Multicenter, Open-label, Efficacy, Safety, Tolerability, and Pharmacokinetic Study of Subcutaneous Ixekizumab With Adalimumab Reference Arm, in Children With Juvenile Idiopathic Arthritis Subtypes of Enthesitis-related Arthritis (Including Juvenile-Onset Ankylosing Spondylitis) and Juvenile Psoriatic Arthritis
Phase: PHASE3
Conditions: Juvenile Psoriatic Arthritis, Enthesitis Related Arthritis
Sponsor: Eli Lilly and Company

Protocol I1F-MC-RHCG (c)
Multicenter, Open-label, Efficacy, Safety, Tolerability, and Pharmacokinetic Study of
Subcutaneous Ixekizumab With Adalimumab Reference Arm, in Children With Juvenile
Idiopathic Arthritis Subtypes of Enthesitis-related Arthritis (Including Juvenile-Onset
Ankylosing Spondylitis) and Juvenile Psoriatic Arthritis
NCT04527380
Approval Date: 01-DEC-2023

I1F-MC-RHCG(c) Clinical Protocol 
Page 1 
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 
Title Page 
Protocol Title: 
Multicenter, Open-label, Efficacy, Safety, Tolerability, and Pharmacokinetic Study 
of Subcutaneous Ixekizumab with Adalimumab Reference Arm, in Children with 
Juvenile Idiopathic Arthritis Subtypes of Enthesitis-related Arthritis (Including 
Juvenile-Onset Ankylosing Spondylitis) and Juvenile Psoriatic Arthritis 
Protocol Number: I1F-MC-RHCG 
Amendment Number: c  
Compound: ixekizumab (LY2439821) 
Brief Title: 
An Open-Label Study of Ixekizumab (LY2439821) in Children with Juvenile 
Idiopathic Arthritis Subtypes of Enthesitis-Related Arthritis (including Juvenile Onset 
Ankylosing Spondylitis) and Juvenile Psoriatic Arthritis 
Study Phase: 3 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Numbers: 
EudraCT Number: 2018-000681-10 
EU CT Number: 2023-507184-19-00 
Approval Date: Protocol Amendment (c) Electronically Signed and Approved by Lilly on 
date provided below. 
Document ID: VV-CLIN-126448 
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Medical Monitor Name and Contact Information will be provided separately.  
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Protocol Amendment Summary of Changes Table  
DOCUMENT HISTORY 
Document 
Date 
Amendment b 
21-Sep-2022 
Amendment a 
06-Nov-2020 
Original Protocol 
06-Feb-2020 
 
Amendment c 
This amendment is considered to be nonsubstantial. 
 
Overall Rationale for the Amendment:  
The purpose of this amendment is to align with EU Clinical Trial Regulation 536/2014 (EU-
CTR) requirements. Lilly also takes the opportunity to include other clarifications, formatting, 
and editorial changes. 
Overall changes, including the above, specific to certain protocol sections, and a brief 
rationale are provided in this table. 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
Added subsections 
 
Regulatory Agency Identifier Numbers: 
EudraCT and EU CT Numbers 
 
Study Population 
 
Ethical Considerations of Benefit/Risk 
 
Data Monitoring Committee 
Compliance with EU-CTR 
Revised LTE Period in Treatment Arms and 
Duration from “156” to “160” 
Alignment as per study 
schema diagram 
4. Objectives and Endpoints 
Revised Exploratory Study Visit for the LTE 
Period from “156” to “264” 
Alignment as per study 
schema diagram 
7.1. Treatments Administered 
Updated authorization in Table RHCG.7.1.as 
defined by EU-CTR and the definition for 
study treatment. 
Revised the start visit for LTE period 
Under treatment regimen table, Dose, long 
term extension treatment period, added a note 
“Participants who are not switching to 
ixekizumab will undergo ETV at Visit 29 
(Week 104).” 
Compliance with EU-CTR 
 
 
Clarification 
7.1.1. Packaging and Labelling 
Added “Participants weighing >25 kg to 
<50.0 kg can opt for at-home administration 
when 40 mg prefilled syringe is made 
available for the trial” 
Provision for at-home 
administration so that the 
doses can be prepared 
manually 
7.7. Concomitant Therapy 
Deleted “for participants entering the LTE” 
Clarification 
9.1.3.1. Childhood Health Assessment 
Questionnaire (CHAQ) 
Revised “Parent’s Global Assessment of 
Well-being” to “CHAQ” 
Correction 
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10.3.1. General Statistical 
Considerations 
Added a paragraph on handling of missing, 
unused, and spurious data 
Compliance with EU-CTR 
10.3.1.3. General Considerations for 
the LTE Period 
Revised the end visit for the LTE period 
Updated to align with the 
start and end visits 
mentioned as per the study 
schema diagram 
Appendix 1. Abbreviations 
Added new abbreviations to the list 
Compliance with EU-CTR 
Appendix 3. 12.3.1. Regulatory and 
Ethical Considerations 
Added language regarding reporting of 
significant issues related to participant’s 
safety, rights, and data integrity 
Appendix 3. 12.3.4. Data Protection 
Updated the required language 
Appendix 5. Adverse Events: 
Definitions and Procedures for 
Recording, Evaluating, Follow-Up, 
and Reporting 
Added details on adverse events 
Added details on SAE regulatory reporting 
Appendix 6. Contraceptive Guidance 
and Collection of Pregnancy 
Information 
Deleted “In an appropriate appendix of the 
protocol, add definitions of WOCBP, women 
of nonchildbearing potential, and 
postmenopausal state as provided in this 
document’s section called “Section 9.2.2.2” 
Correction 
Throughout 
Minor editorial/formatting changes made 
throughout 
For clarity 
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Table of Contents  
Section 
Page  
Title Page .................................................................................................................................... 1 
Protocol Amendment Summary of Changes Table ................................................................. 3 
Table of Contents ....................................................................................................................... 5 
List of Tables ................................................................................................................... 9 
List of Figures ................................................................................................................ 10 
1. 
Synopsis ........................................................................................................................... 11 
2. 
Schedule of Activities ....................................................................................................... 17 
3. 
Introduction ...................................................................................................................... 55 
3.1. 
Study Rationale ........................................................................................................... 55 
3.2. 
Background ................................................................................................................. 55 
3.3. 
Benefit/Risk Assessment ............................................................................................. 60 
4. 
Objectives and Endpoints ................................................................................................. 63 
5. 
Study Design .................................................................................................................... 66 
5.1. 
Overall Design ............................................................................................................ 66 
5.1.1. 
Screening and Baseline Periods .......................................................................... 69 
5.1.2. 
Open-Label Treatment Period ............................................................................. 70 
5.1.3. 
Open-Label Extension Period ............................................................................. 70 
5.1.4. 
Long-Term Extension Period .............................................................................. 71 
5.1.5. 
Post-Treatment Follow-Up Period ...................................................................... 72 
5.2. 
Number of Participants ................................................................................................ 73 
5.3. 
End of Study Definition ............................................................................................... 73 
5.4. 
Scientific Rationale for Study Design ......................................................................... 73 
5.5. 
Justification for Dose................................................................................................... 74 
6. 
Study Population .............................................................................................................. 77 
6.1. 
Inclusion Criteria ......................................................................................................... 77 
6.2. 
Exclusion Criteria ........................................................................................................ 79 
6.2.1. 
Rationale for Exclusion of Certain Study Candidates ......................................... 83 
6.3. 
Lifestyle Restrictions ................................................................................................... 83 
6.4. 
Screen Failures ............................................................................................................ 83 
7. 
Treatments ........................................................................................................................ 85 
7.1. 
Treatments Administered ............................................................................................ 85 
7.1.1. 
Packaging and Labelling ..................................................................................... 88 
7.2. 
Method of Treatment Assignment ............................................................................... 89 
7.2.1. 
Selection and Timing of Doses ........................................................................... 89 
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7.3.
Blinding ....................................................................................................................... 90
7.4.
Dosage Modification ................................................................................................... 90
7.5.
Preparation/Handling/Storage/Accountability .............................................................. 90
7.6.
Treatment Compliance ................................................................................................ 90
7.7.
Concomitant Therapy .................................................................................................. 91
7.8.
Treatment After the End of the Study ......................................................................... 94
7.8.1. 
Study Extensions ................................................................................................. 94
7.8.2. 
Treatment After Study Completion ..................................................................... 94
7.9.
Special Treatment Considerations ............................................................................... 94
8.
Discontinuation Criteria ................................................................................................. 96
8.1.
Discontinuation from Study Treatment ....................................................................... 96
8.1.1. 
Permanent Discontinuation from Study Treatment ............................................. 96
8.1.2. 
Temporary Discontinuation from Study Treatment ............................................ 99
8.2.
Discontinuation from the Study ................................................................................... 99
8.3.
Lost to Follow-Up ..................................................................................................... 100
9.
Study Assessments and Procedures ................................................................................ 101
9.1.
Efficacy Assessments ................................................................................................ 101
9.1.1. 
Primary Efficacy Assessment ........................................................................... 101
9.1.1.1.
JIA ACR 30 Core Set Variables ............................................................. 101
9.1.1.1.1. Physician’s Global Assessment of Disease Activity .................................. 102
9.1.2. 
Secondary Efficacy Assessments ...................................................................... 102
9.1.2.1.
JIA ACR 50, 70, 90, and 100 .................................................................. 102
9.1.2.1.1. 
Percentage of Body Surface Area (BSA) .............................................. 102
9.1.2.1.2. 
Psoriasis Area and Severity Index (PASI) ............................................ 102
9.1.2.1.3. 
Enthesitis Assessment ........................................................................... 103
9.1.3. 
Health Outcomes Measures .............................................................................. 103
9.1.3.1.
Childhood Health Assessment Questionnaire (CHAQ) ...................... 103
9.1.4. 
Exploratory Efficacy Assessments .................................................................... 104
9.1.4.1.
Total and Tender Dactylitic Digit Count ................................................ 104
9.1.4.2.
Juvenile Arthritis Disease Activity Score-27 (JADAS-27) .................. 104
9.1.4.3.
EuroQol-Five Dimensions-Youth (EQ-5D-Y) ....................................... 105
9.1.4.4.
Juvenile Spondyloarthritis Disease Activity Index (JSpADA) ............ 105
9.1.4.5.
Morning Joint Stiffness Duration ............................................................ 106
9.1.5. 
Appropriateness of Assessments ....................................................................... 106
9.2. 
Adverse Events .......................................................................................................... 106
9.2.1. 
Timing and Mechanism for Collecting Events.................................................. 107
9.2.2. 
Serious Adverse Events .................................................................................... 109
9.2.2.1. 
Suspected Unexpected Serious Adverse Reactions .......................... 110
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9.2.2.2. 
Pregnancy ................................................................................................. 110
9.2.2.3. 
Adverse Events of Special Interest ........................................................ 111
9.2.3.
Complaint Handling .......................................................................................... 112
9.3. 
Treatment of Overdose .............................................................................................. 112
9.4. 
Safety ........................................................................................................................ 113
9.4.1.
Physical Examination ........................................................................................ 113
9.4.2.
Tanner Stage Scale ............................................................................................ 113
9.4.3.
Vital Signs ........................................................................................................ 113
9.4.4.
Laboratory Tests ............................................................................................... 113
9.4.5.
Pregnancy Testing ............................................................................................. 114
9.4.6.
Chest X-Ray and Tuberculosis Testing ............................................................. 115
9.4.7.
Uveitis Evaluation ............................................................................................. 116
9.4.8.
Children’s Depression Inventory 2 Short Form (CDI-2) .................................. 117
9.4.9.
Columbia–Suicide Severity Rating Scale (C-SSRS) ........................................ 117
9.4.10.
Self-Harm Supplement Form ............................................................................ 117
9.4.11.
Safety Monitoring ............................................................................................. 117
9.4.11.1. 
Hepatic Safety Monitoring ....................................................................... 118
9.4.11.1.1. 
Hepatic Safety Data Collection ............................................................. 120
9.4.11.2. 
Hepatitis B Monitoring .............................................................................. 120
9.4.11.3. 
Growth Monitoring .................................................................................... 121
9.5.
Pharmacokinetics ....................................................................................................... 121
9.6.
Pharmacodynamics .................................................................................................... 121
9.6.1. 
Immunogenicity Assessments ........................................................................... 121
9.7.
Pharmacogenomics .................................................................................................... 122
9.8.
Biomarkers ................................................................................................................ 122
9.9.
Medical Resource Utilization and Health Economics ............................................... 122
10.
Statistical Considerations ............................................................................................... 123
10.1. Sample Size Determination ....................................................................................... 123
10.2. Populations for Analyses ........................................................................................... 123
10.3. Statistical Analyses ................................................................................................... 124
10.3.1. 
General Statistical Considerations ..................................................................... 124
10.3.1.1.
General Considerations for the OLT Period ........................................ 125
10.3.1.2.
General Considerations for the OLE Period ........................................ 125
10.3.1.3.
General Considerations for the LTE Period ......................................... 125
10.3.1.4.
General Considerations for the Post-Treatment Follow-up (PTFU) 
Period ......................................................................................................... 126
10.3.1.5.
Missing Data Imputation Methods ......................................................... 126
10.3.1.5.1. 
Non-responder Imputation for Clinical Response ................................. 126
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10.3.1.5.2. 
Modified Baseline Observation Carried Forward ................................. 126 
10.3.1.5.3. 
Last Observation Carried Forward ........................................................ 126 
10.3.2. 
Treatment Group Comparability ....................................................................... 127 
10.3.2.1. Participant Disposition ............................................................................. 127 
10.3.2.2. Participant Characteristics ....................................................................... 127 
10.3.2.3. Concomitant Therapy .............................................................................. 127 
10.3.2.4. Treatment Compliance ............................................................................ 127 
10.3.3. 
Efficacy Analyses ............................................................................................. 128 
10.3.3.1. Primary Analyses ...................................................................................... 128 
10.3.3.2. Secondary Analyses ................................................................................ 128 
10.3.3.3. Exploratory Analyses ............................................................................... 129 
10.3.4. 
Safety Analyses ................................................................................................ 129 
10.3.4.1. Adverse Events ......................................................................................... 130 
10.3.4.2. Clinical Laboratory Tests ........................................................................ 131 
10.3.4.3. Vital Signs, Physical Findings, and Other Safety Evaluations ........... 131 
10.3.5. 
Pharmacokinetic/Pharmacodynamic Analyses .................................................. 131 
10.3.6. 
Evaluation of Immunogenicity .......................................................................... 132 
10.3.7. 
Other Analyses .................................................................................................. 132 
10.3.7.1. Subgroup Analyses .................................................................................. 132 
10.3.7.2. Exploratory Analysis ................................................................................ 132 
10.3.8. 
Interim Analyses ............................................................................................... 132 
10.3.9. 
Adjudication Committee ................................................................................... 133 
11. References ...................................................................................................................... 134 
12. Appendices ..................................................................................................................... 142 
Appendix 1. 
Abbreviations .............................................................................................. 142 
Appendix 2. 
Clinical Laboratory Tests ............................................................................ 148 
Appendix 3. 
Study Governance Considerations .............................................................. 152 
Appendix 4. 
Hepatic Monitoring Tests for Treatment- Emergent Abnormality ............. 158 
Appendix 5. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting ......................................................................... 160 
Appendix 6. 
Contraceptive Guidance and Collection of Pregnancy Information ........... 167 
Appendix 7. 
I1F-MC-RHCG Blood Volume Prioritization Tool ................................... 170 
Appendix 8. 
Provisions for Changes in Study Conduct During Exceptional Circumstances  
 
 .................................................................................................................... 178 
Appendix 9. 
Protocol Amendment History ..................................................................... 186 
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List of Tables  
Table 
Page 
Table RHCG.2.1.  Schedule of Activities – Open-Label Treatment Period ...............................17 
Table RHCG.2.2. Schedule of Activities – Open-Label Extension Period 
(V8 through V20) ........................................................................................................................22 
Table RHCG.4.1.  Objectives and Endpoints ..............................................................................63 
Table RHCG.7.1.  Treatment Regimens .....................................................................................85 
Table RHCG.7.2.  Concomitant JIA Therapies ..........................................................................93 
Table RHCG.10.1.  Populations Based on Treatment Period ...................................................123 
Table RHCG.10.2.  Secondary Efficacy and Health Outcomes Analyses OLT, OLE, and LTE 
Periods ............................................................................................................................128 
Table RHCG.10.3.  Summary Statistics OLT Period ...............................................................128 
Table RHCG.10.4.  Summary Statistics OLE Period ...............................................................129 
Table RHCG.10.5  Summary Statistics:  Long-Term Extension Period ...................................129 
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List of Figures 
Figure 
Page 
Figure RHCG.5.1. Illustration of study design for Clinical Protocol I1F-MC-RHCG ...............68 
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1. Synopsis  
Title of Study:  
Multicenter, Open-Label, Efficacy, Safety, Tolerability, and Pharmacokinetic Study of 
Subcutaneous Ixekizumab with Adalimumab Reference Arm, in Children with Juvenile 
Idiopathic Arthritis Subtypes of Enthesitis-related Arthritis (Including Juvenile-Onset 
Ankylosing Spondylitis) and Juvenile Psoriatic Arthritis 
Regulatory Agency Identifier Numbers:  
EudraCT Number: 2018-000681-10 
EU CT Number: 2023-507184-19-00 
Rationale:  
Ixekizumab has been approved for the treatment of plaque psoriasis in adult and pediatric 
participants, and adult psoriatic arthritis (PsA), radiographic axial spondyloarthritis (r-axSpA), 
and non-radiographic axSpA with objective signs of inflammation. Enthesitis related arthritis 
(ERA) and juvenile PsA (JPsA) bear resemblance to adult axSpA and PsA, respectively; 
therefore, therapeutic benefit of ixekizumab is expected in these 2 subtypes of juvenile idiopathic 
arthritis (JIA). There are currently only 2 biologics, both tumor necrosis factor (TNF) inhibitors, 
adalimumab and etanercept, approved for ERA, and only etanercept for JPsA, with certain age 
limitations. Ixekizumab may offer a therapeutic option for ERA and JPsA participants who are 
candidates for an initial biologic disease-modifying antirheumatic drug (bDMARD) therapy, as 
well as participants with primary or secondary efficacy failure or intolerance of prior bDMARD. 
Based on its well-established efficacy and safety profile in JIA, adalimumab was selected as a 
reference product. This study is part of the European Paediatric Investigation Plan (PIP), EMEA-
001050-PIP02-18-M01, with the aim to evaluate the efficacy, safety, tolerability, and 
pharmacokinetics (PK) of ixekizumab when administered to pediatric participants with JIA 
subsets of ERA (including juvenile onset ankylosing spondylitis [JoAS]) and JPsA. 
 
