A 52-Week Multicenter, Randomized, Open-Label, Parallel- Group Study Evaluating the Efficacy and Safety of Ixekizumab Versus Adalimumab in Patients With Psoriatic Arthritis Who Are Biologic Disease-Modifying Anti-Rheumatic Drug Naive
Phase: PHASE4
Conditions: Psoriatic Arthritis
Sponsor: Eli Lilly and Company

Protocol I1F-MC-RHCF (a)  
A 52-Week Multicenter, Randomized, Open-Label, Parallel-Group Study Evaluating the 
Efficacy and Safety of Ixekizumab versus Adalimumab in Patients with Psoriatic Arthritis Who 
Are Biologic Disease-Modifying Anti-Rheumatic Drug Naïve 
 
NCT03151551 
 
Approval Date: 26-May-2017 
 

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Protocol I1F-MC-RHCF(a)
A 52-Week Multicenter, Randomized, Open-Label, Parallel-
Group Study Evaluating the Efficacy and Safety of 
Ixekizumab versus Adalimumab in Patients with Psoriatic
Arthritis Who Are Biologic Disease-Modifying Anti-Rheumatic 
Drug Naive
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)
Study I1F-MC-RHCF is a Phase 3b/4, multicenter, randomized, open-label, parallel-group 
study with blinded outcomes assessments evaluating the efficacy and safety of ixekizumab 
versus adalimumab in patients with psoriatic arthritis who are biologic disease-modifying 
anti-rheumatic drug naive during a 52-week treatment period.  
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on 06 March 2017
Protocol Amendment (a) Electronically Signed and Approved by Lilly on date provided 
below.
Approval Date: 26-May-2017 GMT

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Table of Contents
Section
Page
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................13
3.
Introduction ......................................................................................................................20
3.1.
Study Rationale............................................................................................................20
3.2.
Background..................................................................................................................20
3.3.
Benefit/Risk Assessment..............................................................................................23
4.
Objectives and Endpoints..................................................................................................24
5.
Study Design.....................................................................................................................26
5.1.
Overall Design .............................................................................................................26
5.1.1.
Screening Period (Period 1)..................................................................................28
5.1.2.
Open-Label Treatment Period (Period 2)..............................................................28
5.1.3.
Post-Treatment Follow-Up Period (Period 3) .......................................................29
5.2.
Number of Participants.................................................................................................30
5.3.
End of Study Definition ...............................................................................................30
5.4.
Scientific Rationale for Study Design...........................................................................30
5.5.
Justification for Dose ...................................................................................................30
6.
Study Population...............................................................................................................33
6.1.
Inclusion Criteria..........................................................................................................33
6.2.
Exclusion Criteria ........................................................................................................34
6.3.
Lifestyle Restrictions....................................................................................................39
6.4.
Screen Failures.............................................................................................................39
7.
Treatments........................................................................................................................40
7.1.
Treatments Administered .............................................................................................40
7.1.1.
Administration of Investigational Product ............................................................41
7.1.2.
Packaging and Labeling .......................................................................................41
7.2.
Method of Treatment Assignment ................................................................................42
7.2.1.
Selection and Timing of Doses.............................................................................42
7.3.
Blinding .......................................................................................................................42
7.4.
Dosage Modification....................................................................................................43
7.5.
Preparation/Handling/Storage/Accountability...............................................................43
7.6.
Treatment Compliance .................................................................................................43
7.7.
Concomitant Therapy...................................................................................................44
7.8.
Treatment after the End of the Study............................................................................48

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7.8.1.
Study Extensions..................................................................................................48
7.8.2.
Continued Access.................................................................................................48
7.8.3.
Special Treatment Considerations ........................................................................49
8.
Discontinuation Criteria ....................................................................................................50
8.1.
Discontinuation from Study Treatment.........................................................................50
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................50
8.1.2.
Temporary Discontinuation from Study Treatment...............................................52
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................52
8.2.
Discontinuation from the Study....................................................................................52
8.3.
Lost to Follow-Up........................................................................................................53
9.
Study Assessments and Procedures ...................................................................................54
9.1.
Efficacy Assessments...................................................................................................54
9.1.1.
Primary Efficacy Assessments .............................................................................54
9.1.1.1.
Combined Endpoint of American College of 
Rheumatology 50 Responder Index and Psoriasis Area 
and Severity Index 100 ...................................................................................54
9.1.2.
Secondary Efficacy Assessments..........................................................................54
9.1.2.1.
Psoriasis Area and Severity Index (PASI 75, PASI 90, 
PASI 100).......................................................................................................54
9.1.2.2.
Percentage of Body Surface Area ...................................................................55
9.1.2.3.
American College of Rheumatology 20 Responder Index ...............................55
9.1.2.3.1.
American College of Rheumatology Core Set...........................................55
9.1.2.4.
American College of Rheumatology 50 and 70 
Responder Index.............................................................................................57
9.1.2.5.
Individual Components of the American College of 
Rheumatology Core Set..................................................................................57
9.1.2.6.
Psoriatic Arthritic Response Criteria...............................................................57
9.1.2.7.
Minimal Disease Activity ...............................................................................57
9.1.2.8.
Modified Composite Psoriatic Disease Activity Index ....................................58
9.1.2.9.
Leeds Enthesitis Index....................................................................................58
9.1.2.10.
Spondyloarthritis Research Consortium of Canada .........................................58
9.1.2.11.
Leeds Dactylitis Index-Basic ..........................................................................58
9.1.2.12.
Nail Psoriasis Severity Index Fingernails........................................................59
9.1.2.13.
Disease Activity Score based on C-Reactive Protein.......................................59
9.1.2.14.
Static Physician Global Assessment................................................................59
9.1.3.
Appropriateness of Assessments ..........................................................................60
9.2.
Adverse Events ............................................................................................................60
9.2.1.
Serious Adverse Events........................................................................................61
9.2.1.1.
Adverse Events of Special Interest..................................................................61

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9.2.1.2.
Suspected Unexpected Serious Adverse Reactions..........................................63
9.2.2.
Complaint Handling.............................................................................................63
9.3.
Treatment of Overdose.................................................................................................63
9.4.
Safety...........................................................................................................................63
9.4.1.
Vital Signs ...........................................................................................................63
9.4.2.
Laboratory Tests ..................................................................................................64
9.4.3.
Columbia Suicide Severity Rating Scale...............................................................64
9.4.4.
Other Tests...........................................................................................................64
9.4.4.1.
Physical Examination .....................................................................................64
9.4.4.2.
Chest X-Ray and Tuberculosis Testing ...........................................................64
9.4.5.
Safety Monitoring ................................................................................................65
9.4.5.1.
Hypertension ..................................................................................................65
9.4.5.2.
Hepatic Monitoring ........................................................................................66
9.4.5.3.
Neutropenia....................................................................................................66
9.4.5.4.
Hepatitis B Monitoring...................................................................................67
9.5.
Pharmacokinetics .........................................................................................................67
9.6.
Pharmacodynamics ......................................................................................................67
9.7.
Genetics .......................................................................................................................68
9.8.
Biomarkers...................................................................................................................68
9.9.
Health Outcome/Quality of Life Measures ...................................................................68
9.9.1.
Itch Numeric Rating Scale....................................................................................68
9.9.2.
Fatigue Severity Numeric Rating Scale Score.......................................................68
9.9.3.
Medical Outcomes Study 36-Item Short Form Health Survey 
Physical Component Summary and Mental Component 
Summary Scores ..................................................................................................68
9.9.4.
European Quality of Life—5 Dimensions 5 Level [EQ-5D-
5L])......................................................................................................................68
9.9.5.
Dermatology Life Quality Index...........................................................................69
9.9.6.
Treatment Satisfaction Questionnaire...................................................................69
10.
Statistical Considerations ..................................................................................................70
10.1. Sample Size Determination ..........................................................................................70
10.2. Populations for Analyses..............................................................................................70
10.3. Statistical Analyses ......................................................................................................71
10.3.1.
General Statistical Considerations ........................................................................71
10.3.1.1.
General Considerations for Analyses during Period 2 
(Open-Label Treatment Period) ......................................................................71
10.3.1.2.
Missing Data Imputation ................................................................................71
10.3.1.2.1.
Nonresponder Imputation..........................................................................71
10.3.1.2.2.
Last Observation Carried Forward ............................................................72

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10.3.1.3.
Adjustment for Multiple Comparisons ............................................................72
10.3.2.
Treatment Group Comparability...........................................................................72
10.3.2.1.
Patient Disposition..........................................................................................72
10.3.2.2.
Patient Characteristics ....................................................................................72
10.3.2.3.
Concomitant Therapy .....................................................................................73
10.3.2.4.
Treatment Compliance....................................................................................73
10.3.3.
Efficacy Analyses ................................................................................................73
10.3.3.1.
Primary Analysis Method ...............................................................................73
10.3.3.1.1.
Categorical Variables................................................................................73
10.3.3.1.2.
Continuous Variables................................................................................73
10.3.3.2.
Secondary Analysis Method ...........................................................................74
10.3.3.2.1.
Categorical Variables................................................................................74
10.3.3.2.2.
Continuous Variables................................................................................74
10.3.3.3.
Methodology for Noninferiority Test..............................................................74
10.3.4.
Safety Analyses....................................................................................................74
10.3.4.1.
Adverse Events...............................................................................................75
10.3.4.2.
Clinical Laboratory Tests................................................................................75
10.3.4.3.
Vital Signs, Physical Findings, and Other Safety 
Evaluations.....................................................................................................76
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................76
10.3.6.
Other Analyses.....................................................................................................76
10.3.6.1.
Subgroup Analyses.........................................................................................76
10.3.7.
Interim Analyses..................................................................................................76
11.
References ........................................................................................................................78
12.
Appendices .......................................................................................................................83

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List of Tables
Table
Page
Table RHCF.2.1. Study Drug Administration Schedule.............................................................18
Table RHCF.4.1. Objectives and Endpoints...............................................................................24
Table RHCF.7.1. Treatment Regimens......................................................................................40
Table RHCF.7.2. Concomitant Medications Permitted/Not Permitted in the Open-Label 
Treatment Period from Week 0 to Week 24 for Treatment of PsA and 
Chronic Conditions........................................................................................44
Table RHCF.7.3. Concomitant Medications Permitted/Not Permitted in the Open-Label 
Treatment Period from Week 24 to Week 52 for Treatment of PsA and 
Chronic Conditions........................................................................................46
Table RHCF.7.4. Allowed Concomitant Medications in the Post-Treatment Follow-Up 
Period (Period 3)............................................................................................47

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List of Figures
Figure
Page
Figure RHCF.5.1.
Illustration of study design for Clinical Protocol I1F-MC-RHCF. .............27

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................84
Appendix 2.
Clinical Laboratory Tests...............................................................................89
Appendix 3.
Study Governance Considerations..................................................................90
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................93
Appendix 5.
Protocol Amendment I1F-MC-RHCF(a) Summary:  A 52-Week 
Multicenter, Randomized, Open-Label, Parallel-Group Study 
Evaluating the Efficacy and Safety of Ixekizumab versus Adalimumab 
in Patients with Psoriatic Arthritis Who Are Biologic Disease-
Modifying Anti-Rheumatic Drug Naive.........................................................94

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1.
Synopsis
Title of Study:
A 52-Week Multicenter, Randomized, Open-Label, Parallel-Group Study Evaluating the Efficacy and Safety of 
Ixekizumab versus Adalimumab in Patients with Psoriatic Arthritis Who Are Biologic Disease-Modifying 
Anti-Rheumatic Drug Naive
Rationale: 
The purpose of this trial is to compare the efficacy and safety of ixekizumab with adalimumab in patients with 
psoriatic arthritis (PsA) who are biologic disease-modifying anti-rheumatic drug (bDMARD) naive.  Adalimumab, a 
widely used tumor necrosis factor inhibitor, was chosen as an active comparator because of its well-established 
efficacy and safety profile; treatment with adalimumab is a standard of care.  As additional therapies become 
available, an important question is whether agents with different mechanisms of action have comparable clinical 
efficacy and safety.  To date, no results of a direct comparator study in patients with PsA comparing 2 bDMARDs
have been published.  This type of study design is important for informing evidence-based treatment decisions with 
regards to a tumor necrosis factor inhibitor.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary
To assess whether ixekizumab
is superior to adalimumab at 
Week 24 in the treatment of 
patients with active PsA as 
measured by American College 
of Rheumatology 50 (ACR50) 
and Psoriasis Area and Severity 
Index 100 (PASI 100)  

Proportion of patients simultaneously achieving ACR50 and PASI 100 
at Week 24 
Major Secondary Objectives:
To assess whether ixekizumab
is noninferior to adalimumab at 
Week 24 in the treatment of 
patients with active PsA as 
measured by ACR50
To assess whether ixekizumab 
is superior to adalimumab at 
Week 24 in the treatment of 
patients with active PsA as 
measured by PASI 100

Proportion of patients achieving ACR50 in each treatment group at 
Week 24

Proportion of patients achieving PASI 100 in each treatment group at 
Week 24
Other Secondary Objectives:
To assess the effect of treatment 
with ixekizumab compared with 
adalimumab as measured by 
efficacy and quality of life 
outcomes
PsA Endpoints
Time course of response to treatment over 52 weeks as measured by:

Proportion of patients achieving ACR20, ACR50, and ACR70 responses

Change from baseline in individual components of the American 
College of Rheumatology (ACR) Core Set - tender joint count, swollen 
joint count, patient’s pain assessment, Patient’s Global Assessment of 
Disease Activity, Physician’s Global Assessment of Disease Activity, 

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Objectives
Endpoints
C-reactive protein (CRP), and Health Assessment 
Questionnaire‒Disability Index (HAQ-DI) score

Proportion of patients simultaneously achieving ACR50 and 
PASI 100 response

Change from baseline in the Disease Activity Score (28 diarthrodial 
joint count) based on C-reactive protein (DAS28-CRP)

Proportion of patients achieving Minimal Disease Activity (MDA)

Proportion of patients achieving Psoriatic Arthritis Response Criteria
(PsARC)

Change from baseline in Modified Composite Psoriatic Disease Activity 
Index (CPDAI) score 

Proportion of patients achieving low disease activity or remission 
according to the Modified Composite Psoriatic Disease Activity Index
definition

Proportion of patients with HAQ-DI improvement ≥0.35

Change from baseline in the Spondyloarthritis Research Consortium of 
Canada (SPARCC) Enthesitis Index score in patients with enthesitis at 
baseline (ie, baseline SPARCC Enthesitis Index score >0)

Change from baseline in the Leeds Enthesitis Index (LEI) score in 
patients with enthesitis at baseline (ie, baseline LEI score >0)

Proportion of patients with resolution in enthesitis in the subgroup of 
patients with enthesitis at baseline as measured by the SPARCC 
Enthesitis Index (ie, baseline SPARCC Enthesitis Index score >0)

Proportion of patients with resolution in enthesitis in the subgroup of 
patients with enthesitis at baseline as measured by the LEI (ie, baseline 
LEI score >0)

Change from baseline in the Leeds Dactylitis Index-Basic (LDI-B) score 
in patients with dactylitis at baseline (ie, baseline LDI-B score >0)

Proportion of patients with resolution in dactylitis in the subgroup of 
patients with dactylitis at baseline as measured by the LDI-B (ie,
baseline LDI-B score >0)
Psoriasis/Nail Endpoints
Time course of response to treatment over 52 weeks as measured by:

Change from baseline in body surface area (BSA) 

Proportion of patients who achieve the following PASI scores:  
PASI 75, PASI 90, or PASI 100 (defined as 75%, 90%, and 100% 
improvement from baseline in PASI criteria, respectively)

Proportion of patients achieving an absolute PASI score ≤1 or ≤2 or ≤3

Change from baseline in the Nail Psoriasis Severity Index (NAPSI)
Fingernails score in the subgroup of patients with fingernail 
involvement at baseline (ie, baseline NAPSI Fingernails score >0)
QoL Endpoints
Time course of response to treatment over 52 weeks as measured by:

Change from baseline in the Itch Numeric Rating Scale (NRS) score

Proportion of patients with Itch NRS score equal to 0 

Change from baseline in Fatigue Severity NRS score

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Objectives
Endpoints

Change from baseline in Medical Outcomes Study 36-Item Short Form 
Health Survey (SF-36) 
o
Physical Component Summary score 
o
Mental Component Summary score

Change from baseline in measures of health utility (European Quality of 
Life–5 Dimensions 5 Level health outcomes instrument [EQ-5D-5L])

Change from baseline in Dermatology Life Quality Index (DLQI) 
total score

Change from baseline in Treatment Satisfaction Questionnaire 
Safety

Change from baseline in Columbia‒Suicide Severity Rating 
Scale (C-SSRS)
Summary of Study Design:  
Study I1F-MC-RHCF is a Phase 3b/4, multicenter, randomized, open-label, parallel-group study with blinded 
outcomes assessments evaluating the efficacy and safety of ixekizumab versus adalimumab in patients with PsA 
who are bDMARD naive during a 52-week treatment period.
Treatment Groups and Duration:  
Ixekizumab:  80 mg subcutaneous (SC) injection
A starting dose of ixekizumab 160 mg (two 80-mg SC injections) will be administered at randomization (Visit 2 
[Week 0]) for all patients

Patients with moderate-to-severe plaque psoriasis (Ps), defined as PASI ≥12, static Physician’s Global 
Assessment (sPGA) ≥3, and BSA ≥10%, will receive ixekizumab 80 mg given as 1SC injection every 
2 weeks (Q2W) from Week 2 to Week 12 and every 4 weeks (Q4W) thereafter

Patients not meeting criteria for moderate-to-severe plaque Ps at randomization will receive ixekizumab 
80 mg given as 1 SC injection Q4W starting at Week 4
Adalimumab:  40 mg SC injection

Patients with moderate-to-severe plaque Ps, defined as PASI ≥12, sPGA ≥3, and BSA ≥10%, will receive a 
starting dose of adalimumab 80 mg (two 40-mg SC injections) administered at randomization (Visit 2 
[Week 0]) followed by 40 mg given as 1 SC injection Q2W starting  at Week 1 

Patients not meeting criteria for moderate-to-severe plaque Ps will receive a starting dose of adalimumab 
40 mg given as 1 SC injection at randomization (Visit 2 [Week 0]) followed by 40 mg given as 1 SC 
injection Q2W starting at Week 2

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The study will consist of 3 periods:

Period 1:  Screening Period (Visit 1) up to 28 days before randomization (Visit 2)

Period 2:  Open-Label Treatment Period (Visit 2 through Visit 11) from Week 0 to Week 52

Period 3: Post-Treatment Follow-Up Period occurring from last treatment visit during Period 2 or Early 
Termination Visit (ETV) up to a minimum of 12 weeks after that visit 
Number of Planned Patients:  

Enrolled/Randomized: 550 (275 ixekizumab; 275 adalimumab)
Statistical Analysis:
The total sample size for the study will be 550 patients randomized in a 1:1 ratio to ixekizumab or adalimumab 
(patients per treatment group) in Period 2.
A significance level of 0.05 is assumed for testing ixekizumab versus adalimumab.  
Sample size was calculated assuming the proportion of patients simultaneously achieving ACR50 and PASI 100 as
13.6% and 31.3% in the adalimumab and ixekizumab treatment groups, respectively, as observed in the 
conventional synthetic disease-modifying anti-rheumatic drug (csDMARD)-experienced population from 
Study RHAP. According to the nQuery software, a total sample size of 550 patients (with 275 patients per treatment 
group) using a 2-sided Fisher's exact test at a 0.05 level of significance would yield approximately 99% power for 
testing ixekizumab versus adalimumab.
This sample size would yield 78% power for testing the noninferiority of ixekizumab to adalimumab at a one-sided 
0.025 level of significance based on a noninferiority margin of –12% and using ACR50 response rates of 43.8% and 
44.1% as observed for the ixekizumab and adalimumab treatment groups, respectively, in the csDMARD-
experienced population from Study RHAP.  For testing superiority of ixekizumab to adalimumab based on PASI 
100 response rates of 46.9% and 23.7% as observed for ixekizumab and adalimumab in the csDMARD-experienced 
population from Study RHAP, this sample size would yield 99% power using a 2-sided Fisher's exact test at 0.05 
level of significance.  

