th
T helper
TNF
tumor necrosis factor
TNFi
TNF inhibitor
TPO
third-party organization
ULN
upper limit of normal
USPI
United States Package Insert
VAS
visual analog scale
WBC
white blood cell

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Appendix 2.
Clinical Laboratory Tests
Hematologya,b
Serum Chemistrya,b
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume (MCV)
Chloride
Mean cell hemoglobin concentration (MCHC)
Phosphorus
Leukocytes (WBC)
Total bilirubin
Platelets
Direct bilirubin
Alkaline phosphatase
Absolute counts of:
Alanine aminotransferase (ALT/SGPT)
Neutrophils, segmented
Aspartate aminotransferase (AST/SGOT)
Neutrophils, juvenile (bands)
Blood urea nitrogen (BUN)
Lymphocytes
Uric acid
Monocytes
Creatinine
Eosinophils
Calcium
Basophils
Glucoseg
Albumin
Urinalysis (dipsitck)a,b
Cholesterol (total)
color
Total protein
Specific gravity
CPK 
pH
Triglycerides
Protein
Gamma-Glutamyl Transferase (GGT)
Glucoseg
Ketones
Bilirubin
Urobilinogen
Blood
Nitrite
Urine creatinine
Leukocyte esterase
Urinalysis (microscopic):
Sediment, cells, casts
Immunogenicity
Ixekizumab serum concentration
Other Testsa
Human immunodeficiency virus antibody (HIV)c,d
Hepatitis B Surface antigen (HBsAg)c,d
Pregnancy Test (serum and urine)e
Anti-Hepatitis B Core antibody (HBcAb)c,d
Anti-Hepatitis B Surface antibody (HBsAb)d
Follicle stimulating hormone (FSH)d,f
Anti-Hepatitis C antibodyc,d
HBV DNAc,d
Tuberculosisd

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Clinical Safety Laboratory Tests
Abbreviations:  CPK = creatine phosphokinase; DNA = deoxyribonucleic acid; HBV = hepatitis B virus; RBC = 
red blood cells; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic 
transaminase; WBC = white blood cells.
a
Assayed by sponsor-designated laboratory.
b
Unscheduled blood chemistry, urinalysis, and hematology panels may be performed at the discretion of the 
investigator.
c
See exclusion criteria (Section 6.2).
d
Test required at Visit 1 only to determine eligibility of patient for the study (note: with the exception of those 
patients who require further HBV monitoring [Section 9.4.6.3]).
e
Serum pregnancy test (women <60 years of age who are still of childbearing potential) and urine pregnancy test 
(women of childbearing potential).  Patients will undergo urine pregnancy self-testing at home on a monthly 
basis during periods between scheduled visits until Week 24.  During these intervisit periods, the site must call 
the patient each month to obtain her pregnancy test results.  Additional urine pregnancy testing can be performed 
at the investigator’s discretion.  Patients determined to be pregnant will be discontinued from treatment and will 
no longer be administered study drug (see Section 8.1.1).
f
Women ≥40 and <60 years of age who have had a cessation of menses for ≥12 months will have an FSH test 
confirming nonchildbearing potential (≥40 mIU/mL).  FSH test will be performed centrally.
g
non-fasting glucose.

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Appendix 3.
Study Governance Considerations

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Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for:

ensuring that the patient 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 patient 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 study drug.

answering any questions the patient/may have throughout the study and sharing in 
a timely manner any new information that may be relevant to the patients 
willingness to continue his or her participation in the study.

ensuring that a copy of the ICF is provided to the participant or the participant’s 
legal representative and is kept on file.

ensuring that the medical record includes a statement that written informed 
consent was obtained before the participant was enrolled in the study and the date 
the written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF.
Appendix 3.1.2.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.
Appendix 3.1.3.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Council for Harmonisation (ICH) 
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s).  All ICFs 
must be compliant with the ICH guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the protocol and related amendments and addenda, current Investigator Brochure 
(IB) and updates during the course of the study

informed consent form 

other relevant documents (e.g., curricula vitae, advertisements)

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Appendix 3.1.4.
Regulatory Considerations
This study will be conducted in accordance with the protocol and with the:

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

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.5.
Investigator Information
Physicians with a specialty in dermatology or other relevant specialties with appropriate 
experience in diagnosis and treatment of patients with psoriasis will participate as investigators 
in this clinical trial.
Appendix 3.1.6.
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.
Appendix 3.1.7.
Final Report Signature
The investigator will sign the final clinical study report (CSR) for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The CSR coordinating investigator will sign the final CSR 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 investigator with the most analyzable and enrolled patients will serve as the CSR 
coordinating investigator.  If this investigator is unable to fulfill this function, another 
investigator will be chosen by Lilly to serve as the CSR coordinating investigator.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.