 
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Objective(s)/Endpoints:  
 
Objectives 
Endpoints 
Primary 
 To evaluate the efficacy of ixekizumab in 
children with JIA subtypes of ERA (including 
JoAS) and JPsA based on the JIA American 
College of Rheumatology (ACR) 30 response 
Percentage of participants meeting the JIA ACR 30 
response criteria at Week 16 
Secondary for the Open Label Treatment 
(OLT) and Open Label Extension (OLE) 
Periods 
 To evaluate the efficacy of ixekizumab in 
children with JIA subtypes of ERA (including 
JoAS) and JPsA based on the other clinical 
responses, disease activity, and physical 
function measures 
 To evaluate the efficacy of adalimumab 
(reference arm) in children with JIA subtypes 
of ERA (including JoAS) and JPsA based on 
JIA ACR 30 and the other clinical responses, 
disease activity, and physical function measures 
The following outcomes will be assessed at each regular 
study visita: 
 
Percentage of participants meeting the JIA 
ACR 30/50/70/90/100 response criteria 
 
Changes from baseline in each of the 6 individual 
components of the JIA ACR core set variables as 
follows: 
o 
Number of active joints 
o 
Number of joints with limited range of 
motion 
o 
Physician’s Global Assessment of Disease 
Activity 
o 
Parent’s Global Assessment of Well-Being 
o 
Physical function as measured by the 
Childhood Health Assessment Questionnaire 
(CHAQ) 
o 
Acute-phase reactant (high-sensitivity C- 
reactive protein [hsCRP]) and erythrocyte 
sedimentation rate (ESR) 
 
Change from baseline in Psoriasis Area and Severity 
Index (PASI) for JPsA participants with at least 
3% Body Surface Area (BSA) at baseline 
 
Change from baseline in Leeds Enthesitis Index 
(LEI) for participants with enthesitis at baseline 
 
Proportion of participants with disease flare (flare 
defined as worsening of ≥30% from baseline in at 
least 3 of the 6 JIA ACR core set criteria and an 
improvement of ≥30% in no more than 1 of the 
criteria) 
 To characterize ixekizumab pharmacokinetics 
(PK) in children with JIA subtypes of ERA 
(including JoAS) and JPsA 
 
Trough concentrations of ixekizumab in 
participants with JIA subtypes of ERA (including 
JoAS) and JPsA 
 To evaluate the potential development of anti- 
ixekizumab antibodies and their impact on the 
efficacy and safety of ixekizumab in children 
with JIA subtypes of ERA (including JoAS) 
and JPsA 
 
Percentage of participants with anti-ixekizumab 
antibodies 
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Objectives 
Endpoints 
 Describe the safety of ixekizumab in 
participants with JIA subtypes of ERA 
(including JoAS) and JPsA 
 
Adverse events (AEs) including serious adverse 
events (SAEs) 
 
Safety parameters including but not limited to 
infections, injection site reactions, and laboratory 
data including B-, T-cell, and natural killer (NK)- 
cell levels, white blood cell (WBC) count, red 
blood cell (RBC) count, alanine aminotransferase 
(ALT), aspartate aminotransferase (AST) 
Secondary for the Long-Term Extension (LTE) 
Period 
 To evaluate the long-term safety, tolerability, 
and efficacy of ixekizumab in children with 
JIA subtypes of ERA (including JoAS) and 
JPsA 
The following outcomes will be assessed at each regular 
study visita: 
 
AEs including SAEs and adverse events of special 
interest (AESIs) 
 
Safety parameters including but not limited to 
infections, injection site reactions, and laboratory 
evaluations (including chemistry and hematology) 
 
Permanent and temporary discontinuations of the 
study intervention 
 
Vital signs, growth, and development 
Abbreviations: ERA = enthesitis-related arthritis; ETV – early termination visit; JIA = juvenile 
idiopathic arthritis; JoAS = juvenile onset ankylosing spondylitis; JPsA = juvenile psoriatic 
arthritis. 
a During the OLE period, regular visits and assessments will occur every 3 months (Visits 8, 11, 14, 
17, 20, 23, 26 and 29/ETV). Participants will also have monthly treatment visits to the site 
primarily for dispensation and/or administration of study drug. 
Summary of Study Design:  
Study I1F-MC-RHCG (RHCG) is a multicenter, randomized, open-label study of subcutaneous 
(SC) ixekizumab, with adalimumab as a reference arm, followed by an open-label extension 
(OLE) period with ixekizumab and adalimumab in children from 2 to less than 18 years of age 
with JIA subtypes of ERA (including JoAS) and JPsA. The long-term extension (LTE) period 
will evaluate the safety, tolerability, and efficacy of ixekizumab in children with JIA subtypes of 
ERA and JPsA. 
Treatment Arms and Duration:  
The study consists of 2 arms. Participants in the ixekizumab arm will receive SC ixekizumab at 
the following dosing regimens: 
 
 every 4 weeks (Q4W) 
 
 
 
 Q4W 
 
 
 Q4W 
 
Participants in the adalimumab arm (reference arm) will receive SC adalimumab at the following 
dosing regimens: 
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 
 every 2 weeks (Q2W) 
 
 
 Q2W 
 
 
Study RHCG will be conducted in 4 parts: 
 Open-label treatment (OLT) Period: 16 weeks. 
 OLE Period: 88 weeks. 
 LTE Period: 160 weeks. 
 Post-treatment follow-up (PTFU; Visits 801, 802, and 803): 4 to 12 weeks 
after the last visit. 
Participants who complete the OLT period may continue to the OLE period of the study. 
Participants who complete the OLT and OLE periods of this study may participate in an 
open-label LTE period. 
Participants receiving adalimumab during the OLT period who did NOT attain a JIA ACR 30 
response at Week 16 will be switched to ixekizumab in the OLE period. Participants receiving 
adalimumab during the OLT period who did attain a JIA ACR 30 response at Week 16 will be 
given the option to switch or not to switch to ixekizumab in the OLE period. The decision to 
switch for participants who achieved a JIA ACR 30 response will be left to the 
participant/participant’s caregiver and investigator. A switch from adalimumab to ixekizumab 
during the OLE period may also occur at any other visit after Week 16 based on the 
participant/participant’s caregiver and investigator’s decision. After switching to ixekizumab, the 
participants will not have the option to resume adalimumab treatment during the remainder of the 
trial participation. Any adalimumab participants that complete the open label extension period of 
the study will be reassigned to ixekizumab starting with Treatment Period 3 (refer to Section 6.1 
for additional details). Adalimumab participants who choose not to switch to ixekizumab at the 
end of the open label period will enter the PTFU and be considered study completers. 
Participant who do not enroll in the LTE study or discontinued early (participants who have 
received at least 1 dose of study drug) should enter the PTFU period and complete through Visit 
802. Participants may be followed beyond Visit 802 for continued monitoring of their neutrophil 
counts if determined by the sponsor/investigator that additional monitoring is needed. If a 
participant discontinues study drug early, the participant will complete the early termination visit 
(ETV) and then enter the PTFU period. 
Study Population:  
This study will enroll participants aged 2 to less than 18 years at baseline, with at least 3 active 
peripheral joints diagnosed with JIA and fulfilling the ILAR classification criteria for ERA 
(including JoAS) or JPsA but no other JIA category. Participants classified as ERA will have to 
be at least 6 years of age, which is aligned with the classification criteria. Eligible participants 
will have body weight of at least 10.0 kg at baseline. For the participants’ safety, medical 
conditions such as active uveitis, active IBD, and personal or first-degree family history of IBD 
may preclude participation in the study.  
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Number of Participants:  
At least 100 participants from 2 to less than 18 years of age with a diagnosis before age 16 years 
of JIA subsets of ERA (including JoAS) or JPsA are planned to enter the OLT period. 
 For participants who are naive to bDMARD treatment (bDMARD-naive), at 
least 20 participants will be randomized to ixekizumab and at least 20 
participants will be randomized to adalimumab. Randomization will be 
stratified based on the subtype of JIA (ERA or JPsA). 
 The remaining participants (approximately 60 participants) who are either 
bDMARD- naive or have had an inadequate response or intolerance to 
bDMARD treatment (bDMARD-IR) will be assigned to ixekizumab. 
 For all participants who complete the OLE, participants entering into the 
LTE will be assigned to ixekizumab. 
 
Ethical Considerations of Benefit/Risk:  
As only 2 bDMARDs, both TNF inhibitors, are currently approved to treat ERA and/or JPsA, 
and not all patients achieve an adequate primary response to them or may experience secondary 
treatment failure or intolerance, there is a high unmet need for bDMARDs with a different 
mechanism of action in these 2 JIA subtypes.  
Based on the demonstrated comprehensive efficacy of ixekizumab in axSpA and PsA as well as 
acceptable safety profile, the reasonable probability of a positive benefit/risk warrants this study 
to be conducted. 
Statistical Analysis:  
A Bayesian analysis will be utilized to assess the primary endpoint of JIA ACR 30 response rate 
at Week 16. A positive study will satisfy at least 80% posterior probability of a JIA ACR 30 
response rate greater than 50% in ixekizumab-treated participants, otherwise the study will be 
considered negative. 
Categorical data will be summarized using descriptive statistics. The counts/proportions and 95% 
confidence interval will be reported. Continuous data will be summarized using descriptive 
statistics; mean, standard deviation, minimum, maximum, and median will be reported. 
Descriptive summaries will be provided by treatment assignment (ixekizumab, adalimumab), JIA 
subtype (ERA, JPsA), bDMARD experience (bDMARD-naive or bDMARD-IR), and 
demographic features including sex and age group. 
Pharmacokinetic data will be summarized using descriptive statistics. 
An interim analysis will be performed to determine if the study should be stopped for futility 
when 40 ixekizumab-treated participants have completed 16 weeks of treatment. If the observed 
JIA ACR 30 response rate is less than 40% at interim, futility will be declared, and the study will 
be terminated after the applicable required regulatory agreements are obtained. All safety data 
will be descriptively summarized using corresponding populations. 
Approved on 01 Dec 2023 GMT

I1F-MC-RHCG(c) Clinical Protocol 
Page 16 
Data Monitoring Committee: 
Yes 
Approved on 01 Dec 2023 GMT

I1F-MC-RHCG(c) Clinical Protocol 
Page 17 
 
 
 
2. Schedule of Activities  
Table RHCG.2.1. 
Schedule of Activities – Open-Label Treatment Period 
Screening 
Open-Label Treatment Period 
Notes 
Visit No 
V1 
V2 
Baseline 
V3 
V4 
V5 
V6 
V7 
Baseline laboratory samples should be taken 
before administration of investigational 
product. 
Study Week 
W0 
W2 
W4 
W8 
W12 
W16 
Study Days (Approximately) 
-42 to -7d 
0 
14 ± 7d 
28 ± 7d 
56 ± 7d 
84 ± 7d 
112 ± 7d 
Informed consent and assent 
X 
Parent/legal guardian signs (informed 
consent form) and participant signs (assent 
form) (as appropriate) per local 
requirements. 
Signatures should be obtained before any 
study assessments, examinations, or 
procedures. If participant turns 18 during 
study, informed consent form is signed. 
Complete medical history 
X 
Including TB exposure. 
Review pre-existing conditions 
X 
X 
Immunization history record 
X 
Immunizations occurred prior to study 
entry. 
Immunization record 
X 
X 
Immunizations occurred during the 
participation in the study. 
Demographics 
X 
Full date of birth (day, month, and year), 
sex, and ethnicity. 
In countries where full date of birth is not 
permitted to be collected, country-specific 
adjustments will be made to collect only 
month and year. 
Physical examination 
X 
X 
Excluding pelvic, rectal, and breast 
examinations. 
Height 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
Weight to be recorded to nearest 10th of a 
kilogram. 
Occipital frontal circumference 
measurement 
X 
X 
Only in children up to 3 years of age. 
Habits 
X 
Including caffeine, alcohol, and tobacco 
consumption. 
Assessment only for participants 12 years of 
age or older. 
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I1F-MC-RHCG(c) Clinical Protocol 
Page 18 
 
 
 
Screening 
Open-Label Treatment Period 
Notes 
Visit No 
V1 
V2 
Baseline 
V3 
V4 
V5 
V6 
V7 
Baseline laboratory samples should be taken 
before administration of investigational 
product. 
Study Week 
W0 
W2 
W4 
W8 
W12 
W16 
Study Days (Approximately) 
-42 to -7d 
0 
14 ± 7d 
28 ± 7d 
56 ± 7d 
84 ± 7d 
112 ± 7d 
Vital signs (BP, pulse, body 
temperature) 
X 
X 
X 
X 
X 
X 
X 
At baseline (Visit 2, Week 0), BP and pulse 
measured at least 30 minutes pre- and post- 
injection. BP and pulse should be measured 
pre- and post-injection at the other visits. 
Inclusion/exclusion criteria 
X 
X 
Previous JIA therapy 
X 
Concomitant medications, including 
medications for indication 
X 
X 
X 
X 
X 
X 
X 
AEs 
X 
X 
X 
X 
X 
X 
X 
See Section 9.2.2.3 for a complete list of 
AESIs. IBD events will be adjudicated. 
Randomization 
X 
Dispense study drug 
X 
X 
X 
X 
X 
X 
See Section 7.1, for details. 
Administer study drug 
X 
X 
X 
X 
X 
X 
Ixekizumab is administered on site Q4W. 
Adalimumab is administered at home Q2W. 
For training purposes, the first doses may be 
administered at the site. See Section 7.1, for 
administration details. 
Clinician Reported Measures 
Joint Assessment 
X 
X 
X 
X 
X 
X 
X 
Enthesitis Assessment 
X 
X 
X 
X 
X 
X 
It includes LEI and active enthesitis count. 
Dactylitic Count 
X 
X 
X 
X 
X 
X 
Physician’s Global Assessment of 
Disease Activity 
X 
X 
X 
X 
X 
X 
Clinical Sacroiliitis 
X 
X 
X 
X 
X 
X 
Back Mobility (Schober’s Test) 
X 
X 
X 
X 
X 
X 
Body Surface Area (BSA) 
X 
X 
X 
X 
X 
X 
Psoriasis Area and Severity Index 
(PASI) 
X 
X 
X 
X 
X 
X 
Columbia–Suicide Severity Rating 
Scale – Screening 
X 
Assessment only for participants 7 years of 
age or older at screening. 
Columbia–Suicide Severity Rating 
X 
X 
X 
X 
X 
X 
Assessment only for participants 7 years of 
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I1F-MC-RHCG(c) Clinical Protocol 
Page 19 
 
 
 
Scale – Since Last Assessed 
age or older. 
Screening 
Open-Label Treatment Period 
Notes 
Visit No 
V1 
V2 
Baseline 
V3 
V4 
V5 
V6 
V7 
Baseline laboratory samples should be taken 
before administration of investigational 
product. 
Study Week 
W0 
W2 
W4 
W8 
W12 
W16 
Study Days (Approximately) 
-42 to -7d 
0 
14 ± 7d 
28 ± 7d 
56 ± 7d 
84 ± 7d 
112 ± 7d 
Self-Harm Supplement Form 
X 
X 
X 
X 
X 
X 
X 
Assessment only for participants 7 years of 
age or older. 
Uveitis Evaluation 
X 
X 
X 
X 
X 
X 
X 
Active uveitis to be excluded at screening. 
Investigators will assess if the participant 
has developed uveitis since last visit. 
Patient/Parent Administered 
Measures 
Childhood Health Assessment 
Questionnaire (CHAQ) 
X 
X 
X 
X 
X 
X 
Tanner Stage Scale 
X 
X 
Assessment only for participants 8 years or 
older. 
Once the participant reaches the score of 5 
on this scale, no further assessments are 
needed. 
EQ-5D-Y 
X 
X 
X 
Assessment only for participants 4 years or 
older. 
Children’s Depression Inventory 2 
Short Form (CDI-2) 
X 
X 
X 
X 
Assessment only for participants 7 years of 
age or older 
Pain Numeric Rating Scale 
X 
X 
X 
X 
X 
X 
Morning Joint Stiffness Duration 
X 
X 
X 
X 
X 
X 
Parent’s Global Assessment of 
Well-Being 
X 
X 
X 
X 
X 
X 
Laboratory Tests 
Acute phase reactant (hsCRP) 
X 
X 
X 
X 
X 
X 
Acute phase reactant (ESR) 
X 
X 
X 
X 
X 
X 
To be performed locally and before the 
study drug administration at Week 16 
RF 
X 
RF test not required if past result available. 
HLA-B27 
X 
HLA-B27 test not required if past result is 
available. 
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I1F-MC-RHCG(c) Clinical Protocol 
Page 20 
 
 
 
Screening 
Open-Label Treatment Period 
Notes 
Visit No 
V1 
V2 
Baseline 
V3 
V4 
V5 
V6 
V7 
Baseline laboratory samples should be taken 
before administration of investigational 
product. 
Study Week 
W0 
W2 
W4 
W8 
W12 
W16 
Study Days (Approximately) 
-42 to -7d 
0 
14 ± 7d 
28 ± 7d 
56 ± 7d 
84 ± 7d 
112 ± 7d 
Read PPD (if applicable) 
X 
See Section 9.4.5 for details. 
To be performed locally. 
Chest x-ray 
X 
Only for participants with a positive or 
repeated not negative TB test(s) and 
according to local guidelines. See 
Section 9.4.5 for details 
HIV/HCV 
X 
HCV antibody positive results require a 
follow-up test for HCV RNA. See 
Section 5.1.1 for details. 
HBV (HBsAg, HBcAb, HBsAb) 
X 
X 
Positive test for HBcAb requires a follow- 
up test for HBV DNA. See Section 5.1.1  
for details. 
Serum pregnancy test 
X 
Section 5.1.1 for details. Performed 
centrally. Females only. 
Urine pregnancy test 
X 
X 
X 
X 
X 
Section 5.1.1 for details. Performed locally. 
Females only. 
Clinical chemistry 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
May not be feasible in younger (non-toilet 
trained) participants. Failure to obtain will 
not be considered a protocol violation. 
Cell flow cytometry panel (B, T, 
CD4+T, CD8+T, and NK cells) 
X 
X 
Participants may not have flow cytometry 
testing due to blood volume limitations. 
Immunogenicity testing 
X 
X 
X 
X 
See Section 9.6.1. All samples for 
immunogenicity should be taken pre-dose 
when applicable and possible. 
PK sample 
X 
X 
X 
X 
At visits where study drug will be 
administered, PK samples should be 
collected prior to administration of study 
drug. 
QuantiFERON®-TB Gold, T-Spot 
or PPD (if applicable) 
X 
See Section 9.4.5 for details. 
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I1F-MC-RHCG(c) Clinical Protocol 
Page 21 
 
 
 
 
Abbreviations: AE = adverse event; AESI = adverse events of special interest; BP = blood pressure; d = days; EQ-5D-Y = European Quality of Life-5 
Dimensions-Youth; ESR = erythrocyte sedimentation rate; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface antibody; HBsAg = 
hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HLA-B27 = human leukocyte 
antigen-B27; hsCRP = high-sensitivity C-reactive protein; IBD = inflammatory bowel disease; JIA = juvenile idiopathic arthritis; LEI = Leeds 
Enthesitis Index; 
NK = natural killer; PPD = purified protein derivative; PK = pharmacokinetics; Q2W = every 2 weeks; Q4W = every 4 weeks; RF = rheumatoid 
factor; TB = tuberculosis; V = study visit; W = study week. 
Note: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described 
in the sponsor-provided weight-based prioritization chart. 
Approved on 01 Dec 2023 GMT

I1F-MC-RHCG(c) Clinical Protocol 
Page 22 
 
 
 
 
Table RHCG.2.2. 
Schedule of Activities – Open-Label Extension Period (V8 through V20) 
 