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2. Schedule of Activities
Study Schedule, Protocol I1F-MC-RHCF
Screen-
ing 
Period 1
Treatment Phase:  Study Drug Administration
Baseline
Open-Label Treatment Period 2
a
Visit No (V)
V1
V2
V3b
V4
V5
V6
V7
V8
Study Week (W)
W0
W1
W4
W8
W12
W16
W24
Study Days 
-28d
0d
7 ± 2d
28 ± 2d
56 ± 2d
84 ± 4d
112 ± 4d
168 ± 4d
Informed consent
X
Complete medical history
X
Review preexisting 
conditions
X
Age, sex
X
Physical examination
c
X
X
PsA classification criteria 
(CASPAR criteria)
X
Inclusion/exclusion criteria
X
X
Height
X
Temperature
X
Weight
X
Sitting blood pressure and 
pulse
X
X
d
X
X
X
X
X
Habits (tobacco, alcohol 
use)
X
Concomitant medications
X
X
X
X
X
X
X
X
Review adverse events
X
X
X
X
X
X
X
X
Randomization
X
Administer Study Drug
See Table RHCF.2.1e
Dispense Study Drug and 
Study Drug Administration 
Log
X
X
X
X
X
X
Collect/Review/Enter Data 
from Study Drug 
Administration Log
X
X
X
X
X
X
Clinical Efficacy
Patient-Rated Assessments
Patient’s Assessment of 
Pain VAS
X
X
X
X
X
X
Patient’s Global 
Assessment of Disease 
Activity VAS
X
X
X
X
X
X
HAQ-DI
X
X
X
X
X
X
Itch NRS
X
X
X
X
X
X
SF-36
X
X
X
X
X

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Screen-
ing 
Period 1
Treatment Phase:  Study Drug Administration
Baseline
Open-Label Treatment Period 2
a
Visit No (V)
V1
V2
V3b
V4
V5
V6
V7
V8
Study Week (W)
W0
W1
W4
W8
W12
W16
W24
Study Days 
-28d
0d
7 ± 2d
28 ± 2d
56 ± 2d
84 ± 4d
112 ± 4d
168 ± 4d
EQ-5D-5L
X
X
X
X
X
Fatigue Severity NRS
X
X
X
X
X
DLQI
X
X
X
X
X
X
Clinician-Rated or Administered Assessments
TJC/SJC (68/66 joints)
X
X
X
X
X
X
X
Physician’s Global 
Assessment of Disease 
Activity VAS
X
X
X
X
X
X
PASI
X
X
X
X
X
X
% Body Surface Area
X
X
X
X
X
X
X
Enthesitis Assessment 
(SPARCC and LEI)
X
X
X
X
X
X
LDI-B
X
X
X
X
sPGA
X
NAPSI Fingernails
X
X
X
X
C-SSRS 
X
X
X
X
X
X
X
Self-Harm Supplement 
Form and Self-Harm 
Follow-Up Form
X
X
X
X
X
X
X
Treatment Satisfaction 
Questionnaire
X
X
Laboratory Tests
Administer TB testf
X
Chest x-ray
Xg
ECG
Xh
FSH
Xi
HIV/HCV
X
HBV Panelj
X
HBV DNAk
X
X
X
X
Serum pregnancy testl
X
Urine pregnancy testm
X
X
X
Serum chemistry
X
Xn
X
X
X
Hematology
X
X
X
X
X
Urinalysis
X
X
X
RF
X
hs-CRP
X
X
X
X
X
X

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Study Schedule, Protocol I1F-MC-RHCF 
Treatment Phase:  Study Drug Administration
Open-Label Treatment Period 2a
Visit No (V)
V9
V10
V11
ETV
Study Week (W)
W32
W40
W52
Study Days
224 ± 4d
280 ± 4d
364 ± 4d
Physical examination
c
X
X
Weight
X
X
Sitting blood pressure and pulse
X
X
X
X
Concomitant medications
X
X
X
X
Review adverse events
X
X
X
X
Administer Study Drug
See Table RHCF.2.1
e
Dispense Study Drug and Study Drug 
Administration Log
X
X
Collect/Review/Enter Data from the Study 
Drug Administration Log
X
X
X
X
Clinical Efficacy
Patient-Rated Assessments
Patient’s Assessment of Pain VAS
X
X
X
X
Patient’s Global Assessment of Disease 
Activity VAS
X
X
X
X
HAQ-DI
X
X
X
X
Itch NRS
X
X
X
X
SF-36
X
X
X
EQ-5D-5L
X
X
X
Fatigue Severity NRS
X
X
X
DLQI
X
X
X
X
Clinician-Rated or Administered Assessments
TJC/SJC (68/66 joints)
X
X
X
X
Physician’s Global Assessment of Disease 
Activity VAS
X
X
X
X
PASI
X
X
X
X
% Body Surface Area
X
X
X
X
Enthesitis Assessment (SPARCC and LEI)
X
X
X
X
LDI-B
X
X
X
X
NAPSI Fingernails
X
X
X
X
C-SSRS
X
X
X
X
Self-Harm Supplement Form and Self-Harm 
Follow-Up Form
X
X
X
X
Treatment Satisfaction Questionnaire
X
X
Laboratory Tests
HBV DNA
k
X
X
X
Urine pregnancy test
m
X
X
X
X
Serum chemistry
X
X
X
Hematology
X
X
X
Urinalysis
hs-CRP
X
X
X
X

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Study Schedule, Protocol I1F-MC-RHCF
Post-Treatment Follow-Up Period 3o
Required Visits
As Needed
Visit No (V)
V801
V802
V803
Study Week (W)
LTV + 4W
LTV + 12W
LTV + 24W
Study Days
+/- 14d
+/- 14d
+/- 14d
Concomitant medications
X
X
X
Review adverse events
X
X
X
Clinician-Rated or Administered Assessments
C-SSRS
X
X
X
Self-Harm Supplement Form 
and Self-Harm Follow-Up 
Form
X
X
X
Vital Signs/Laboratory Tests
Sitting blood pressure and pulse
X
X
X
HBV Panelj
X
HBV DNAk
X
Serum chemistry
X
X
X
Hematology
X
X
X
Abbreviations:  CASPAR = Classification for Psoriatic Arthritis; C-SSRS = Columbia–Suicide Severity Rating 
Scale; d = day; DLQI = Dermatology Life Quality Index; DNA = deoxyribonucleic acid;
ECG = electrocardiogram; EQ-5D-5L = European Quality of Life–5 Dimensions 5 Level health outcomes 
instrument; ETV = Early Termination Visit; Fatigue Severity NRS = Fatigue Severity Numeric Rating Scale; 
FSH = follicle-stimulating hormone; HAQ-DI = Health Assessment Questionnaire‒Disability Index;
HBcAb = anti-hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus;
HCV = hepatitis C virus; HIV = human immunodeficiency virus; hs-CRP = high sensitivity (assay) C-reactive 
protein; Itch NRS = Itch Numeric Rating Scale; LDI-B = Leeds Dactylitis Index-Basic; LEI = Leeds Enthesitis 
Index; LTV = last treatment visit during Period 2 or Early Termination Visit; NAPSI Fingernails = Nail Psoriasis 
Severity Index Fingernails; PASI = Psoriasis Area and Severity Index; PPD = purified protein derivative; 
PsA = psoriatic arthritis; RF = rheumatoid factor; SF-36 = Medical Outcomes Study 36-Item Short Form Health 
Survey; SJC = swollen joint count; SPARCC = Spondyloarthritis Research Consortium of Canada; sPGA = static 
Physician Global Assessment of psoriasis; TB = tuberculosis; TJC = tender joint count; VAS = visual analog 
scale.
a If a patient discontinues the study drug early, the patient will complete the ETV and then enter the Post-Treatment 
Follow-Up Period of the protocol.
b Visit 3 will be a phone visit.
c One complete physical examination (excluding pelvic, rectal, and breast examinations) will be performed at Visit 
1 (screening). All remaining physical examinations throughout the study 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.
d Sitting blood pressure and pulse rate must be measured before study drug dosing and 1 hour postdose at Visit 2 
(Week 0).
e At randomization (Visit 2) for patients randomized to ixekizumab and for patients with moderate-to-severe plaque 
Ps symptoms randomized to adalimumab, the second injection of study drug will be administered by the patient 
or caregiver under site personnel supervision for injection training purposes.  Thereafter, study drug will be 
administered by the patient or caregiver.
f
In countries where the QuantiFERON®-TB Gold test or T-SPOT® is available, either test may be used instead of 
the purified PPD TB test.  The QuantiFERON®-TB Gold test may be performed locally or centrally; the 
T-SPOT® must be performed locally.  PPD tests must be read 48 to 72 hours after Visit 1.  See Section 9.4.4.2
for TB testing details.

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Study Schedule, Protocol I1F-MC-RHCF
g A chest x-ray (posterior-anterior view) will be taken at screening (Visit 1) and assessed locally, unless one has 
been obtained within the past 6 months and the x-ray or results are available for review.
h Obtain ECG within 1 week of Visit 2 (prior to the first dose); assessed locally.
i
For female patients ≥40 and <60 years of age who have had a cessation of menses for at least 12 months, a
follicle-stimulating hormone (FSH) test will be performed to confirm nonchildbearing potential (FSH 
≥40 mIU/mL).
j
All patients will be tested for HBV. 
k Patients who meet criteria for HBV monitoring (see Section 9.4.5.4) will be identified by the central laboratory at 
baseline and monitored according to the study schedule.
l
Only for females of childbearing potential.
m Only for females of childbearing potential.  Additional urine pregnancy testing can be performed at the 
investigator’s discretion or per applicable regulations/guidance.
n Visit 2 should be a fasting visit.
o Patients receiving study drug who discontinue at any time prior to the end of the study or who complete the study 
(Week 52) will enter the Post-Treatment Follow-Up Period occurring from last treatment visit or ETV up to a 
minimum of 12 weeks after that visit. Visit 803 will only occur if a patient’s neutrophil counts have not returned 
to the criteria defined in Sections 5.1.3 and 8.1.1.

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Table RHCF.2.1.
Study Drug Administration Schedule
Visit
2
3
4
5
6
7
8
Weeks 
0a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Ixekizumab 80 mg 
Q2W/Q4W
Moderate-to-Severe 
Plaque Psb
X
(160 mg)
X
X
X
X
X
X
X
X
X
Ixekizumab 80 mg 
Q4Wc
X
(160 mg)
X
X
X
X
X
X
Adalimumab 40 mg 
Q2Wd
X
(40 mg)
X
X
X
X
X
X
X
X
X
X
X
X
Adalimumab 40 mg 
Q2W
Moderate-to-Severe 
Plaque Pse
X
(80 mg)
X
X
X
X
X
X
X
X
X
X
X
X
Visit
9
10
11
Weeks 
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
Ixekizumab 80 mg 
Q2W/Q4W 
Moderate-to-Severe
Plaque Psb
X
X
X
X
X
X
Ixekizumab 80 mg 
Q4Wc
X
X
X
X
X
X
Adalimumab 40 mg 
Q2Wd
X
X
X
X
X
X
X
X
X
X
X
X
X
Adalimumab 40 mg 
Q2W
Moderate-to-Severe
Plaque Pse
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations:  BSA = body surface area; PASI = Psoriasis Area and Severity Index; Ps = psoriasis; Q2W = every 2 weeks; Q4W = every 4 weeks; 
SC = subcutaneous; sPGA = static Physician Global Assessment of psoriasis.
a Starting dose.

I1F-MC-RHCF(a) Clinical Protocol
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Study Drug Administration Schedule
b Patients with moderate-to-severe plaque Ps, defined as PASI ≥12, sPGA ≥3, and BSA ≥10%, will receive ixekizumab 80 mg given as 1 SC injection Q2W 
from Week 2 to Week 12 and Q4W thereafter.
c Patients not meeting criteria for moderate-to-severe plaque Ps will receive ixekizumab 80 mg given as 1 SC injection Q4W starting at Week 4.
d Patients not meeting criteria for moderate-to-severe plaque Ps will receive a starting dose of adalimumab 40 mg given as 1 SC injection at randomization 
(Visit 2 [Week 0]) followed by 40 mg given as 1 SC injection Q2W starting at Week 2.
e Patients with moderate-to-severe plaque Ps, defined  as PASI ≥12, sPGA ≥3, and BSA ≥10%, will receive a starting dose of adalimumab 80 mg (two 40-mg 
SC injections) administered at randomization (Visit 2 [Week 0]) followed by 40 mg given as 1 SC injection Q2W starting at Week 1.  

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3.
Introduction
3.1.
Study Rationale
During the last decade, the treatment of psoriatic arthritis (PsA) has significantly changed.  
Methotrexate (MTX) or other conventional synthetic disease-modifying anti-rheumatic drugs 
(csDMARD) such as sulfasalazine or leflunomide are usually initiated as a first line of treatment. 
In patients with active PsA and an inadequate response or intolerance to a csDMARD, the use of 
a biologic DMARD (bDMARD) is recommended according to the European League Against 
Rheumatism (EULAR) and Group for Research and Assessment of Psoriasis and Psoriatic 
Arthritis (GRAPPA) working group (Gossec et al. 2016; Coates et al. 2016).  
Based on current treatment recommendations, a tumor necrosis factor (TNF) inhibitor is the 
usual first option for a bDMARD, mainly because of the long-term experience and the 
well-established efficacy and safety profile of these agents. Five TNF inhibitors have been 
approved and are available in major markets for the treatment of PsA to-date: etanercept, 
infliximab, adalimumab, golimumab, and certolizumab. In addition, biosimilars of infliximab, 
etanercept, and adalimumab (Amjevita package insert, 2016) have been recently approved for 
use in PsA.  New bDMARDs targeting different mechanisms of action have also been approved 
for the treatment of PsA, with ustekinumab targeting the IL-12/IL-23 pathway, secukinumab and 
brodalumab targeting the IL-17 pathway, and apremilast, an oral molecule, inhibiting 
phosphodiesterase 4 (PDE 4).  As additional therapies become available, an important question is 
whether bDMARDs with different mechanisms of action have comparable clinical efficacy and 
safety.  Ixekizumab has been studied in patients with active PsA in a study that included 
adalimumab as an active control reference arm (Mease et al. 2017).  Yet to date, no results of a 
direct comparator study in patients with PsA comparing 2 bDMARDs have been published.  This 
type of study design is important for informing evidence-based treatment decisions with regard 
to a TNF inhibitor.
In this study, adalimumab has been chosen as the active comparator, as it is recognized as a 
standard of care for a bDMARD in the treatment of active PsA. 
3.2.
Background
PsA is an immune-mediated chronic inflammatory disorder commonly associated with psoriasis 
(Ps) that occurs in 0.04% to 1% of the general population but in 6% to 42% of patients with 
psoriasis.  It is a progressive, destructive disease that results in deformities, impaired physical 
function, loss of QoL, and increased mortality (Kavanaugh et al 2016).  PsA also has a 
considerable negative impact on multiple physical and emotional aspects of patients’ lives 
(Gladman et al. 2005; Rosen et al. 2012).  Patients with PsA have reported poorer health-related 
QoL compared to the general population and to Ps patients (Husted et al. 1997; Rosen et al. 
2012) and suffer from a similar level of functional impairment to patients with rheumatoid 
arthritis (RA) (Husted et al. 2013).
The current standard of care for PsA includes nonsteroidal anti-inflammatory drugs; 
intra-articular and/or systemic glucocorticoids; conventional synthetic disease-modifying 

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anti-rheumatic drugs (csDMARDs) such as MTX, sulfasalazine (SSZ), leflunomide, and 
cyclosporine A; and biologic agents such as TNF inhibitors (Gossec et al. 2012; Smolen et al. 
2014, Gossec et al. 2016). Although leflunomide has been shown to be effective in improving 
signs and symptoms of PsA as assessed by Psoriatic Arthritic Response Criteria (PsARC) and 
American College of Rheumatology 20 score (ACR20), there is only weak evidence that other 
csDMARDs are effective, though limited controlled clinical trial data are available (Gossec et al. 
2012; Mease and Armstrong 2014, Gossec et al. 2016).  In a recent randomized controlled trial 
of patients with PsA treated with MTX, no significant improvement was demonstrated in 
peripheral arthritis (Kaltwasser et al. 2004, Kingsley et al. 2012).  Additionally, csDMARDs 
have not demonstrated efficacy in treating axial involvement, enthesitis, or dactylitis, though 
limited data are available (Gossec et al. 2012; Mease and Armstrong 2014). SSZ was effective 
for axial manifestations in an open-label trial, but not for enthesitis or dactylitis (Clegg et al. 
1996; Dougados et al. 1995).  Data on radiographic progression on MTX has not been conclusive 
and only analyzed in a small case-control study; for SSZ, radiographic progression was not 
prevented in a small case-control study of 20 SSZ-treated patients and 20 matched controls (Ash
et al. 2012).
In patients with PsA, TNF inhibitors are effective in treating signs and symptoms, inhibiting or 
slowing structural progression (mainly bone degradation), and improving skin lesions 
(Kavanaugh et al. 2006; Mease et al. 2005; Mease et al. 2000; Mease et al. 2004; Kavanaugh
et al. 2009; Antoni et al. 2005a; Antoni et al. 2005b).  However, between 30% and 40% of 
patients with PsA have a partial response while others become resistant or intolerant to treatment 
and continue to accrue disability (Rudwaleit et al. 2010; Nash and Clegg 2005).  In addition, 
infections, malignancies, blood dyscrasias, peripheral neuropathy, and central nervous system 
and spinal cord demyelination can present as major problems in some patients treated with these 
agents (Deepak et al. 2013; Ruderman 2012; Singh et al. 2011).  Therefore, there is an unmet 
need for alternative effective medications with a different mechanism of action and an improved 
safety profile for patients with PsA.
Ixekizumab (LY2439821) is a humanized immunoglobulin G subclass 4 monoclonal antibody 
that neutralizes the cytokine IL-17A (also known as IL-17).  Ixekizumab was developed by 
humanization and optimization of a mouse anti-human IL-17 antibody.  It has a high affinity for 
and neutralizes the activity of both human and monkey IL-17.  It has high specificity to IL-17A 
and has no cross-reactivity to other IL-17 family members (IL-17B-F). Ixekizumab blocks IL-17 
binding to the IL-17 receptor (IL-17R).
A total of 7339 patients (5689 patients with psoriasis, 532 patients with RA, and 1118 patients
with PsA) have been treated with at least 1 dose of ixekizumab.  The efficacy of ixekizumab in 
patients with moderate-to-severe plaque psoriasis has been evaluated in 3 large, 
placebo-controlled, Phase 3 studies (Studies RHAZ, RHBA, and RHBC) involving a total of 
2328 patients treated with ixekizumab and 791 patients treated with placebo.  Ixekizumab was 
found to be superior to placebo in all 3 studies during both the induction and maintenance phases.  
In the 2 studies with etanercept as an active comparator during the induction phase, ixekizumab 

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was found to be superior to etanercept. Based on these results, ixekizumab has been approved 
for the treatment of moderate-to-severe psoriasis worldwide.
In patients with PsA, Study RHAP was designed to assess whether ixekizumab 80 mg every 
2 weeks (Q2W) or 80 mg every 4 weeks (Q4W) was superior to placebo in the treatment of 
bDMARD-naive patients with active PsA.  Significantly more patients treated with ixekizumab 
achieved an ACR20, ACR50, and ACR70 response compared with placebo-treated patients at 
Week 24 (all comparisons p≤.001; nonresponder imputation method):

ACR20 response - IXEQ2W (62.1%), IXEQ4W (57.9%) versus placebo (30.2%) 

ACR50 response - IXEQ2W (46.6%), IXEQ4W (40.2%) versus placebo (15.1%).  

ACR70 response - IXEQ2W (34.0%), IXEQ4W (23.4%) versus placebo (5.7%).  
Among patients with psoriasis at baseline affecting ≥3% body surface area (BSA), a significantly 
greater percentage of patients achieved PASI 75,PASI 90, and PASI 100 Week 24 (all 
comparisons (p<.001).

PASI 75 - IXEQ2W (79.7%), IXEQ4W (71.2%) versus placebo (10.4%).  

PASI 90 - IXEQ2W (67.8%), IXEQ4W (56.2%) versus placebo (6.0%)

PASI 100 - IXEQ2W (52.5%), IXEQ4W (42.5%) versus placebo (3.0%)
At Week 24, improvements from baseline in physical function, measured by Health Assessment 
Questionnaire-Disability Index (HAQ-DI), were significantly greater in patients receiving 
IXEQ4W (−0.44), IXEQ2W (−0.50) than in those receiving placebo (−0.18) (p≤.001).  The 
improvement from baseline in Short Form (36 Items) Health Survey Physical Component Score 
was also significantly greater at Week 24 for patients receiving IXEQ4W (7.5) and IXEQ2W 
(8.2) compared with those receiving placebo (2.9) (p≤.01).  For patients with dactylitis and 
LDI-B >0 at baseline, significantly greater improvements in mean LDI-B scores at Week 24 
(post hoc analysis) were observed for the IXEQ4W and IXEQ2W groups compared with the 
placebo group (p≤.01) and complete resolution of dactylitis symptoms (LDI-B=0) at Week 24 
(post hoc analysis) occurred at a greater rate in the IXEQ4W (80%) and IXEQ2W (77%) groups 
than in the placebo group (25%) (p≤.001).  For patients with nail involvement at baseline, mean 
changes from baseline in the NAPSI score at Week 24 were significantly greater for the 
IXEQ4W (−14.0) and IXEQ2W (−15.5) groups than for the placebo group (−2.4) (p≤.001).  
Progression of structural damage, measured by changes from baseline in mTSS at Week 24, was 
significantly less in the IXEQ4W (0.17) and IXEQ2W (0.08) groups than in the placebo group 
(0.49) (p≤.01).  
There was not a statistically significant difference between either ixekizumab group, compared 
with the placebo group, for the major secondary endpoints of change from baseline to Week 12 
in Leeds Enthesitis Index (LEI) (Mease et al. 2017).
Significant therapeutic effects for the signs and symptoms of PsA, physical function, progression 
of structural damage, and skin manifestations of psoriasis were observed for many endpoints as 
early as 1 week after initiation of therapy.  Effects were observed in the overall bDMARD-naive
population and the subpopulation with csDMARD experience.  The findings were clinically 

I1F-MC-RHCF(a) Clinical Protocol
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significant and indicated that ixekizumab offers a potential therapeutic option for patients with 
active PsA who are bDMARD naive.  Although adalimumab 40 mg Q2W was used as the active 
control for comparison with placebo, this study was not powered to compare ixekizumab with 
adalimumab.  In addition, the Phase 3 clinical development program conducted in patients with 
active PsA includes 2 additional studies:  Study RHBE in patients who are bDMARD 
experienced, and Study RHBF, a withdrawal study conducted in csDMARD-inadequate 
responder (IR) and bDMARD-naive patients.
Study I1F-MC-RHCF (RHCF) is a Phase 3b/4, multicenter, randomized, open-label, 
parallel-group study with blinded outcomes assessments evaluating the efficacy and safety of 
ixekizumab versus adalimumab in patients with PsA who are bDMARD naive during a 52-week 
treatment period.  The primary objective of this study is to assess whether ixekizumab is superior 
to adalimumab as measured by the proportion of patients simultaneously achieving ACR50 and 
PASI 100 at Week 24.  In addition, the effects of ixekizumab on extra-articular manifestations of 
PsA such as skin, fingernails, enthesitis, dactylitis, and the impact on QoL will be evaluated.  
This study also evaluates the long-term efficacy and safety of ixekizumab in PsA for up to 
1 year.  
3.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of ixekizumab are to be found in the 
Investigator’s Brochure (IB) and the product labeling.  
More detailed information about the known and expected benefits and risks of adalimumab may 
be found in the product labeling.