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Appendix 3.2.
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 sponsor start-up training to instruct the investigators and study 
coordinators.  This training will give instruction on the protocol, the completion 
of the CRFs, and study procedures

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and verify data reported to detect potential errors 
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives 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 original source 
documents.
Appendix 3.2.1.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An electronic data capture (EDC) system will be used in this study for the collection of CRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Clinical outcome assessment (COA) data (questionnaires) will be collected by the investigator 
site personnel from the patient, via a paper source document and will be transcribed by the 
investigator site personnel into the EDC system.
Additionally, electronic Clinical Outcome Assessment (eCOA) data (questionnaires, scales, 
rating scales etc.) will be directly recorded by the subject/investigator site personnel, into an
instrument (e.g., hand held tablet). The eCOA data will serve as the source documentation and 
the investigator does not maintain a separate, written or electronic record of these data.
Data collected via the sponsor-provided data capture system(s) will be stored at a third-party site.  
The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture system(s).  Prior to decommissioning, the investigator will 
receive an archival copy of pertinent data for retention.

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Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and electronic transfers will be provided to the investigator 
for review and retention.  Data will subsequently be transferred from the central vendor to the 
Lilly Clinical Laboratory Results Modernization database.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.
Appendix 3.4.
Publication Policy
The publication policy for Study I1F-MC-RHCR is described in the letters of agreement between
the Sponsor and the investigators and institutions.

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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 patients in consultation with the Lilly, or its designee, clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
RBC
Hepatic Serologiesa,b
WBC
Hepatitis A antibody, total
Neutrophils, segmented
Hepatitis A antibody, IgM
Lymphocytes
Hepatitis B surface antigen
Monocytes
Hepatitis B surface antibody
Eosinophils
Hepatitis B Core antibody
Basophils
Hepatitis C antibody
Platelets
Hepatitis E antibody, IgG
Hepatitis E antibody, IgM
Hepatic Chemistrya
Total bilirubin
Anti-nuclear antibodya
Direct bilirubin
Alkaline phosphatase
Alkaline Phosphatase Isoenzymesa
ALT
AST
Anti-smooth muscle antibody (or anti-actin 
antibody)a
GGT
CPK
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; 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.
Protocol Amendment I1F-MC-RHCR(b) 
Summary: A 24 Week Multicenter, Randomized, Double 
Blind, Parallel Group Study Comparing the Efficacy and 
Safety of Ixekizumab to Guselkumab in Patients with 
Moderate to Severe Plaque Psoriasis
Overview
Protocol I1F-MC-RHCR(a) A 24 Week Multicenter, Randomized, Double Blind, Parallel Group 
Study Comparing the Efficacy and Safety of Ixekizumab to Guselkumab in Patients with 
Moderate to Severe Plaque Psoriasis 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 and rationale for the changes made to this protocol are described in the 
following table:

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Amendment Summary for Protocol I1F-MC-RHCR Amendment (b)
Section # and Name
Description of Change
Brief Rationale
5.1 Overall Design
Added the following clarification to “the other
appropriate means” of patient blinding by the 
Unblinded Site Personnel:
“physical barrier means communicated to the 
sponsor for final approval.”
Improve clarity 
5.2 Number of Participants
Rephrased 1st sentence of the 2nd paragraph and 
replaced “treatment with” with “exposure to” in the 
last sentence of the 2nd paragraph.
Improve clarity 
6.2 Exclusion Criteria
Exclusion criteria # [15]
Removed the restriction of participation in any 
study investigating other IL-17 antagonists.
Based on recent protocol review and feedback 
received, a decision was made to be consistent 
regarding the current or recent use of other IL-17 
antagonists. This amendment is to be consistent 
with the eligible population despite of the source of 
the exposure. Prior exposure to other IL-17 
antagonist in clinical trial settings will be allowed 
as long as all other inclusion/exclusion criteria are 
respected; especially > 5 half-lives washout period 
before baseline visit (Week 0, Visit 2). As specified 
in Section 5.2 of the protocol, the patient 
population with previous exposure to another IL-17 
antagonist(s) will be limited to approximately 15% 
of the total patient population.