Open-Label Extension Treatment Period 
Notes 
Visit No 
V8 
V9 
(TV) 
V10 
(TV)- 
V11 
V12 
(TV) 
V13 
(TV) 
V14 
V15 
(TV) 
V16 
(TV) 
V17 
V18 
(TV) 
V19 
(TV) 
V20 
Treatment visits (TV) are intended for 
the dispensation and/or site 
administration of the study treatment. 
Study Week 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
W56 
W60 
W64 
W68 
Study Days 
(Approximately) 
140 
± 7d 
168 ± 
7d 
196 ± 
7d 
224 ± 
7d 
252 ± 
7d 
280 ± 
7d 
308 ± 
7d 
336 ± 
7d 
364 ± 
7d 
392 ± 
7d 
420 ± 
7d 
448 ± 
7d 
476 ± 
7d 
Immunization record 
X 
X 
X 
Immunizations occurred during the 
participation in the study. 
Physical 
examination 
X 
X 
X 
Excluding pelvic, rectal, and breast 
examinations. 
Height 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Occipital frontal 
circumference 
measurement 
X 
X 
X 
X 
Only in children up to 3 years of age. 
Habits 
X 
Including caffeine, alcohol, and 
tobacco consumption. 
Assessment only for participants 
12 years of age or older. 
Vital signs (BP, 
pulse, body 
temperature) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BP and pulse should be measured at 
least pre-injection. 
Concomitant 
medications 
X 
X 
X 
X 
X 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 9.2.2.3 for a complete 
list of adverse events of special 
interest (AESI). IBD events will be 
adjudicated. During TV AEs are 
collected if spontaneously reported. 
Dispense study drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 7.1 for details 
Administer study 
drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 7.1 for administration 
details and see Table RHCG.7.1 for 
treatment regimens. 
Approved on 01 Dec 2023 GMT

I1F-MC-RHCG(c) Clinical Protocol 
Page 23 
 
 
 
 
Schedule of Activities – Open-Label Extension Period 
Open-Label Extension Treatment Period 
Notes 
Visit No 
V8 
V9 
(TV) 
V10 
(TV)- 
V11 
V12 
(TV) 
V13 
(TV) 
V14 
V15 
(TV) 
V16 
(TV) 
V17 
V18 
(TV) 
V19 
(TV) 
V20 
Treatment visits (TV) are intended 
for the dispensation and/or site 
administration of the study treatment. 
Study Week 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
W56 
W60 
W64 
W68 
Study Days 
(Approximately) 
140 
± 7d 
168 ± 
7d 
196 ± 
7d 
224 ± 
7d 
252 ± 
7d 
280 ± 
7d 
308 ± 
7d 
336 ± 
7d 
364 ± 
7d 
392 ± 
7d 
420 ± 
7d 
448 ± 
7d 
476 ± 
7d 
Clinician Reported 
Measures 
Joint Assessment 
X 
X 
X 
X 
X 
Enthesitis 
Assessment 
X 
X 
X 
X 
X 
It includes LEI and active enthesitis 
count. 
Dactylitic Count 
X 
X 
X 
X 
X 
Physician’s Global 
Assessment of 
Disease Activity 
X 
X 
X 
X 
X 
Clinical Sacroiliitis 
X 
X 
X 
X 
X 
Back Mobility 
(Schober’s Test) 
X 
X 
X 
X 
X 
Body Surface Area 
(BSA) 
X 
X 
X 
X 
X 
Psoriasis Area and 
Severity Index 
(PASI) 
X 
X 
X 
X 
X 
Columbia–Suicide 
Severity Rating 
Scale – Since Last 
Assessed 
X 
X 
X 
X 
X 
Assessment only for participants 
7 years of age or older. 
Self-Harm 
Supplement Form 
X 
X 
X 
X 
X 
Assessment only for participants 
7 years of age or older. 
Uveitis Evaluation 
X 
X 
X 
X 
X 
Investigators will assess if the 
participant has developed uveitis 
since last visit. 
Approved on 01 Dec 2023 GMT

I1F-MC-RHCG(c) Clinical Protocol 
Page 24 
 
 
 
Open-Label Extension Treatment Period 
Notes 
Visit No 
V8 
V9 
(TV) 
V10 
(TV)- 
V11 
V12 
(TV) 
V13 
(TV) 
V14 
V15 
(TV) 
V16 
(TV) 
V17 
V18 
(TV) 
V19 
(TV) 
V20 
Treatment visits (TV) are intended 
for the dispensation and/or site 
administration of the study treatment. 
Study Week 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
W56 
W60 
W64 
W68 
Study Days 
(Approximately) 
140 
± 7d 
168 ± 
7d 
196 ± 
7d 
224 ± 
7d 
252 ± 
7d 
28 0± 
7d 
308 ± 
7d 
336 ± 
7d 
364 ± 
7d 
392 ± 
7d 
420 ± 
7d 
448 ± 
7d 
476 ± 
7d 
Patient/Parent 
Administered 
Measures 
Childhood Health 
Assessment 
Questionnaire 
(CHAQ) 
X 
X 
X 
X 
X 
Tanner Stage Scale 
X 
X 
Assessment only for participants 
8 years or older. 
Once the participant reaches the 
score of 5 on this scale, no further 
assessments are needed. 
EQ-5D-Y 
X 
X 
X 
X 
X 
Assessment only for participants 
4 years or older. 
Children’s 
Depression 
Inventory 2 Short 
Form (CDI-2) 
X 
X 
X 
X 
X 
Assessment only for participants 
7 years of age or older. 
Pain Numeric Rating 
Scale 
X 
X 
X 
X 
X 
Morning Joint 
Stiffness Duration 
X 
X 
X 
X 
X 
Parent’s Global 
Assessment of 
Well-Being 
X 
X 
X 
X 
X 
To be completed by caregiver until 
participant is ≥14 years of age, at 
which time, the participant will 
complete their own questionnaires. 
Laboratory Tests 
Acute phase reactant 
(hsCRP) 
X 
X 
X 
X 
X 
Acute phase reactant 
(ESR) 
X 
X 
X 
X 
X 
To be performed locally. 
Approved on 01 Dec 2023 GMT

I1F-MC-RHCG(c) Clinical Protocol 
Page 25 
 
 
 
Open-Label Extension Treatment Period 
Notes 
Visit No 
V8 
V9 
(TV) 
V10 
(TV)- 
V11 
V12 
(TV) 
V13 
(TV) 
V14 
V15 
(TV) 
V16 
(TV) 
V17 
V18 
(TV) 
V19 
(TV) 
V20 
Treatment visits (TV) are intended 
for the dispensation and/or site 
administration of the study treatment. 
Study Week 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
W56 
W60 
W64 
W68 
Study Days 
(Approximately) 
140 
± 7d 
168 ± 
7d 
196 ± 
7d 
224 ± 
7d 
252 ± 
7d 
280 ± 
7d 
308 ± 
7d 
336 ± 
7d 
364 ± 
7d 
392 ± 
7d 
420 ± 
7d 
448 ± 
7d 
476 ± 
7d 
HBV DNA (if 
applicable) 
X 
X 
X 
Positive for HBcAb require a follow 
up test for HBV DNA. See 
Section 5.1.1 for details. 
Urine pregnancy test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 5.1.1 for details. Females 
only. To be performed locally. 
In each case of delayed menstrual 
period (over 1 month between 
menstruations), confirmation of 
absence of pregnancy is strongly 
recommended. This recommendation 
also applies to women of childbearing 
potential (WOCBP) with infrequent or 
irregular menstrual cycles. 
Clinical chemistry 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
Cell flow cytometry 
panel (B, T, CD4+T, 
CD8+T, and NK 
cells) 
X 
X 
X 
X 
Participants may not have flow 
cytometry testing due to blood 
volume limitations. 
Immunogenicity 
testing 
X 
X 
X 
See Section 9.6.1. All samples for 
immunogenicity should be taken pre- 
dose when applicable and possible. 
PK sample 
X 
X 
X 
At visits where study drug will be 
administered, PK samples should be 
collected prior to administration of 
study drug. 
Approved on 01 Dec 2023 GMT

I1F-MC-RHCG(c) Clinical Protocol 
Page 26 
 
 
 
Schedule of Activities – Open-Label Extension Period (V21 onwards) 
Open-Label Extension Treatment Period 
Notes 
Visit No 
V21 (TV) 
V22 
(TV) 
V23 
V24 
(TV) 
V25 
(TV) 
V26 
V27 
(TV) 
V28 
(TV) 
V29 
Treatment visits (TV) are intended for the 
dispensation and/or site administration of 
the study treatment. 
V803 is an additional follow- up based 
on neutrophil count 
(Section 5.1.4). 
Study Week 
W72 
W76 
W80 
W84 
W88 
W92 
W96 
W100 
W104 
Study Days 
(Approximately) 
504 ± 
7d 
532 ± 
7d 
560 ± 
7d 
588 ± 
7d 
616 ± 
7d 
644 
± 7d 
672 ± 
7d 
700 ± 
7d 
728 ± 
7d 
Immunization record 
X 
X 
X 
Immunizations occurred during the 
participation in the study. 
Physical examination 
X 
X 
X 
Excluding pelvic, rectal, and breast 
examinations. 
Symptom-directed 
physical examination 
X 
X 
X 
Includes an assessment of rash, serositis, 
splenomegaly, hepatomegaly, or 
generalized lymphadenopathy attributable 
to JIA. 
Height 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (BP, pulse, 
body temperature) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BP and pulse should be measured at least 
pre-injection. 
Concomitant medications 
X 
X 
X 
Approved on 01 Dec 2023 GMT

I1F-MC-RHCG(c) Clinical Protocol 
Page 27 
 
Open-Label Extension Treatment Period 
Notes 
Visit No 
V21 (TV) V22 
(TV) 
V23 
V24 
(TV) 
V25 (TV) 
V26 
V27 
(TV) 
V28 (TV)
V29 
Treatment visits (TV) are intended for 
the dispensation and/or site 
administration of the study treatment. 
V803 is an additional follow- up based 
on neutrophil count (Section 5.1.4). 
Study Week 
W72 
W76 
W80 
W84 
W88 
W92 
W96 
W100 
W104 
Study Days 
(Approximately) 
504 ± 
7d 
532 ± 
7d 
560 ± 
7d 
588 ± 
7d 
616 ± 
7d 
644 
± 7d 
672 ± 
7d 
700 ± 
7d 
728 ± 
7d 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 9.2.2.3 for a complete list of 
adverse events of special interest (AESI). 
IBD events will be adjudicated. 
During TV AEs are collected if 
spontaneously reported. 
Dispense study drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 7.1 for details 
Administer study drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 7.1  for administration 
details and see 
Table RHCG.7.1 for treatment 
regimens. 
Clinician 
Reported 
Measures 
Joint Assessment 
X 
X 
X 
Enthesitis Assessment 
X 
X 
X 
It includes LEI and active enthesitis 
count. 
Dactylitic Count 
X 
X 
X 
Physician’s Global 
Assessment of 
Disease Activity 
X 
X 
X 
Clinical Sacroiliitis 
X 
X 
X 
Approved on 01 Dec 2023 GMT

I1F-MC-RHCG(c) Clinical Protocol 
Page 28 
 
 
 
 
Open-Label Extension Treatment Period 
Notes 
Visit No 
V21 (TV) V22 
(TV) 
V23 
V24 
(TV) 
V25 (TV) 
V26 
V27 
(TV) 
V28 (TV)
V29 
Treatment visits (TV) are intended for 
the dispensation and/or site 
administration of the study treatment. 
V803 is an additional follow- up based 
on neutrophil count (Section 5.1.4). 
Study Week 
W72 
W76 
W80 
W84 
W88 
W92 
W96 
W100 
W104 
Study Days 
(Approximately) 
504 ± 
7d 
532 ± 
7d 
560 ± 
7d 
588 ± 
7d 
616 ± 
7d 
644 
± 7d 
672 ± 
7d 
700 ± 
7d 
728 ± 
7d 
Back Mobility 
(Schober’s Test) 
X 
X 
X 
Body Surface Area 
(BSA) 
X 
X 
X 
Psoriasis Area and 
Severity Index (PASI) 
X 
X 
X 
Columbia–Suicide 
Severity Rating Scale – 
Since Last Assessed 
X 
X 
X 
Assessment only for participants 7 years 
of age or older. 
Self-Harm Supplement 
Form 
X 
X 
X 
Assessment only for participants 7 years 
of age or older. 
Self-Harm Follow-Up 
Form 
X 
X 
X 
A Self-Harm Follow-Up Form must be 
completed for each discrete event 
identified on the Self-Harm Supplement 
Form. If no events are reported in a 
certain visit, the form is not applicable. 
Uveitis Evaluation 
X 
X 
X 
Investigators will assess if the participant 
has developed uveitis since last visit. 
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I1F-MC-RHCG(c) Clinical Protocol 
Page 29 
 
 
 
 
Open-Label Extension Treatment Period 
Notes 
Visit No 
V21 (TV) V22 
(TV) 
V23 
V24 
(TV) 
V25 (TV) 
V26 
V27 
(TV) 
V28 (TV)
V29 
Treatment visits (TV) are intended for 
the dispensation and/or site 
administration of the study treatment. 
V803 is an additional follow- up based 
on neutrophil count (Section 5.1.4). 
Study Week 
W72 
W76 
W80 
W84 
W88 
W92 
W96 
W100 
W104 
Study Days 
(Approximately) 
504 ± 
7d 
532 ± 
7d 
560 ± 
7d 
588 ± 
7d 
616 ± 
7d 
644 
± 7d 
672 ± 
7d 
700 ± 
7d 
728 ± 
7d 
Patient/ Parent 
Administered 
Measures 
Childhood Health 
Assessment Questionnaire 
(CHAQ) 
X 
X 
X 
Tanner Stage Scale 
X 
X 
Assessment only for participants 8 years 
or older. 
Once the participant reaches the score of 
5 on this scale, no 
further assessments are needed. 
EQ-5D-Y 
X 
X 
X 
Assessment only for participants 4 years 
or older. 
Children’s 
Depression 
Inventory 2 Short Form 
(CDI-2) 
X 
X 
X 
Assessment only for participants 7 years 
of age or older. 
Pain Numeric Rating 
Scale 
X 
X 
X 
Morning Joint Stiffness 
Duration 
X 
X 
X 
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I1F-MC-RHCG(c) Clinical Protocol 
Page 30 
 
 
 
 
Open-Label Extension Treatment Period 
Notes 
Visit No 
V21 (TV) V22 
(TV) 
V23 
V24 
(TV) 
V25 (TV) 
V26 
V27 
(TV) 
V28 (TV)
V29 
Treatment visits (TV) are intended for 
the dispensation and/or site 
administration of the study treatment. 
V803 is an additional follow- up based 
on neutrophil count (Section 5.1.4). 
Study Week 
W72 
W76 
W80 
W84 
W88 
W92 
W96 
W100 
W104 
Study Days 
(Approximately) 
504 ± 
7d 
532 ± 
7d 
560 ± 
7d 
588 ± 
7d 
616 ± 
7d 
644 
± 7d 
672 ± 
7d 
700 ± 
7d 
728 ± 
7d 
Parent’s Global 
Assessment of Well-
Being 
X 
X 
X 
To be completed by caregiver until 
participant is ≥14 years of age, at which 
time, the participant will complete their 
own questionnaires. 
Laboratory Tests 
Acute phase reactant 
(hsCRP) 
X 
X 
X 
Acute phase reactant 
(ESR) 
X 
X 
X 
To be performed locally. 
HBV DNA (if 
applicable) 
X 
X 
X 
Positive for HBcAb require a 
follow-up test for HBV DNA. See 
Section 5.1.1 for details. 
Urine pregnancy test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 5.1.1 for details. Females only. 
To be performed locally. 
In each case of delayed menstrual period 
(over 1 month between menstruations), 
confirmation of absence of pregnancy is 
strongly recommended. This 
recommendation also applies to women 
of childbearing potential (WOCBP) with 
infrequent or irregular menstrual cycles. 
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I1F-MC-RHCG(c) Clinical Protocol 
Page 31 
 
 
 
 
Open-Label Extension Treatment Period 
Notes 
Visit No 
V21 (TV) V22 
(TV) 
V23 
V24 
(TV) 
V25 (TV) 
V26 
V27 
(TV) 
V28 (TV)
V29 
Treatment visits (TV) are intended for 
the dispensation and/or site 
administration of the study treatment. 
V803 is an additional follow- up based 
on neutrophil count (Section 5.1.4). 
Study Week 
W72 
W76 
W80 
W84 
W88 
W92 
W96 
W100 
W104 
Study Days 
(Approximately) 
504 ± 
7d 
532 ± 
7d 
560 ± 
7d 
588 ± 
7d 
616 ± 
7d 
644 
± 7d 
672 ± 
7d 
700 ± 
7d 
728 ± 
7d 
Clinical chemistry 
X 
X 
X 
Includes an assessment of rash, serositis, 
splenomegaly, hepatomegaly, or 
generalized lymphadenopathy attributable 
to JIA. 
Hematology 
X 
X 
X 
Urinalysis 
X 
X 
X 
Cell flow cytometry 
panel (B, T, CD4+T, 
CD8+T, and NK 
cells) 
X 
X 
X 
Participants may not have flow cytometry 
testing due to blood volume limitations. 
Immunogenicity testing 
X 
X 
See Section 9.6.1. All samples for 
immunogenicity should be 
taken pre-dose when applicable and 
possible. 
PK sample 
X 
X 
At visits where study drug will be 
administered, PK samples should be 
collected prior to 
administration of study drug. 
Abbreviations: AE = adverse event; AESI = adverse events of special interest; BP = blood pressure; d = days; ETV = Early Termination Visit; 
EQ-5D-Y = European Quality of Life-5 Dimensions-Youth; ESR = erythrocyte sedimentation rate; ETV = Early Termination Visit; HBcAb = hepatitis 
B core antibody; HBV = hepatitis B virus; hsCRP = high-sensitivity C-reactive protein; IBD = inflammatory bowel disease; JIA = juvenile idiopathic 
arthritis; LEI = Leeds Enthesitis Index; NK = natural killer; PPD = purified protein derivative; PK = pharmacokinetics; TV = treatment visit; V = study 
visit; W = study week, WOCBP = women of childbearing potential. 
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I1F-MC-RHCG(c) Clinical Protocol 
Page 32 
 
Table RHCG.2.3. 
Schedule of Activities – Long Term Extension Period (V30 through V42) 
Notes: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor- 
provided weight-based prioritization chart. 
Visit No 
V30 
V31 
V32 
V33 
V34 
V35 
V36 
V37 
V38 
V39 
V40 
V41 
V42 
Notes 
Study Week 
W108 
W112 
W116 
W120 
W124 
W128 
W132 
W136 
W140 
W144 
W148 
W152 
W156 
Study Days 
(Approximately) 
756 
± 7d 
784 
± 7d 
812 
± 7d 
840 
± 7d 
868 
± 7d 
896 
± 7d 
924 
± 7d 
952 
± 7d 
980 
± 7d 
1008 
± 7d 
1036 
± 7d 
1064 
± 7d 
1092 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are 
intended only for the 
dispensation and on-site 
administration of 
ixekizumab for the 
participants
 who 
have opted for on-site 
administration. 
Immunization 
record 
X 
X 
X 
X 
Immunizations occurred 
during the participation 
in the study. 
Physical 
examination 
X 
X 
X 
X 
X 
Excluding pelvic, rectal, 
and breast examinations. 
Height 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight will be recorded 
for every participant at 
every visit in the Study 
Drug Administration 
Log: 

For participants 
 weight
will be recorded by
study personnel.