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4.
Objectives and Endpoints
Table RHCF.4.1 shows the objectives and endpoints of the study.
Table RHCF.4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess whether ixekizumab
is superior to adalimumab at 
Week 24 in the treatment of 
patients with active PsA as 
measured by American College 
of Rheumatology 50 (ACR50) 
and Psoriasis Area and Severity 
Index 100 (PASI 100)  

Proportion of patients simultaneously achieving ACR50 and PASI 100 
at Week 24 
Major Secondary Objectives:
To assess whether ixekizumab
is noninferior to adalimumab at 
Week 24 in the treatment of 
patients with active PsA as 
measured by ACR50
To assess whether ixekizumab 
is superior to adalimumab at 
Week 24 in the treatment of 
patients with active PsA as 
measured by PASI 100

Proportion of patients achieving ACR50 in each treatment group at 
Week 24

Proportion of patients achieving PASI 100 in each treatment group at 
Week 24
Other Secondary Objectives:
To assess the effect of treatment 
with ixekizumab compared with 
adalimumab as measured by 
efficacy and quality of life 
outcomes
PsA Endpoints
Time course of response to treatment over 52 weeks as measured by:

Proportion of patients achieving ACR20, ACR50, and ACR70 responses

Change from baseline in individual components of the American 
College of Rheumatology (ACR) Core Set - tender joint count, swollen 
joint count, patient’s pain assessment, Patient’s Global Assessment of 
Disease Activity, Physician’s Global Assessment of Disease Activity, 
C-reactive protein (CRP), and Health Assessment 
Questionnaire‒Disability Index (HAQ-DI) score

Proportion of patients simultaneously achieving ACR50 and 
PASI 100 response

Change from baseline in the Disease Activity Score (28 diarthrodial 
joint count) based on C-reactive protein (DAS28-CRP)

Proportion of patients achieving Minimal Disease Activity (MDA)

Proportion of patients achieving Psoriatic Arthritis Response Criteria
(PsARC)

Change from baseline in Modified Composite Psoriatic Disease Activity 
Index (CPDAI) score 

Proportion of patients achieving low disease activity or remission 
according to the Modified Composite Psoriatic Disease Activity Index
definition

Proportion of patients with HAQ-DI improvement ≥0.35

I1F-MC-RHCF(a) Clinical Protocol
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LY2439821
Objectives
Endpoints

Change from baseline in the Spondyloarthritis Research Consortium of 
Canada (SPARCC) Enthesitis Index score in patients with enthesitis at 
baseline (ie, baseline SPARCC Enthesitis Index score >0)

Change from baseline in the Leeds Enthesitis Index (LEI) score in 
patients with enthesitis at baseline (ie, baseline LEI score >0)

Proportion of patients with resolution in enthesitis in the subgroup of 
patients with enthesitis at baseline as measured by the SPARCC 
Enthesitis Index (ie, baseline SPARCC Enthesitis Index score >0)

Proportion of patients with resolution in enthesitis in the subgroup of 
patients with enthesitis at baseline as measured by the LEI (ie, baseline 
LEI score >0)

Change from baseline in the Leeds Dactylitis Index-Basic (LDI-B) score 
in patients with dactylitis at baseline (ie, baseline LDI-B score >0)

Proportion of patients with resolution in dactylitis in the subgroup of 
patients with dactylitis at baseline as measured by the LDI-B (ie,
baseline LDI-B score >0)
Psoriasis/Nail Endpoints
Time course of response to treatment over 52 weeks as measured by:

Change from baseline in body surface area (BSA) 

Proportion of patients who achieve the following PASI scores:  
PASI 75, PASI 90, or PASI 100 (defined as 75%, 90%, and 100% 
improvement from baseline in PASI criteria, respectively)

Proportion of patients achieving an absolute PASI score ≤1 or ≤2 or ≤3

Change from baseline in the Nail Psoriasis Severity Index (NAPSI)
Fingernails score in the subgroup of patients with fingernail 
involvement at baseline (ie, baseline NAPSI Fingernails score >0)
QoL Endpoints
Time course of response to treatment over 52 weeks as measured by:

Change from baseline in the Itch Numeric Rating Scale (NRS) score

Proportion of patients with Itch NRS score equal to 0 

Change from baseline in Fatigue Severity NRS score

Change from baseline in Medical Outcomes Study 36-Item Short Form 
Health Survey (SF-36) 
o
Physical Component Summary score 
o
Mental Component Summary score

Change from baseline in measures of health utility (European Quality of 
Life–5 Dimensions 5 Level health outcomes instrument [EQ-5D-5L])

Change from baseline in Dermatology Life Quality Index (DLQI) 
total score

Change from baseline in Treatment Satisfaction Questionnaire 
Safety

Change from baseline in Columbia‒Suicide Severity Rating 
Scale (C-SSRS)

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5.
Study Design
5.1.
Overall Design
Study RHCF is a Phase 3b/4, multicenter, randomized, open-label, parallel-group study with 
blinded outcomes assessments evaluating the efficacy and safety of ixekizumab versus 
adalimumab in patients with PsA who are bDMARD naive during a 52-week treatment period.
The study will consist of 3 periods:

Period 1:  Screening Period (Visit 1) up to 28 days before randomization (Visit 2)

Period 2:  Open-Label Treatment Period (Visit 2 through Visit 11) from Week 0 to 
Week 52

Period 3:  Post-Treatment Follow-Up Period occurring from last treatment visit during 
Period 2 or Early Termination Visit (ETV) up to a minimum of 12 weeks after that visit  
All patients randomized to ixekizumab will receive a starting dose of 160 mg at randomization 
(Visit 2 [Week 0]).  Patients with moderate-to-severe plaque Ps will receive ixekizumab 80 mg 
Q2W from Week 2 to Week 12 and Q4W thereafter. Patients not meeting criteria for 
moderate-to-severe plaque Ps at randomization will receive ixekizumab 80 mg Q4W starting at 
Week 4.
Patients randomized to adalimumab with moderate-to-severe plaque Ps will receive a starting 
dose of 80 mg at randomization (Visit 2 [Week 0]) followed by 40 mg Q2W starting at Week 1.  
Patients not meeting criteria for moderate-to-severe plaque Ps will receive a starting dose of 
40 mg at randomization (Visit 2) followed by 40 mg Q2W starting at Week 2 (see Section 7.1 for 
details regarding treatments administered).
Figure RHCF.5.1 illustrates the study design.

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Abbreviations:  D = days; LTV = last treatment visit during Period 2 or Early Termination Visit; V = visit; W = week.
a See Section 7.1 for dosing details.
Figure RHCF.5.1.
Illustration of study design for Clinical Protocol I1F-MC-RHCF.

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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 study treatment who have received at least 1 dose of investigational 
product will continue to the ETV before proceeding to the Post-Treatment Follow-Up Period 
(Period 3).  
All treatment groups are described in Section 7, and administration of the investigational product 
is described in Section 7.1.
Excluded and restricted therapies are detailed in Section 7.7.
5.1.1. Screening Period (Period 1)
The duration of the Screening Period (Period 1) will be up to 28 days before randomization at 
(Visit 2) in the Open-Label Treatment Period (Period 2) 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).  See Section 9.4.4.2 for details regarding required 
tuberculosis (TB) testing.  
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.
5.1.2. Open-Label Treatment Period (Period 2)
The Open-Label Treatment Period (Period 2) will occur from Week 0 (randomization; Visit 2) to 
Week 52 (Visit 11).  See Section 7 and Table RHCF.7.1 for treatments administered during the 
Open-Label Treatment Period.
At Week 0 (randomization, Visit 2), routine safety assessments, laboratory tests, and clinical 
efficacy assessments (including height, weight, and temperature, as well as review of habits) will 
be performed on eligible patients according to the Schedule of Activities (Section 2).  Patients 
will be randomized at a 1:1 ratio to either ixekizumab 80 mg or adalimumab 40 mg.  
During the Open-Label Treatment Period, safety and efficacy parameters in participating patients 
will be evaluated according to the Schedule of Activities (Section 2).  
Patients who permanently discontinue from study treatment for any reason during this period 
will continue to the ETV before entering the Post-Treatment Follow-Up Period (Period 3; 
Section 5.1.3).

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5.1.3. Post-Treatment Follow-Up Period (Period 3)
All patients receiving at least 1 dose of investigational product will enter the Post-Treatment 
Follow-Up Period (Period 3), occurring from last treatment visit (LTV) during Period 2 or ETV 
up to a minimum of 12 weeks after that visit.  
The required study visits should occur 4 weeks (Visit 801) and 12 weeks (Visit 802) after the last 
regularly scheduled visit in Period 2 (or the date of the patient’s ETV), except for patients with a 
concurrent infection that requires systemic anti-infective therapy (described below).  
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.  
If, at the last scheduled visit or ETV, a patient’s neutrophil count is <1500 cells/L 
(<1.50 × 103/µL or <1.50 GI/L) and less than the patient's baseline neutrophil count, the 
following measures should be taken:

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 the Post-Treatment 
Follow-Up Period (Period 3) design at Visits 801 (4 weeks after 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.

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 the Post-Treatment Follow-Up Period (Period 3) design, 
Visits 801 (4 weeks post ETV or last regularly scheduled visit), 802, and 803 (if 
necessary); additional visits may be required depending on the degree of neutropenia.

For Visit 801 and subsequent visits, the following monitoring applies:
o
As long as a patient’s neutrophil count is <1000 cells/L (<1.00 × 103/µL or 
<1.00 GI/L) at any follow-up visit, the patient should return for additional visits at 
least Q4W (unscheduled visits may be required).  
o
As long as a patient’s neutrophil count is ≥1000 cells/L and <1500 cells/L 
(≥1.00 × 103/µL and <1.50 × 103/µL 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 (unscheduled visits may be required).  

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o
If at Visit 803 the patient’s neutrophil count remains <1500 cells/L 
(<1.50 × 103/µL or <1.50 GI/L) and less than the patient’s baseline neutrophil 
count or if the investigator deems additional follow-up may be necessary, the 
investigator in consultation with Eli Lilly and Company (Lilly) or qualified 
designee will determine the appropriate management of the patient and the 
appropriate timing of additional contact(s) or visit(s).
o
If at Visit 802 or Visit 803 the patient’s neutrophil count is ≥1500 cells/L 
(≥1.50 × 103/µL 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 deems additional follow-up 
necessary.
For patients who completed or discontinued study treatment and have entered the Post-Treatment 
Follow-Up Period (Period 3), PsA therapy with another agent is allowed, as determined 
appropriate by the investigator.
5.2.
Number of Participants
Approximately 917 participants will be screened (assuming a 40% screen failure rate) to achieve 
randomization of 550 participants (275 per treatment group) and approximately 396 patients are 
expected to complete Week 52 (assuming 72% completion rate at Week 52).  
5.3.
End of Study Definition
End of the trial is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last randomized patient.
5.4.
Scientific Rationale for Study Design
See Section 3.1 for scientific rationale for study design.
5.5.
Justification for Dose
Protocol RHCF will include a starting dose of ixekizumab 160 mg for all patients randomized to 
ixekizumab followed by either ixekizumab 80 mg Q4W for patients not meeting criteria for
moderate-to-severe plaque Ps or ixekizumab 80 mg Q2W (until Week 12) and then Q4W for 
patients with moderate-to-severe Ps. 
Given the similar benefit/risk profile of the 2 dosing regimens studied in the pivotal Phase 3 
studies, the dose justification for patients with PsA includes the following:  
Dose Justification for Patients with PsA without Coexistent Moderate-to-Severe Plaque 
Psoriasis
Rationale:  Studies RHAP and RHBE examined the effect of 2 dose regimens (80 mg Q2W and 
80 mg Q4W) of ixekizumab compared to placebo in patients with active PsA.  Overall, there 
were no clinically meaningful differences between the ixekizumab 80 mg Q2W and Q4W dosing 
regimens (Mease et al. 2017).  The less-frequent ixekizumab regimen (Q4W) provided 
therapeutic benefit comparable to the more frequent regimen (Q2W) across a range of efficacy 

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endpoints up to Week 24 (Studies RHBE and RHAP) with efficacy sustained through Week 52
(Study RHAP) (Mease et al. 2016).  While there were some numeric differences, the overall 
safety profiles were similar for the Q2W and Q4W dosing regimens.  There were no unexpected 
findings in safety analyses, including within subgroups, across the 2 ixekizumab dosing regimens
based on the previously recognized safety profile from the psoriasis clinical development 
program.  The findings were confirmed with the exposure-response analyses of efficacy and 
safety.
Dose Justification for Patients with PsA with Coexistent Moderate-to-Severe Plaque 
Psoriasis
Rationale:  Evidence from the pivotal Phase 3 trials for moderate-to-severe plaque psoriasis 
(Studies RHAZ, RHBA, and RHBC) demonstrated additional clinical benefit on skin measures 
for the ixekizumab 80 mg Q2W dosing regimen versus the Q4W dosing regimen at Week 12
(Gordon et al. 2016).  In the pivotal Phase 3 studies for PsA, this additional clinical benefit was 
observed in patients with PsA who had higher levels of skin involvement (ie, BSA ≥10%) and 
those defined as having coexistent moderate-to-severe plaque psoriasis (Studies RHBE and 
RHAP).  Given there were no meaningful differences in safety between these dosing regimens in 
patients defined as having coexistent moderate-to-severe plaque psoriasis, it is recommended that 
such patients use the dosing regimen approved for patients with moderate-to-severe plaque 
psoriasis.
Dose Justification for the 52-Week Study Duration
In addition, long-term efficacy and safety were evaluated for up to 52 weeks in Study RHAP.  
For patients who remained on ixekizumab after 24 weeks of treatment, durability of the 
therapeutic effects was observed for up to 52 weeks of treatment across relevant clinical domains 
of PsA, including the signs and symptoms of disease activity, as represented by ACR20/50/70 
responses; physical function, as assessed by HAQ-DI; and skin manifestations of psoriasis, as 
assessed by PASI 75/90/100, indicating clinically meaningful responses.  The overall efficacy 
findings when placed in the context of the safety results from the Extension Period for the 
ixekizumab dosing regimens of this global, multicenter study are consistent with a favorable 
benefit/risk profile for the long-term treatment with ixekizumab in patients with active PsA
(Mease et al. 2016).  
Lilly considers it appropriate to evaluate these 2 dose regimens in Study RHCF with regard to:

The positive efficacy results (eg, primary endpoint achieved in the bDMARD naive 
patients) and the currently known safety profile from Study RHAP

The overall consistency of the safety profile of ixekizumab across the patient populations 
studied thus far, including Ps, RA, and PsA

The recommended dose regimen for the treatment of PsA and moderate-to-severe plaque 
psoriasis, respectively.
The evidence indicates a favorable benefit/risk profile that supports the conduct of the proposed 
PsA study, Study RHCF.

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Adalimumab 40 mg subcutaneous (SC) Q2W was selected as the comparator because it is an
approved therapy for the treatment of PsA and reflects the bDMARD treatment considered to be 
a standard of care.  Adalimumab will be dosed according to its approved labelling.  The subset of 
patients with PsA associated with moderate-to-severe plaque psoriasis will receive the dosing 
regimen approved for the treatment of moderate-to-severe plaque psoriasis.  
  

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6.
Study Population
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 at 
screening:
Type of Patient and Disease Characteristics
Patients with a documented diagnosis of PsA for at least 6 months fulfilling the Classification for 
Psoriatic Arthritis (CASPAR) and the activity of disease as defined by the presence of at least 
3 swollen joints (66 joints) and 3 tender joints (68 joints) in patients who are bDMARD naive.  
Patients must have active psoriatic skin lesions (plaque) of plaque psoriasis with a BSA of at 
least 3%.  
Patient Characteristics
[1]
Are male or female patients 18 years or older
[1a]
Male patients agree to use a reliable method of birth control 
during the study.  
[1b] 
Female patients:
Are women of childbearing potential who test negative for pregnancy and agree to
use a reliable method of birth control or remain abstinent during the study and for 
at least 12 weeks after the last dose of investigational product, whichever is 
longer.  Methods of contraception considered acceptable when used properly 
include oral contraceptives, contraceptive patch, injectable or implantable 
contraceptives, intrauterine device, vaginal ring, diaphragm with contraceptive 
gel, or condom with contraceptive foam.
OR
Are women of nonchildbearing potential, defined as:
Women who have had surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation);
OR
Women who are ≥60 years of age;
OR
Women ≥40 and <60 years of age who have had a cessation of menses for
≥12 months and a FSH test confirming nonchildbearing potential (≥40 mIU/mL).

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[2]
Have a documented diagnosis of PsA for at least 6 months and currently 
meet the CASPAR classification criteria.
[3] 
Have active PsA defined as the presence of at least 3/68 tender and at least 
3/66 swollen joints at Visit 1 (Screening) and Visit 2 (Week 0).
[4] 
Have active psoriatic skin lesions (plaque psoriasis) with a BSA ≥3% at 
Visit 1 (Screening) and Visit 2 (Week 0).
[50]
Have had an inadequate response when treated with 1 or more 
csDMARDs.
Informed Consent
[5] 
Have given written informed consent approved by Lilly, or its designee, 
and Institutional Review Board/Ethical Review Board (ERB) governing 
the site.
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening:
[6] 
Are currently enrolled in any other clinical trial involving an 
investigational product or any other type of medical research judged not to 
be scientifically or medically compatible with this study
[7]
Have received any prior, or are currently receiving, treatment with any 
bDMARD therapy or small-molecule for PsA or for psoriasis, including 
investigational therapies (such as but not limited to TNF inhibitors, IL-1 
receptor antagonists, IL-6 inhibitors, anti-IL-12/23p40 therapies, T cell or 
B cell targeted therapies, or Janus kinase inhibitors).  
Exception: previous treatment of phosphodiesterase type 4 inhibitors will be 
permitted. Treatment with phosphodiesterase type 4 inhibitors must have been
discontinued at least 8 weeks before randomization (Visit 2).
[8] 
Have previously completed or withdrawn from this study or any other 
study investigating ixekizumab or other IL-17 inhibitors, eg, anti-IL-17 or 
anti-IL-17 receptor (anti-IL-17R) monoclonal antibodies.
[9] 
Have a history of drug-induced Ps.
[10] 
Have used csDMARDs other than MTX, leflunomide, sulfasalazine, or 
cyclosporine in the 8 weeks prior to randomization (Visit 2).
Have discontinued MTX, sulfasalazine, or cyclosporine within 12 weeks prior to 
randomization.

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If taking MTX, leflunomide, sulfasalazine, or cyclosporine, must have been 
treated for at least 12 weeks prior to randomization and on a stable dose for at 
least 8 weeks prior to randomization, as follows: oral or parenteral MTX = 10 to 
25 mg/week, leflunomide = 20 mg/day, sulfasalazine = up to 3 g/day, or 
cyclosporine up to 5 mg/kg/day. The dose of these allowed concomitant 
medications must remain unchanged during the first 24 weeks of the Open-Label 
Treatment Period unless changes are required for safety issues. Local standard of 
care should be followed for concomitant administration of folic acid with MTX.  
[11] 
Have discontinued leflunomide within 4 weeks prior to randomization or 
have received leflunomide from 4 to 12 weeks prior to randomization and 
have not undergone a drug elimination procedure.
[12] 
Use of oral corticosteroids at average daily doses of >10 mg/day of 
prednisone or its equivalent, or use of variable doses of any oral 
corticosteroids, within 4 weeks prior to randomization (Visit 2).
[13] 
Have received any parenteral glucocorticoid administered by 
intraarticular, intramuscular, or intravenous (IV) injection within 6 weeks 
prior to randomization, or for whom a parenteral injection of 
glucocorticosteroids is anticipated during the first 24 weeks of the 
Open-Label Treatment Period.
[14] 
Concomitant use of nonsteroidal anti-inflammatory drugs or 
cyclooxygenase-2 inhibitors, unless the patient is on a stable dose for at 
least 2 weeks prior to randomization (Visit 2).
[15] 
Use of any opiate analgesic at average daily doses of >30 mg/day of 
morphine or its equivalent or use of variable doses of any opiate analgesic 
within 6 weeks prior to randomization (Visit 2).
[16] 
Have received systemic nonbiologic Ps therapy other than csDMARDs or 
corticosteroids as indicated above (including, but not limited to oral
psoralens and ultraviolet A light therapy oral retinoids, thioguanine, 
hydroxyurea, sirolimus, azathioprine, fumaric acid derivatives, or 
1, 25 dihydroxy vitamin D3 and analogs) or phototherapy (including either 
oral and topical ultraviolet A, ultraviolet B or self-treatment with tanning 
beds or therapeutic sunbathing) within 4 weeks prior to randomization
(Visit 2);
OR
Had topical Ps treatment within the previous 2 weeks prior to randomization
(Visit 2).
Exceptions: weak potency (WHO Group 1 classification) topical steroids will be 
permitted.
[17] 
Patients with plaque Ps, who cannot avoid use of tanning booths for at 
least 4 weeks prior to randomization (Visit 2) and during the study.

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[18] 
Have a known allergy or hypersensitivity to any biologic therapy that 
would pose an unacceptable risk to the patient if participating in this 
study.
[19] 
Have ever received efalizumab or natalizumab or other agents that target 
alpha-4-integrin.
[20] 
Had a live vaccination within 12 weeks prior to randomization (Visit 2), or 
intend to have a live vaccination during the course of the study, or within 
12 weeks of completing treatment in this study, or have participated in a 
vaccine clinical study within 12 weeks prior to randomization.  
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 prior to therapy.  
Note: Killed/inactive or subunit vaccines are expected to be safe; however, their 
efficacy with concomitant ixekizumab treatment is unknown.
[21]
Had a vaccination with Bacillus Calmette-Guérin (BCG) within 12 months 
prior to randomization (Visit 2), or intend to have this vaccination with 
BCG during the course of the study, or within 12 months of completing 
treatment in this study.
[22] 
Have a diagnosis of other inflammatory arthritic syndromes such as RA, 
ankylosing spondylitis, reactive arthritis, or enteropathic arthritis.
[23]
Have active Crohn’s disease or active ulcerative colitis (UC).
[24]
Have fibromyalgia or other chronic pain condition that would confound 
evaluation of the patient.
[25]
Have evidence of active vasculitis or uveitis.
[26]
Have had surgical treatment of a joint within 8 weeks prior to 
randomization or will require such up to Week 24.
[27]
Have had any major surgery within 8 weeks prior to randomization, or 
will require such during the study that in the opinion of the investigator 
and in consultation with Lilly or its designee would pose an unacceptable 
risk to the patient.
[28]
Have diagnosis or history of malignant disease within the 5 years prior to 
randomization (Visit 2). Note: Patients with successfully treated 
basal-cell carcinoma (no more than 3), squamous-cell carcinoma of the 
skin (no more than 2) within the 5 years prior to randomization may 
participate in the study.

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[29]
Presence of significant uncontrolled cerebrocardiovascular events (for 
example, myocardial infarction [MI], unstable angina, unstable arterial 
hypertension, moderate-to-severe [NYHA class III/IV] heart failure, or 
cerebrovascular accident), respiratory, hepatic, renal, gastrointestinal, 
endocrine, hematologic, neurologic or neuropsychiatric disorders, or
abnormal laboratory values, or illicit drug use (including cannabinoids, 
whether legalized or not) at screening 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.
[30]
Have a history of uncompensated heart failure, fluid overload, or MI, or 
evidence of new-onset ischemic heart disease or other serious cardiac 
disease, within 12 weeks prior to randomization (Visit 2).
[31]
Presence of significant uncontrolled neuropsychiatric disorder; have recent
history (within 30 days prior to screening visit (Visit 1) and any time 
between screening visit (Visit 1) and randomization (Visit 2) of a suicide
attempt; or 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 develops suicide-related behaviors as recorded 
on the C-SSRS at screening or randomization (Visit 2); or are clinically 
judged by the investigator to be at risk for suicide.
[32]
Have presence or personal history or family history (first degree relative) 
of demyelinating disorder.
[33]
Patients who have:

in the past 12 weeks prior to randomization:
o
had a serious infection (for example, pneumonia, cellulitis)
o
have been hospitalized for an infection
o
have received IV antibiotics for an infection 

or in the past 24 weeks prior to randomization had a serious bone or joint 
infection, 

or have ever had
o
an infection of an artificial joint
o
an infection that occurs with increased incidence in an 
immunocompromised host (including, but not limited to, 
Pneumocystis jirovecii pneumonia, active histoplasmosis, or 
coccidioidomycosis); or have a known immunodeficiency.
[34]
Have a known immunodeficiency or are immunocompromised to an 
extent such that participation in the study would pose an unacceptable risk 
to the patient.
[35]
Have or had a herpes zoster or any other clinically apparent varicella-
zoster virus infection within 12 weeks prior to randomization (Visit 2).