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Section # and Name
Description of Change
Brief Rationale
6.2 Exclusion Criteria
Exclusion criteria # [22]
Added the following clarifications:
“except for basal cell carcinoma, squamous cell 
carcinoma, skin Bowen’s disease or actinic 
keratosis that have been treated with no evidence of 
recurrence in the past 12 weeks or carcinoma in situ 
of the cervix or non-invasive malignant colon 
polyps that have been removed.”
This addition is to clarify that subjects with the 
types of non-invasive malignancies and 
Non-Melanoma Skin Cancers (NMSC), as 
described in the clarification, can be included in 
this study, if they have been successfully treated 
with no evidence of recurrence.  This is similar to 
other biologicals psoriasis studies and aligned with 
both products labels. In Lilly’s opinion, including 
such patients in this short study (24 weeks of active 
treatment periods) will not pose an increased risk of 
such events since similar populations have 
previously participated in other biological psoriasis 
studies.
6.2.1 Rationale for Exclusion of Certain Study 
Candidates
Removed IL-17 antagonist from the description of 
exclusion criteria and editorial changes. 
For content consistency as a result of changes made 
to Exclusion Criteria #[15].  
7.8 Concomitant Therapy
Table RHCR.7.3
Drug Class “IL 17, IL-23p19  antagonists, other 
than the 2 products used as part of this protocol”:
Removed IL-17 and replaced “treatment with” with 
“exposure to” in the description of Condition for 
Use. 
For content consistency as a result of changes made 
to Exclusion Criteria #[15] and improve clarity.

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
5.1.
Overall Design
Unblinded Site Personnel are also responsible for maintaining the blind of the patient (e.g., by 
means of a blindfold or other appropriate physical barrier means communicated to the sponsor 
for final approval).
5.2.
Number of Participants
Patients with previous biologic use (note:  except concurrent or recent use of any biologic agent 
< 5 half lives) will be can be included in the study provided all inclusion/exclusion criteria, 
including the washout period(s), as specified in (see Sections 6.1 and 6.2).of this protocol are 
respected.  Patients with previous treatment withexposure to another IL-17 antagonist(s) will be 
limited to approximately 15% of the total patient population.
6.2.
Exclusion Criteria
[15] Have previously completed or withdrawn from this study, participated in any other study 
with ixekizumab or guselkumab, have participated in any study investigating other IL 17 
or IL-23p19 antagonists, or have received treatment with ixekizumab.
[22] Have current or a history of lymphoproliferative disease, or signs or symptoms of 
lymphoproliferative disease within 5 years of baseline (Week 0, Visit 2); or have active or 
history of malignant disease within 5 years of baseline (Week 0, Visit 2), except for basal 
cell carcinoma, squamous cell carcinoma, skin Bowen’s disease or actinic keratoses that 
have been treated with no evidence of recurrence in the past 12 weeks or carcinoma in situ 
of the cervix or non-invasive malignant colon polyps that have been removed.
(Note:  patients with history of malignancy with no evidence of recurrence or active 
disease within 5 years of baseline may participate in the study).
6.2.1
Rationale for Exclusion of Certain Study Candidates
Exclusion Criteria [12] through [16] exclude patients who have prior exposure to: guselkumab, 
or any IL-23p19 antagonist, or ixekizumab or any IL 17 antagonist (note: see details in Sections 
6.2 and 5.2), or any patients who are receiving treatment or concomitant medications that could 
have a negative impact on the safety of patients enrolled or confound the results of the study.

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7.8.
Concomitant Therapy
Table RHCR.7.3.
Concomitant Medications Permitted/Not Permitted in the Study and 
Conditions for Use
IL-17, IL-23p19 antagonists, other 
than the 2 products used as part of this 
protocol.
Not 
permitted
Must have never received ixekizumab or IL-23p19 
antagonists; or participated in any study investigating IL 17, 
and IL-23p19 antagonists.  Patient with previous treatment
withexposure to another IL-17 antagonist(s) will be limited 
to approximately15% of the total patient population.

Leo Document ID = 3370197c-0e46-4820-9021-8de9b79bc46c
Approver:
Approval Date & Time: 07-Dec-2018 18:47:26 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 07-Dec-2018 19:02:47 GMT
Signature meaning: Approved
PPD
PPD