For participants 
o
At-home
administration:
weight will be
recorded by the 
participant or
caregiver in the 
Study Drug
Administration
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I1F-MC-RHCG(c) Clinical Protocol 
Page 33 
 
 
 
Notes: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor- 
provided weight-based prioritization chart. 
Visit No 
V30 
V31 
V32 
V33 
V34 
V35 
V36 
V37 
V38 
V39 
V40 
V41 
V42 
Notes 
Study Week 
W108 
W112 
W116 
W120 
W124 
W128 
W132 
W136 
W140 
W144 
W148 
W152 
W156 
Study Days 
(Approximately) 
756 
± 7d 
784 
± 7d 
812 
± 7d 
840 
± 7d 
868 
± 7d 
896 
± 7d 
924 
± 7d 
952 
± 7d 
980 
± 7d 
1008 
± 7d 
1036 
± 7d 
1064 
± 7d 
1092 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are 
intended only for the 
dispensation and on-site 
administration of 
ixekizumab for the 
participants
 
 
 who 
have opted for on-site 
administration. 
Log. 
o Regular and 
on-site 
treatment visits 
(if applicable): 
weight will be 
recorded by the 
study 
personnel. 
Habits 
X 
X 
Including caffeine, 
alcohol, and tobacco 
consumption. 
Assessment only for 
participants 12 years of 
age or older. 
Vital signs (BP, 
pulse, body 
temperature) 
X 
X 
X 
X 
X 
BP and pulse should be 
measured at least pre- 
injection. 
Concomitant 
medications 
X 
X 
X 
X 
X 
Adverse events 
(AEs) 
X 
X 
X 
X 
X 
See Section 9.2.2.3 for a 
complete list of adverse 
events of special interest 
(AESIs). IBD events will 
be adjudicated. 
Investigators will assess 
the AEs during the 
Approved on 01 Dec 2023 GMT
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I1F-MC-RHCG(c) Clinical Protocol 
Page 34 
 
 
 
Notes: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor- 
provided weight-based prioritization chart. 
Visit No 
V30 
V31 
V32 
V33 
V34 
V35 
V36 
V37 
V38 
V39 
V40 
V41 
V42 
Notes 
Study Week 
W108 
W112 
W116 
W120 
W124 
W128 
W132 
W136 
W140 
W144 
W148 
W152 
W156 
Study Days 
(Approximately) 
756 
± 7d 
784 
± 7d 
812 
± 7d 
840 
± 7d 
868 
± 7d 
896 
± 7d 
924 
± 7d 
952 
± 7d 
980 
± 7d 
1008 
± 7d 
1036 
± 7d 
1064 
± 7d 
1092 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are 
intended only for the 
dispensation and on-site 
administration of 
ixekizumab for the 
participants
 
 
 who 
have opted for on-site 
administration. 
regular visits. 
Dispense 
ixekizumab 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 6.1 for 
details. 
Participants 
 
who opt for at-home 
administration will have 
the study drug dispensed 
during the regular visits 
only (that is, every 
12 weeks). 
The rest of the 
participants will have the 
study drug dispensed 
during both the treatment 
visits and regular visits 
(that is, every 4 weeks). 
Train on 
ixekizumab 
administration 
X 
X 
X 
X 
X 
Only for participants 
 who opt for at- 
home administration 
and/or their caregivers. 
See Section 7.1 for 
details. This training will 
occur throughout the 
study for those 
participants who reach 
 and opt for at- 
home administration. 
Approved on 01 Dec 2023 GMT
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I1F-MC-RHCG(c) Clinical Protocol 
Page 35 
 
 
 
Notes: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor- 
provided weight-based prioritization chart. 
Visit No 
V30 
V31 
V32 
V33 
V34 
V35 
V36 
V37 
V38 
V39 
V40 
V41 
V42 
Notes 
Study Week 
W108 
W112 
W116 
W120 
W124 
W128 
W132 
W136 
W140 
W144 
W148 
W152 
W156 
Study Days 
(Approximately) 
756 
± 7d 
784 
± 7d 
812 
± 7d 
840 
± 7d 
868 
± 7d 
896 
± 7d 
924 
± 7d 
952 
± 7d 
980 
± 7d 
1008 
± 7d 
1036 
± 7d 
1064 
± 7d 
1092 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are 
intended only for the 
dispensation and on-site 
administration of 
ixekizumab for the 
participants
 
 
 who 
have opted for on-site 
administration. 
Administer 
ixekizumab 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Sections 7.1 for on- 
site and at-home 
administration details 
and Table RHCG.7.1 for 
treatment regimens. 
During regular visit, all 
participants (regardless 
of their weight) will 
receive ixekizumab 
injection on-site. 
Clinician-Reported Measures 
Joint Assessment 
X 
X 
X 
X 
X 
Enthesitis 
Assessment 
X 
X 
X 
X 
X 
It includes LEI and 
active enthesitis count. 
Dactylitic Count 
X 
X 
X 
X 
X 
Physician’s 
Global 
Assessment of 
Disease Activity 
X 
X 
X 
X 
X 
Clinical 
Sacroiliitis 
X 
X 
X 
X 
X 
Back Mobility 
(Schober’s Test) 
X 
X 
X 
X 
X 
Body Surface 
Area (BSA) 
X 
X 
X 
X 
X 
Psoriasis Area 
and Severity 
X 
X 
X 
X 
X 
Approved on 01 Dec 2023 GMT
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I1F-MC-RHCG(c) Clinical Protocol 
Page 36 
 
 
 
Notes: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor- 
provided weight-based prioritization chart. 
Visit No 
V30 
V31 
V32 
V33 
V34 
V35 
V36 
V37 
V38 
V39 
V40 
V41 
V42 
Notes 
Study Week 
W108 
W112 
W116 
W120 
W124 
W128 
W132 
W136 
W140 
W144 
W148 
W152 
W156 
Study Days 
(Approximately) 
756 
± 7d 
784 
± 7d 
812 
± 7d 
840 
± 7d 
868 
± 7d 
896 
± 7d 
924 
± 7d 
952 
± 7d 
980 
± 7d 
1008 
± 7d 
1036 
± 7d 
1064 
± 7d 
1092 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are 
intended only for the 
dispensation and on-site 
administration of 
ixekizumab for the 
participants
 
 
 who 
have opted for on-site 
administration. 
Index (PASI) 
Columbia– 
Suicide Severity 
Rating Scale – 
Since Last 
Assessed 
X 
X 
X 
X 
X 
Assessment only for 
participants 7 years of 
age or older. 
Self-Harm 
Follow-Up Form 
X 
X 
X 
X 
X 
A Self-Harm Follow-Up 
Form must be completed 
for each discrete event 
identified on the Self- 
Harm Supplement Form. 
If no events are reported 
in a certain visit, the 
form is not applicable. 
Uveitis Evaluation 
X 
X 
X 
X 
X 
Investigators will assess 
if the participant has 
developed uveitis since 
last visit. 
Study Drug Administration Log (Paper) 
Dispense Study 
Drug 
Administration 
Log 
X 
X 
X 
X 
X 
Dispensed only to 
participants 
 
who have opted for at- 
home administration. 
Check compliance 
with Study Drug 
Administration 
Log 
X 
X 
X 
X 
See Section 6.4. 
Approved on 01 Dec 2023 GMT
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I1F-MC-RHCG(c) Clinical Protocol 
Page 37 
 
 
 
Notes: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor- 
provided weight-based prioritization chart. 
Visit No 
V30 
V31 
V32 
V33 
V34 
V35 
V36 
V37 
V38 
V39 
V40 
V41 
V42 
Notes 
Study Week 
W108 
W112 
W116 
W120 
W124 
W128 
W132 
W136 
W140 
W144 
W148 
W152 
W156 
Study Days 
(Approximately) 
756 
± 7d 
784 
± 7d 
812 
± 7d 
840 
± 7d 
868 
± 7d 
896 
± 7d 
924 
± 7d 
952 
± 7d 
980 
± 7d 
1008 
± 7d 
1036 
± 7d 
1064 
± 7d 
1092 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are 
intended only for the 
dispensation and on-site 
administration of 
ixekizumab for the 
participants
 
 
 who 
have opted for on-site 
administration. 
Participant-/Parent-Administered Measures 
Childhood Health 
Assessment 
Questionnaire 
(CHAQ) 
X 
X 
X 
X 
X 
Tanner Stage 
Scale 
X 
X 
Assessment only for 
participants 8 years or 
older. 
If participants reached 
the score of 5 on this 
scale in Study RHCG, 
they do not have to 
complete this assessment 
in LTE. 
Once the participant 
reaches the score of 5 on 
this scale during LTE, no 
further assessments are 
needed. 
EQ-5D-Y 
X 
X 
X 
X 
X 
Assessment only for 
participants 4 years or 
older. 
Children’s 
Depression 
Inventory 2 Short 
Form (CDI-2) 
X 
X 
X 
X 
X 
Assessment only for 
participants 7 years of 
age or older. 
Pain Numeric 
X 
X 
X 
X 
X 
Approved on 01 Dec 2023 GMT
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I1F-MC-RHCG(c) Clinical Protocol 
Page 38 
 
 
 
Notes: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor- 
provided weight-based prioritization chart. 
Visit No 
V30 
V31 
V32 
V33 
V34 
V35 
V36 
V37 
V38 
V39 
V40 
V41 
V42 
Notes 
Study Week 
W108 
W112 
W116 
W120 
W124 
W128 
W132 
W136 
W140 
W144 
W148 
W152 
W156 
Study Days 
(Approximately) 
756 
± 7d 
784 
± 7d 
812 
± 7d 
840 
± 7d 
868 
± 7d 
896 
± 7d 
924 
± 7d 
952 
± 7d 
980 
± 7d 
1008 
± 7d 
1036 
± 7d 
1064 
± 7d 
1092 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are 
intended only for the 
dispensation and on-site 
administration of 
ixekizumab for the 
participants
 
 
 who 
have opted for on-site 
administration. 
Rating Scale 
Morning Joint 
Stiffness Duration 
X 
X 
X 
X 
X 
Laboratory Tests 
Acute phase 
reactant (hsCRP) 
X 
X 
X 
X 
X 
Acute phase 
reactant (ESR) 
X 
X 
X 
X 
X 
To be performed locally. 
Administer TB 
test(s) (if 
applicable) 
TB testing required only based on clinical assessment of TB risk and according to local regulations and/or local standard of care (Section 9.4.6; Appendix 2). 
QuantiFERON®-TB Gold, T-Spot or PPD (if applicable) (Section 9.4.6; Appendix 2). 
PPD to be read locally. 
HCV antibody 
X 
HCV antibody positive 
results require a follow- 
up test for HCV RNA. 
See Section 9.4.4 for 
details. 
HBV (HBsAg, 
HBcAb, HBsAb) 
X 
See Section 9.4.4 for 
details. 
HBV DNA (if 
applicable) 
X 
X 
X 
X 
X 
Positive for HbcAb 
require a follow up test 
for HBV DNA. See 
Section 9.4.11.2 for 
details. 
Urine pregnancy 
test 
X 
X 
X 
X 
X 
See Section 9.4.5 and 
Appendix 6 for details. 
Females only. 
To be performed locally. 
Approved on 01 Dec 2023 GMT
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I1F-MC-RHCG(c) Clinical Protocol 
Page 39 
 
 
 
 
Notes: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor- 
provided weight-based prioritization chart. 
Visit No 
V30 
V31 
V32 
V33 
V34 
V35 
V36 
V37 
V38 
V39 
V40 
V41 
V42 
Notes 
Study Week 
W108 
W112 
W116 
W120 
W124 
W128 
W132 
W136 
W140 
W144 
W148 
W152 
W156 
Study Days 
(Approximately) 
756 
± 7d 
784 
± 7d 
812 
± 7d 
840 
± 7d 
868 
± 7d 
896 
± 7d 
924 
± 7d 
952 
± 7d 
980 
± 7d 
1008 
± 7d 
1036 
± 7d 
1064 
± 7d 
1092 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are 
intended only for the 
dispensation and on-site 
administration of 
ixekizumab for the 
participants
 
 
 who 
have opted for on-site 
administration. 
Clinical 
chemistry 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
PK sample 
X 
X 
X 
X 
X 
At regular visits (i.e., 
when ixekizumab is 
administered on site to 
all the participants), PK 
samples should be 
collected prior to 
administration of 
ixekizumab. 
Immunogenicity 
sample 
X 
X 
X 
X 
X 
See Section 9.6.1. All 
samples for 
immunogenicity should 
be taken predose when 
applicable and possible. 
Abbreviations: BP = blood pressure; d = days; EQ-5D-Y = European Quality of Life-5 Dimensions-Youth; HBcAb = hepatitis B core antibody; 
HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; IBD = inflammatory bowel disease; LEI = 
Leeds Enthesitis Index; No = number; PK = pharmacokinetics; PPD = purified protein derivative; TB = tuberculosis; V = study visit; W = study 
week. 
Approved on 01 Dec 2023 GMT
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I1F-MC-RHCG(c) Clinical Protocol 
Page 40 
 
 
 
Table RHCG.2.4. 
Schedule of Activities – Long Term Extension Period (V43 through V54) 
 
Note: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor-provided 
weight-based prioritization chart. 
Visit No 
V43 
V44 
V45 
V46 
V47 
V48 
V49 
V50 
V51 
V52 
V53 
V54 
Notes 
Study Week 
W160 
W164 
W168 
W172 
W176 
W180 
W184 
W188 
W192 
W196 
W200 
W204 
Study Days 
(Approximately) 
1120 
± 7d 
1148 
± 7d 
1176 
± 7d 
1204 
± 7d 
1232 
± 7d 
1260 
± 7d 
1288 
± 7d 
1316 
± 7d 
1344 
± 7d 
1372 
± 7d 
1400 
± 7d 
1428 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are intended only for 
the on-site administration of the 
ixekizumab for the participants 
 
 who have opted 
for on-site administration. 
Immunization 
record 
X 
X 
X 
X 
Immunizations occurred during the 
participation in the study. 
Physical 
examination 
X 
X 
X 
X 
Excluding pelvic, rectal, and breast 
examinations. 
Height 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight will be recorded for every 
participant at every visit in the Study 
Drug Administration Log: 
 
For participants 
 
weight will be recorded by study 
personnel. 
 
For participants 
 
o 
At-home administration: 
weight will be recorded by 
the participant or caregiver 
in the Study Drug 
Administration Log. 
o 
Regular and on-site 
treatment visits (if 
applicable): weight will be 
recorded by the study 
personnel. 
Vital signs (BP, 
pulse, body 
temperature) 
X 
X 
X 
X 
BP and pulse should be measured at 
least pre-injection. 
Concomitant 
medications 
X 
X 
X 
X 
Adverse events 
(AEs) 
X 
X 
X 
X 
See Section 9.2.2.3 for a complete list 
Approved on 01 Dec 2023 GMT
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I1F-MC-RHCG(c) Clinical Protocol 
Page 41 
 
 
 
Note: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor-provided 
weight-based prioritization chart. 
Visit No 
V43 
V44 
V45 
V46 
V47 
V48 
V49 
V50 
V51 
V52 
V53 
V54 
Notes 
Study Week 
W160 
W164 
W168 
W172 
W176 
W180 
W184 
W188 
W192 
W196 
W200 
W204 
Study Days 
(Approximately) 
1120 
± 7d 
1148 
± 7d 
1176 
± 7d 
1204 
± 7d 
1232 
± 7d 
1260 
± 7d 
1288 
± 7d 
1316 
± 7d 
1344 
± 7d 
1372 
± 7d 
1400 
± 7d 
1428 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are intended only for 
the on-site administration of the 
ixekizumab for the participants 
 
 who have opted 
for on-site administration. 
of AESIs. IBD events will be 
adjudicated. 
Investigators will assess the AEs 
during the regular visits. 
Dispense study 
intervention 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 6.1 for details. 
 
Participants 
 who have 
opted for at-home administration 
will have ixekizumab dispensed 
during the regular visits only 
(i.e., every 12 weeks). 
 
The rest of the participants will 
have the study drug dispensed 
during both the treatment visits 
and regular visits (that is, every 
4 weeks). 
Train on 
ixekizumab 
administration 
X 
X 
X 
X 
Only for participants 
 who 
opt for at-home administration and/or 
for their caregivers. See Section 7.1 
for details. 
This training will occur throughout 
the study for those participants who 
reach 
 and opt for at-home 
administration. 
Administer 
ixekizumab 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Sections 7.1 for on-site and at- 
home administration details and for 
treatment regimens. 
During regular visit, all participants 
(regardless of their weight) will 
receive ixekizumab injection on site. 
Approved on 01 Dec 2023 GMT
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I1F-MC-RHCG(c) Clinical Protocol 
Page 42 
 
 
 
Note: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor-provided 
weight-based prioritization chart. 
Visit No 
V43 
V44 
V45 
V46 
V47 
V48 
V49 
V50 
V51 
V52 
V53 
V54 
Notes 
Study Week 
W160 
W164 
W168 
W172 
W176 
W180 
W184 
W188 
W192 
W196 
W200 
W204 
Study Days 
(Approximately) 
1120 
± 7d 
1148 
± 7d 
1176 
± 7d 
1204 
± 7d 
1232 
± 7d 
1260 
± 7d 
1288 
± 7d 
1316 
± 7d 
1344 
± 7d 
1372 
± 7d 
1400 
± 7d 
1428 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are intended only for 
the on-site administration of the 
ixekizumab for the participants 
 
 who have opted 
for on-site administration. 
Clinician-Reported Measures 
Joint Assessment 
X 
X 
X 
X 
Enthesitis 
Assessment 
X 
X 
X 
X 
It includes LEI and active enthesitis 
count. 
Dactylitic Count 
X 
X 
X 
X 
Physician’s Global 
Assessment of 
Disease Activity 
X 
X 
X 
X 
Clinical Sacroiliitis 
X 
X 
X 
X 
Back Mobility 
(Schober’s Test) 
X 
X 
X 
X 
Body Surface Area 
(BSA) 
X 
X 
X 
X 
Psoriasis Area and 
Severity Index 
(PASI) 
X 
X 
X 
X 
Columbia–Suicide 
Severity Rating 
Scale – Since Last 
Assessed 
X 
X 
X 
X 
Assessment only for participants 
7 years of age or older. 
Self-Harm 
Supplement Form 
X 
X 
X 
X 
Assessment only for participants 
7 years of age or older. 
Uveitis Evaluation 
X 
X 
X 
X 
Investigators will assess if the 
participant has developed uveitis 
since last visit. 
Study Drug Administration Log (Paper) 
Dispense Study 
Drug 
Administration Log 
X 
X 
X 
X 
Dispensed only to participants 
 who have opted for at-home 
administration. 
Check compliance 
with Study Drug 
X 
X 
X 
X 
See Section 6.4. 
Approved on 01 Dec 2023 GMT
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I1F-MC-RHCG(c) Clinical Protocol 
Page 43 
 
 
 
Note: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor-provided 
weight-based prioritization chart. 
Visit No 
V43 
V44 
V45 
V46 
V47 
V48 
V49 
V50 
V51 
V52 
V53 
V54 
Notes 
Study Week 
W160 
W164 
W168 
W172 
W176 
W180 
W184 
W188 
W192 
W196 
W200 
W204 
Study Days 
(Approximately) 
1120 
± 7d 
1148 
± 7d 
1176 
± 7d 
1204 
± 7d 
1232 
± 7d 
1260 
± 7d 
1288 
± 7d 
1316 
± 7d 
1344 
± 7d 
1372 
± 7d 
1400 
± 7d 
1428 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are intended only for 
the on-site administration of the 
ixekizumab for the participants 
 
 who have opted 
for on-site administration. 
Administration Log 
Participant-/Parent-Administered Measures 
Childhood Health 
Assessment 
Questionnaire 
(CHAQ) 
X 
X 
X 
X 
Tanner Stage Scale 
X 
Assessment only for participants 
8 years or older. 
Once the participant reaches the score 
of 5 on this scale during LTE, no 
further assessments are needed. 
EQ-5D-Y 
X 
X 
X 
X 
Assessment only for participants 
4 years or older. 
Children’s 
Depression 
Inventory 2 Short 
Form (CDI-2) 
X 
X 
X 
X 
Assessment only for participants 
7 years of age or older 
Pain Numeric 
Rating Scale 
X 
X 
X 
X 
Morning Joint 
Stiffness Duration 
X 
X 
X 
X 
Parent’s Global 
Assessment of 
Well-Being 
X 
X 
X 
X 
To be completed by caregiver until 
participant is >14 years of age, at 
which time, the participant will 
complete their own questionnaires. 
Laboratory Tests 
Acute phase 
reactant (hsCRP) 
X 
X 
X 
X 
Acute phase 
reactant (ESR) 
X 
X 
X 
X 
To be performed locally. 
Administer TB 
TB testing required only based on clinical assessment of TB risk and according to local regulations and/or local 
QuantiFERON-TB Gold, T-Spot or 
Approved on 01 Dec 2023 GMT
CCI