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[36]
Have evidence or suspicion of active or latent TB (refer to Section 9.4.4.2
for details on determining full TB exclusion criteria).
[37]
Have any other active or recent infection other than mentioned above 
within 4 weeks of randomization (Visit 2) that, in the opinion of the 
investigator, would pose an unacceptable risk to the patient if participating 
in the study.
Note:  These patients may be rescreened one time ≥4 weeks after documented 
resolution of symptoms.
[38]
Have a sitting systolic blood pressure >160 mm Hg or diastolic blood 
pressure >100 mm Hg.
Note: Determined by 2 consecutive elevated readings. If an initial sitting blood 
pressure reading exceeds this limit, the blood pressure may be repeated once after 
the patient has rested sitting for ≥10 minutes. If the repeat value is less than the 
criterion limits, the second value may be accepted.
[39]
Are positive for human immunodeficiency virus serology (HIV), ie, 
positive for human immunodeficiency virus antibody (HIVAb).
[40]
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.
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 9.4.5.4.
[41]
Have evidence of or test positive for hepatitis C virus (HCV). A positive 
test for HCV is defined as: positive for hepatitis C antibody (anti-
HCVAb) and positive via a confirmatory test for HCV (for example, HCV 
polymerase chain reaction).
[42]
Laboratory tests may not be repeated unless there is a technical error 
or clinical reason to believe a result may be erroneous. Laboratory 
tests can be repeated a maximum of 1 time, and results must be received 
and reviewed prior to randomization (Visit 2). For eligibility, the most 
recent lab panel must not meet any of the following criteria:
[42a]
Neutrophil count <1500 cells/μL
[42b]
Lymphocyte count <800 cells/μL
[42c]
Platelet count <100,000 cells/μL
[42d]
Aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) >2.5 times the upper limit of normal (ULN)

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[42e]
Total white blood cell count <3000 cells/μL
[42f]
Hemoglobin <8.5 g/dL (85.0 g/L) for male patients and 
<8.0 g/dL (80 g/L) for female patients
[42g]
Serum creatinine >2.0 mg/dL
[42h]
Have clinical laboratory test results at screening that are outside 
the normal reference range for the population and are 
considered clinically significant, per investigator assessment.
[43]
Have any condition or contraindication as addressed in the local labelling
for adalimumab that would preclude the patient from participating in this 
protocol.
[44]
Have any other condition that precludes the patient from following and 
completing the protocol, in the opinion of the investigator.
[45]
Are women who are breastfeeding.
[46]
Are study 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 its designee or are employees of third-party 
organizations involved in the study.
[48]
Are currently enrolled in, or discontinued from a clinical trial involving an 
investigational product or nonapproved use of a drug or device within the 
last 4 weeks or a period of at least 5 half-lives of the last administration of 
the drug, whichever is longer, or are concurrently enrolled in any other 
type of medical research judged not to be scientifically or medically 
compatible with this study.
[49]
Are unwilling or unable to comply with the use of a data collection device 
to directly record data from the patient.
6.3.
Lifestyle Restrictions
Patients should be instructed to inform the blood bank of their participation in this study and 
consult with the investigator before donating blood or blood products during participation in the 
study.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened under the following circumstances:  patients who test positive for latent TB at 
screening may be rescreened following appropriate treatment as described in Section 9.4.4.2.  
Additionally, patients who do not qualify at screening under Exclusion Criterion [37] may be 
rescreened once, 4 or more weeks after documented resolution of symptoms.  When rescreening 
is performed, the individual must sign a new ICF and will be assigned a new study identification 
number.

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7. Treatments
7.1.
Treatments Administered
This study involves a comparison of ixekizumab with adalimumab.  Table RHCF.7.1 shows the 
treatment regimens.  
Table RHCF.7.1.
Treatment Regimens
Name of Drug
Starting Dose
Dosage
Frequency
Route of 
Administration
Ixekizumab
160 mg for all patients
80 mg
Q2W from Week 2 to 
Week 12 and Q4W thereafter 
for patients with moderate-to-
severe plaque Ps
SC injection
Q4W starting at Week 4 for 
patients not meeting criteria 
for moderate-to-severe 
plaque Ps
Adalimumab
80 mg for patients with 
moderate-to-severe 
plaque Ps 
40 mg
Q2W starting at Week 1 for
patients with moderate-to-
severe plaque Ps
SC injection
40 mg for patients not
meeting criteria for 
moderate-to-severe 
plaque Ps
Q2W starting at Week 2 for 
patients not meeting criteria 
for moderate-to-severe 
plaque Ps
Abbreviations:  Ps = psoriasis; Q2W = every 2 weeks; Q4W = every 4 weeks; SC = subcutaneous.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational agent(s) to the patient/site 
personnel 

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

at the end of the study returning all unused medication to Lilly, or its designee,
unless the sponsor and sites have agreed all unused medication is to be destroyed 
by the site, as allowed by local law

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7.1.1. Administration of Investigational Product
Injections will be administered subcutaneously by the patient or caregiver after training by the 
clinical staff.
Training: At randomization (Visit 2), patients randomized to ixekizumab and patients with 
moderate-to-severe plaque Ps symptoms randomized to adalimumab will receive 2 injections.  
For training purposes, the proper procedures for administration of the initial injection will be 
performed by clinical staff.  The second injection of study drug will be administered by the 
patient or caregiver under site personnel supervision.  Thereafter, study drug should be 
administered by the patient or caregiver.  If additional training is necessary, an injection may be 
administered by the patient or caregiver under the supervision of clinical staff.
Administration: If the patient is unable to administer the injection, a caregiver who will also be 
trained under supervision of site staff may administer the study drug.  All subsequent injections 
will be administered by the patient or caregiver and should be administered unsupervised by the 
clinical staff (see Section 2).  It is recommended that for these subsequent injections, the 
patient/caregiver administer the study drug outside the trial site, preferably at the patient’s home.  
If the patient or caregiver is not able to administer the second injection of the starting dose or any 
dose throughout the study, study site personnel may administer that injection.
Refer to the appropriate directions for use provided by the sponsor for the study drug.  
Study Drug Administration Logs will be dispensed to each patient as needed for recording 
pertinent data about each injection; details of the use of these logs are provided in Section 7.2.1.
Observation: Patients should remain under observation for at least 1 hour after dosing at
randomization (Visit 2) to allow for observation for any AEs and collection of postinjection
sitting BP and pulse measurements approximately 1 hour after administration of study drug (see 
Section 2).
7.1.2. Packaging and Labeling
Clinical trial materials will be labeled according to the country’s regulatory requirements.  All 
investigational products will be stored, inventoried, reconciled, and destroyed according to 
applicable regulations.  
Ixekizumab will be supplied as an injectable solution in 1-mL, single-dose, prefilled, disposable 
manual syringes with study-specific labels. Each syringe of ixekizumab is designed to deliver 
ixekizumab 80 mg.  
Adalimumab 40 mg will be supplied as single-dose, prefilled, disposable manual syringes with 
study-specific labels.  
Syringes will be supplied in cartons with the appropriate quantity of syringes specific to the 
planned dispensing schedule of the investigational product.

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7.2.
Method of Treatment Assignment
Patients who meet all Visit 1 and Visit 2 eligibility criteria for enrollment will be randomized at 
Visit 2 (Week 0) in a 1:1 ratio to open-label treatment with ixekizumab or adalimumab at 
Week 0 (Visit 2).  Assignment to treatment groups will be determined by a computer-generated 
random sequence using an interactive web-response system (IWRS).  The IWRS will be used to 
assign investigational product to each patient.  Site personnel will confirm that they have located 
the correct investigational product by entering a confirmation number found on the 
investigational product into the IWRS.  The randomization will be stratified by concomitant 
csDMARD use at baseline (Yes vs No) and moderate-to-severe plaque psoriasis involvement
(Yes vs No). 
7.2.1. Selection and Timing of Doses
Patients taking ixekizumab or adalimumab will receive the open-label study drug beginning on 
the day of Visit 2 (Week 0).  
Study drug should be administered on the same day of the week, at approximately the same time 
each day, as much as possible. If an injection is missed, the missed dose should be administered 
as soon as possible.  Injection(s) for missed dose(s) should not be given within 5 days of the next 
scheduled dose; injections should be ≥5 days apart. Dates of subsequent study visits should not 
be modified according to this delay.
A paper Study Drug Administration Log will be completed by randomized patients for each 
injection throughout study participation.  The data from the Study Drug Administration Log must 
be transcribed into the electronic case report form (eCRF) by site personnel.
Patients will be instructed to contact their study site in the event of an injection problem.  In 
addition, site personnel review all Study Drug Administration Logs at each visit to identify any 
product complaints, and they will complete a product complaint form for each operation failure 
reported on a Study Drug Administration Log (see Section 9.2.2 for additional instructions 
regarding complaint handling).
7.3.
Blinding
This is an open-label study where treatment allocation is revealed after randomization.  
Specifically:

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
A blinded assessor will complete the following assessments:
o
TJC/SJC
o
Psoriasis Area and Severity Index (PASI)
o
Percentage of BSA
o
Enthesitis
o
LDI-B
o
NAPSI Fingernails
o
sPGA
The blinded rater must not know the patient’s treatment allocation and is not allowed to be 
otherwise involved in the study procedures.  
The patients will be clearly instructed not to communicate with the blinded assessor except for 
communication required to conduct the blinded data assessment.  During each procedure 
conducted by a blinded assessor, a third person from the study site (eg, a nurse) will be present to 
observe and document that blinding of the assessor is maintained.  If a blinded assessor is 
unintentionally unblinded, he/she must be replaced as an assessor.  
The availability of a blinded assessor is a prerequisite for study site selection.
7.4.
Dosage Modification
Not applicable.  
7.5.
Preparation/Handling/Storage/Accountability
Investigational products will be supplied by Lilly or its representative, in accordance with current 
Good Manufacturing Practices, and will be supplied with lot numbers, expiry dates, and 
certificates of analysis, as applicable.  
Investigational product will be stored refrigerated (2C to 8C; 36F to 46F) in its original 
carton to protect from light.  Investigational product should not be frozen or shaken.  
Sites will be required to monitor temperature of the on-site storage conditions of investigational 
products.  
7.6.
Treatment Compliance
Every attempt will be made to select patients who have the ability to understand and comply with 
study instructions.  The investigator is responsible for discussing methods to ensure high 
treatment compliance with the patient before randomization.  
Randomized patients will record the date and time of administration of investigational product in 
a Study Drug Administration Log throughout their participation in the study.  The data from the 
Study Drug Administration Log must be transcribed into the eCRF by site personnel.  
Patient compliance with study medication will be assessed at each visit.  Compliance will be 
assessed by review of the Study Drug Administration Log, return of empty investigational 
product packaging, and/or direct questioning.  

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The patient should be instructed to retain all empty study drug packaging after using up the 
medication and to bring the empty packaging and any unused medication to the study site at each 
visit, so that the site staff can record the amount of medication used since the last visit.  
Deviation(s) from the prescribed dosage regimen should be documented.
If a patient is noncompliant with study procedures and/or study drug administration, the 
investigator should assess the patient to determine the reason for noncompliance and educate 
and/or manage the patient as appropriate to improve compliance.  If, in consultation with Lilly or 
its designee, the noncompliance is deemed to be significant or if further noncompliance occurs, 
the patient should be discontinued from the study (see Section 10.3.2.4 Treatment Compliance).
In some circumstances, it may be necessary to temporarily interrupt treatment (see Section 8.1.2
and Section 9.4.5).  Any necessary interruption of treatment should be considered when 
determining noncompliance.  
7.7.
Concomitant Therapy
All concomitant medication taken during the study must be recorded on the Concomitant 
Medication case report form (eCRF) at the study visits indicated in the Schedule of Activities 
(Section 2).  Treatment with concomitant PsA 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 below.  Patients taking permitted PsA medications should be on stable doses at 
randomization (Visit 2) and through the first 24 weeks of the Open-Label Treatment Period, as 
specified below, unless changes are required for safety reasons.  Table RHCF.7.2, Table
RHCF.7.3, and Table RHCF.7.4 summarize concomitant medications that are and are not 
permitted and the conditions for use during the study for those which are permitted.
Table RHCF.7.2.
Concomitant Medications Permitted/Not Permitted in the 
Open-Label Treatment Period from Week 0 to Week 24 for 
Treatment of PsA and Chronic Conditions 
Drug Class
As Needed
Chronic Use
Conditions for Use
bDMARDs
N
N
Not allowed 
PDE4 or JAK inhibitors
N
N
Not allowed
csDMARDs
N
Y
Stable dose allowed. Stable doses with no dose 
adjustments, changes, and/or introduction of a 
new csDMARD
Allowed doses:

Oral or parenteral MTX; 10 to 25 mg/week

Leflunomide:  up to 20 mg/day

Sulfasalazine:  up to 3 g/day

Cyclosporine:  up to 5 mg/kg/day
Live vaccines (including 
BCG)
N
N
Not allowed
Phototherapy
N
N
Not allowed

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Drug Class
As Needed
Chronic Use
Conditions for Use
NSAIDs, COX-2 
inhibitors
N
Y
Stable doses with no dose adjustments, changes, 
and/or introduction of a new NSAID.
Allowed up to the maximum recommended doses 
for pain.
Aspirin (doses not exceeding 350 mg/day) may 
be taken to manage cardiovascular risk.
Opiate analgesics
N
Y
Stable doses with no dose adjustments, changes, 
and/or introduction of a new opiate analgesic.
May be used at average daily doses ≤30 mg/day 
of morphine or its equivalent
Nonopiod analgesics 
(paracetamol and 
acetaminophen)
Y
Y
Allowed up to the maximum recommended doses 
for pain.
May be administered as needed basis during the 
study, but should be withheld within 24 hours of 
a visit.
May be used at doses ≤1000 mg for 
premedication for allergic/hypersensitivity 
reactions from injections (see Section 7.8.3) 
Topical steroids
Y
Y
Weak potency (WHO Group 1 classification
only as needed, but not within 24 hours of PASI 
assessment 
Oral corticosteroids
N
Y
Stable doses with no dose adjustments, changes, 
and/or introduction of a new oral corticosteroid
Allowed doses:
≤ an average daily dose of 10 mg/day of 
prednisone or equivalent)
Intravascular and IM 
glucocorticoid
N
N
Not allowed
Intra-articular 
glucocorticoid
N
N
Not allowed
Inhaled steroids
Y
Y
As needed or regular use for asthma is permitted
Nasal corticosteroids
Y
Y
Use for allergies is permitted
Medicated shampoos
Topical
moisturizers/emollients 
and other 
nonprescription topical 
products
Bath oils and oatmeal 
bath preparations
Y
Y
Shampoos that do not contain >3% salicylic acid, 
corticosteroids, coal tar, or vitamin D3 analogs
Topical moisturizers/emollients and other 
nonprescription topical products that do not 
contain, urea, >3% salicylic acid, alpha- or beta-
hydroxyl acids, corticosteroids, or vitamin D3 
analogs
Allowed
These topical therapies are not to be used within 
12 hours prior to a study visit

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Abbreviations:  BCG = Bacillus Calmette-Guérin; bDMARD = biological disease-modifying anti-rheumatic drugs; 
COX-2 = cyclooxygenase-2; csDMARD = conventional synthetic disease-modifying anti-rheumatic drugs; 
IM = intramuscular; JAK = Janus kinase; MTX = methotrexate; N = No; NSAID = nonsteroidal anti-
inflammatory drug; PASI = Psoriasis Area and Severity Index; PDE4 = phosphodiesterase type 4; Y = Yes; 
WHO = World Health Organization.
Table RHCF.7.3.
Concomitant Medications Permitted/Not Permitted in the 
Open-Label Treatment Period from Week 24 to Week 52 for 
Treatment of PsA and Chronic Conditions 
Drug Class
As Needed
Chronic Use
Conditions for Use
bDMARDs 
N
N
Not allowed 
PDE4 or JAK inhibitors
N
N
Not allowed
csDMARDs
N
Y
Allowed doses:

Oral or parenteral MTX; 10 to 25 mg/week

Leflunomide:  up to 20 mg/day

Sulfasalazine:  up to 3 g/day

Cyclosporine:  up to 5 mg/kg/day 
Live vaccines (including 
BCG)
N
N
Not allowed
Phototherapy
N
N
Not allowed
NSAIDs, COX-2 
inhibitors
Y
Y
Allowed up to the maximum recommended doses 
for pain. 
Aspirin (doses not exceeding 350 mg/day) may 
be taken to manage cardiovascular risk.
Opiate analgesics
Y
Y
Allowed
Nonopiod analgesics 
(paracetamol and 
acetaminophen)
Y
Y
Allowed up to the maximum recommended doses 
for pain.
May be administered as needed basis during the 
study, but should be withheld within 24 hours of 
a visit.
May be used at doses ≤1000 mg for 
premedication for allergic/hypersensitivity 
reactions from injections (see Section 7.8.3) 
Topical steroids
Y
Y
Allowed as needed, but not within 24 hours of 
PASI assessment 
Oral corticosteroids
Y
Y
Allowed doses:
≤ an average daily dose of 10 mg/day of 
prednisone or equivalent) 
Intravascular and IM 
glucocorticoid
N
N
Not allowed
Intra-articular 
glucocorticoid
N
N
Allowed on a limited basis:  it is recommended 
that there be no more than 1 injection (one 
injection = one large joint or up to 5 small joints 
or one soft tissue)
Inhaled steroids
Y
Y
As needed or regular use for asthma is permitted
Nasal corticosteroids
Y
Y
Use for allergies is permitted

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Drug Class
As Needed
Chronic Use
Conditions for Use
Medicated shampoos
Topical
moisturizers/emollients 
and other 
nonprescription topical 
products
Bath oils and oatmeal 
bath preparations
Y
Y
Allowed
Topical moisturizers/emollients and other 
nonprescription topical products that do not 
contain, urea, >3% salicylic acid, alpha- or beta-
hydroxyl acids, corticosteroids, or vitamin D3 
analogs
Allowed
These topical therapies are not to be used within 
12 hours prior to a study visit
Abbreviations:  BCG = Bacillus Calmette-Guérin; bDMARD = biological disease-modifying anti-rheumatic drugs; 
COX-2 = cyclooxygenase-2; csDMARD = conventional synthetic disease-modifying anti-rheumatic drugs; 
IM = intramuscular; JAK = Janus kinase; MTX = methotrexate; N = No; NSAID = nonsteroidal anti-
inflammatory drug; PASI = Psoriasis Area and Severity Index; PDE4 = phosphodiesterase type 4; Y = Yes; 
WHO = World Health Organization.
Table RHCF.7.4.
Allowed Concomitant Medications in the Post-Treatment Follow-Up 
Period (Period 3)
Drug Class
As Needed
Chronic Use
Conditions for Use
bDMARDs 
Y
Y
Allowed 
Follow local guidance; at the discretion of 
investigator
PDE4 or JAK inhibitors
Y
Y
Allowed
Follow local guidance; at the discretion of the 
investigator
csDMARDs
Y
Y
Allowed
Live vaccines (including 
BCG)
N
N
Not allowed
Phototherapy
Y
Y
Allowed
NSAIDs, COX-2 
inhibitors
Y
Y
Allowed 
Opiate analgesics
Y
Y
Allowed 
Nonopiod analgesics 
(paracetamol and 
acetaminophen)
Y
Y
Allowed 
Topical steroids
Y
Y
Allowed 
Oral corticosteroids
Y
Y
Allowed 
Intravascular and IM 
glucocorticoid
Y
Y
Allowed 
Intra-articular 
glucocorticoid
Y
Y
Allowed 
Inhaled steroids
Y
Y
As needed or regular use for asthma is permitted
Nasal corticosteroids
Y
Y
Use for allergies is permitted

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Drug Class
As Needed
Chronic Use
Conditions for Use
Medicated shampoos
Topical
moisturizers/emollients 
and other 
nonprescription topical 
products
Bath oils and oatmeal 
bath preparations
Y
Y
Allowed
Abbreviations:  BCG = Bacillus Calmette-Guérin; bDMARDs = biological disease-modifying anti-rheumatic drugs; 
COX-2 = cyclooxygenase-2; csDMARD = conventional synthetic disease-modifying anti-rheumatic drugs; 
IM = intramuscular; JAK = Janus kinase; MTX = methotrexate; N = No; NSAID = nonsteroidal anti-
inflammatory drug; PASI = Psoriasis Area and Severity Index; PDE4 = phosphodiesterase type 4; Y = Yes; 
WHO = World Health Organization.
To avoid any possible drug interactions for those patients randomized to adalimumab, please 
refer to the product labeling for adalimumab for further concomitant therapy restrictions.
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.  
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.
7.8.
Treatment after the End of the Study
7.8.1. Study Extensions
Not applicable.
7.8.2. Continued Access
Investigational product will not be made available to patients after the conclusion of the study.

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7.8.3. Special Treatment Considerations
All biological agents carry the risk of systemic allergic/hypersensitivity reactions.  
Clinical manifestations of these reactions may include, but are not limited to:

skin rash

pruritus (itching)

urticaria (hives)

angioedema (eg, swelling of the lips and/or tongue)

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 after an injection.  If a patient experiences an acute 
allergic/hypersensitivity reaction after an injection of investigational product, he or she should be 
managed appropriately and given instruction to receive relevant supportive care.  
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 (eg, injection-site erythema, 
injection-site pruritus).  Patients who develop clinically significant systemic 
allergic/hypersensitivity reactions after administration of investigational product who do not 
respond to symptomatic medication or result in clinical sequelae should be discontinued from 
study treatment and not receive further doses of investigational product, with or without 
premedication (see Section 8).  Medications considered appropriate for premedication include 
(but are not restricted to) acetaminophen/paracetamol up to 1000 mg and antihistamines (eg, oral 
diphenhydramine, 50 mg) given 30 to 60 minutes before investigational product injection.  
Patients may self-premedicate at home before administration of investigational product, 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 Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Discontinuation of the investigational product 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:

alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8X upper 
limit of normal (ULN)

alanine aminotransferase or AST >5X ULN for more than 2 weeks

alanine aminotransferase or AST >3X ULN and total bilirubin level (TBL) 
>2X ULN or prothrombin time >1.5X ULN

alanine aminotransferase or AST >3X ULN with the appearance of fatigue, 
nausea, vomiting, right upper-quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%)

alkaline phosphatase (ALP) >3X ULN

alkaline phosphatase >2.5X ULN and TBL >2X ULN

alkaline phosphatase >2.5X ULN 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 investigational product in the following 
circumstances:

Neutrophil (segmented) counts (see Section 9.4.5.3 for information on monitoring for 
neutropenia)
o
<500 cells/uL
o
≥500 and <1000 cells/uL (based on 2 test results; the second test performed
within 1 week from knowledge of the initial result).
o
≥1000 and <1500 cells/uL (based on 3 test results) and an infection that is not 
fully resolved.

Total white blood cell count <2000 cells/μL.

Lymphocyte count <500 cells/μL.

Platelet count <50,000 cells/μL.

Changes in blood pressure defined as sitting systolic blood pressure at ≥160 mm Hg plus 
≥20 mm Hg increase from baseline (Visit 2 [Week 0]), and/or diastolic blood pressure at 
≥100 mm Hg plus ≥10 mm Hg increase from baseline, that do not respond following 
maximal allowed intervention (see Section 9.4.5.1 for information on monitoring 
hypertension).

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
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 
of the investigational product and appropriate measures being taken.  In this case, Lilly or
its designee is to be notified immediately.

Clinically significant systemic hypersensitivity reaction after SC administration of 
investigational product 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 nonmelanoma skin cancers over any 12-month period during the 
study.

The patient develops symptoms suggestive of a lupus-like syndrome and is positive for 
antibodies against double-stranded DNA.

If the patient, for any reason, requires treatment with another therapeutic agent that has 
been demonstrated to be effective for the treatment of PsA or Ps, discontinuation from 
the study occurs prior to introduction of the new agent.

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study.

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 
develops suicide-related behaviors as recorded on the C-SSRS.  It is recommended that 
the subject be assessed by a psychiatrist or appropriately trained professional to assist in 
deciding whether the subject is to be discontinued from the study.

The patient develops any condition or contraindication as addressed in the local labelling
for adalimumab that would preclude the patient from continuing in this protocol.

The investigator or attending physician decides that the patient should be withdrawn from 
the study.

The patient requests to be withdrawn from the study.