I1F-MC-RHCG(c) Clinical Protocol 
Page 44 
 
 
 
 
Note: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor-provided 
weight-based prioritization chart. 
Visit No 
V43 
V44 
V45 
V46 
V47 
V48 
V49 
V50 
V51 
V52 
V53 
V54 
Notes 
Study Week 
W160 
W164 
W168 
W172 
W176 
W180 
W184 
W188 
W192 
W196 
W200 
W204 
Study Days 
(Approximately) 
1120 
± 7d 
1148 
± 7d 
1176 
± 7d 
1204 
± 7d 
1232 
± 7d 
1260 
± 7d 
1288 
± 7d 
1316 
± 7d 
1344 
± 7d 
1372 
± 7d 
1400 
± 7d 
1428 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are intended only for 
the on-site administration of the 
ixekizumab for the participants 
 
 who have opted 
for on-site administration. 
test(s) (if 
applicable) 
standard of care (Section 9.4.6; Appendix 2). 
PPD (if applicable) (Section 9.4.6; 
Appendix 2). 
PPD to be read locally. 
HBV DNA (if 
applicable) 
X 
X 
X 
X 
Positive for HbcAb requires a follow 
up test for HBV DNA. See 
Section 5.1.1 for details. 
Urine pregnancy 
test 
X 
X 
X 
X 
See Section 5.1.1 and Appendix 2 for 
details. Females only. To be 
performed locally. 
Clinical chemistry 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
PK sample 
X 
X 
At regular visits (for example, when 
ixekizumab is administered on site to 
all the participants), PK samples 
should be collected prior to 
administration of ixekizumab. 
Immunogenicity 
sample 
X 
X 
See Section 9.6.1. All samples for 
immunogenicity should be taken 
predose when applicable and 
possible. 
Abbreviations: AESI = adverse event of special interest; BP = blood pressure; d = days; EQ-5D-Y = European Quality of Life-5 Dimensions-
Youth; ESR = erythrocyte sedimentation rate; HBcAb = hepatitis B core antibody; HBV = hepatitis B virus; hsCRP = high-sensitivity C-
reactive protein; IBD = inflammatory bowel disease; LEI = Leeds Enthesitis Index; No = number; PK = pharmacokinetics; PPD = purified 
protein derivative; TB = tuberculosis; V = study visit; W = study week. 
Approved on 01 Dec 2023 GMT
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I1F-MC-RHCG(c) Clinical Protocol 
Page 45 
 
 
 
Table RHCG.2.5. 
Schedule of Activities – Long Term Extension Period (V55 through V66) 
 
Note: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor provided 
weight-based prioritization chart. 
Visit No 
V55 
V56 
V57 
V58 
V59 
V60 
V61 
V62 
V63 
V64 
V65 
V66 
Notes 
Study Week 
W208 
W212 
W216 
W220 
W224 
W228 
W232 
W236 
W240 
W244 
W248 
W252 
Study Days 
(Approximately) 
1456 
± 7d 
1484 
± 7d 
1512 
± 7d 
1540 
± 7d 
1568 
± 7d 
1596 
± 7d 
1624 
± 7d 
1652 
± 7d 
1680 
± 7d 
1708 
± 7d 
1736 
± 7d 
1764 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are intended only for 
the dispensation and on-site 
administration of ixekizumab for the 
participants 
 
 who have 
opted for on-site administration. 
Immunization 
record 
X 
X 
X 
X 
Immunizations occurred during the 
participation in the study. 
Physical 
examination 
X 
X 
X 
X 
Excluding pelvic, rectal, and breast 
examinations. 
Height 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight will be recorded for every 
participant at every visit in the Study 
Drug Administration Log: 
 
For participants 
 
weight will be recorded by study 
personnel. 
 
For participants
 
o 
At-home administration: 
weight will be recorded by 
the participant or caregiver 
in the Study Drug 
Administration Log. 
o 
Regular and on-site 
treatment visits (if 
applicable): weight will be 
recorded by the study 
personnel. 
Vital signs (BP, 
pulse, body 
temperature) 
X 
X 
X 
X 
BP and pulse should be measured at 
least pre-injection. 
Concomitant 
medications 
X 
X 
X 
X 
Adverse events 
(AEs) 
X 
X 
X 
X 
See Section 9.2 for a complete list of 
AESIs. IBD events will be 
Approved on 01 Dec 2023 GMT
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I1F-MC-RHCG(c) Clinical Protocol 
Page 46 
 
 
 
Note: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor provided 
weight-based prioritization chart. 
Visit No 
V55 
V56 
V57 
V58 
V59 
V60 
V61 
V62 
V63 
V64 
V65 
V66 
Notes 
Study Week 
W208 
W212 
W216 
W220 
W224 
W228 
W232 
W236 
W240 
W244 
W248 
W252 
Study Days 
(Approximately) 
1456 
± 7d 
1484 
± 7d 
1512 
± 7d 
1540 
± 7d 
1568 
± 7d 
1596 
± 7d 
1624 
± 7d 
1652 
± 7d 
1680 
± 7d 
1708 
± 7d 
1736 
± 7d 
1764 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are intended only for 
the dispensation and on-site 
administration of ixekizumab for the 
participants 
 
 who have 
opted for on-site administration. 
adjudicated. 
Investigators will assess the AEs 
during the regular visits. 
Dispense 
ixekizumab 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 6.1 for details. 
 
Participants 
 who opt 
for at-home administration will 
have the study drug dispensed 
during the regular visits only 
(that is, every 12 weeks). 
 
The rest of the participants will 
have the study drug dispensed 
during both the treatment visits 
and regular visits (that is, every 
4 weeks). 
Train on 
ixekizumab 
administration 
X 
X 
X 
X 
Only for participants 
 who 
opt for at-home administration and/or 
their caregivers. See Section 7.2 for 
details. 
This training will occur throughout 
the study for those participants who 
reach 
 and opt for at-home 
administration. 
Administer 
ixekizumab 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Sections 7.2 for on-site and at- 
home administration details and for 
treatment regimens. 
During regular visit, all participants 
(regardless of their weight) will 
receive ixekizumab injection on site. 
Clinician-Reported Measures 
Joint Assessment 
X 
X 
X 
X 
Enthesitis 
X 
X 
X 
X 
It includes LEI and active enthesitis 
Approved on 01 Dec 2023 GMT
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I1F-MC-RHCG(c) Clinical Protocol 
Page 47 
 
 
 
Note: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor provided 
weight-based prioritization chart. 
Visit No 
V55 
V56 
V57 
V58 
V59 
V60 
V61 
V62 
V63 
V64 
V65 
V66 
Notes 
Study Week 
W208 
W212 
W216 
W220 
W224 
W228 
W232 
W236 
W240 
W244 
W248 
W252 
Study Days 
(Approximately) 
1456 
± 7d 
1484 
± 7d 
1512 
± 7d 
1540 
± 7d 
1568 
± 7d 
1596 
± 7d 
1624 
± 7d 
1652 
± 7d 
1680 
± 7d 
1708 
± 7d 
1736 
± 7d 
1764 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are intended only for 
the dispensation and on-site 
administration of ixekizumab for the 
participants 
 
 who have 
opted for on-site administration. 
Assessment 
count. 
Dactylitic Count 
X 
X 
X 
X 
Physician’s Global 
Assessment of 
Disease Activity 
X 
X 
X 
X 
Clinical Sacroiliitis 
X 
X 
X 
X 
Back Mobility 
(Schober’s Test) 
X 
X 
X 
X 
Body Surface Area 
(BSA) 
X 
X 
X 
X 
Psoriasis Area and 
Severity Index 
(PASI) 
X 
X 
X 
X 
Columbia–Suicide 
Severity Rating 
Scale – Since Last 
Assessed 
X 
X 
X 
X 
Assessment only for participants 
7 years of age or older. 
Self-Harm 
Supplement Form 
X 
X 
X 
X 
Assessment only for participants 
7 years of age or older. 
Uveitis Evaluation 
X 
X 
X 
X 
Investigators will assess if the 
participant has developed uveitis 
since last visit. 
Study Drug Administration Log (Paper) 
Dispense Study 
Drug 
Administration Log 
X 
X 
X 
X 
Dispensed only to participants 
 who have opted for at-home 
administration. 
Check compliance 
with Study Drug 
Administration Log 
X 
X 
X 
X 
See Section 6.4. 
Participant/Parent-Administered Measures 
Childhood Health 
X 
X 
X 
X 
Approved on 01 Dec 2023 GMT
CCI
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I1F-MC-RHCG(c) Clinical Protocol 
Page 48 
 
 
 
Note: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor provided 
weight-based prioritization chart. 
Visit No 
V55 
V56 
V57 
V58 
V59 
V60 
V61 
V62 
V63 
V64 
V65 
V66 
Notes 
Study Week 
W208 
W212 
W216 
W220 
W224 
W228 
W232 
W236 
W240 
W244 
W248 
W252 
Study Days 
(Approximately) 
1456 
± 7d 
1484 
± 7d 
1512 
± 7d 
1540 
± 7d 
1568 
± 7d 
1596 
± 7d 
1624 
± 7d 
1652 
± 7d 
1680 
± 7d 
1708 
± 7d 
1736 
± 7d 
1764 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are intended only for 
the dispensation and on-site 
administration of ixekizumab for the 
participants 
 
 who have 
opted for on-site administration. 
Assessment 
Questionnaire 
(CHAQ) 
Tanner Stage Scale 
X 
Assessment only for participants 
8 years or older. 
Once the participant reaches the score 
of 5 on this scale during LTE, no 
further assessments are needed. 
EQ-5D-Y 
X 
X 
X 
X 
Assessment only for participants 
4 years or older. 
Children’s 
Depression 
Inventory 2 Short 
Form (CDI-2) 
X 
X 
X 
X 
Assessment only for participants 
7 years of age or older 
Pain Numeric 
Rating Scale 
X 
X 
X 
X 
Morning Joint 
Stiffness Duration 
X 
X 
X 
X 
Parent’s Global 
Assessment of 
Well-Being 
X 
X 
X 
X 
To be completed by caregiver until 
participant is ≥14 years of age, at 
which time, the participant will 
complete their own questionnaires. 
Laboratory Tests 
Acute phase 
reactant (hsCRP) 
X 
X 
X 
X 
Acute phase 
reactant (ESR) 
X 
X 
X 
X 
To be performed locally. 
Administer TB 
test(s) (if 
applicable) 
TB testing required only based on clinical assessment of TB risk and according to local regulations and/or local 
standard of care (Section 9.4.6; Appendix 2). 
QuantiFERON-TB Gold, T-Spot or 
PPD (if applicable) (Section 9.4.6; 
Appendix 2). 
PPD to be read locally. 
Approved on 01 Dec 2023 GMT
CCI

I1F-MC-RHCG(c) Clinical Protocol 
Page 49 
 
 
 
 
Note: Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor provided 
weight-based prioritization chart. 
Visit No 
V55 
V56 
V57 
V58 
V59 
V60 
V61 
V62 
V63 
V64 
V65 
V66 
Notes 
Study Week 
W208 
W212 
W216 
W220 
W224 
W228 
W232 
W236 
W240 
W244 
W248 
W252 
Study Days 
(Approximately) 
1456 
± 7d 
1484 
± 7d 
1512 
± 7d 
1540 
± 7d 
1568 
± 7d 
1596 
± 7d 
1624 
± 7d 
1652 
± 7d 
1680 
± 7d 
1708 
± 7d 
1736 
± 7d 
1764 
± 7d 
Treatment Visits 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment visits are intended only for 
the dispensation and on-site 
administration of ixekizumab for the 
participants 
 
 who have 
opted for on-site administration. 
HBV DNA (if 
applicable) 
X 
X 
X 
X 
Positive for HBcAb requires a follow 
up test for HBV DNA. See 
Section 5.1.1 for details. 
Urine pregnancy 
test 
X 
X 
X 
X 
See Section 5.1.1 for details. Females 
only. 
To be performed locally. 
Clinical chemistry 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
PK sample 
X 
X 
At regular visits (i.e., when 
ixekizumab is administered on site to 
all the participants), PK samples 
should be collected prior to 
administration of ixekizumab. 
Immunogenicity 
sample 
X 
X 
See Section 9.6.1. All samples for 
immunogenicity should be taken 
predose when applicable and 
possible. 
Abbreviations: AESI = adverse event of special interest; BP = blood pressure; d = days; EQ-5D-Y = European Quality of Life-5 Dimensions-
Youth; ESR = erythrocyte sedimentation rate; HBcAb = hepatitis B core antibody; HBV = hepatitis B virus; hsCRP = high-sensitivity C-
reactive protein; IBD = inflammatory bowel disease; LEI = Leeds Enthesitis Index; No = number; PK = pharmacokinetics; PPD = purified 
protein derivative; TB = tuberculosis; V = study visit; W = study week. 
Approved on 01 Dec 2023 GMT
CCI

I1F-MC-RHCG(c) Clinical Protocol 
Page 50 
 
 
 
Table RHCG.2.6. 
Schedule of Activities – Long Term Extension Period (V67 through V69) 
 
Notes: 
 
Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor 
provided weight-based prioritization chart. 
 
If ETV occurs on the same day as the scheduled visit, any assessments/procedures conducted during the scheduled visit should not be repeated for a separate ETV. 
 
The required post-treatment follow-up visits should occur for all study participants, except for those with concurrent infections (see Section 5.1.5 for details). 
Visit No 
V67 
V68 
V69 
Early 
termination 
Post-Treatment Follow-Up Period 
(PTFU) 
Notes 
ETV 
V801 
V802 
V803 
V803 is an additional follow-up based on neutrophil 
count (Section 5.1.5). 
Study Week 
W256 
W260 
W264 
Any Week 
LV (or ETV) 
+ 4W 
LV (or ETV) 
+ 8W 
LV (or ETV) 
+ 12W 
Study Days 
(Approximately) 
1792 
± 7d 
1820 
± 7d 
1848 
± 7d 
Any Day 
± 7d 
± 7d 
± 7d 
Treatment Visits 
X 
X 
Treatment visits are intended only for the dispensation 
and on-site administration of ixekizumab for the 
participants 
 
 who have opted for on-site administration. 
Immunization 
record 
X 
X 
Immunizations occurred during the participation in the 
study. 
Physical 
examination 
X 
X 
Excluding pelvic, rectal, and breast examinations. 
Height 
X 
X 
Weight 
X 
X 
X 
X 
Weight will be recorded for every participant at every 
visit in the Study Drug Administration Log: 
 
For participants 
 weight will be recorded 
by study personnel. 
 
For participants 
 
o 
At-home administration: weight will be 
recorded by the participant or caregiver in the 
Study Drug Administration Log. 
o 
Regular and on-site treatment visits (if 
applicable): weight will be recorded by the 
study personnel. 
Vital signs (BP, 
pulse, body 
temperature) 
X 
X 
BP and pulse should be measured at least pre-injection. 
Concomitant 
medications 
X 
X 
X 
X 
X 
Adverse events 
(AEs) 
X 
X 
X 
X 
X 
See Section 9.2.2.3 for a complete list of AESIs. IBD 
events will be adjudicated. 
Investigators will assess the AEs during the regular 
Approved on 01 Dec 2023 GMT
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I1F-MC-RHCG(c) Clinical Protocol 
Page 51 
 
 
 
Notes: 
 
Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor 
provided weight-based prioritization chart. 
 
If ETV occurs on the same day as the scheduled visit, any assessments/procedures conducted during the scheduled visit should not be repeated for a separate ETV. 
 
The required post-treatment follow-up visits should occur for all study participants, except for those with concurrent infections (see Section 5.1.5 for details). 
Visit No 
V67 
V68 
V69 
Early 
termination 
Post-Treatment Follow-Up Period 
(PTFU) 
Notes 
ETV 
V801 
V802 
V803 
V803 is an additional follow-up based on neutrophil 
count (Section 5.1.5). 
Study Week 
W256 
W260 
W264 
Any Week 
LV (or ETV) 
+ 4W 
LV (or ETV) 
+ 8W 
LV (or ETV) 
+ 12W 
Study Days 
(Approximately) 
1792 
± 7d 
1820 
± 7d 
1848 
± 7d 
Any Day 
± 7d 
± 7d 
± 7d 
Treatment Visits 
X 
X 
Treatment visits are intended only for the dispensation 
and on-site administration of ixekizumab for the 
participants 
 
 who have opted for on-site administration. 
visits. 
Dispense 
ixekizumab 
X 
X 
See Section 6.1 for details. 
 
Participants 
 who opt for at-home 
administration will have the study drug dispensed 
during the regular visits only (that is, every 
12 weeks). 
 
The rest of the participants will have the study drug 
dispensed during both the treatment visits and 
regular visits (that is, every 4 weeks). 
Administer 
ixekizumab 
X 
X 
See Sections 7.1 for on-site and at-home administration 
details for treatment regimens. 
During regular visit, all participants (regardless of their 
weight) will receive ixekizumab injection on site. 
Clinician-Reported Measures 
Joint Assessment 
X 
X 
Enthesitis 
Assessment 
X 
X 
It includes LEI and active enthesitis count. 
Dactylitic Count 
X 
X 
Physician’s Global 
Assessment of 
Disease Activity 
X 
X 
Clinical Sacroiliitis 
X 
X 
Back Mobility 
(Schober’s Test) 
X 
X 
Body Surface Area 
(BSA) 
X 
X 
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Notes: 
 
Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor 
provided weight-based prioritization chart. 
 
If ETV occurs on the same day as the scheduled visit, any assessments/procedures conducted during the scheduled visit should not be repeated for a separate ETV. 
 
The required post-treatment follow-up visits should occur for all study participants, except for those with concurrent infections (see Section 5.1.5 for details). 
Visit No 
V67 
V68 
V69 
Early 
termination 
Post-Treatment Follow-Up Period 
(PTFU) 
Notes 
ETV 
V801 
V802 
V803 
V803 is an additional follow-up based on neutrophil 
count (Section 5.1.5 ). 
Study Week 
W256 
W260 
W264 
Any Week 
LV (or ETV) 
+ 4W 
LV (or ETV) 
+ 8W 
LV (or ETV) 
+ 12W 
Study Days 
(Approximately) 
1792 
± 7d 
1820 
± 7d 
1848 
± 7d 
Any Day 
± 7d 
± 7d 
± 7d 
Treatment Visits 
X 
X 
Treatment visits are intended only for the dispensation 
and on-site administration of ixekizumab for the 
participants 
 
 who have opted for on-site administration. 
Psoriasis Area and 
Severity Index 
(PASI) 
X 
X 
Columbia–Suicide 
Severity Rating 
Scale – Since Last 
Assessed 
X 
X 
Assessment only for participants 7 years of age or older. 
Self-Harm 
Supplement Form 
X 
X 
Assessment only for participants 7 years of age or older. 
Uveitis Evaluation 
X 
X 
Investigators will assess if the participant has developed 
uveitis since last visit. 
Study Drug Administration Log (Paper) 
Return Study Drug 
Administration Log 
(participant to site) 
X 
X 
The Study Drug Administration Log needs to be 
collected only from the participants 
 who have 
opted for at-home administration. 
Participant-/Parent-Administered Measures 
Childhood Health 
Assessment 
Questionnaire 
(CHAQ) 
X 
X 
Tanner Stage Scale 
X 
X 
Assessment only for participants 8 years or older. 
Once the participant reaches the score of 5 on this scale 
during LTE, no further assessments are needed. 
EQ-5D-Y 
X 
X 
Assessment only for participants 4 years or older. 
Children’s 
Depression 
X 
X 
Assessment only for participant 7 years of age or older 
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Notes: 
 
Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor 
provided weight-based prioritization chart. 
 
If ETV occurs on the same day as the scheduled visit, any assessments/procedures conducted during the scheduled visit should not be repeated for a separate ETV. 
 
The required post-treatment follow-up visits should occur for all study participants, except for those with concurrent infections (see Section 5.1.5 for details). 
Visit No 
V67 
V68 
V69 
Early 
termination 
Post-Treatment Follow-Up Period 
(PTFU) 
Notes 
ETV 
V801 
V802 
V803 
V803 is an additional follow-up based on neutrophil 
count (Section 5.1.5). 
Study Week 
W256 
W260 
W264 
Any Week 
LV (or ETV) 
+ 4W 
LV (or ETV) 
+ 8W 
LV (or ETV) 
+ 12W 
Study Days 
(Approximately) 
1792 
± 7d 
1820 
± 7d 
1848 
± 7d 
Any Day 
± 7d 
± 7d 
± 7d 
Treatment Visits 
X 
X 
Treatment visits are intended only for the dispensation 
and on-site administration of ixekizumab for the 
participants 
 
 who have opted for on-site administration. 
Inventory 2 Short 
Form (CDI-2) 
Pain Numeric 
Rating Scale 
X 
X 
Morning Joint 
Stiffness Duration 
X 
X 
Parent’s Global 
Assessment of 
Well-Being 
X 
X 
To be completed by caregiver until participant is 
>14 years of age, at which time, the participant will 
complete their own questionnaires. 
Laboratory Tests 
Acute phase 
reactant (hsCRP) 
X 
X 
Acute phase 
reactant (ESR) 
X 
X 
To be performed locally. 
Administer TB 
test(s) (if 
applicable) 
TB testing required only based on clinical assessment of TB risk and according to local 
regulations and/or local standard of care Section 9.4.6; Appendix 2). 
QuantiFERON-TB Gold, T-Spot or PPD (if applicable) 
(Section 9.4.6; Appendix 2) 
PPD to be read locally. 
HBV DNA (if 
applicable) 
X 
X 
X 
Positive for HBcAb requires a follow up test for HBV 
DNA. See Section 9.4.4 for details. 
Urine pregnancy 
test 
X 
X 
X 
X 
X 
See Section 9.4.5 and Appendix 6 for details. Females 
only. To be performed locally. 
Clinical chemistry 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
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Notes: 
 
Due to blood volume restrictions, some laboratory tests may not be collected. Laboratory samples are recommended to be collected as described in the sponsor 
provided weight-based prioritization chart. 
 
If ETV occurs on the same day as the scheduled visit, any assessments/procedures conducted during the scheduled visit should not be repeated for a separate ETV. 
 
The required post-treatment follow-up visits should occur for all study participants, except for those with concurrent infections (see Section 5.1.5 for details). 
Visit No 
V67 
V68 
V69 
Early 
termination 
Post-Treatment Follow-Up Period 
(PTFU) 
Notes 
ETV 
V801 
V802 
V803 
V803 is an additional follow-up based on neutrophil 
count (Section 5.1.5). 
Study Week 
W256 
W260 
W264 
Any Week 
LV (or ETV) 
+ 4W 
LV (or ETV) 
+ 8W 
LV (or ETV) 
+ 12W 
Study Days 
(Approximately) 
1792 
± 7d 
1820 
± 7d 
1848 
± 7d 
Any Day 
± 7d 
± 7d 
± 7d 
Treatment Visits 
X 
X 
Treatment visits are intended only for the dispensation 
and on-site administration of ixekizumab for the 
participants 
 
 who have opted for on-site administration. 
Urinalysis 
X 
X 
PK sample 
X 
X 
X 
At regular visits (i.e., when ixekizumab is administered 
on site to all the participants), PK samples should be 
collected prior to administration of ixekizumab. 
Immunogenicity 
sample 
X 
X 
X 
See Section 9.6.1. All samples for immunogenicity 
should be taken predose when applicable and possible. 
Abbreviations: AESI = adverse events of special interest; BP = blood pressure; d = days; DNA = deoxyribonucleic acid; EQ-5D-Y = European Quality of 
Life-5 Dimensions-Youth; ESR = erythrocyte sedimentation rate; ETV = Early Termination Visit; HBcAb = hepatitis B core antibody; HBV = hepatitis 
B virus; hsCRP = high-sensitivity C-reactive protein; IBD = inflammatory bowel disease; LEI = Leeds Enthesitis Index; LV = Last Visit; No = number; 
PK = pharmacokinetics; PPD = purified protein derivative; RNA = ribonucleic acid; TB = tuberculosis; V = study visit; W = study week. 
 
 
Notes: If ETV occurs on the same day as the scheduled visit, any assessments/ procedures conducted during the scheduled visit should not be repeated for 
a separate ETV. Post-Treatment Follow-Up Period — This applies only to participants who do not enter the long-term extension study. Treatment 
Visits are intended for the dispensation and/or site administration of the study treatment. Because of blood volume restrictions, some laboratory tests 
may not be collected. Laboratory samples are recommended to be collected as described in the sponsor provided weight-based prioritization chart. 
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3. Introduction  
 
3.1. Study Rationale  
 
This study is part of the European Paediatric Investigation Plan (PIP), EMEA-001050-
PIP02-18- M01, with the aim to evaluate the efficacy, safety, tolerability, and 
pharmacokinetics (PK) of ixekizumab when administered to pediatric patients with 
juvenile idiopathic arthritis (JIA) categories of enthesitis-related arthritis (ERA) (including 
juvenile onset ankylosing spondylitis [JoAS]) and juvenile psoriatic arthritis (JPsA). 
The study will include participants who are naive to biologic disease-modifying 
antirheumatic drugs (bDMARD-naive) and participants with an inadequate response 
(IR) or intolerance to treatment with at least one bDMARD (bDMARD-IR). The 
inclusion of bDMARD-naive and bDMARD-IR patients in this study is based on the 
unmet needs in both ERA and JPsA subsets of JIA. Adalimumab will serve as a 
reference arm in bDMARD-naive patients, allowing for a descriptive assessment in the 
same study as in bDMARD-naive patients on ixekizumab, thus providing assay 
sensitivity and context for the efficacy data. 
The rationale for the long-term extension (LTE) period is to evaluate the long-term safety, 
tolerability, and efficacy of ixekizumab when administered to pediatric patients with JIA 
categories of ERA (including JoAS) and JPsA. In addition to the established safety profile 
for adult psoriasis, psoriatic arthritis, and axial spondyloarthritis, further assessments for 
the safety, tolerability, and efficacy data from this study are intended to establish a better 
understanding of the long-term benefit-risk relationship for ixekizumab in pediatric 
patients with ERA and JPsA. 
3.2. Background  
Disease background: Juvenile idiopathic arthritis and its categories of enthesitis-related arthritis 
and juvenile psoriatic arthritis  
Juvenile idiopathic arthritis is a heterogeneous group of diseases characterized by 
idiopathic arthritis that starts before the age of 16 years and persists for at least 6 weeks. 
Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children and 
a leading cause of short- and long-term disability (Ravelli and Martini 2007). The 
incidence and prevalence estimates for JIA vary greatly from 1.6 to 23 and from 3.8 to 
400/100,000, respectively, depending on the classification, methodology, timing, and 
geography (Thierry et al. 2014). 
According to the current second revision of the International League of Associations for 
Rheumatology (ILAR) classification of JIA, the group consists of 7 relatively homogeneous, 
mutually exclusive categories based on predominant clinical and laboratory features: systemic 
arthritis, oligoarthritis (persistent or extended), polyarthritis rheumatoid factor (RF) negative, 
polyarthritis RF positive, psoriatic arthritis (PsA), ERA, and undifferentiated arthritis (Petty et 
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al. 2004). Some forms of JIA are typically only seen in children, while others may be 
considered as childhood counterparts of adult diseases (Martini et al. 2019). 
Enthesitis-related arthritis is characterized by the association of arthritis and enthesitis 
and is considered as the pediatric counterpart of ankylosing spondylitis (AS) or axial 
spondyloarthritis (axSpA). Other typical ERA features are: axial involvement, human 
leukocyte antigen-B27 (HLA-B27) positivity, acute anterior uveitis, and positive family 
history of spondyloarthritis (SpA) or related conditions (Colbert 2010; Tse and Laxer 
2012). Enthesitis-related arthritis accounts for about 5% to 10% of all JIA cases, with a 
higher prevalence in non-Western European countries (Martini et al. 2019). Enthesitis-
related arthritis mainly affects male patients and typically starts in late childhood or 
adolescence (Burgos-Vargas et al. 1997; Ravelli and Martini 2007; Consolaro et al. 
2019). The most common sites of enthesitis are the calcaneal insertions of the Achilles 
tendon, plantar fascia, and tarsal area. Arthritis usually affects the joints of the lower 
extremities, including the hip. Axial (sacroiliac joint) involvement is of rarer occurrence 
than in adults and typically occurs later in the disease course. In addition to anterior 
uveitis, inflammatory bowel disease (IBD) may be an extra-articular manifestation. 
Although ERA is often remitting, some patients may develop cardiopulmonary and 
cerebrovascular complications, which are also leading causes of shorter life expectancy 
(Giancane et al. 2016). 
The JPsA category by ILAR criteria requires the simultaneous presence of arthritis and 
psoriasis or, if psoriasis is absent, the presence of arthritis and at least 2 of the following: 
(1) family history of psoriasis in a first-degree relative; (2) nail psoriasis (nail pitting or 
onycholysis); (3) dactylitis (Petty et al. 1998; Petty et al. 2004). Juvenile psoriatic 
arthritis represents about 2% to 11% of JIA cases and occurs with a biphasic distribution; 
early peak is at 2 to 4 years and later peak at 9 to 11 years of age (Ravelli and Martini 
2007). The current JPsA category may however be heterogeneous and in need of further 
refinement (Martini et al. 2019.). 
Treatment of juvenile idiopathic arthritis categories of enthesitis-related arthritis and 
juvenile psoriatic arthritis 
The goal of JIA treatment is rapid suppression of inflammation to reduce pain, prevent 
joint damage, maintain physical function and quality of life, and promote normal growth 
and development. Pharmacologic first-line treatment for patients with non-systemic JIA 
consists of nonsteroidal anti-inflammatory drugs (NSAIDs); intra-articular or short-term 
systemic use of corticosteroids may be considered in selected more severe cases. 
Persistent arthritis requires disease-modifying antirheumatic drug (DMARD) therapy. 
Methotrexate (MTX) is the most commonly used conventional synthetic DMARD 
(csDMARD), but a substantial proportion of patients do not achieve adequate response, 
may lose disease control over time or experience tolerability problems (Ringold et al. 
2013; Hinze et al. 2015). 
Biologic DMARDs (bDMARDs) have greatly improved treatment outcomes and 
prognosis of JIA. Current biologic treatment options for JIA include agents targeting 
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tumor necrosis factor (TNF) (etanercept, adalimumab), IL-6 (tocilizumab), CD28 
(abatacept), and IL-1 (anakinra and canakinumab) (Giancane et al. 2016). 
There are only 2 approved bDMARDs – the TNF inhibitors adalimumab and etanercept – 
for the treatment of ERA, while etanercept is the only bDMARD approved for the 
treatment of JPsA. 
Adalimumab is a fully human monoclonal antibody against TNF and is approved in the 
EU for the treatment of active ERA in patients ≥6 years of age who have had an IR or 
intolerance to conventional therapy. Adalimumab is also approved in the EU for the 
treatment of pediatric plaque psoriasis, pediatric Crohn’s disease, pediatric chronic non-
infectious anterior uveitis, as well as polyarticular JIA (Humira® Summary of Product 
Characteristics [SmPC] 2020). 
The safety and efficacy of adalimumab in ERA were assessed in a 12-week multicenter, 
randomized, double-blind, placebo-controlled study in 46 patients aged 6 to 17 years, 
followed by an open-label extension period. The primary endpoint was the percent change 
in the number of active joints with arthritis at Week 12, which was significantly greater in 
the adalimumab group than placebo group (-62.6% vs. -11.6%). Juvenile idiopathic 
arthritis American College of Rheumatology (ACR) 30/50/70/90 responses were achieved 
in 71%/68%/55%/42% of adalimumab-treated patients at Week 12, which was 
significantly more than on placebo (20%) for JIA ACR 70. Improvements were sustained 
through Week 52 of the open label adalimumab extension (Burgos-Vargas et al. 2015). 
Long-term effectiveness and acceptable safety profile of adalimumab with or without 
MTX have since been confirmed in larger registry studies in patients with non-systemic 
JIA, including ERA and JPsA (Klein et al. 2019). 
Etanercept, a recombinant TNF receptor fusion protein, is approved in the EU for the 
treatment of JPsA and ERA in adolescents ≥12 years, for plaque psoriasis in children and 
adolescents 
≥6 years, and for RF positive or negative polyarthritis, as well as extended oligoarthritis 
(Enbrel SmPC® 2019). Long-term extension studies of the original JIA trial cohorts and 
national registries have confirmed sustained clinical benefit and acceptable safety profile 
(Horneff et al. 2014; Constantin et al. 2016; Foeldvari et al. 2019). Etanercept has also 
been shown to reduce the progression of radiographic joint damage (Nielsen et al. 2008) 
and improve growth velocity and bone status in JIA patients (Billiau et al. 2010; Giannini 
et al. 2010). A drawback of etanercept in ERA and JPsA may be its lack of therapeutic 
impact on concomitant anterior uveitis and IBD (van der Heijde et al. 2017; Ward et al. 
2019). 
Although the currently approved bDMARDs enable significant improvements in JIA, 
there is still a substantial proportion of patients who fail to adequately respond or do not 
achieve long- lasting remission (Hinze et al. 2015). Thus, there is an unmet need for 
novel treatments, particularly those with alternative mechanisms of action. 
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Investigational product ixekizumab  
Ixekizumab is an immunoglobulin (Ig) G subclass 4 (IgG4) monoclonal antibody that 
binds with a high affinity and specificity to interleukin (IL)-17A, a key proinflammatory 
cytokine in the pathophysiology of plaque psoriasis, PsA and axSpA (Leonardi et al. 2012; 
Taams et al. 2018; Robinson et al. 2019). 
Interleukin-17A, a member of the IL-17 family, is mainly produced by inflammatory Th17 
cells, a subset of T helper cells, but also by other T cells, neutrophils, and mast cells. 
Animal studies established the role of IL-17 signaling in ankylosing enthesitis and bone 
remodeling (Abe et al. 2009; Glatigny et al. 2012), and prophylactic administration of 
anti-IL-17 antibodies blocked the development of ankylosis in a spontaneous ankylosis 
mouse model (Ebihara et al. 2015). 
Ixekizumab is approved in the EU (Taltz® SmPC), US (Taltz US package insert [USPI]), 
and several other countries for the treatment of adult patients with: 
 