The investigator or Lilly stops the patient’s participation in the study or Lilly stops the 
study for medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and good clinical practice (GCP).

The patient becomes HBV DNA positive.  The patient should be referred to a specialist 
physician.

The patient is diagnosed with an active TB infection.
If in consultation with Lilly or its designee noncompliance is deemed to be significant or if
further noncompliance occurs, the patient may be discontinued from the study (see 
Section 10.3.2.4 Treatment Compliance).
Any patient who permanently discontinues the study treatment for any reason will stop treatment 
and continue to the ETV prior to entering the Post-Treatment Follow-Up Period (Period 3).

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8.1.2. Temporary Discontinuation from Study Treatment 
In some circumstances, it may be necessary to temporarily interrupt treatment as a result of 
abnormal laboratory values (see Section 8.1.1), AEs (see Section 9.2), hypertension (see 
Section 9.4.5.1) abnormal hepatic laboratory values (see Section 9.4.5.2), neutropenia (see 
Section 9.4.5.3), hepatitis B laboratory findings (see Section 9.4.5.4), or inflammatory bowel 
disease (IBD) events (see Section 9.2.1.1) that may have an unclear relationship to 
investigational product.  See Section 9.4.4.2 for details regarding managing patients who test 
positive for TB at any time during the study.
Patients requiring surgery at any time during the study should interrupt administration of the 
investigational product beginning 8 weeks before the surgery, or as early as possible within 
8 weeks of surgery, and resume administration of the investigational product only after complete 
wound healing.
8.1.3. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the sponsor CRP and the investigator to 
determine if the patient may continue in the study.  If both 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 
investigational product.
8.2.
Discontinuation from the Study
Some possible reasons that may lead to permanent discontinuation include:

enrollment in any other clinical trial involving an investigational product 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 (GCP)

investigator decision
o
the investigator decides that the patient should be discontinued from the study
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

subject decision
o
the patient or the patient’s designee requests to be withdrawn from the study
Any patient who discontinues the study for any reason will stop treatment and continue to the
ETV prior to entering the Post-Treatment Follow-Up Period (Period 3).

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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 who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.  Site personnel must, at a minimum, make 2 phone attempts 
and send a certified letter or its equivalent in that region.

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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).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 4 lists the hepatic monitoring tests for treatment-emergent abnormality.
All study assessments except for the C-SSRS, Self-Harm, and Self-Harm Follow-Up will be 
completed electronically. 
For all assessments, the same assessor should perform each assessment for a given patient during 
the study to minimize interobserver variation.
9.1.
Efficacy Assessments
9.1.1. Primary Efficacy Assessments
9.1.1.1.
Combined Endpoint of American College of Rheumatology 50 Responder 
Index and Psoriasis Area and Severity Index 100 
In order to be considered a responder to the primary efficacy measure at Week 24 in this study, a 
patient must simultaneously achieve both ACR50 and PASI 100 responses.
ACR50 response is an efficacy measure for which a patient must satisfy the following:
1) ≥50% improvement from baseline in TJC and
2) ≥50% improvement from baseline in SJC and
3) ≥50% improvement from baseline in at least 3 of the following 5 ACR Core Set criteria:
a.
Patient’s Assessment of Pain Visual Analog Scale (VAS)
b. PatGA VAS
c.
PGA VAS
d. patient’s assessment of physical function as measured by the HAQ-DI
e.
acute-phase reactant as measured by high sensitivity (assay) CRP (hs-CRP)
PASI 100 is described in Section 9.1.2.1.  Patients achieving PASI 100 are defined as having an 
improvement of 100% in the PASI compared to baseline.
9.1.2. Secondary Efficacy Assessments
9.1.2.1.
Psoriasis Area and Severity Index (PASI 75, PASI 90, PASI 100)
The PASI will be administered by a blinded assessor.  The PASI is an accepted primary efficacy 
measurement for this phase of development of psoriasis 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 psoriasis 
up to 72 for the most severe disease (Fredriksson and Pettersson 1978).  The PASI has been the 
most frequently used endpoint and measure of psoriasis severity in clinical trials (EMA 2004; 

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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.  As minimum treatment response, 
the European and German guidelines mention a PASI 50 response.  Higher levels of clearance 
(PASI 90), as well as complete resolution of psoriasis (PASI 100), have become additional 
endpoints because of the increasing recognition of the association of higher clearance with 
greater health-related QoL (Puig 2015).  
Patients achieving PASI 75, 90, or 100 are defined as having an improvement of at least 75%, 
90%, or 100%, respectively, in the PASI compared to baseline.
Absolute PASI scores of ≤1, ≤2, or ≤3 may be considered as treatment targets for the 
management of plaque psoriasis.
9.1.2.2.
Percentage of Body Surface Area
The blinded assessor will evaluate the percentage involvement of psoriasis on each patient’s 
BSA on a continuous scale from 0% (no involvement) to 100% (full involvement), in which 1% 
corresponds to the size of the patient’s hand (including the palm, fingers, and thumb) (National 
Psoriasis Foundation [NPF] 2009).
9.1.2.3.
American College of Rheumatology 20 Responder Index
ACR20 response is a secondary efficacy measure for which a patient must satisfy the following:
1) ≥20% improvement from baseline in tender joint count (TJC) and
2) ≥20% improvement from baseline in swollen joint count (SJC) and
3) ≥20% improvement from baseline in at least 3 of the following 5 ACR Core Set criteria:
a.
Patient’s Assessment of Pain VAS
b. PatGA VAS
c.
PGA VAS
d. patient’s assessment of physical function as measured by the HAQ-DI
e.
acute-phase reactant as measured by high sensitivity (assay) CRP (hs-CRP)
9.1.2.3.1. American College of Rheumatology Core Set
a.
Tender Joint Count
TJC joint assessments will be performed by a blinded assessor. 
For ACR measures, the number of tender and painful joints will be determined by examination 
of 68 joints (34 joints on each side of the patient’s body).  Any joints that require intra-articular 
injections during the study (according to Section 7.7) should be excluded from evaluation from 
the time of the injection to the conclusion of the study.
Joints will be assessed for tenderness by pressure and joint manipulation on physical 
examination.  The patient will be asked for pain sensations on these manipulations and watched 
for spontaneous pain reactions.  Any positive response on pressure, movement, or both will then 
be translated into a single tender-versus-nontender dichotomy.
Missing, replaced, ankylosed, or arthrodesed joints will be identified by the investigator at the 
Screening Visit and will be excluded from evaluation during the trial.

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b.
Swollen Joint Count
SJC joint assessments will be performed by a blinded assessor.  
For ACR measures, the number of swollen joints will be determined by examination of 66 joints 
(33 joints on each side of the patient’s body).  Any joints that require intra-articular injections 
during the study (according to Section 7.7) should be excluded from evaluation from the time of 
the injection to the conclusion of the study.
Joints will be classified as either swollen or not swollen.  Swelling is defined as palpable 
fluctuating synovitis of the joint.  Swelling secondary to osteoarthritis will be assessed as not 
swollen, unless there is unmistakable fluctuation.  Dactylitis should be counted as 1 swollen 
joint.
Missing, replaced, ankylosed, or arthrodesed joints will be identified by the investigator at the 
Screening Visit and will be excluded from evaluation during the trial.
c.
Patient’s Assessment of Pain Visual Analog Scale
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.  The Patient’s Assessment of Pain VAS should be 
administered prior to the TJC and SJC examinations.
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.
d.
Patient’s Global Assessment of Disease Activity Visual Analog Scale
The patient’s overall assessment of his or her PsA activity will be recorded using the 100-mm 
horizontal VAS.  Patients will be asked, “Considering all the ways your PsA has affected you, 
how do you feel your PsA is today?” where the left end represents “very well” and the right end 
represents “very poor.”
e.
Physician’s Global Assessment of Disease Activity Visual Analog Scale
The investigator, who must be a physician, will be asked to give an overall assessment of the 
severity of the patient’s current PsA activity using a 100-mm horizontal VAS, where 0 represents 
no disease activity and 100 represents extremely active disease.  
f.
Patient’s Assessment of Physical Function as Assessed by the Health Assessment 
Questionnaire-Disability Index
The HAQ-DI is a patient-reported standardized questionnaire that is commonly used in PsA to 
measure disease-associated disability (assessment of physical function).  It consists of 
24 questions referring to 8 domains:  dressing/grooming, arising, eating, walking, hygiene, reach, 
grip, and other daily activities (Fries et al. 1980; Fries et al. 1982).

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The disability section of the questionnaire scores the patient’s self-perception on the degree of 
difficulty (0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty, and 
3 = unable to do), covering the 8 domains.  The reported use of special aids or devices and/or the 
need for assistance of another person to perform these activities is also assessed.  The scores for 
each of the functional domains will be averaged to calculate the functional disability index.  An 
MCID is a clinically relevant change in a patient’s status. The HAQ-DI MCID has been 
estimated to be about 0.35 for patients with PsA (Mease et al. 2011).  Details of scoring and 
calculations are presented in the statistical analysis plan (SAP).
g.
C-Reactive Protein
CRP will be the ACR Core Set measure of acute-phase reactant.  It will be measured with a high 
sensitivity assay at the central laboratory to help assess the effect of ixekizumab on the patient’s 
PsA.
9.1.2.4.
American College of Rheumatology 50 and 70 Responder Index 
ACR50 and ACR70 responses are secondary efficacy endpoints and are improvements of at least 
50% and of at least 70%, respectively, in the multiple disease assessment ACR criteria.  The 
ACR50 and ACR70 are calculated similarly to ACR20, as described in Section 9.1.2.3.
9.1.2.5.
Individual Components of the American College of Rheumatology 
Core Set
The individual components of the ACR Core Set will be measured including TJC (68 joint 
count), SJC (66 joint count), Patient’s Assessment of Pain VAS, PatGA VAS, PGA VAS, 
Patient’s Assessment of Physical Function as measured by the HAQ-DI, and CRP 
(Section 9.1.2.3.1).
9.1.2.6.
Psoriatic Arthritic Response Criteria
The PsARC is a composite criteria reported in terms of the percentage of patients achieving 
response according to the following criteria: PGA, PatGA, TJC, and SJC. Overall response is 
defined by improvement from the baseline assessment in 2 of the 4 criteria, 1 of which must be a 
joint count; there must not be worsening in any of the 4 criteria:
1. At least 30% reduction in TJC
2. At least 30% reduction in SJC
3. At least a 1 point reduction in physician’s assessment
4. At least a 1 point reduction in patient’s assessment
The PsARC response was modified in this study by using the PGA and the PatGA on a 100 mm 
VAS described in Section 9.1.2.3.1 instead of a 5-point Likert scale in the original criteria. The 
results from the 2 VAS measures were assessed as a difference from baseline (in mm), but 
criteria 3 and 4, above, were changed to “at least a 20 mm reduction” (Clegg 1996).
9.1.2.7.
Minimal Disease Activity
The MDA score has been developed based on current expert opinion and uses a composite of 
7 key outcome measures used in PsA to encompass all of the domains of the disease to measure 

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the overall state of a patient’s disease (Coates et al. 2010a; Coates and Helliwell 2010b).  The 
overall state of disease activity is deemed a useful target of treatment by both the patient and the 
physician, given current treatment possibilities and limitations. Preliminary validation work 
supports the use of the MDA criteria in both observational cohorts and in interventional trial 
cohorts. The PsA MDA criteria have evidence supporting their use within the OMERACT filter 
of truth, discrimination, and feasibility.

MDA:  Patients are classified as achieving MDA if they fulfill 5 of 7 outcome measures:  
TJC ≤1; SJC ≤1; psoriasis activity and severity index (PASI total score) ≤1 or BSA ≤3; 
patient pain VAS score of ≤15; patient global disease activity VAS score of ≤20; 
HAQ-DI score ≤0.5; and tender entheseal points ≤1.
9.1.2.8.
Modified Composite Psoriatic Disease Activity Index
The Modified CPDAI is a validated instrument intended to assess composite psoriatic disease 
activity and response to therapy (Mumtaz et al. 2011).  This instrument assesses individual 
domains involved as well as the global effect of disease in all dimensions by which each patient 
may be affected.  Domains include peripheral arthritis as assessed by the number of tender and 
swollen joints and the HAQ-DI, skin as assessed by the PASI and the DLQI, enthesitis as 
assessed by the number of sites with enthesitis and the HAQ-DI, and dactylitis as assessed by the 
number of digits affected and the HAQ-DI.  Scores range from 0 to 12, with a higher score 
indicating higher disease activity.
9.1.2.9.
Leeds Enthesitis Index
If the patient has enthesitis, the LEI will be administered by a blinded assessor.  The LEI has 
been developed specifically for use in PsA.  It measures enthesitis at 6 sites (lateral epicondyle, 
left and right, medial femoral condyle, left and right, Achilles tendon insertion, left and right) 
(Healy and Helliwell 2008).  Each site is assigned a score of 0 (absent) or 1 (present); the results 
from each site are then added to produce a total score (range 0 to 6).
9.1.2.10. Spondyloarthritis Research Consortium of Canada
If the patient has enthesitis, the SPARCC will be administered by a blinded assessor.  The 
SPARCC enthesitis index evaluates tenderness in a total of 16 enthesitis sites: the greater 
trochanter (right/left [R/L]), quadriceps tendon insertion into the patella (R/L), patellar ligament 
insertion into the patella and tibial tuberosity (R/L), Achilles tendon insertion (R/L), plantar 
fascia insertion (R/L), medial and lateral epicondyles (R/L), and the supraspinatus insertion 
(R/L) (Mease 2011). Tenderness at each site is quantified on a dichotomous basis:  
0 = nontender and 1 = tender.  The results from each site are then added to produce a total score 
(range 0 to 16).
9.1.2.11. Leeds Dactylitis Index-Basic
If the patient has dactylitis, the LDI-B will be administered by a blinded assessor.  The LDI-B 
has been developed to measure the severity of dactylitis.  Once the presence of dactylitis is 
established in each digit, the ratio of the circumference of the affected digit to the circumference 
of the digit on the opposite hand or foot is measured (Helliwell et al. 2005). Each dactylitic digit 
is defined by a minimum increase of 10% in circumference over the contra-lateral digit. If the 

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same digits on each hand or foot are thought to be involved, the clinician will refer to a table of 
normative values (provided to study sites) for a value which will be used to provide the 
comparison. If the ratio is >1.1, then subtract 1 from the calculated ratio and multiply it by 100 
and the tenderness score of 0 (not tender) or 1 (tender). Otherwise, if the ratio of the 
circumference of the digit is ≤1.1, then the LDI-B score is set to 0.  Tenderness is assessed in the 
area between the joints.  The results of each digit are then added to produce a total score (Healy 
and Helliwell 2007).
9.1.2.12. Nail Psoriasis Severity Index Fingernails
If the patient has fingernail Ps, the NAPSI Fingernails will be administered by a blinded 
assessor.  Site personnel should ensure that the patient makes their nails available for assessment 
during the study.  The NAPSI Fingernails is a numeric, reproducible, objective tool for 
evaluation of nail Ps.  This scale is used to evaluate the severity of nail bed Ps and nail matrix Ps 
by area of involvement in the nail unit.  In this study, only fingernail involvement will be 
assessed.  The fingernail is divided with imaginary horizontal and longitudinal lines into 
quadrants.  Each fingernail is given a score for nail bed Ps (0 to 4) and nail matrix Ps (0 to 4) 
depending on the presence (1) or absence (0) of any of the features of nail Ps in each quadrant.  
The NAPSI Fingernails score of a nail is the sum of scores in nail bed and nail matrix from each 
quadrant (thus a maximum of 8).  Each fingernail is evaluated, and the sum of all the nails is the 
total NAPSI Fingernails score.  Thus, the sum of the scores from all fingernails is 0 to 80.
9.1.2.13. Disease Activity Score based on C-Reactive Protein
The DAS28-CRP is a measure of disease activity in 28 joints that consists of a composite 
numerical score utilizing the following variables:  TJC, SJC, hs-CRP (measured in mg/L), and 
PatGA recorded by patients on a 0 to 100 mm VAS.
For DAS28-CRP, the 28 joints to be examined and assessed as tender or not tender for TJC and 
as swollen or not swollen for SJC (Section 9.1.2.3.1) are a subset of those assessed for the TJC 
and SJC, and include 14 joints on each side of the patient’s body:  the 2 shoulders, the 2 elbows, 
the 2 wrists, the 10 metacarpophalangeal joints, the 2 interphalangeal joints of the thumb, the 
8 proximal interphalangeal joints, and the 2 knees (Smolen et al. 1995).  The following equation 
will be used to calculate the DAS28 (Vander Cruyssen et al. 2005):










96
.
0
014
.
0
1
ln
36
.
0
28
28
.
0
28
56
.
0
28







VAS
CRP
SJC
TJC
CRP
DAS
9.1.2.14. Static Physician Global Assessment
If the patient has plaque Ps, the static Physician Global Assessment of psoriasis (sPGA) will be 
administered by the blinded assessor. The sPGA is the assessor’s determination of the patient’s 
Ps lesions overall at a given time point.  The sPGA is recommended as an endpoint to use to 
assess efficacy in the treatment of Ps (EMEA 2004).  Overall lesions are categorized by 
descriptions for induration, erythema, and scaling.  For the analysis of responses, the patient’s Ps
is assessed at a given time point on a 6 point scale in which 0 = cleared, 1 = minimal, 2 = mild, 
3 = moderate; 4 = severe, 5 = very severe.

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9.1.3. 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 investigational 
product or the study, or that caused the patient to discontinue the investigational product 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.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the informed consent form (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, 
investigational product, via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device and/or study procedure and the AE.
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 investigational product 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 any dosage modifications, or discontinuations of treatment.  

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9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following 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

considered significant by the investigator for any other reason:  important medical 
events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious, based upon appropriate medical judgment.
Although all AEs occurring after signing the ICF are recorded in the eCRF, SAE reporting 
begins after the patient has signed the ICF and has received investigational product.  However, if 
an SAE occurs after signing the ICF, but prior to receiving investigational product, it needs to be 
reported ONLY 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.  
Pregnancy (during maternal or paternal exposure to investigational product) 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.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
9.2.1.1.
Adverse Events of Special Interest
The following adverse events of special interest will be evaluated in particular to determine the 
safety and tolerability of ixekizumab over the range of doses selected for this clinical study.

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Adverse events of special interest for ixekizumab are:

cytopenias (leukopenia, neutropenia, and thrombocytopenia)

liver function test changes/enzyme elevations (ALT, AST, bilirubin, and ALP)

infections

injection-site reactions

allergic reactions/hypersensitivities

cerebrocardiovascular events

malignancies

depression and suicide/self-injury 

inflammatory bowel disease (Crohn’s disease and UC) 

interstitial lung disease (ILD)
Sites will provide details on some of these AEs as instructed on the eCRF.  Investigators will 
also educate patients and/or caregivers about the symptoms of allergic/hypersensitivity reactions 
and will provide instructions on dealing with these reactions (see Section 7.8.3).  
Data on cerebrocardiovascular events will be collected and the events will be adjudicated by an 
external Clinical Events Committee (CEC) made up of a chairman, 2 cardiologists, and a 
neurologist. 

Cerebrocardiovascular events are defined as:
o
Death (Cardiovascular)
o
MI
o
Hospitalization for Unstable Angina 
o
Hospitalization for Heart Failure
o
Serious Arrhythmia 
o
Hospitalization for Hypertension
o
Resuscitated Sudden Death 
o
Cardiogenic Shock due to MI
o
Coronary Revascularization Procedure 

Neurologic
o
Cerebrovascular Event:  Transient Ischemic Attack or Stroke (Hemorrhagic, 
Ischemic and Undetermined)

Peripheral Vascular Events
o
Peripheral Arterial Event
o
Peripheral Revascularization Procedure
Data on suspected IBD, as identified by events possibly indicative of UC and Crohn’s disease, 
will be collected and the events will be adjudicated by an external CEC made up of 
gastroenterologists with expertise in IBD.  
The role of the CEC is to adjudicate defined clinical events, in a blinded, consistent, and 
unbiased manner throughout the course of a study. The importance of the CEC is to ensure that 
all events that have been reported are evaluated uniformly by a single group.

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9.2.1.2.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 Code of Federal Regulations 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 recording and expedited reporting of SUSARs that are consistent with global 
regulations and the associated detailed guidances.
9.2.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
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.
Complaints related to concomitant medications are reported directly to the manufacturers of 
those medications/devices in accordance with the package insert.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

Reviewing all Study Drug Administration Logs to identify any product complaints

Recording a complete description of the product complaints reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

Faxing the completed product complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
9.3.
Treatment of Overdose
Refer to the ixekizumab IB and product labeling and the adalimumab product labeling.
9.4.
Safety
9.4.1. Vital Signs
For each patient, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).  
Vital signs (sitting blood pressure and pulse rate) will be measured after the patient has been 
resting for a minimum of 10 minutes at times indicated in the study schedule (Section 2).  At 
randomization (Visit 2), sitting blood pressure and pulse rate must be measured before 
administration of the investigational product and again approximately 1 hour after 
administration.  Any clinically significant findings from vital signs measurements that result in a 
diagnosis and that occur after the patient receives the first dose of study treatment should be 

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reported to Lilly or its designee as an AE via eCRF.  Additional measurements of vital signs may 
be performed at the discretion of the investigator.
9.4.2. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). 
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of investigational product should be reported to Lilly or its 
designee as an AE via eCRF.
9.4.3. Columbia Suicide Severity Rating Scale
The C-SSRS (Posner et al. 2007; Columbia University Medical Center [WWW]) is a scale that 
captures the occurrence, severity, and frequency of suicide-related ideations and behaviors 
during the assessment period.  The C-SSRS must be administered by appropriately trained site 
personnel.  The tool was developed by the National Institute of Mental Health Treatment of 
Adolescent Suicide Attempters (TASA) trial group for the purpose of being a counterpart to the 
Columbia Classification Algorithm of Suicide Assessment (C-CASA) categorization of suicidal 
events.  Patients will be assessed according to the Schedule of Activities (Section 2).
The Self-Harm Supplement Form, completed according to the Schedule of Activities, is a one-
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. This information is then documented in the eCRF. 
9.4.4. Other Tests 
9.4.4.1.
Physical Examination
One complete physical examination (excluding pelvic, rectal, and breast examinations) will be 
performed at Visit 1 (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 throughout the study are indicated in the Schedule of Activities (Section 2) and 
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.
9.4.4.2.
Chest X-Ray and Tuberculosis Testing
X-ray:  At Visit 1, a posterior-anterior view chest x-ray will be obtained locally, unless the x-ray
or results from a chest x-ray obtained within 6 months before randomization (Visit 2) are 
available.  The chest x-ray or results will be reviewed by the investigator or designee to exclude 
patients with active TB infection.
TB testing: Patient history of TB test results should be assessed prior to screening (Visit 1).