 moderate-to-severe plaque psoriasis in patients who are candidates for systemic 
therapy; 
 active PsA; 
 active radiographic axSpA/ankylosing spondylitis (r-axSpA/AS); and 
 active non-radiographic axSpA (nr-axSpA) in patients with objective 
signs of inflammation. 
In addition, ixekizumab has recently been approved for the treatment of moderate-to-
severe plaque psoriasis in children from the age of 6 years and adolescents who are 
candidates for systemic therapy (Taltz SmPC and Taltz USPI). 
The efficacy and safety of ixekizumab in adult patients with active PsA was primarily 
assessed in two Phase 3 randomized, double-blind, placebo-controlled studies involving 
780 patients in total: SPIRIT-P1 (I1F-MC-RHAP) study in bDMARD-naive patients 
(Mease et al. 2017) and SPIRIT-P2 (I1F-MC-RHBE) study in patients who failed prior 
TNF inhibitor therapy for lack of efficacy or intolerance (Nash et al. 2017). In both 
studies the treatment with ixekizumab 80 mg administered by subcutaneous (SC) injection 
every 4 weeks (Q4W) or every 2 weeks (Q2W) with a starting dose of 160 mg 
ixekizumab, resulted in significant improvements in clinical disease activity, physical 
function and health-related quality of life compared to placebo at Week 24. 
The ACR 20/50/70 response rates at Week 24 in patients treated with the approved 
ixekizumab dosing regimen Q4W were 58%/40%/23% in SPIRIT-P1 and 53%/35%/22% 
in SPIRIT-P2, which was significantly higher than placebo (30%/15%/6% and 
20%/5%/0%, respectively) (Mease et al. 2017; Nash et al. 2017). The ACR 20/50/70 
response rates at Week 24 on the active reference adalimumab arm in SPIRIT-P1 were 
57%/39%/26% (Mease et al. 2017). In patients with pre-existing dactylitis or enthesitis, 
significantly more patients treated with ixekizumab Q4W than placebo achieved 
resolution at Week 24: 78% versus 24% and 39% versus 21%, respectively (Gladman et 
al. 2019). Among patients with ≥3% body surface area (BSA), higher proportions of 
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patients treated with ixekizumab Q4W than placebo attained Psoriasis Area and Severity 
Index (PASI) 75/90/100 responses (PASI75 67% vs. 9% at Week 12). Significant 
inhibition of radiographic progression on ixekizumab compared with placebo was 
demonstrated in SPIRIT-1 study at Week 24 (Taltz SmPC). Improvements in all PsA 
domains were maintained during open-label extension treatment with ixekizumab through 
1 year (Genovese et al. 2018; van der Heijde et al. 2018; Kavanaugh et al. 2019). 
Further, in a Phase 4 direct comparative study of ixekizumab versus adalimumab in 
bDMARD naive adult PsA patients (SPIRIT-H2H; I1F-MC-RHCF), ixekizumab was 
superior to adalimumab in the simultaneous achievement of ACR50 and PASI 100 
responses at Week 24 (36%/28% respectively). Ixekizumab was non-inferior to 
adalimumab in achieving ACR50 response (51%/47% respectively) and superior in 
achieving PASI 100 response (60%/47% respectively). Significantly better results on 
ixekizumab compared with adalimumab were also seen for composite measures of 
disease activity and resolution of enthesitis (Humira SmPC 2020; Mease et al. 2020). 
The efficacy and safety of ixekizumab were assessed in 960 patients with active 
axSpA in 3 randomized, double-blind, placebo-controlled studies: COAST-V (I1F-
MC-RHBV) in bDMARD-naive patients with r-axSpA/AS (van der Heijde et al. 
2018), COAST-W (I1F-MC-RHBW) in patients with r-axSpA/AS with IR or 
intolerance to TNF inhibitors (Deodhar et al. 2019), and COAST-X (I1F-MC-
RHBX) in bDMARD-naive patients with nr-axSpA (Deodhar et al. 2020). Treatment 
with ixekizumab either at 80 mg Q4W or Q2W resulted in significant improvements 
compared with placebo in measures of disease activity, physical function, health 
related quality of life as well as spinal inflammation measured by magnetic 
resonance imaging (MRI) at Week 16 in both r-axSpA/AS studies (van der Heijde et 
al. 2018; Deodhar et al. 2019). Significantly more patients treated with the approved 
ixekizumab dosing regimen Q4W vs placebo achieved assessment in ankylosing 
spondylitis (ASAS)-40 response at Week 16: 48% vs 18% in COAST-V and 25% vs 
13% in COAST-W; by comparison, ASAS40 response was achieved in 36% of 
patients treated with adalimumab as the active reference drug in COAST-V study. 
Further, significant improvements in ixekizumab compared with placebo were seen 
in both studies in the individual components of the ASAS response, including 
patient global assessment and spinal pain. Therapeutic effects of ixekizumab were 
maintained through Week 52 across the measures of disease activity, function, and 
objective inflammation (Dougados et al. 2019; Taltz SmPC 2020). Consistent 
therapeutic effects and safety profile of ixekizumab were recently demonstrated also 
in patients with non-radiographic axSpA with objective signs of inflammation 
(Deodhar et al. 2020). 
The efficacy and safety of ixekizumab in pediatric participants (6 to <18 years old) with 
moderate-to-severe plaque psoriasis were assessed in a Phase 3, randomized, double-
blind, placebo-controlled study of ixekizumab (IXORA-PEDS/I1F-MC-RHCD; Paller et 
al. 2020). A total of 171 participants were studied (115 participants on ixekizumab and 
56 on placebo). 
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Ixekizumab was administered subcutaneously Q4W; the doses were weight-based (see 
Section 5.5 for details). Treatment with ixekizumab was superior to placebo for both 
coprimary endpoints at Week 12 (p<0.001): 
 ≥75% improvement in PASI 75: Ixekizumab Q4W, 89%; placebo, 25% 
 A static Physician’s Global Assessment score of 0 or 1 (sPGA 0,1): Ixekizumab 
Q4W, 81%; placebo, 11% 
Overall, treatment with ixekizumab in Study RHCD resulted in rapid and statistically 
significant improvements, compared with placebo, in skin involvement, itch, and health-
related quality of life. These improvements persisted through 48 weeks of treatment. 
In Study RHCD, the safety profile of ixekizumab was overall consistent with that seen 
in adult participants, with the exception of frequencies of conjunctivitis (2.6%), 
influenza (1.7%), and urticaria (1.7%), which were greater in pediatric participants 
compared to adults. In the IXORA-PEDs Randomized Clinical Trial that ran for 108 
weeks, there were no new safety findings during Weeks 48 to 108 of the trial, including 
no new cases of inflammatory bowel disease or candida infection. (Paller et al. 2022). 
3.3. Benefit/Risk Assessment  
Based on the efficacy of ixekizumab demonstrated in the clinical studies of axSpA and 
PsA in adult patients (described in Section 3.2), as well as the pediatric study in plaque 
psoriasis, significant therapeutic benefits may be expected in pediatric patients with ERA 
and JPsA, which share clinical, imaging, immunopathologic, and genetic similarities with 
axSpA and PsA, respectively. 
Across the approved indications of adult and pediatric plaque psoriasis, PsA, r-
axSpA/AS, and nr-axSpA, ixekizumab has been shown to have a comparable risk 
profile. 
Most common (≥1%) adverse reactions associated with ixekizumab treatment are 
injection site reactions, upper respiratory tract infections, nausea, and tinea infections. In 
clinical trials in adult patients with plaque psoriasis, the ixekizumab group had a higher 
rate of infections than the placebo group (27% vs. 23%). Upper respiratory tract 
infections, oral candidiasis, conjunctivitis and tinea infections occurred more frequently in 
the ixekizumab group than in the placebo group. A similar increase in the risk of infection 
was seen in placebo-controlled trials in patients with pediatric psoriasis, PsA and AS. 
Serious hypersensitivity reactions, including angioedema and urticaria (each ≤0.1%), 
occurred in the ixekizumab group in clinical trials. Anaphylaxis, including cases leading 
to hospitalization, has been reported in post marketing use with ixekizumab. 
Ixekizumab has been evaluated so far in one placebo-controlled pediatric trial, which was 
conducted in patients with moderate-to-severe plaque psoriasis 6 to less than 18 years of 
age. A total of 171 patients were studied (115 patients on ixekizumab and 56 on placebo). 
 
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Overall, the safety profile observed in pediatric patients with plaque psoriasis treated with 
ixekizumab Q4W is consistent with the safety profile in adult patients with plaque 
psoriasis with the exception of frequencies of conjunctivitis (2.6%), influenza (1.7%), and 
urticaria (1.7%). Cases of new or exacerbations of Crohn’s disease and ulcerative colitis 
have been reported and are considered to be an uncommon adverse effect. Crohn’s disease 
occurred at a greater frequency in the ixekizumab group (0.9%) than the placebo group 
(0%) during the 12-week, placebo-controlled period. In adult patients with plaque 
psoriasis, Crohn’s disease and ulcerative colitis, including exacerbations, occurred at a 
greater frequency in the ixekizumab 80 mg Q2W group (Crohn’s disease 0.1%, ulcerative 
colitis 0.2%) than the placebo group (0%) during the 12-week, placebo- controlled period 
of clinical trials. In adult patients with AS, Crohn’s disease and ulcerative colitis, 
including exacerbations, occurred in 2 patients (1.0%) and 1 patient (0.5%), respectively, 
in the ixekizumab 80 mg Q4W group, and 1 patient (0.5%) and 0%, respectively, in the 
placebo group during the 16-week, placebo-controlled period. Of these patients, serious 
events occurred in 1 patient in the ixekizumab 80 mg Q4W group and 1 patient in the 
placebo group. 
Other adverse drug reactions and potential risks associated with ixekizumab treatment 
include: cytopenias (usually mild) and liver enzyme elevations. Data from clinical trials 
do not suggest an association between ixekizumab treatment and cerebrocardiovascular 
events, depression/suicidality, or malignancies. There are insufficient human data to 
establish the safety of ixekizumab during pregnancy. 
Section 9.2.1 describes adverse events of special interest (AESI) in this protocol. 
Risk mitigation measures added to the protocol to address the important potential 
risks include appropriate inclusion and exclusion criteria, safety monitoring, and 
temporary and permanent discontinuation criteria. 
More information about the known and expected benefits and risks, serious adverse 
events (SAEs) and reasonably anticipated adverse events (AEs) of ixekizumab 
(LY2439821) are to be found in the Investigator’s Brochure (IB). 
Adalimumab was selected as an active reference treatment as it is 1 of the 2 bDMARDs 
that are currently approved for the treatment of ERA. There is also positive clinical 
experience with adalimumab in JPsA (Klein et al. 2019), and well-established efficacy 
and safety in adult axSpA and PsA. Adalimumab has 2 main advantages over etanercept, 
which is the other bDMARD approved for ERA: (1) adalimumab is approved for a 
broader age range of ERA patients than etanercept (≥6 years vs. ≥12 years of age); (2) 
adalimumab as an anti-TNF monoclonal antibody is efficacious in the treatment of IBD 
(Crohn’s disease and ulcerative colitis), as well as for prevention of acute anterior uveitis 
attacks, which are both important comorbidities in SpA and SpA-like diseases (van der 
Heijde et al. 2017; Ward et al. 2019). Etanercept is approved for the treatment of JPsA; 
however, in children and adolescents ≥12 years of age only (Enbrel SmPC 2019). 
As adalimumab is not approved for JPsA, and JPsA patients included in this study may be 
<6 years of age and weigh <15 kg, the approved dose of adalimumab for the treatment of 
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polyarticular JIA will be used in JPsA patients weighing 10 to <15.0 kg (Humira SmPC 
2020). 
Adalimumab has a well-established safety profile across 14 approved indications (Humira 
SmPC 2020): rheumatoid arthritis (RA), JIA (polyarticular JIA and ERA), axSpA (AS and 
axSpA without radiographic evidence of AS), PsA, adult and pediatric Crohn’s disease, 
ulcerative colitis, adult and pediatric psoriasis, hidradenitis suppurativa, and adult and 
pediatric uveitis. The most commonly reported adverse reactions are infections (such as 
nasopharyngitis, upper respiratory tract infection and sinusitis), injection site reactions 
(erythema, itching, hemorrhage, pain or swelling), headache and musculoskeletal pain. 
Serious adverse reactions have been reported for adalimumab. Tumor necrosis factor 
antagonists, such as adalimumab, affect the immune system and their use may affect the 
body’s defense against infection and cancer. Fatal and life-threatening infections 
(including sepsis, opportunistic infections and tuberculosis [TB]), hepatitis B virus (HBV) 
reactivation and various malignancies (including leukemia, lymphoma and hepatosplenic 
T-cell lymphoma) have also been reported with use of adalimumab. Serious 
hematological, neurological, and autoimmune reactions have also been reported. These 
include rare reports of pancytopenia; aplastic anemia; central and peripheral demyelinating 
events; and reports of lupus, lupus-related conditions, and Stevens-Johnson syndrome. In 
general, the AEs in pediatric patients were similar in frequency and type to those seen in 
adult patients. More detailed information about the known and expected benefits and risks 
of adalimumab may be found in the Summary of Product Characteristics (Humira SmPC 
2020). 
As only 2 bDMARDs, both TNF inhibitors, are currently approved to treat ERA and/or 
JPsA, and not all patients achieve an adequate primary response to them or may 
experience secondary treatment failure or intolerance, there is a high unmet need for 
bDMARDs with a different mechanism of action in these 2 JIA subtypes. Based on the 
demonstrated comprehensive efficacy of ixekizumab in axSpA and PsA as well as 
acceptable safety profile, the reasonable probability of a positive benefit/risk warrants this 
study to be conducted. 
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4. Objectives and Endpoints  
Table RHCG.4.1 shows the objectives and endpoints of the study. 
 
Table RHCG.4.1. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 To evaluate the efficacy of ixekizumab in children 
with JIA subtypes of ERA (including JoAS) and 
JPsA based on the JIA American College of 
Rheumatology (ACR) 30 response 
Percentage of participants meeting the JIA ACR 30 
response criteria at Week 16 
Secondary for the Open Label Treatment (OLT) and 
Open Label Extension (OLE) Periods 
 To evaluate the efficacy of ixekizumab in children 
with JIA subtypes of ERA (including JoAS) and 
JPsA based on the other clinical responses, disease 
activity and physical function measures 
 To evaluate the efficacy of adalimumab (reference 
arm) in children with JIA subtypes of ERA 
(including JoAS) and JPsA based on JIA ACR 30 
and the other clinical responses, disease activity and 
physical function measures 
The following outcomes will be assessed at each regular 
study visita: 
 
Percentage of participants meeting the JIA ACR 
30/50/70/90/100 response criteria 
 
Changes from baseline in each of the 6 individual 
components of the JIA ACR core set variables as 
follows: 
o 
Number of active joints 
o 
Number of joints with limited range of 
motion 
o 
Physician’s Global Assessment of Disease 
Activity 
o 
Parent’s Global Assessment of Well-Being 
o 
Physical function as measured by the 
Childhood Health Assessment 
Questionnaire (CHAQ) 
o 
Acute-phase reactant (high-sensitivity 
C-reactive protein [hsCRP]) and 
erythrocyte sedimentation rate (ESR) 
 
Change from baseline in Psoriasis Area and Severity 
Index (PASI) for JPsA participants with at least 3% 
Body Surface Area (BSA) at baseline 
 
Change from baseline in Leeds Enthesitis Index 
(LEI) for participants with enthesitis at baseline 
 
Proportion of participants with disease flare (flare 
defined as worsening of ≥30% from baseline in at 
least 3 of the 6 JIA ACR core set criteria and an 
improvement of ≥30% in no more than 1 of the 
criteria) 
 
To characterize ixekizumab pharmacokinetics (PK) 
in children with JIA subtypes of ERA (including 
JoAS) and JPsA 
 
Trough concentrations of ixekizumab in 
participants with JIA subtypes of ERA (including 
JoAS) and JPsA 
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Objectives and Endpoints 
Objectives 
Endpoints 
 To evaluate the potential development of anti- 
ixekizumab antibodies and their impact on the 
efficacy and safety of ixekizumab in children 
with JIA subtypes of ERA (including JoAS) 
and JPsA 
 
Percentage of participants with anti-
ixekizumab antibodies 
 
Describe 
the 
safety 
of 
ixekizumab 
in 
participants with JIA subtypes of ERA 
(including JoAS) and JPsA 
 
Adverse events (AEs) including serious 
adverse events (SAEs) 
 
Safety parameters including but not limited to 
infections, injection site reactions, and 
laboratory data including B-, T-cell, and natural 
killer (NK)- cell levels, white blood cell (WBC) 
count, red blood cell (RBC) count, alanine 
aminotransferase (ALT), aspartate 
aminotransferase (AST) 
Secondary for the Long-Term Extension (LTE) 
Period 
 
To evaluate the long-term safety, efficacy, 
and tolerability of ixekizumab in children 
with JIA subtypes of ERA (including JoAS) 
and JPsA 
The following outcomes will be assessed at each 
regular study visita: 
 
AEs including SAEs and adverse events 
of special interest (AESIs) 
 
Safety parameters including but not limited 
to infections, injection site reactions, and 
laboratory evaluations (including chemistry 
and hematology) 
 
Permanent and temporary discontinuations 
of the study intervention 
 
Vital signs, growth, and development 
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Abbreviations: ERA = enthesitis-related arthritis; ETV = Early Termination Visit; JIA = juvenile 
idiopathic arthritis; JoAS = juvenile onset ankylosing spondylitis; JPsA = juvenile psoriatic 
arthritis. 
a During the OLE period, regular visits and assessments will occur every 3 months (Visits 8, 11, 14, 
17, 20, 23, 26, and 29/ETV). Participants will also have monthly treatment visits to the site 
primarily for dispensation and/or administration of study drug. 
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5. Study Design  
 
5.1. Overall Design  
 
Study I1F-MC-RHCG (RHCG) is a multicenter, open-label, Phase 3 study of 
ixekizumab with adalimumab as a randomized reference arm in participants with JIA 
categories of ERA (including JoAS) and JPsA from 2 to less than 18 years of age, who 
are bDMARD-naive or bDMARD-IR as per investigator’s judgement. 
The study will be conducted in 5 parts, which includes screening and post-treatment 
follow up (PTFU) periods, in a 5-year study. The open-label treatment (OLT) period will 
include the OLT with ixekizumab or adalimumab up to Week 16. The open-label 
extension (OLE) period will provide OLT with ixekizumab or adalimumab up to Week 
104. The LTE will provide OLT with ixekizumab only. The total study duration will 
include the screening period, 5-year treatment period, and PTFU period. Out of 100 
participants, 40 will be randomly assigned into 1:1 ratio among naive bDMARD 
participants either to treatment arm (ixekizumab) or reference arm (adalimumab), and the 
remaining 60 participants will be randomly allocated either to naive or bDMARD-IR 
group at Visit 2 (Week 1). Participants receiving ixekizumab during the OLT period will 
continue to receive ixekizumab during the OLE period. Participants receiving 
adalimumab during the OLT period who did NOT attain a JIA ACR 30 response at Week 
16 will be switched to ixekizumab in the OLE period. Participants receiving adalimumab 
during the OLT period who did attain a JIA ACR 30 response at Week 16 will be given 
the option to switch or not to switch to ixekizumab in the OLE period. The decision to 
switch for participants who achieved a JIA ACR 30 response at Week 16 will be left to the 
participant/participant’s caregiver and investigator. A switch from adalimumab to 
ixekizumab during the OLE period may also occur at any other visit after Week 16 based 
on the participant/participant’s caregiver and investigator’s decision. After switching to 
ixekizumab, the participants will not have the option to resume adalimumab treatment 
during the remainder of the trial participation. 
Participants who complete the OLT and OLE are eligible to enter the LTE part of the 
study period. All participants entering the LTE portion of the study period will receive 
weight-based ixekizumab at Week 104. Participants who were previously assigned to 
adalimumab will be switched to ixekizumab as described in Section 7.1 Treatments 
Administered. If a participant previously assigned to adalimumab does not want to 
switch to ixekizumab in the LTE period of the study, the patient should initiate the early 
termination visit (ETV) process at Week 104. These participants will be considered to 
have completed the study. Participants who have completed PTFU will have completed 
the study. Participants who have received at least 1 dose of study drug and who 
discontinued early (patients who have received at least 1 dose of study drug) should enter 
the PTFU period and complete through Visit 802. Participants may be followed beyond 
Visit 802 for continued monitoring of their neutrophil counts or because of any other 
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safety concerns if determined by the sponsor/investigator that additional monitoring is 
needed. If a participant discontinues study drug early, the participant will complete the 
ETV and then enter the PTFU period. 
Interim analyses are described in Section 10.3.8. An interim analysis will be performed to 
determine if the study should be stopped for futility when 40 ixekizumab--treated 
participants have completed 16 weeks of treatment. 
The study will enroll at least 100 participants with JIA categories of ERA or JPsA. Among 
participants who are bDMARD-naive, at least 20 participants will be randomized to 
ixekizumab and at least 20 participants will be randomized to adalimumab. 
Randomization will be stratified based on the subset of JIA (ERA or JPsA). 
The remaining participants (approximately 60 participants) who are either bDMARD-
naive or bDMARD-IR will be assigned to ixekizumab. 
The LTE period will include the following on-site visits: 
 Regular visits (every 12 weeks, with the exception of Visits 30 and 31/Weeks 
108 and 112): both for participants 
 