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Patients with no TB test results on file:  Patients will be tested at screening (Section 2).  A
PPD skin test response of ≥5 mm induration, between approximately 48 and 72 hours after test 
application, regardless of BCG vaccination history, will be considered a positive result.  In 
countries where the QuantiFERON-TB® Gold test or T-SPOT.TB test is available and in the 
judgment of the investigator preferred as an alternative to the PPD skin test for the evaluation of 
TB infection, it may be used instead of the PPD test and will be performed and read locally.  If 
the QuantiFERON-TB® Gold test or the T-SPOT.TB test is indeterminate, 1 retest using the 
same TB test method is allowed.  If the retest is indeterminate, then the patient is excluded from 
the study.
Patients with a positive TB test performed at screening but with no other evidence of active TB 
may be rescreened 1 time and may be enrolled without repeating the TB test based on the 
following requirements:  

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

meet all other inclusion and exclusion criteria for participation
If rescreening 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 with negative TB test results on file:  Patients with documentation of a negative test 
result within 3 months before randomization (Visit 2) should not be administered a TB test at 
Visit 1.  Documentation of PPD test results must include a record of the size of the induration 
response; otherwise a retest at screening (Visit 1) will be required to determine patient 
eligibility.
Patients with positive TB test results on file:  Patients with prior history of a positive TB test 
should not perform a TB test at Visit 1.  Documentation of this history and of at least 4 weeks of 
appropriate latent TB treatment prior to randomization (Visit 2) is required for study eligibility.  
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.
9.4.5. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
9.4.5.1.
Hypertension
Patients who experience changes in sitting blood pressure defined as systolic blood pressure at 
≥160 mm Hg plus ≥20 mm Hg increase from baseline (Week 0, Visit 2) and/or diastolic blood 
pressure at ≥100 mm Hg plus ≥10 mm Hg increase from baseline (Week 0, Visit 2) on 

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2 consecutive visits should receive intervention for the management of hypertension.  
Intervention could include the maximal intervention of withholding the dose of investigational 
product and/or the introduction of an anti-hypertensive agent (see Section 8.1.1 for criteria for 
patient discontinuation related to hypertension).
9.4.5.2.
Hepatic Monitoring
If a study patient/subject experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL 
≥2X ULN, clinical and laboratory monitoring should be initiated by the investigator.  Details for 
hepatic monitoring depend upon the severity and persistence of observed laboratory test 
abnormalities.  To ensure patient/subject safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly CRP regarding collection of specific recommended 
clinical information and follow-up laboratory tests (see Appendix 4).
9.4.5.3.
Neutropenia
Patients with neutrophil counts <1500 cells/L should be managed for neutropenia as follows:

<500 cells/L, see Discontinuation Criteria (Section 8.1.1)

≥500 cells/L and <1000 cells/L, see Discontinuation Criteria (Section 8.1.1)

≥1000 cells/L and <1500 cells/L (based on 3 test results), and the patient has a 
concurrent infection that requires systemic anti-infective therapy (for example, antibiotic, 
antifungal agent, antiviral agent):
o
The dose of investigational product 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 and the infection has resolved or is resolving, the 
patient may resume dosing of investigational product and evaluation at scheduled 
visits.  If the neutrophil count remains ≥1000 cells/L and <1500 cells/L, 
investigational product should continue to be withheld and a repeat neutrophil count 
should again be performed within another 4 weeks.  If, after 2 repeat tests, the 
neutrophil count still remains ≥1000 cells/L and <1500 cells/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 (based on 3 test results), and the patient has no 
concurrent infection that requires systemic anti-infective therapy (for example, antibiotic, 
antifungal agent, antiviral agent):

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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.
Repeat testing should be performed at 4- to 8-week intervals until the neutrophil 
count has returned to ≥1500 cells/L.  If the patient has 3 or more postbaseline
neutrophil counts of ≥1000 cells/L and <1500 cells/L, no value of <1000 cells/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 
is described in Section 5.1.3.
9.4.5.4.
Hepatitis B Monitoring
Patients who are HBsAg- and HBcAb+ at screening, regardless of other hepatitis B testing 
results, will have a serum HBV DNA specimen obtained to be analyzed by the central 
laboratory.  Such 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.
Any enrolled patient with a positive HBV DNA test result 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 (for example, infectious disease or hepatologist subspecialists) on whether to continue 
any immunosuppressant therapy including investigational product for a period of time while 
antiviral therapy is being initiated.  Timing of withdrawal from investigational product 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 investigational product, 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 3).
9.5.
Pharmacokinetics
Not applicable.
9.6.
Pharmacodynamics
Not applicable.

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9.7.
Genetics
Not applicable.
9.8.
Biomarkers 
Not applicable.
9.9.
Health Outcome/Quality of Life Measures
9.9.1. Itch Numeric Rating Scale
The Itch NRS is a patient-administered, 11 point horizontal scale anchored at 0 and 10, with 
0 representing “no itch” and 10 representing “worst itch imaginable.”  Overall severity of a 
patient’s itching from Ps is indicated by selecting the number that best describes the worst level 
of itching in the past 24 hours.
9.9.2. Fatigue Severity Numeric Rating Scale Score
The Fatigue Severity NRS is a patient-administered single-item 11-point horizontal scale 
anchored at 0 and 10, with 0 representing “no fatigue” and 10 representing “as bad as you can 
imagine.”  Patients rate their fatigue (weariness, tiredness) by selecting the one number that
describes their worst level of fatigue during the past 24 hours.
9.9.3. Medical Outcomes Study 36-Item Short Form Health Survey 
Physical Component Summary and Mental Component 
Summary Scores
The SF-36 is a 36-item, patient-completed measure designed to be a short, multipurpose 
assessment of health in the areas of physical functioning, role-physical, role-emotional, bodily 
pain, vitality, social functioning, mental health, and general health.  The 2 overarching domains 
of mental well-being and physical well-being are captured by the Mental Component Summary
and Physical Component Summary scores, respectively.  The summary scores range from 0 to 
100, with higher scores indicating better levels of function and/or better health.  Items are 
answered on Likert scales of varying lengths.  The SF-36 acute version (Version 2) will be used, 
which has a 1 week recall period (SF-36 Health Survey Update page [WWW]).
9.9.4. European Quality of Life—5 Dimensions 5 Level [EQ-5D-5L])
The EQ-5D-5L is a standardized measure of health status used to provide a simple, generic 
measure of health for clinical and economic appraisal.  The EQ-5D-5L consists of 2 components:  
a descriptive system of the respondent’s health and a rating of his/her current health state using a 
0- to 100-mm VAS.  The descriptive system comprises the following 5 dimensions:  mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression.  Each dimension has 5 levels:  
no problems, slight problems, moderate problems, severe problems, and extreme problems.  The 
respondent is asked to indicate his/her health state by selecting in the box associated with the 
most appropriate statement in each of the 5 dimensions.  It should be noted that the numerals 1 to 
5 have no arithmetic properties and should not be used as a cardinal score.  The VAS records the 

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respondent’s self-rated health on a vertical VAS, in which the endpoints are labeled “best 
imaginable health state” and “worst imaginable health state.”  This information can be used as a 
quantitative measure of health outcome.  The EQ-5D-5L health states, defined by the EQ-5D-5L 
descriptive system, may be converted into a single summary index by applying a formula that 
essentially attaches values (also called weights) to each of the levels in each dimension (EuroQol
Group [WWW]).
9.9.5. Dermatology Life Quality Index
The 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).
9.9.6. Treatment Satisfaction Questionnaire
The Treatment Satisfaction Questionnaire is a clinician-administered questionnaire which 
provides an assessment of the patient’s opinion of the effectiveness, safety, and overall 
satisfaction of the study medication. Patients will be asked to respond to questionnaire items 
using a 4-point Likert scale (from “very satisfied” to “very dissatisfied”).

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10.
Statistical Considerations
10.1. Sample Size Determination
Approximately 550 patients who meet all criteria for enrollment at Visits 1 and 2 will be
randomized in a 1:1 ratio at Week 0 (Visit 2) in Period 2 to ixekizumab or adalimumab 
(275 patients per treatment group). 
Sample size was calculated assuming the proportion of patients simultaneously achieving
ACR50 and PASI 100 as 13.6% and 31.3% in the adalimumab and ixekizumab treatment groups, 
respectively, as observed in the csDMARD-experienced population from Study RHAP. 
According to the nQuery software, a total sample size of 550 (with 275 per treatment group) 
using a 2-sided Fisher's exact test at 0.05 level of significance would yield 99% power for testing 
ixekizumab versus adalimumab.
This sample size would yield 78% power for testing the noninferiority of ixekizumab to 
adalimumab at a one-sided 0.025 level of significance based on a noninferiority margin of –12% 
and using ACR50 response rates of 43.8% and 44.1% as observed for the ixekizumab and 
adalimumab treatment groups, respectively, in the csDMARD-experienced population from 
Study RHAP.  For testing superiority of ixekizumab to adalimumab based on PASI 100 response 
rates of 46.9% and 23.7% as observed for ixekizumab and adalimumab in the csDMARD-
experienced population from Study RHAP, this sample size would yield 99% power using a 
2-sided Fisher's exact test at 0.05 level of significance.
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Entered
All participants who sign informed consent
Randomized
Participants who met all entry criteria and were assigned a study treatment
Intent-to-treat (ITT)
The ITT population consists of all randomized patients. Even if the patients do 
not take the assigned treatment, do not receive the correct treatment, or 
otherwise do not follow the protocol, they will be analyzed according to the 
treatment group to which they were assigned. Unless otherwise specified, 
efficacy and health outcomes analyses for Period 2 will be conducted on the ITT 
population.
Safety
The safety population consists of all randomized patients who received at least 1 
dose of study treatment in Period 2. Patients will be analyzed according to the 
treatment group to which they were assigned. Safety analyses for Period 2 will 
be conducted on this analysis set.
Post-treatment follow-up 
The post-treatment follow-up population consists of all randomized patients 
who received at least 1 dose of study treatment during Period 2 and have entered 
the Post-Treatment Follow-Up Period. Patients will be analyzed according to 
the treatment group to which they were assigned in Period 2. Safety analyses 
for Period 3 (Post-Treatment Follow-Up Period) will be conducted on this 
analysis set.

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10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly.
Any changes to the data analysis methods related to the primary and major secondary endpoints 
described in the protocol, and the justification for making the change, will be documented in the 
SAP and/or the clinical study report (CSR).  Additional exploratory analyses of the data may be 
conducted as deemed appropriate.
Complete details of the planned analyses will be documented in the SAP.
10.3.1.1. General Considerations for Analyses during Period 2 (Open-Label 
Treatment Period)
Baseline will be defined as the last available value before the first injection of the study drug for 
both efficacy, health outcomes, and safety analyses.  In most cases, this will be the measurement 
recorded at Week 0 (Visit 2). 
Categorical data for baseline variables will be summarized as frequency counts and percentages.  
Continuous data for baseline variables will be summarized using the mean, standard deviation, 
minimum, maximum, median, and number of observations. 
Comparisons of ixekizumab versus adalimumab will be performed for all outcome variables at 
all visits in Period 2; however, the primary time point of interest is Week 24.  
Change from baseline at a particular visit will be calculated as the value at that visit minus the 
baseline value.
For outcome measures that are not collected at each post-baseline visit, data may exist at visits 
where the outcome measure was not scheduled to be collected, due to early discontinuation 
visits.  In these situations, data from the early discontinuation visit that does not correspond to 
the planned collection schedule will be excluded from any mixed-effects models for repeated 
measures (MMRM) analysis.  However, the data will still be used in other analyses, including 
shift analyses, change from baseline analyses using last observation carried forward (LOCF) 
imputation method, and other categorical analyses.
10.3.1.2. Missing Data Imputation
The methods for imputation of missing data to be used in this study are described below.
10.3.1.2.1.Nonresponder Imputation
Missing data for categorical efficacy and health outcome measures will be imputed using the 
nonresponder imputation (NRI) method.  Patients will be considered nonresponders if they do 
not meet the clinical response criteria or have missing clinical response data at the time point of 
analysis.  Randomized patients without at least one post-baseline observation will also be defined 
as nonresponders for the NRI analysis.

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10.3.1.2.2.Last Observation Carried Forward
Missing data for continuous efficacy and health outcomes variables will be imputed using LOCF 
method.  For patients discontinuing investigational product or having missing data at a visit, the 
last nonmissing post-baseline observation before discontinuation or before the visit with missing 
data will be carried forward to the corresponding time point.  Randomized patients without at 
least one post-baseline observation will not be included in LOCF analyses.
In addition to NRI and LOCF, other imputation methods may be used as deemed appropriate.
10.3.1.3. Adjustment for Multiple Comparisons
A multiple testing strategy for the primary and major secondary endpoints will be implemented 
to control the family-wise type I error rate at a 2-sided α level of 0.05.  The primary and major 
secondary endpoints will be sequentially tested in the following order to compare ixekizumab vs 
adalimumab, using the primary analysis method.
1. Test 1 for Primary Endpoint – Proportion of patients simultaneously achieving ACR50 
and PASI 100 at Week 24: A superiority test of the primary endpoint will be performed 
at an overall 2-sided α = 0.05 using the methods described in Section 10.3.3.1.1.
2. Test 2 for Major Secondary Endpoint #1 – Proportion of patients achieving ACR50 at 
Week 24:  If the test for the primary endpoint is significant, then a noninferiority test for 
the major secondary endpoint #1 will be performed using the methods described in 
Section 10.3.3.3.
3. Test 3 for Major Secondary Endpoint #2 – Proportion of patients achieving PASI 100 at 
Week 24:  If the test for major secondary endpoint #1 is significant, then a superiority test 
for major secondary endpoint #2 will be performed using the methods described in 
Section 10.3.3.1.1.
If a test in this sequence is not significant, all subsequent tests will be considered nonsignificant.  
There will be no adjustment for multiple comparisons for any other analyses.
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
A detailed description of patient disposition will be provided at the end of the study.  All patients
who discontinue from the study treatment and the study will be identified, and the extent of their
participation in the study will be reported. Patient disposition will be summarized and will 
include reasons for discontinuation. The reasons for discontinuation during Period 2 will be 
tested between treatment groups using Fisher’s exact test.  
10.3.2.2. Patient Characteristics
Baseline characteristics, clinical, and health outcome measurements will be summarized for the
ITT population.  Baseline characteristics will include sex, age, age category, weight, BMI, race, 
geographic region, baseline disease severity, duration of disease, previous nonbiologic systemic 
therapy, and previous biologic therapy.  Baseline clinical measurements will include ACR 
component scores, PASI total score, DAS28-CRP, CRP, Modified CPDAI, HAQ-DI, Itch NRS 
score, NAPSI Fingernails, SPARCC Enthesitis Index, LEI, LDI-B, and other QoL scores.

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Treatment group comparisons between ixekizumab and adalimumab will be conducted using 
Fisher’s exact test for categorical data and an analysis of variance model with treatment as a 
factor for continuous data.  
10.3.2.3. Concomitant Therapy 
Previous and concomitant medications (including concomitant topical products such as 
emollients and other nonprescription topical products) will be summarized for patients who enter 
each treatment period and will be presented by World Health Organization Anatomic 
Therapeutic Class (WHOATC) Level 1 and generic name.  Treatment group comparisons 
between ixekizumab and adalimumab in Period 2 will be conducted using Fisher’s exact test.
10.3.2.4. Treatment Compliance
Treatment compliance with investigational product will be summarized for patients who enter 
Period 2. A patient will be considered compliant overall to ixekizumab or adalimumab if he/she 
is missing no more than 20% of the expected doses, does not miss 2 consecutive doses, and does 
not double-dose (that is, take more injections at the same time point than specified in the 
protocol).  Proportions of patients compliant by visit and overall will be compared between 
treatment groups during Period 2 using Fisher’s exact test.
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analysis Method
10.3.3.1.1.Categorical Variables
Unless specified otherwise, the primary analysis method for the categorical efficacy and health 
outcome variables will be using a logistic regression model with treatment, concomitant 
csDMARD use at baseline (Yes vs No), and moderate-to-severe plaque psoriasis involvement 
(Yes vs No) as factors and NRI method.  Treatment group comparisons will be made at all visits 
up to Week 52 and odds ratios and their corresponding 95% confidence intervals (CIs) will be 
reported.
10.3.3.1.2.Continuous Variables
Unless specified otherwise, the primary analysis method for all continuous efficacy and health 
outcome variables will be using a MMRM analysis.  The model will include treatment group, 
concomitant csDMARD use (Yes vs No) at baseline, moderate-to-severe plaque psoriasis
involvement (Yes vs No), baseline value, visit, baseline-by-visit interaction, and treatment-by-
visit interaction as fixed factors.  The covariance structure to model the within-patient errors will 
be unstructured.  If the unstructured covariance matrix results in a lack of convergence, the 
heterogeneous Toeplitz covariance structure, followed by the heterogeneous autoregressive 
covariance structure will be used.  The Kenward-Roger method will be used to estimate the 
denominator degrees of freedom.  Type III tests for the least squares means will be used for the 
statistical comparison; the 95% CI will also be reported.  Treatment group comparisons at all 
visits up to Week 52 will be made. 

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10.3.3.2. Secondary Analysis Method
10.3.3.2.1.Categorical Variables
Secondary analyses for treatment comparisons on the categorical efficacy variables will be 
conducted using a Fisher’s exact test.  
10.3.3.2.2.Continuous Variables
Secondary analyses for treatment comparisons on continuous outcome variables will be 
performed using an analysis of covariance (ANCOVA) model and LOCF imputation method.  
The details of the analysis model will be presented in the SAP.
10.3.3.3. Methodology for Noninferiority Test 
For assessing noninferiority of ixekizumab to adalimumab, missing data will be imputed using 
the NRI method.  Noninferiority analysis will be performed on the ITT population using a 
prespecified fixed margin approach.  There is no universally accepted value for what is 
considered to be a clinically unimportant difference between 2 treatments for a particular 
efficacy measure.  We will consider the points from EMEA Committee for Medicinal Products 
for Human Use (CHMP) (CHMP 2005) and FDA guidance (2016) which state that an 
appropriate noninferiority margin should be based on both clinical and statistical grounds.  
The null hypothesis will be rejected if the lower bound of the 2-sided 95% CI for the difference 
in proportions of responders on ixekizumab minus adalimumab is greater than the prespecified 
margin, meaning ixekizumab will be deemed noninferior to adalimumab.  If the lower bound of 
the CI exceeds 0 (the corresponding p-value will also be produced), then ixekizumab will be 
deemed superior to adalimumab.  The 95% CIs for the difference in proportions will be 
calculated using the simple asymptotic method, without continuity correction (that is, normal 
approximation to the binomial distribution).
Based on EMEA CHMP (CHMP 2005), FDA guidance (2016), and Weinblatt et al. (2013), a 
noninferiority margin of −12.0% for ACR50 between ixekizumab and adalimumab (ie, response 
rate of ixekizumab – response rate of adalimumab) is considered appropriate.  This noninferiority 
margin represents an approximately 50% preservation of the adalimumab treatment effect (based 
on the difference between adalimumab and placebo) observed in a historical Phase 3 study for 
adalimumab 40 mg twice weekly compared with placebo (Mease et al 2005) and Study RHAP.
If it is deemed appropriate to perform noninferiority tests on endpoints other than ACR50, the 
details about selection of noninferiority margins for the other endpoints will be presented in the 
SAP.
10.3.4. Safety Analyses
Safety will be assessed by summarizing and analyzing AEs, laboratory analytes including 
neutrophil counts, vital signs, and concomitant medications.  The duration of exposure will also 
be summarized.
The primary safety analyses will focus on comparisons of ixekizumab versus adalimumab in 
Period 2. Fisher's exact test will be used for all AEs and other categorical safety data.  
Continuous vital sign and laboratory values will be analyzed using ANCOVA method with 

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treatment and baseline value in the model. Other continuous safety variables will be analyzed by 
t-tests, unless otherwise stated.  
Summaries of safety data collected during the Post-Treatment Follow-Up Period (Period 3) will 
be presented separately.  Unless otherwise specified, the follow-up baseline is defined as the last 
nonmissing assessment on or prior to the Week 52 (Visit 11) or early discontinuation visit.
The categorical safety measures will be summarized with incidence rates.  The mean change of 
the continuous safety measures will be summarized by visits. 
10.3.4.1. Adverse Events
AEs are classified based on the Medical Dictionary for Regulatory Activities (MedDRA).  A 
TEAE is defined as an event that first occurred or worsened in severity after the first dose of 
study treatment and on or prior to the date of the last visit within the treatment period.  Both the 
date/time of the event and the date/time of the dose (ie, injection) are considered when 
determining TEAEs.  For each TEAE, the severity is recorded according to the patient’s or 
physician’s perceived severity of the event (mild, moderate, or severe).  A follow-up emergent 
adverse event (FEAE) is defined as an event that first occurred or worsened in severity after the 
date of Week 52 (Visit 11) or the ETV.  For events that are sex-specific, the denominator and 
computation of the percentage will only include subjects from the given sex.  
An overall summary of AEs will be provided for Period 2, including the number and percentage 
of subjects who experienced TEAEs, TEAEs by maximum severity, death, SAEs, TEAEs related 
to study drug, discontinuations from treatment due to an AE, and treatment-emergent adverse 
events of special interest.  TEAEs (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 (SOC) and 
preferred term.  
In addition to general safety parameters, safety information on specific topics of adverse events
of special interest will also be presented.  Potential adverse events of special interest will be 
identified by a standardized MedDRA query (SMQ) or a Lilly-defined MedDRA preferred term 
listing.
Follow-Up emergent AEs, SAEs including deaths, and AEs that lead to study discontinuation 
will be summarized by MedDRA system organ class and preferred term for Period 3.  
10.3.4.2. Clinical Laboratory Tests
Laboratory assessments will be analyzed 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 laboratory tests:  
o
Treatment-emergent abnormal value = a change from normal at all baseline visits 
to abnormal at any time postbaseline.

For continuous laboratory tests:  

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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 
postbaseline.
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 
postbaseline.
10.3.4.3. Vital Signs, Physical Findings, and Other Safety Evaluations
Vital signs will be analyzed as mean changes from baseline and as incidence of abnormal values
and will be summarized for both predose and postdose at Week 0 (Week 2) and Week 52 
(Visit 11), as applicable.
Suicide-related thoughts and behaviors and self-injurious behavior with no suicidal intent, based 
on the C-SSRS, will be listed by patient.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
Not applicable.
10.3.6. Other Analyses
10.3.6.1. Subgroup Analyses 
Subgroup analysis will be conducted using the ITT population.
Subgroups to be evaluated will include concomitant csDMARD use at baseline (Yes vs No), 
concomitant MTX use at baseline (Yes vs No), sex (male vs female), age group (<65 vs ≥65).  A 
detailed description of the subgroup variables will be provided in the SAP.
A logistic regression model with treatment, subgroup, and the interaction of subgroup by 
treatment included as factors will be used. The subgroup-by-treatment interaction will be tested 
at the significance level of 0.10. Treatment group differences will be evaluated within each 
category of the subgroup using Fisher’s exact test, regardless of whether the interaction is 
statistically significant. Missing data will be imputed using NRI. If any group within the 
subgroup is less than 10% of the total population, only summaries of the efficacy data will be 
provided (ie, no inferential testing will be performed).
10.3.7. Interim Analyses
An interim database lock will occur, and the analysis will be performed at the time (that is, a 
cutoff date) when the last patient completes Visit 8 (Week 24), completes ETV, or discontinues 
from Period 2.  This database lock will include all data collected by the cutoff date including data 
after Week 24 from the Open-Label Treatment Period (Period 2) and follow-up data from 
patients who have begun Post-Treatment Follow-Up Period (Period 3).  
This interim database lock at Week 24 will be considered the primary database lock for this 
study because all primary and major secondary study objectives will be assessed at this time. 
Since the primary time point of interest is Week 24, efficacy and health outcomes data will be 

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reported up to Week 24 because of the lack of complete data for all patients beyond this visit. 
However, all safety data collected up to the cutoff date will be reported.
A final database lock will occur after all enrolled patients have completed or discontinued the 
Post-Treatment Follow-Up Period (Period 3).  After the final database lock, all efficacy, health 
outcomes, and safety data collected until study completion will be reported.
There will be no data monitoring committee.

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11.
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arthritis: results of the IMPACT 2 trial. Ann Rheum Dis. 2005a;64(8):1150–1157.
Antoni CE, Kavanaugh A, Kirkham B Tutuncu Z, Burmester GR, Schneider U, Furst DE, 
Molitor J, Keystone E, Gladman D, Manger B, Wassenberg S, Weier R, Wallace DJ, Weisman 
MH, Kalden JR, Smolen J. Sustained benefits of infliximab therapy for dermatologic and 
articular manifestations of psoriatic arthritis: results from the Infliximab Multinational 
Psoriatic Arthritis Controlled Trial (IMPACT). Arthritis Rheum. 2005b;52(4):1227-1236.
Ash Z, Gaujoux-Viala C, Gossec L, Hensor EM, FitzGerald O, Winthrop K, van der Heijde D, 
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12.
Appendices

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Appendix 1.
Abbreviations and Definitions
Term
Definition
ACR
American College of Rheumatology 
ACR Core Set
Consists of 7 disease activity measurements:  tender joint count, swollen joint count, 
patient’s assessment of pain, Patient’s Global Assessment of Disease Activity, 
Physician’s Global Assessment of Disease Activity, Patient’s Assessment of Physical 
Function, and an acute-phase reactant value. 
ACR Responder
ACR20 Responder 
A patient who has at least 20% improvement in both tender and swollen joint counts 
and at least 20% improvement in a minimum of 3 of the following 5 criteria:  patient’s 
assessment of arthritis pain, Patient’s Global Assessment of Disease Activity, 
Physician’s Global Assessment of Disease Activity, Patient’s Assessment of Physical 
Function (Health Assessment Questionnaire-Disability Index), and an acute-phase 
reactant value (CRP or ESR). 
ACR50 Responder 
A patient who has at least 50% improvement in both tender and swollen joint counts 
and at least 50% improvement in a minimum of 3 of the following 5 criteria:  patient’s 
assessment of arthritis pain, Patient’s Global Assessment of Disease Activity, 
Physician’s Global Assessment of Disease Activity, Patient’s Assessment of Physical 
Function (Health Assessment Questionnaire-Disability Index), and an acute-phase 
reactant value (CRP or ESR). 
ACR70 Responder 
A patient who has at least 70% improvement in both tender and swollen joint counts 
and at least 70% improvement in a minimum of 3 of the following 5 criteria:  patient’s 
assessment of arthritis pain, Patient’s Global Assessment of Disease Activity, 
Physician’s Global Assessment of Disease Activity, Patient’s Assessment of Physical 
Function (Health Assessment Questionnaire-Disability Index), and an acute-phase 
reactant value (CRP or ESR). 
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.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
audit
A systematic and independent examination of the trial-related activities and documents 
to determine whether the evaluated trial-related activities were conducted, and the data 
were recorded, analyzed, and accurately reported according to the protocol, applicable 
standard operating procedures, good clinical practice (GCP), and the applicable 
regulatory requirement(s).
BCG
Bacillus Calmette-Guérin
bDMARD
Biologic disease-modifying anti-rheumatic drug (see also DMARD); examples of 
biologics include—but are not limited to—etanercept (Enbrel®), adalimumab 
(Humira®), and infliximab (Remicade®)

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blinding
A procedure in which one or more parties to the trial are kept unaware of the treatment 
assignment(s).  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; measured in 1% increments with area of patient’s hand including 
palm, fingers and thumb = 1%
CASPAR
Classification for Psoriatic Arthritis
CEC
Clinical Events Committee; responsible for adjudicating cerebrocardiovascular AEs to 
achieve consistency in reporting
CI
confidence interval
clinical research 
physician
Individual responsible for the medical conduct of the study.  Responsibilities of the 
CRP may be performed by a physician, clinical research scientist, global safety 
physician or other medical officer.
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements 
defined by the laboratory generating the data and that Lilly is confident that results are 
accurate.  Confirmation will either occur immediately after initial testing or will require 
that samples be held to be retested at some defined time point, depending on the steps 
required to obtain confirmed results.
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.
CRP
C-reactive protein
CSR
clinical study report
C-SSRS
Columbia–Suicide Severity Rating Scale
DAS28-CRP
Disease Activity Score (28 diarthrodial joint count) based on C-reactive protein 
DLQI
Dermatology Life Quality Index
DNA
deoxyribonucleic acid
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.
efficacy
Efficacy is the ability of a treatment to achieve a beneficial intended result.
end of study (trial)
End of study (trial) is the date of the last visit or last scheduled procedure shown in the 
Study Schedule for the last active subject in the study.
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
enthesitis
Inflammation of tendons and ligaments that can manifest as localized pain and 
tenderness.
EQ-5D-5L
European Quality of Life–5 Dimensions 5 Level 

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ERB
Ethical 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.
ETV
Early Termination Visit
EU
European Union
FSH
follicle-stimulating hormone
GCP
good clinical practice
HAQ-DI
Health Assessment Questionnaire-Disability Index
HBcAb+
positive for anti-hepatitis B core antibody
HBsAb+
positive for anti-hepatitis B surface antibody
HBsAg+
positive for hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HIVAb
human immunodeficiency virus antibody
hs-CRP
high sensitivity (assay) C-reactive protein
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
ICF
informed consent form
ICH
International Conference on Harmonisation
IL
Interleukin (eg, IL-17; a proinflammatory cytokine produced by Th17 cells)
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.  
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational product
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.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
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.
ERB
Ethical 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.
IV
intravenous
IWRS
interactive web-response system
LDI-B
Leeds Dactylitis Index—Basic

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legal representative
An individual, judicial, or other body authorized under applicable law to consent on 
behalf of a prospective patient, to the patient’s participation in the clinical study.
LEI
Leeds Enthesitis Index
LOCF
last observation carried forward
MDA
Minimal Disease Activity
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MMRM
mixed-effects model repeated measures
Modified CPDAI
Modified Composite Psoriatic Disease Activity Index 
MTX
methotrexate
NAPSI Fingernails
Nail Psoriasis Severity Index Fingernails
NRI
nonresponder imputation
NRS
numeric rating scale
PASI
Psoriasis Area and Severity Index
patient
A study participant who has the disease or condition for which the investigational 
product is targeted.
PPD
purified protein derivative
Ps
psoriasis
PsA
psoriatic arthritis
PsARC
Psoriatic Arthritic Response Criteria
QoL
quality of life
Q2W
every 2 weeks
Q4W
every 4 weeks
RA
rheumatoid arthritis
randomize
Refers to a method of treatment assignment.  The point of randomization in this trial is 
the point at which treatment is assigned and the patient begins treatment; thus, patients 
who are randomized in the trial are those who have been assigned to a treatment.
registration
The act of assigning a registration number to the subject indicating that the registration 
center/sponsor/principal investigator or subinvestigator has verified that the subject 
meets the inclusion criteria and none of the exclusion criteria.
rescreen
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
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. 
SF-36
Medical Outcomes Study 36-Item Short Form Health Survey 
SJC
swollen joint count
sPGA
static Physician Global Assessment of psoriasis
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
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, which and does not necessarily have to have a causal 
relationship with this treatment.
TJC
tender joint count
TNF
tumor necrosis factor
UC
ulcerative colitis

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ULN
upper limit of normal
VAS
visual analog scale

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Appendix 2.
Clinical Laboratory Tests 
Assays to be performed by the central laboratory unless otherwise noted.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Platelets
Alkaline phosphatase 
Alanine aminotransferase (ALT)
Absolute counts of:
Neutrophils, segmented
Lymphocytes
Monocytes
Eosinophils
Basophils
Aspartate aminotransferase (AST)
Triglycerides
Total cholesterol
HDL/LDL cholesterol
GGT
Proteins (total)
Blood urea nitrogen (BUN)
Other Tests
Creatinine
Human immunodeficiency virus antibody (HIV)
Hepatitis B Surface antigen (HBsAg)
Anti-Hepatitis B Surface antibody (HBsAb)
Anti-Hepatitis B Core antibody (HBcAb)
Anti-Hepatitis C antibody
Purified Protein Derivative (PPD)a
QuantiFERON®-TB Golda 
T-SPOT.TBa
HBV DNA
HCV RNA
Rheumatoid factor (RF)
Uric acid 
Calcium
Glucose, fasting at Visit 2 but nonfasting throughout 
study, if clinically indicated
Albumin
Creatine Phosphokinase (CPK)
hs-CRP
Urinalysis
Specific gravity
pH
Protein
Glucose
Ketones
Blood
Urine leukocyte esterase
Pregnancy Test (females only)
Serum
Urine
b
FSH
Abbreviations:  FSH = follicle-stimulating hormone; GGT = gamma-glutamyl transferase; HDL = high-density 
lipoprotein; HIVab = human immunodeficiency virus antibody; LDL = low-density lipoprotein; RBC = red blood 
cells; WBC = white blood cells.
a
Test may be done by the physician, nurse, or at the local laboratory.
b
Assay to be performed by study site or self-administered by patient.  Additional urine pregnancy testing can be 
performed at the investigator’s discretion.  If required per local regulations, testing can occur at other intervals 
during the study treatment period and/or follow-up period.

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Appendix 3.
Study Governance Considerations
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 potential risks and benefits of participating in 
the study

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 investigational product.

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 
patient’s willingness to continue his or her participation in the trial.
Appendix 3.1.2.
Ethical Review
The investigator or an appropriate local representative must give assurance that the ERB was 
properly constituted and convened as required by International Conference on 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 current IB and updates during the course of the study

informed consent form 

relevant curricula vitae
Appendix 3.1.3.
Regulatory Considerations
This study will be conducted in accordance with:

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

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Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.4.
Investigator Information
Physicians with a specialty in rheumatology will participate as investigators in this clinical trial.
Appendix 3.1.5.
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 3.1.6.
Final Report Signature
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 CSR coordinating investigator will be selected by the sponsor.  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.
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

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the eCRFs, and 
study procedures

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and evaluate eCRF data and use standard computer edits to detect errors in 
data collection

conduct a quality review of the database
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.

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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
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Electronic patient-reported outcome (ePRO) measures (for example, a rating scale) are entered 
into an ePRO instrument (tablet) at the time that the information is obtained.  In these instances 
where there is no prior written or electronic source data at the site, the ePRO instrument record 
will serve as the source.  In these instances where there are prior written source data that are 
subsequently entered into ePRO, the written record will serve as the source.
If ePRO records are stored at a third party site, study sites will have continuous access to the 
source documents during the study and will receive an archival copy at the end of the study for 
retention.
Any data for which the ePRO instrument record will serve to collect source data will be 
identified and documented by each site in that site’s study file.
Case report form data will be encoded and stored in a clinical trial database.  Data managed by a 
central vendor, such as laboratory test data, will be stored electronically in the central vendor’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse.
Any data for which paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient will include a paper diary to collect a dosing schedule.
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 or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.

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

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Appendix 5.
Protocol Amendment I1F-MC-RHCF(a)
Summary:  A 52-Week Multicenter, Randomized, Open-
Label, Parallel-Group Study Evaluating the Efficacy and 
Safety of Ixekizumab versus Adalimumab in Patients 
with Psoriatic Arthritis Who Are Biologic Disease-
Modifying Anti-Rheumatic Drug Naive
Overview
Protocol I1F-MC-RHCF (A 52-Week Multicenter, Randomized, Open-Label, Parallel-Group 
Study Evaluating the Efficacy and Safety of Ixekizumab versus Adalimumab in Patients with 
Psoriatic Arthritis Who Are Biologic Disease-Modifying Anti-Rheumatic Drug Naive) has been 
amended.  The new protocol is indicated by amendment (a) 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-RHCF Amendment (a)
Section # and Name
Description of Change
Brief Rationale
All protocol sections
Minor editorial changes.
Minor corrections made as needed.
1. Synopsis
Replaced “<” with “≤” for PASI score 1, 2, or 3 
Updated Statistical Analysis section 
Corrected symbols.
Modified based on observations from the 
csDMARD-experienced population from 
Study RHAP.
2. Schedule of Activities
Footnote e:  Removed that study drug will be administered by the patient or 
caregiver “at home”.
Footnote j:  Added a missing letter “A” to the beginning of the sentence.
Footnote m: Added that additional pregnancy could be performed at the 
investigator’s discretion or per applicable regulations/guidance.  Deleted 
reference to local regulations.
Removed “at home” to make the instruction less 
specific.
Minor editorial correction.
Updated language to allow for more frequent 
pregnancy testing for any reason. 
Table RHCF.2.1 Study 
Drug Administration 
Schedule
Added “plaque” before Ps.
Corrected footnote order.
Minor editorial corrections.
3.3 Benefit/Risk 
Assessment 
Replaced “SPC” with “product labeling.”
SPC is specific to EU; “product labeling” is more 
general.
4. Objectives and 
Endpoints
Replaced “<” with “≤” for PASI score 1, 2, or 3
Corrected symbols.
5.2 Number of 
Participants
Clarified wording.
Minor editorial change.
6.1. Inclusion Criteria
Added Inclusion Criterion 50: Have had an inadequate response when 
treated with 1 or more csDMARDs.
Patients must meet this additional inclusion 
criterion.  Number 50 is the next number in the 
inclusion/exclusion list; however, this criterion was 
included in the inclusion criteria section.
6.2. Exclusion Criteria
Exclusion Criterion 10:  Clarified that the dose of the allowed concomitant 
medications MTX, leflunomide, sulfasalazine, or cyclosporine must remain 
unchanged during the first 24 weeks only of the Open-Label Treatment 
Period.  Deleted hydroxychloroquine.
Exclusion Criterion 13:  Clarified that patients anticipating needing a 
parenteral injection of glucocorticosteroids during the first 24 weeks only of 
the Open-Label Treatment Period are excluded.
Exclusion Criterion 33:  Clarified that patients who have had an infection of 
Exclusion Criteria 10 and 13 apply to the first 24 
weeks only of the 52-week Open-Label Treatment 
Period. 
Hydroxychloroquine was removed as a csDMARD.
Minor editorial changes.
Exclusion Criterion 33 was changed to exclude 
patients with infection of an artificial joint.

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Section # and Name
Description of Change
Brief Rationale
an artificial joint are excluded.
7. Treatments
Added Section 7.1.1 Administration of Investigational Product.
Packaging and Labeling was renumbered to Section 7.1.2.
Added to provide specific information regarding 
the administration of study drug.
Minor editorial changes.
7.2. Method of Treatment 
Assignment
Clarified that the randomization will be stratified by “concomitant”
csDMARD use “at baseline.”
Stratification will occur by concomitant csDMARD 
use at baseline.
Minor editorial changes.
7.3. Blinding
Added sPGA and Percentage of Body Surface Area to the list of blinded 
assessor rated assessment.
Previously missing from the list.
7.7. Concomitant Therapy 
Added a sentence clarifying that PsA medications should remain at a stable 
dose for the first 24 weeks of Open-Label Treatment unless changes are 
required for safety reasons.
Replace SPC with product labeling.
Added for consistency.
Table RHCF.7.2
Concomitant Medications
Permitted/Not Permitted 
in the Open-Label 
Treatment Period from 
Week 0 to Week 24 for 
Treatment of PsA and 
Chronic Conditions
Table RHCF.7.3 
Concomitant Medications
Permitted/Not Permitted 
in the Open-Label 
Treatment Period from 
Week 24 to Week 52 for 
Treatment of PsA and 
Chronic Conditions
Table RHCF.7.4 Allowed 
Concomitant Medications 
in the Post-Treatment 
Table RHCF.7.2: For opiate analgesics, added stable doses with no dose 
adjustments, changes, and/or introduction of new opiate analgesics as a 
condition for use.
Table RHCF.7.2 and 7.3: Removed hydroxychloroquine.
All 3 tables:  Removed the abbreviation IV from the abbreviations lists and 
spelled out intravascular in each table.
Previously inconsistent compared to oral steroids 
and to the exclusion criteria.  
Hydroxychloroquine was removed as a csDMARD.
The abbreviation IV is defined as intravenous.
Minor formatting changes.

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Section # and Name
Description of Change
Brief Rationale
Follow-Up Period 
(Period 3)
8.1.1. Permanent 
Discontinuation from 
Study Treatment
Added an “X” to the final bullet in the list of permanent discontinuation for
study treatment.
“alkaline phosphatase >2.5X ULN with the appearance of fatigue, nausea, 
vomiting, right quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)”
Corrected typo.
9.1.2.1. Psoriasis Area and 
Severity Index (PASI 75, 
PASI 90, PASI 100) 
Replaced “<” with “≤” for PASI score 1, 2, or 3.
Corrected symbols.
9.1.2.3.1 American 
College of Rheumatology 
Core Set
Moved/added a sentence to the beginning of each assessment description 
stating that TJC and SJC assessments will be performed by a blinded 
assessor.
Minor editorial changes.
9.1.2.11. Leeds Dactylitis 
Index-Basic 
Added the derivation for this assessment from the Statistical Analysis Plan 
(SAP) for Study I1F-MC-RHBE (RHBE).
The derivation was updated in this SAP. 
9.1.2.14. Static Physician 
Global Assessment
Replaced physician with assessor for the determination of the patient’s Ps
lesions overall at a given time point.
Assessor is the appropriate role for this.
9.3. Treatment of 
Overdose
Replace SPC with product labeling.
SPC is specific to EU; “product labelling” is more 
general.
10.1. Sample Size 
Determination
Updated language.
Modified based on observations from the 
csDMARD-experienced population from 
Study RHAP.
10.3.1.1. General 
Considerations for 
Analyses during Period 2 
(Open-Label Treatment 
Period)
Included a statement that the primary time point of interest is Week 24.
Clarification.
10.3.1.3. Adjustment for 
Multiple Comparisons
Modified number 3 to remove noninferiority.
The major secondary endpoint is superiority rather 
than noninferiority.
Minor editorial changes.
10.3.2.2. Patient 
Characteristics
Removed CASPAR as a baseline clinical measurement.
Not collecting CASPAR scores at baseline;
CASPAR is only an inclusion criterion.
10.3.3.1.1. Categorical 
Variables
Added “concomitant” csDMARD use at “baseline”. 
Included that treatment group comparisons will be made at all visits up to 
Clarified that the model will include concomitant 
csDMARD use at baseline.

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Section # and Name
Description of Change
Brief Rationale
Week 52 and odds ratios and their corresponding 95% confidence intervals
(CIs) will be reported.
Added additional information to clarify that 
treatment group comparisons will be made at Week 
52 and that odds ratios and their corresponding
95% CIs will be reported.
10.3.3.1.2. Continuous 
Variables
Added “concomitant” csDMARD use at “baseline”.
Clarified that the model will include concomitant 
csDMARD use at baseline.
Minor editorial changes.
10.3.3.3. Methodology for 
Noninferiority Test
Percent preservation of the adalimumab treatment effect was modified from 
60% to 50%.
Correction.
10.3.6.1. Subgroup 
Analysis
Added that subgroups to be evaluated will include “concomitant” csDMARD 
use and MTX use “at baseline”.
Clarified.
Minor editorial changes.
10.3.7 Interim Analysis
Added “(Period 2)” after Open-Label Treatment Period.
Added a statement that since Week 24 is the primary time point of interest 
efficacy and health outcomes data will be reported up to Week 24 because of
the lack of complete data for all patients beyond this visit. However, all 
safety data collected up to the cutoff date will be reported.
Added a statement that after the final database lock, all efficacy, health 
outcomes, and safety data collected until study completion will be reported.
Minor editorial change.
Clarified.
Appendix 1. 
Abbreviations and 
Definitions
Removed SPC.
SPC is no longer used in the protocol.
Appendix 2. Clinical 
Laboratory Tests
Deleted one instance of “cholesterol” from the table as it was included twice.
Repetitive.

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Note:  The numbering system used for inclusion and exclusion criteria provides a unique number 
for each criterion and allows for efficiency in data collection.  In case an amendment to the 
protocol adds a criterion, that criterion will receive the next available number, regardless of 
whether it is an inclusion or exclusion criterion.  In this amendment, the additional inclusion 
criterion is numbered 50, but remains in the inclusion criteria section.
1.
Synopsis
Objective(s)/Endpoints:
Psoriasis/Nail Endpoints
Time course of response to treatment over 52 weeks as measured by:

Change from baseline in body surface area (BSA) 

Proportion of patients who achieve the following PASI scores:  PASI 75, PASI 90, or PASI 100 (defined as 
75%, 90%, and 100% improvement from baseline in PASI criteria, respectively)

Proportion of patients achieving an absolute PASI score < ≤1 or < ≤2 or < ≤3

Change from baseline in the Nail Psoriasis Severity Index (NAPSI) Fingernails score in the subgroup of 
patients with fingernail involvement at baseline (ie, baseline NAPSI Fingernails score >0)
Statistical Analysis:
A significance level of 0.05 is assumed for testing each dosing regimen of ixekizumab versus adalimumab.  
Sample size was calculated assuming the proportion of patients simultaneously achieving ACR50 and PASI 100 as
13.2 13.6% and 28.8 31.3% in the adalimumab and ixekizumab treatment groups, respectively, as observed in the 
conventional synthetic disease-modifying anti-rheumatic drug (csDMARD)-experienced population from
Study RHAP. According to the nQuery software, a total sample size of 550 patients (with 275 patients per treatment 
group) using a 2-sided Fisher's exact test at a 0.05 level of significance would yield approximately 99% power for 
testing ixekizumab versus adalimumab.
This sample size would yield 79 78% power for testing the noninferiority of ixekizumab to adalimumab at a one-
sided 0.025 level of significance based on a noninferiority margin of –12% and using ACR50 response rates of 42.5
43.8% and 44.1% as observed for in the ixekizumab and adalimumab treatment groups, respectively, in the 
csDMARD-experienced population from Study RHAP, respectively.  For testing superiority of ixekizumab to 
adalimumab based on PASI 100 response rates of 42.5 46.9% and 23.5 23.7% as observed for ixekizumab and 
adalimumab in the csDMARD-experienced population from Study RHAP, this sample size would yield 99% power 
using a 2-sided Fisher's exact test at 0.05 level of significance.  
2.
Schedule of Activities
Table footnotes:

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e At randomization (Visit 2) for patients randomized to ixekizumab and for patients with moderate-to-severe plaque 
Ps symptoms randomized to adalimumab, the second injection of study drug will be administered by the patient 
or caregiver under site personnel supervision for injection training purposes.  Thereafter, study drug will be 
administered by the patient or caregiver at home.
j
All patients will be tested for HBV.
m Only for females of childbearing potential.  Additional urine pregnancy testing can be performed at the 
investigator’s discretion or per applicable regulations/guidance.  If required per local regulations, testing can 
occur at other intervals during the study treatment period and/or follow-up period.

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Table RHCF.2.1. 
Study Drug Administration Schedule
Visit
2
3
4
5
6
7
8
Weeks 
0a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Ixekizumab 80 mg 
Q2W/Q4W
Moderate-to-Severe 
Plaque Psb
X
(160 mg)
X
X
X
X
X
X
X
X
X
Ixekizumab 80 mg 
Q4Wc
X
(160 mg)
X
X
X
X
X
X
Adalimumab 40 mg 
Q2Wd
X
(40 mg)
X
X
X
X
X
X
X
X
X
X
X
X
Adalimumab 40 mg 
Q2W
Moderate-to-Severe 
Plaque Pse
X
(80 mg)
X
X
X
X
X
X
X
X
X
X
X
X
Visit
9
10
11
Weeks 
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
Ixekizumab 80 mg 
Q2W/Q4W 
Moderate-to-Severe
Plaque Psb
X
X
X
X
X
X
Ixekizumab 80 mg 
Q4Wc
X
X
X
X
X
X
Adalimumab 40 mg 
Q2Wd
X
X
X
X
X
X
X
X
X
X
X
X
X
Adalimumab 40 mg 
Q2W
Moderate-to-Severe
Plaque Pse
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations:  BSA = body surface area; PASI = Psoriasis Area and Severity Index; Ps = psoriasis; Q2W = every 2 weeks; Q4W = every 4 weeks; 
SC = subcutaneous; sPGA = static Physician Global Assessment of psoriasis.
a Starting dose.

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Study Drug Administration Schedule
b Patients with moderate-to-severe plaque Ps, defined as PASI ≥12, sPGA ≥3, and BSA ≥10%, will receive ixekizumab 80 mg given as 1 SC injection Q2W 
from Week 2 to Week 12 and Q4W thereafter.
c Patients not meeting criteria for moderate-to-severe plaque Ps will receive ixekizumab 80 mg given as 1 SC injection Q4W starting at Week 4.
de Patients not meeting criteria for moderate-to-severe plaque Ps will receive a starting dose of adalimumab 40 mg given as 1 SC injection at randomization 
(Visit 2 [Week 0]) followed by 40 mg given as 1 SC injection Q2W starting at Week 2.
ed Patients with moderate-to-severe plaque Ps, defined  as PASI ≥12, sPGA ≥3, and BSA ≥10%, will receive a starting dose of adalimumab 80 mg (two 40-mg 
SC injections) administered at randomization (Visit 2 [Week 0]) followed by 40 mg given as 1 SC injection Q2W starting at Week 1.  
d   Patients with moderate-to-severe plaque Ps, defined  as PASI ≥12, sPGA ≥3, and BSA ≥10%, will receive a starting dose of adalimumab 80 mg (two 40-mg 
SC injections) administered at randomization (Visit 2 [Week 0]) followed by 40 mg given as 1 SC injection Q2W starting at Week 1.  
e Patients not meeting criteria for moderate-to-severe plaque Ps will receive a starting dose of adalimumab 40 mg given as 1 SC injection at randomization 
(Visit 2 [Week 0]) followed by 40 mg given as 1 SC injection Q2W starting at Week 2.

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3.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of ixekizumab are to be found in the 
Investigator’s Brochure (IB) and the product labeling Summary of Product Characteristics 
(SPC).  
More detailed information about the known and expected benefits and risks of adalimumab may 
be found in the SPC product labeling.
4. 
Objectives and Endpoints
Table RHCF.4.1.
Psoriasis/Nail Endpoints
Time course of response to treatment over 52 weeks as measured by:

Change from baseline in body surface area (BSA) 

Proportion of patients who achieve the following PASI scores:  PASI 75, PASI 90, or PASI 100 (defined as 
75%, 90%, and 100% improvement from baseline in PASI criteria, respectively)

Proportion of patients achieving an absolute PASI score < ≤1 or < ≤2 or < ≤3

Change from baseline in the Nail Psoriasis Severity Index (NAPSI) Fingernails score in the subgroup of 
patients with fingernail involvement at baseline (ie, baseline NAPSI Fingernails score >0)
5.2. 
Number of Participants
Approximately 917 participants will be screened (assuming a 40% screen failure rate) to achieve 
randomization of 550 participants (275 per treatment group) and approximately 396 patients are 
expected to complete Week 52 have approximately 396 participants evaluable (assuming 72% 
completion rate at Week 52) at the completion of the study.
6.1. 
Inclusion Criteria
Patient Characteristics
…
[4] 
Have active psoriatic skin lesions (plaque psoriasis) with a BSA ≥3% at 
Visit 1 (Screening) and Visit 2 (Week 0).
[50]
Have had an inadequate response when treated with 1 or more 
csDMARDs.
6.2. 
Exclusion Criteria
…
[10] 
Have used csDMARDs other than MTX, leflunomide, sulfasalazine, or
cyclosporine or hydroxychloroquine in the 8 weeks prior to randomization 
(Visit 2).

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Have discontinued MTX, sulfasalazine, hydroxychloroquine, or cyclosporine 
within 12 weeks prior to randomization.
If taking MTX, leflunomide, sulfasalazine, or cyclosporine, must have been 
treated for at least 12 weeks prior to randomization and on a stable dose for at 
least 8 weeks prior to randomization, as follows: oral or parenteral MTX = 10 to 
25 mg/week, leflunomide = 20 mg/day, sulfasalazine = up to 3 g/day, 
hydroxychloroquine = up to 400 mg/day, or cyclosporine up to 5 mg/kg/day. The 
dose of these allowed concomitant medications must remain unchanged during 
the first 24 weeks of the Open-Label Treatment Period unless changes are 
required for safety issues. Local standard of care should be followed for 
concomitant administration of folic acid with MTX.
…
[13] 
Have received any parenteral glucocorticoid administered by 
intraarticular, intramuscular, or intravenous (IV) injection within 6 weeks 
prior to randomization, or for whom a parenteral injection of 
glucocorticosteroids is anticipated during the first 24 weeks of the
Open-Label Treatment Period.
…
[33]
Patients who have:

in the past 12 weeks prior to randomization:
o
had a serious infection (for example, pneumonia, cellulitis)
o
have been hospitalized for an infection
o
have received IV antibiotics for an infection 

or in the past 24 weeks prior to randomization had a serious bone or joint 
infection, 

or have ever had
o
an infection of an artificial joint
o
an infection that occurs with increased incidence in an 
immunocompromised host (including, but not limited to, 
Pneumocystis jirovecii pneumonia, active histoplasmosis, or 
coccidioidomycosis); or have a known immunodeficiency.
7.1.1.
Administration of Investigational Product
Injections will be administered subcutaneously by the patient or caregiver after training by the 
clinical staff.
Training:  At randomization (Visit 2), patients randomized to ixekizumab and patients with 
moderate-to-severe plaque Ps symptoms randomized to adalimumab will receive 2 injections.  
For training purposes, the proper procedures for administration of the initial injection will be 
performed by clinical staff.  The second injection of study drug will be administered by the 
patient or caregiver under site personnel supervision.  Thereafter, study drug should be 

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administered by the patient or caregiver.  If additional training is necessary, an injection may be 
administered by the patient or caregiver under the supervision of clinical staff.
Administration:  If the patient is unable to administer the injection, a caregiver who will also be 
trained under supervision of site staff may administer the study drug.  All subsequent injections 
will be administered by the patient or caregiver and should be administered unsupervised by the 
clinical staff (see Section 2).  It is recommended that for these subsequent injections, the 
patient/caregiver administer the study drug outside the trial site, preferably at the patient’s home.  
If the patient or caregiver is not able to administer the second injection of the starting dose or any 
dose throughout the study, study site personnel may administer that injection.
Refer to the appropriate directions for use provided by the sponsor for the study drug.  
Study Drug Administration Logs will be dispensed to each patient as needed for recording 
pertinent data about each injection; details of the use of these logs are provided in Section 7.2.1.
Observation:  Patients should remain under observation for at least 1 hour after dosing at 
randomization (Visit 2) to allow for observation for any AEs and collection of postinjection 
sitting BP and pulse measurements approximately 1 hour after administration of study drug (see 
Section 2).
7.1.1. 7.1.2.
Packaging and Labeling
7.2. 
Method of Treatment Assignment 
Patients who meet all Visit 1 and Visit 2 eligibility criteria for enrollment will be randomized at 
Visit 2 (Week 0) in a 1:1 ratio to open-label treatment with ixekizumab or adalimumab at 
Week 0 (Visit 2).  Assignment to treatment groups will be determined by a computer-generated 
random sequence using an interactive web-response system (IWRS).  The IWRS will be used to 
assign investigational product to each patient.  Site personnel will confirm that they have located 
the correct investigational product by entering a confirmation number found on the 
investigational product into the IWRS.  The randomization will be stratified by concomitant
csDMARD use at baseline (Yes, vs No) and moderate-to-severe plaque psoriasis involvement
(Yes, vs No) severity of plaque psoriasis moderate-to-severe (Yes, No).
7.3. 
Blinding
This is an open-label study where treatment allocation is revealed after randomization.  
Specifically:

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
A blinded assessor will complete the following assessments:
o
TJC/SJC
o
Psoriasis Area and Severity Index (PASI)
o
Percentage of BSA
o
Enthesitis
o
LDI-B
o
NAPSI Fingernails
o
sPGA
7.7. 
Concomitant Therapy
All concomitant medication taken during the study must be recorded on the Concomitant 
Medication case report form (eCRF) at the study visits indicated in the Schedule of Activities 
(Section 2).  Treatment with concomitant PsA 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 below.  Patients taking permitted PsA medications should be on stable doses at 
randomization (Visit 2) and through the first 24 weeks of the Open-Label Treatment Period, as 
specified below, unless changes are required for safety reasons.  Table RHCF.7.2, 
Table RHCF.7.3, and Table RHCF.7.4 summarize concomitant medications that are and are not 
permitted and the conditions for use during the study for those which are permitted.
Table RHCF.7.2.
Concomitant Medications Permitted/Not Permitted in the Open-Label 
Treatment Period from Week 0 to Week 24 for Treatment of PsA and Chronic Conditions 
Drug Class
As Needed
Chronic Use
Conditions for Use
…
csDMARDs
N
Y
Stable dose allowed. Stable doses with no dose 
adjustments, changes, and/or introduction of a 
new csDMARD
Allowed doses:

Oral or parenteral MTX; 10 to 25 mg/week

Leflunomide:  up to 20 mg/day

Sulfasalazine:  up to 3 g/day

Hydroxychloroquine:  up to 400 mg/day

Cyclosporine:  up to 5 mg/kg/day
…
Opiate analgesics
N
Y
Stable doses with no dose adjustments, changes, 
and/or introduction of a new opiate analgesic.
May be used at average daily doses ≤30 mg/day 
of morphine or its equivalent
…
IntravascularV and IM 
glucocorticoid
N
N
Not allowed
…

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Abbreviations:  BCG = Bacillus Calmette-Guérin; bDMARD = biological disease-modifying anti-rheumatic drugs; 
COX-2 = cyclooxygenase-2; csDMARD = conventional synthetic disease-modifying anti-rheumatic drugs; 
IM = intramuscular; IV = intravascular; JAK = Janus kinase; MTX = methotrexate; N = No; 
NSAID = nonsteroidal anti-inflammatory drug; PASI = Psoriasis Area and Severity Index; 
PDE4 = phosphodiesterase type 4; Y = Yes; WHO = World Health Organization.
Table RHCF.7.3.
Concomitant Medications Permitted/Not Permitted in the Open-Label 
Treatment Period from Week 24 to Week 52 for Treatment of PsA and Chronic Conditions 
Drug Class
As Needed
Chronic Use
Conditions for Use
…
csDMARDs
N
Y
Allowed doses:

Oral or parenteral MTX; 10 to 25 mg/week

Leflunomide:  up to 20 mg/day

Sulfasalazine:  up to 3 g/day

Hydroxychloroquine:  up to 400 mg/day

Cyclosporine:  up to 5 mg/kg/day 
…
IntravascularV and IM 
glucocorticoid
N
N
Not allowed
…
Abbreviations:  BCG = Bacillus Calmette-Guérin; bDMARD = biological disease-modifying anti-rheumatic drugs; 
COX-2 = cyclooxygenase-2; csDMARD = conventional synthetic disease-modifying anti-rheumatic drugs; 
IM = intramuscular; IV = intravascular; JAK = Janus kinase; MTX = methotrexate; N = No; 
NSAID = nonsteroidal anti-inflammatory drug; PASI = Psoriasis Area and Severity Index; 
PDE4 = phosphodiesterase type 4; Y = Yes; WHO = World Health Organization.
Table RHCF.7.4.
Allowed Concomitant Medications in the Post-Treatment Follow-Up 
Period (Period 3)
Drug Class
As Needed
Chronic Use
Conditions for Use
…
IntravascularV and IM 
glucocorticoid
Y
Y
Allowed 
…
Abbreviations:  BCG = Bacillus Calmette-Guérin; bDMARDs = biological disease-modifying anti-rheumatic drugs; 
COX-2 = cyclooxygenase-2; csDMARD = conventional synthetic disease-modifying anti-rheumatic drugs; 
IM = intramuscular; IV = intravascular; JAK = Janus kinase; MTX = methotrexate; N = No; 
NSAID = nonsteroidal anti-inflammatory drug; PASI = Psoriasis Area and Severity Index; 
PDE4 = phosphodiesterase type 4; Y = Yes; WHO = World Health Organization.
To avoid any possible drug interactions for those patients randomized to adalimumab, please 
refer to the SPC product labeling for adalimumab for further concomitant therapy restrictions.

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8.1.1.
Permanent Discontinuation from Study Treatment
Discontinuation of the investigational product 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:
…

alkaline phosphatase >2.5X ULN with the appearance of fatigue, nausea, 
vomiting, right quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
9.1.2.1. 
Psoriasis Area and Severity Index (PASI 75, PASI 90, PASI 100)
…
Absolute PASI scores of < ≤1, < ≤2, or< ≤3 may be considered as treatment targets for the 
management of plaque psoriasis.
9.1.2.3.1. 
American College of Rheumatology Core Set
a.
Tender Joint Count
TJC joint assessments will be performed by a blinded assessor. 
…
b.
Swollen Joint Count
SJC joint assessments will be performed by a blinded assessor.  
…
Missing, replaced, ankylosed, or arthrodesed joints will be identified by the investigator at the 
Screening Visit and will be excluded from evaluation during the trial.
TJC/SJC joint assessments will be performed by a blinded assessor.  
9.1.2.11. 
Leeds Dactylitis Index-Basic
If the patient has dactylitis, the LDI-B will be administered by a blinded assessor.  The LDI-B 
has been developed to measure the severity of dactylitis.  Once the presence of dactylitis is 
established in each digit, the ratio of the circumference of the affected digit to the circumference 
of the digit on the opposite hand or foot is measured (Helliwell et al. 2005).  Each dactylitic digit 
is defined by a minimum increase of 10% in circumference over the contra-lateral digit. If the 
same digits on each hand or foot are thought to be involved, the clinician will refer to a table of 
normative values (provided to study sites) for a value which will be used to provide the 
comparison. The calculated ratio is then multiplied by a tenderness score of 0 (not tender) or 
1 (tender).  If the ratio is >1.1, then subtract 1 from the calculated ratio and multiply it by 100 
and the tenderness score of 0 (not tender) or 1 (tender). Otherwise, if the ratio of the 
circumference of the digit is ≤1.1, then the LDI-B score is set to 0.  Tenderness is assessed in the 
area between the joints.  The results of each digit are then added to produce a total score (Healy 
and Helliwell 2007).

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9.1.2.14.  
Static Physician Global Assessment
If the patient has plaque Ps, the static Physician Global Assessment of psoriasis (sPGA) will be 
administered by the blinded assessor. The sPGA is the assessor’s physician’s determination of 
the patient’s Ps lesions overall at a given time point.  The sPGA is recommended as an endpoint 
to use to assess efficacy in the treatment of Ps (EMEA 2004).  Overall lesions are categorized by 
descriptions for induration, erythema, and scaling.  For the analysis of responses, the patient’s Ps 
is assessed at a given time point on a 6 point scale in which 0 = cleared, 1 = minimal, 2 = mild, 3 
= moderate; 4 = severe, 5 = very severe.
9.3.
Treatment of Overdose
Refer to the ixekizumab IB and product labeling SPC and the adalimumab product labeling SPC.
10.1. 
Sample Size Determination
Sample size was calculated assuming the proportion of patients simultaneously achieving
ACR50 and PASI 100 as 13.2 13.6% and 28.8 31.3% in the adalimumab and ixekizumab 
treatment groups, respectively, as observed in the csDMARD-experienced population from
Study RHAP. According to the nQuery software, a total sample size of 550 (with 275 per 
treatment group) using a 2-sided Fisher's exact test at 0.05 level of significance would yield 99% 
power for testing ixekizumab versuss adalimumab.
This sample size would yield 79 78% power for testing the noninferiority of ixekizumab to 
adalimumab at a one-sided 0.025 level of significance based on a noninferiority margin of –12% 
and using ACR50 response rates of 42.5 43.8% and 44.1% as observed for the ixekizumab and 
adalimumab treatment groups, respectively, in the csDMARD-experienced population from 
Study RHAP in the ixekizumab and adalimumab treatment groups, respectively.  For testing 
superiority of ixekizumab to adalimumab based on PASI 100 response rates of 42.5 46.9% and 
23.5 23.7% as observed for ixekizumab and adalimumab in the csDMARD-experienced 
population from Study RHAP, this sample size would yield 99% power using a 2-sided Fisher's 
exact test at 0.05 level of significance.
10.3.1.1. 
General Considerations for Analyses during Period 2 (Open-Label 
Treatment Period)
…
Comparisons of ixekizumab versus adalimumab will be performed for all outcome variables at 
all visits in Period 2; however, the primary time point of interest is Week 24.  
10.3.1.3. 
Adjustment for Multiple Comparisons
…

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3.  
Test 3 for Major Secondary Endpoint #2 – Proportion of patients achieving PASI 100 at 
Week 24:  If the test for major secondary endpoint #1 is significant, then a superiority
noninferiority test for major secondary endpoint #2 will be performed, followed by a test 
for superiority.  The noninferiority test will be performed using the methods described in 
Section 10.3.3.3, and the superiority test will be performed using the methods described 
in Section 10.3.3.1.1.
10.3.2.2. 
Patient Characteristics
Baseline characteristics, clinical, and health outcome measurements will be summarized for the
ITT population.  Baseline characteristics will include sex, age, age category, weight, BMI, race, 
geographic region, baseline disease severity, duration of disease, previous nonbiologic systemic 
therapy, and previous biologic therapy.  Baseline clinical measurements will include CASPER,
ACR component scores, PASI total score, DAS28-CRP, CRP, Modified CPDAI, HAQ-DI, Itch 
NRS score, NAPSI Fingernails, SPARCC Enthesitis Index, LEI, LDI-B, and other QoL scores.
10.3.3.1.1. 
Categorical Variables
Unless specified otherwise, the primary analysis method for the categorical efficacy and health 
outcome variables will be using a logistic regression model with treatment, concomitant
csDMARD use at baseline (Yes vs No) (yes or no), and severity of plaque psoriasis moderate-to-
severe plaque psoriasis involvement (Yes vs No) (yes or no) as factors and NRI method.  
Treatment group comparisons will be made at all visits up to Week 52 and odds ratios and their 
corresponding 95% confidence intervals (CIs) will be reported. 
10.3.3.1.2. 
Continuous Variables
Unless specified otherwise, the primary analysis method for all continuous efficacy and health 
outcome variables will be using a MMRM analysis.  The model will include treatment group, 
concomitant csDMARD use (Yes vs No) at baseline, moderate-to-severe plaque psoriasis 
involvement (Yes vs No) severity of plaque psoriasis, baseline value, visit, baseline-by-visit
interaction, and treatment-by-visit interaction as fixed factors.  The covariance structure to model 
the within-patient errors will be unstructured.  If the unstructured covariance matrix results in a 
lack of convergence, the heterogeneous Toeplitz covariance structure, followed by the 
heterogeneous autoregressive covariance structure will be used.  The Kenward-Roger method 
will be used to estimate the denominator degrees of freedom.  Type III tests for the least squares
means will be used for the statistical comparison; the 95% confidence interval (CI) will also be 
reported.  Treatment group comparisons at all visits up to Week 52 will be tested made.
10.3.3.3. 
Methodology for Noninferiority Test
…
Based on EMEA CHMP (CHMP 2005), FDA guidance (2016), and Weinblatt et al. (2013), a 
noninferiority margin of −12.0% for ACR50 between ixekizumab and adalimumab (ie, response 
rate of ixekizumab – response rate of adalimumab) is considered appropriate.  This noninferiority 
margin represents an approximately 60 50% preservation of the adalimumab treatment effect 

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(based on the difference between adalimumab and placebo) observed in a historical Phase 3 
study for adalimumab 40 mg twice weekly compared with placebo (Mease et al 2005) and Study 
RHAP.
10.3.6.1.  
Subgroup Analyses 
…
Subgroups to be evaluated will include concomitant csDMARD use at baseline (Yes vs No), 
concomitant MTX use at baseline (Yes or vs No), sex (male vs female), age group (<65 vs ≥65).  
A detailed description of the subgroup variables will be provided in the SAP.
10.3.7. 
Interim Analyses
An interim database lock will occur, and the analysis will be performed at the time (that is, a 
cutoff date) when the last patient completes Visit 8 (Week 24), completes ETV, or discontinues 
from Period 2.  This database lock will include all data collected by the cutoff date including data 
after Week 24 from the Open-Label Treatment Period (Period 2) and follow-up data from 
patients who have begun Post-Treatment Follow-Up Period (Period 3).  
This interim database lock at Week 24 will be considered the primary database lock for this 
study because all primary and major secondary study objectives will be assessed at this time. 
Since the primary time point of interest is Week 24, efficacy and health outcomes data will be 
reported up to Week 24 because of the lack of complete data for all patients beyond this visit. 
However, all safety data collected up to the cutoff date will be reported. 
A final database lock will occur after all enrolled patients have completed or discontinued the 
Post-Treatment Follow-Up Period (Period 3).  After the final database lock, all efficacy, health 
outcomes, and safety data collected until study completion will be reported.
Appendix 2.
Clinical Laboratory Tests
…
Other Tests
Creatinine
Human immunodeficiency virus antibody (HIV)
Hepatitis B Surface antigen (HBsAg)
Anti-Hepatitis B Surface antibody (HBsAb)
Anti-Hepatitis B Core antibody (HBcAb)
Anti-Hepatitis C antibody
Purified Protein Derivative (PPD)a
QuantiFERON®-TB Golda 
T-SPOT.TBa
HBV DNA
HCV RNA
Rheumatoid factor (RF)
Uric acid 
Calcium
Glucose, fasting at Visit 2 but nonfasting throughout 
study, if clinically indicated
Albumin
Cholesterol
Creatine Phosphokinase (CPK)
hs-CRP

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Appendix 1. Abbreviations and Definitions
…
Term
Definition
SPC
Summary of Product Characteristics

Leo Document ID = 77544431-841d-40bb-b76d-8d2be706f300
Approver: 
Approval Date & Time: 26-May-2017 13:01:47 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 26-May-2017 13:26:53 GMT
Signature meaning: Approved
PPD
PPD