o During regular visits, ixekizumab will be administered on site to all 
participants (regardless of their weight). 
 Treatment visits (every 4 to 8 weeks starting with Visit 32/Week 116): for participants 
 (and those participants 
 who have opted to receive ixekizumab on 
site). 
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Abbreviations: ACR = American College of Rheumatology; bDMARD = biologic disease-modifying antirheumatic drug; ERA = enthesitis-related 
arthritis; ETV = early termination visit; IR = inadequate response; JIA = juvenile idiopathic arthritis; JPsA = juvenile psoriatic arthritis; LV = last visit; 
OLE = open- label extension; OLT = open-label treatment; PTFU = post-treatment follow up; Q2W = every other week; Q4W = every 4 weeks; TV = 
treatment visit; V = visit; W = week 
a Participants who are bDMARD-naive will be randomized to ixekizumab or adalimumab in a 1:1 ratio. At least 20 participants will be randomized to 
ixekizumab and 20 participants to adalimumab. Randomization will be stratified based on the category of JIA (ERA or JPsA). The remaining 
participants (approximately 60 participants) who are bDMARD-naive or bDMARD-IR will be assigned to ixekizumab. 
b Participants receiving adalimumab during the OLT period who did NOT attain a JIA ACR 30 response at Week 16 will be switched to ixekizumab in the 
OLE period. Participants receiving adalimumab during the OLT period who did attain a JIA ACR 30 response at Week 16 will be given the option to 
switch or not to switch to ixekizumab in the OLE period. 
c Regular visits will occur every 3 months, but participants will have monthly TVs to the site primarily for injection purposes. Participants who are treated 
with adalimumab through Week 104 may decide not to switch to ixekizumab at Week 104 and enter the PTFU period. 
Figure RHCG.5.1. 
Illustration of study design for Clinical Protocol I1F-MC-RHCG.
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5.1.1. Screening and Baseline Periods  
The Screening Period is from 7 up to 42 days prior to baseline. At screening, the parent or 
legal guardian will sign the informed consent form (ICF) and the participant will sign the 
assent form (as appropriate) per local requirements prior to any study assessments, 
examinations, or procedures being performed (Appendix 3). All screening procedures will be 
performed according to the Schedule of Activities (Section 2). 
The preferred TB test is QuantiFERON® TB Gold test. In countries where the 
QuantiFERON®- TB Gold test is not available or due to investigator’s judgement (e.g., need 
to reduce the volume of blood collected), T-spot or the purified protein derivative (PPD) test 
may be used. In the case of selecting the PPD test, the participant must return within 48 to 72 
hours to read the skin test. The PPD test result does not need to be read at the site, but must be 
assessed by a trained healthcare professional, and documented results provided to the site as 
soon as possible. 
Treatment with concomitant JIA therapies and topical corticosteroids during the study is 
permitted only as described in Section 7.7. Participants will remain on background MTX, 
other csDMARDs and oral, topical or ophthalmic corticosteroids if participants are on stable 
doses of these treatments at screening (see Sections 6.2 and 7.7. for details). 
Participants with a positive HCV antibody will return to the site and have an HCV RNA 
sample drawn, which will be processed centrally. Results must be known prior to enrollment. 
Participants who are positive for HCV antibody and negative for HCV RNA may be enrolled. 
Participants with a positive hepatitis B core antibody (HBcAb) will return to the site and have 
an HBV DNA sample drawn, which will be processed centrally. Results must be known prior 
to enrollment. Any enrolled participant who is HBcAb positive, regardless of hepatitis B 
surface antibody (HBsAb) status or level, must undergo HBV DNA testing per the Schedule of 
Activities (Section 2). 
Pregnancy tests will be given prior to the first dose of investigational product for females 
≥10 years of age (<10 years at investigator discretion) if menarche has been reached or if there 
is reason to believe the participant is sexually active. Pregnancy test results from baseline 
must be known prior to first dose of investigational product. 
Investigators should review the vaccination status of the participant and ensure that the 
participant is up-to-date with all live immunizations and follow the local requirements for 
vaccination guidelines and schedule for immunosuppressed participants. 
Participants who meet all the inclusion and none of the exclusion criteria (Section 6) will 
continue to baseline. At baseline, study eligibility for each participant will be reviewed based 
on all inclusion and exclusion criteria (Section 6). 
Laboratory samples will be collected at screening and baseline and all assessments should be 
completed before the participant takes the first dose of investigational product. Owing to 
blood volume restrictions, some laboratory tests may not be collected for younger or lighter 
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weight participants based on Institutional Review Board (IRB) blood volume limitations. 
Laboratory samples are recommended to be collected as described in a sponsor-provided 
weight-based prioritization chart. 
5.1.2. Open-Label Treatment Period  
In the OLT period, participants will be randomly assigned to receive either SC ixekizumab 
Q4W or SC adalimumab Q2W for approximately 16 weeks. Evaluation of the primary 
endpoint will occur at Week 16. Randomization will be stratified based on the category of JIA 
(ERA or JPsA). 
Among bDMARD-naive participants, at least 20 participants will be randomized to 
ixekizumab and at least 20 participants will be randomized to adalimumab. The remaining 
participants (approximately 60 participants) who are either bDMARD-naive or bDMARD-IR, 
will be assigned to ixekizumab. 
Ixekizumab dosing will be as follows: 
 
 Q4W thereafter; 
 
 Q4W thereafter; 
 
 Q4W thereafter. 
Adalimumab dosing will be as follows: 
 Q2W; 
and 
 Q2W. Dosing of ixekizumab or 
adalimumab may not be changed in the OLT period. 
Participants should remain under observation for at least 1 hour after the first ixekizumab dose 
to monitor for safety. Following the first injection, and if no problems occur with that 
injection, participants will be observed for 30 minutes following injection at all other study 
visits. 
At Week 0 (baseline; Visit 2), routine safety assessments; laboratory tests; health 
outcomes assessments; and clinical, efficacy, and safety assessments will be performed 
on eligible participants according to the Schedule of Activities (Section 2). 
Female participants of childbearing potential (age 10 and older if menarche has been reached 
or if there is reason to believe the participant is sexually active, or younger participants per 
investigator assessment of sexual maturity) will undergo a urine pregnancy test at the clinic on 
a monthly basis during scheduled regular visits through Week 104. Additional urine 
pregnancy testing may be performed at the investigator’s discretion. Participants determined 
to be pregnant will be discontinued from treatment and will no longer be administered study 
drug (see Section 8.1). 
Participants who discontinue the study for any reason during this period will stop treatment 
and continue to the ETV prior to entering the PTFU. 
5.1.3. Open-Label Extension Period  
In the OLE period, all participants who were receiving ixekizumab in the OLT period will 
continue to receive ixekizumab for approximately 88 weeks. 
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Participants receiving adalimumab during the OLT period who did NOT attain a JIA ACR 
30 response at Week 16 will be switched to ixekizumab in the OLE period. Participants 
receiving adalimumab during the OLT period who did attain a JIA ACR 30 response at 
Week 16 will be given the option to switch or not to switch to ixekizumab in the OLE 
period. Participants who are switched over to ixekizumab treatment after the OLT period 
will be treated as a separate group. The decision to switch for participants who achieved a 
JIA ACR 30 response will be left to the participant/participant’s caregiver and investigator. 
A switch from adalimumab to ixekizumab during the OLE period may also occur at any 
other visit after Week 16 based on the participant/participant’s caregiver and investigator’s 
decision. For switching participants, the first ixekizumab dose can occur at any study visit 
during OLE period and after a minimum of 2 weeks after the last adalimumab dose (e.g., the 
subject that received the last dose of adalimumab at Week 14 will receive the first dose of 
ixekizumab at Week 16). 
Switching from adalimumab to ixekizumab for a safety reason requires a washout period of 
sufficient length to allow the safety issue/parameter to resolve. 
The participants switching to ixekizumab will not receive the starting ixekizumab dose but 
will receive the appropriate regular ixekizumab dose according to their weight at each visit. 
After switching to ixekizumab, the participants will not have the option to resume 
adalimumab treatment during the remainder of the trial participation. Rationale/justification 
for switching will be captured for any participant switching to ixekizumab and recorded in the 
participant’s case report form. 
Weight will be recorded, and dosing of ixekizumab and adalimumab will be adjusted during the 
OLE period according to the participant’s weight at each visit. 
 
5.1.4. Long-Term Extension Period  
All procedures during the LTE period will be performed according to the Schedule of 
Activities (Section 2). 
Study Visits  
Participants 
 will have the option to self-administer ixekizumab at home (or have 
their caregivers administer it) after both the participants and their caregivers have received 
the appropriate training (see the SoA and Section 6.1 for details). 
The LTE period will include the following on-site visits: 
 Regular visits (every 12 weeks, with the exception of Visits 30 and 31/Weeks 108 
and 112): both for participants 
 
o During regular visits, ixekizumab will be administered on site to all participants 
(regardless of their weight) 
 Treatment visits (every 4 to 8 weeks starting with Visit 32/Week 116): for participants 
 (and those participants 
 who have opted to receive ixekizumab on 
site) 
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Weight will be recorded, and dosing of ixekizumab will be adjusted during the LTE period 
according to the participant’s weight at each visit. 
5.1.5. Post-Treatment Follow-Up Period  
Participants who have received at least 1 dose of study drug (including those who do not enter 
in the LTE period or discontinued early) should enter the PTFU period for a minimum of 12 
weeks after their last regularly scheduled visits (or the date of their ETV). Required study 
visits should occur at 4 weeks after and at 8 weeks after the last regularly scheduled visit (or 
the date of the participant’s ETV) (Visits 801 and 802, respectively), except for participants 
with concurrent infections that require systemic anti-infective therapy (described below). 
If, at the last scheduled visit or ETV, a participant’s neutrophil count is <1500 cells/L 
(<1.50 × 103/µL or <1.50 GI/L) and less than the participant's baseline neutrophil count, 
the following measures should be taken: 
 Participants with concurrent infection: If there is a concurrent infection that 
requires systemic anti-infective therapy, the participant 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 PTFU period design at Visits 801 (4 weeks after resolution of infection), 802 
(8 weeks after last visit), and 803 (if necessary; 12 weeks after last visit); 
additional visits may be required depending on the degree of neutropenia. 
 Participants 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 PTFU period 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 participant’s neutrophil count is <1000 cells/L (<1.00 × 
103/µL or <1.00 GI/L) at any follow-up visit, the participant should return 
for additional visits at least Q4W (unscheduled visits may be required). 
o As long as a participant’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 participant should return for additional 
visit(s) at least every 4 to 8 weeks (unscheduled visits may be required). 
o If at Visit 803 the participant’s neutrophil count remains <1500 cells/L 
(<1.50 × 103/µL or <1.50 GI/L) and less than the participant’s baseline 
neutrophil count or if the investigator deems additional follow-up may be 
necessary, the investigator in consultation with Lilly or qualified designee 
will determine the appropriate management of the participant and the 
appropriate timing of additional contact(s) or visit(s). 
o If at Visit 802 or Visit 803 the participant’s neutrophil count is ≥1500 
cells/L (≥1.50 × 103/µL or ≥1.50 × 103/µL) or greater than or equal to the 
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participant’s baseline neutrophil count (whichever is lower), the 
participant’s participation in the study will be considered complete unless 
the investigator deems additional follow-up necessary. 
 
5.2. Number of Participants  
At least 100 participants from 2 to less than 18 years of age with a diagnosis of JIA categories 
of ERA and JPsA are planned to enter the OLT period. 
 For participants who are bDMARD-naive, at least 20 participants will be randomized 
to ixekizumab and at least 20 participants will be randomized to adalimumab. 
Randomization will be stratified based on the category of JIA (ERA or JPsA). 
 The remaining participants (approximately 60 participants) who are either 
bDMARD- naive or bDMARD-IR will be assigned to ixekizumab. 
 
5.3. End of Study Definition  
A participant is considered to have completed the study if he/she has completed all required 
phases of the study including the last visit or the last scheduled procedure shown in the 
Schedule of Activities (Section 2). Participants on adalimumab completing Visit 29/Week 104 
are considered to have completed the study treatment if they do not wish to continue on 
ixekizumab. 
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA for the last participant in the trial globally. 
5.4. Scientific Rationale for Study Design  
This is an open-label study to assess the efficacy, safety, tolerability, and PK of ixekizumab 
in children with JIA during the OLT period (Week 0 to Week 16), followed by an OLE 
period, including adalimumab as a randomized reference arm. The total study duration will 
be about 2 years, with the addition of 3 years of ixekizumab treatment in the LTE period. 
Although the currently approved bDMARDs enable significant improvements in JIA, there is 
still a substantial proportion of participants who fail to adequately respond or do not achieve 
long-lasting remission (Hinze et al. 2015). Thus, there is an unmet need for novel treatments, 
particularly those with alternative mechanisms of action. The 2 categories of JIA included in 
this study – ERA and JPsA – are considered juvenile counterparts of adult axSpA and PsA, 
respectively. Ixekizumab has been shown before to be efficacious in improving signs and 
symptoms, physical function, and quality of life in adult participants with axSpA and JPsA at 
an acceptable safety profile. Hence, there is a potential for this study to demonstrate a 
clinically relevant benefit of ixekizumab therapy in participants with ERA and JPsA. 
According to the PIP, the study will enroll participants aged 2 to less than 18 years. 
Participants with JPsA will be enrolled considering this age range. Participants with ERA 
will have to be at least 6 years or older at enrollment, as the disease typically starts at this 
age, which is also reflected in the classification criteria. Further, the classification criteria for 
ERA have low specificity if applied in younger children. 
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Study treatment will be provided during 2 study periods (OLT and OLE). Study treatment in 
OLT is designed to evaluate the primary endpoint, which is the percentage of participants 
meeting the JIA ACR 30 response criteria at Week 16. Evaluation of the primary endpoint at 
the Week 16 time point is appropriate, based on previous clinical trials. 
Participants that do not achieve JIA ACR 30 response at Week 16 while on adalimumab, will 
be switched to ixekizumab without a washout period, due to a high need for treatment 
change/escalation. Evidence from studies in adult participants with IBD or RA suggests no 
significant safety risk is associated with direct switching between different monoclonal 
antibodies (Smolen et al. 2016; Mahagna and Ben-Horin 2019). To decrease any potential 
safety risk in switching participants, the minimum required period between the last 
adalimumab and first ixekizumab dose will be 2 weeks, and no higher starting dose of 
ixekizumab will be applied (van der Heijde et al. 2018). 
The OLE period allows for long-term evaluation of safety and durability of efficacy in 
participants who receive ixekizumab. The PTFU will allow for continued safety monitoring 
after the last dose. 
The open-label Bayesian approach is considered methodologically acceptable. The inclusion 
of adalimumab reference arm, with 1:1 randomization of bDMARD-naive participants to 
either ixekizumab or adalimumab, will allow for descriptive comparative statistics, thus 
providing assay sensitivity and context for ixekizumab efficacy data. 
An active adalimumab reference arm was used before in the Phase 3 randomized 
placebo-controlled trials of ixekizumab in bDMARD-naive adult participants with PsA and 
axSpA (Mease et al. 2017; van der Heijde et al. 2018). 
The inclusion of bDMARD-IR participants is driven by the unmet need in participants who 
had primary or secondary failure or intolerance to bDMARD therapy, including adalimumab. 
The long-term open-label extension period allows participants with JIA to receive treatment 
with ixekizumab for an extended time and provides for collection of longer-term safety, 
tolerability, and efficacy data for ixekizumab in JIA subtypes of ERA and JPsA. 
5.5. Justification for Dose  
The efficacy, safety, and PK data from the Phase 3 program in adults with PsA were used to 
guide the dose and dosing regimen for investigation in pediatric participants with PsA in this 
study. The adult PK model and the adult ACR exposure response model in PsA participants 
were used to simulate the expected PK and pharmacodynamic (PD) responses across a range 
of ages and weights in pediatric participants to support the selection of the weight categories, 
the doses, and the dosing frequency to be used in this study. The recommended doses have 
been selected to target exposures in pediatric participants to be within the range of exposures 
observed in the Phase 3 adult PsA and axSpA studies with the 80 mg Q2W and 80 mg Q4W 
doses, which both had a positive benefit/risk ratio. 
The dose is weight based, and it will be determined based on the participant’s weight at Visit 
2. If a participant changes weight category, dosing will not be adjusted up to Week 16 in the 
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OLT period. The dose will be adjusted according to the participant’s weight during the OLE 
period and the LTE period. 
Results from the modeling and simulation analyses support the following doses, dosing 
frequencies, and weight categories to be used in this study: 
 
 Q4W 
 
 
 Q4W 
 
 
 Q4W 
 
In addition, results have since become available from a study in which ixekizumab was 
administered to pediatric participants age 6 years to <18 years with moderate-to-severe 
psoriasis (Study RHCD). 
 
Results show that ixekizumab was efficacious across all weight categories. Mean ixekizumab 
 for the 
 dosing regimens were 
3.91 
 of the study, respectively, and compare well to the 
 reported in the adult pivotal Phase 3 psoriasis 
studies at Week 12 of 3.48 µg/mL. There were limited PK data in participants weighing 
<25 kg. 
Therefore, the pediatric psoriasis data confirms that the exposures achieved with the 
recommended dosing regimens for this study are similar to those achieved with the adult 
 
 Q4W dosing regimen. 
 Q4W dosing regimen is the recommended 
dosing regimen in adult participants with PsA and r-axSpA (AS), therefore this provides 
further support for their use in this study of JIA categories JPsA and ERA. 
Participants in the adalimumab arm (reference arm) will receive SC adalimumab at the 
following dosing regimen: 
 
 Q2W for 
 
 
 Q2W for 
 
Due to the similarities between the JIA subtypes of ERA and JPsA and because they are 
typically treated with the same therapies and doses, the same dose of adalimumab was selected 
for participants with ERA (as per the approved label) and JPsA. Because JPsA participants 
included in this study may be <6 years of age and weight <15 kg, the approved dose of 
adalimumab for the treatment of polyarticular JIA will be used in JPsA participants weighing 
10 to <15.0 kg (SmPC; EMA 2020). 
Participants treated with adalimumab who did not attain ACR 30 response at Week 16 will be 
switched to ixekizumab. As these participants are considered non-responders to adalimumab, 
a long washout period will not be required before the first ixekizumab dose, which can occur 
at a minimum 2 weeks after the last adalimumab dose. Switching from adalimumab to 
ixekizumab for a safety reason requires a washout period of sufficient length to allow the 
safety issue/parameter to resolve. To decrease potential safety risk in the transitional period, 
no higher ixekizumab starting dose will be administered to switching participants, and they 
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will receive regular ixekizumab doses according to their weight at each visit. The same dosing 
scheme will be used in participants who will switch from adalimumab to ixekizumab in the 
OLE period or at the completion of the OLE when entering the LTE at participant/caregiver’s 
or investigator’s discretion (minimum 2 weeks between the last adalimumab and first 
ixekizumab dose, no ixekizumab starting dose). 
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6. Study Population  
The study will include participants aged 2 to less than 18 years at baseline, diagnosed with JIA 
and fulfilling the ILAR classification criteria for ERA (including JoAS) or JPsA but no other 
JIA category (Petty et al. 2004). Participants classified as ERA will have to be at least 6 years 
of age, which is aligned with the classification criteria. Participants will have to have active 
disease at enrollment, defined as at least 3 active peripheral joints; active sacroiliitis or 
enthesitis may be present but are not part of the inclusion criteria. The uniform inclusion 
criteria related to disease activity will allow the use of the same composite primary endpoint, 
namely JIA ACR 30 response, in both study population subsets, ERA and JPsA, which will 
facilitate data comparison. All participants will have to have body weight of at least 10.0 kg at 
baseline, which is to comply with the dosing instructions for ixekizumab and adalimumab. For 
the participants’ safety, active uveitis, active IBD, and personal or first-degree family history of 
IBD will not be permitted at enrollment. Detailed Inclusion and Exclusion criteria are defined 
in Sections 6.1 and 6.2, respectively. The study population is expected to be representative of 
the general ERA and JpSA populations, allowing for a reliable assessment of ixekizumab 
efficacy in these 2 JIA categories, without an undue safety risk. 
Prospective approvals of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, are not permitted. 
6.1. Inclusion Criteria  
Participants are eligible to be included in the study only if they meet all of the following 
criteria at enrollment: 
Type of Participant and Disease Characteristics  
[1] 
Have a diagnosis with onset before the age of 16 years of any of the 
following categories of JIA as defined by the ILAR criteria (Petty et al. 
2004): 
 ERA 
 JPsA 
[2] 
Have at least 3 active peripheral joints at screening and baseline. Active 
peripheral joint is defined as the presence of joint swelling or, in the 
absence of swelling, joint with limitation of motion plus pain on motion 
and/or tenderness on palpation. 
Participant Characteristics  
[3] 
Participants with ERA must be from 6 to less than 18 years of age at 
screening and baseline. 
Participants with JPsA must be from 2 to less than 18 years of age 
at screening and baseline. 
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Full date of birth will be collected except in countries in which it is not 
allowed. 
[4] 
Participants must weigh at least 10.0 kg. 
[5] 
Male or nonpregnant, non-breastfeeding female participants. 
Participants of childbearing potential who are abstinent (if this is complete 
abstinence, as their preferred and usual lifestyle). 
Total abstinence is defined as refraining from intercourse during the entirety 
of the study and for at least 12 weeks following the last dose of 
investigational product. Periodic abstinence such as calendar, ovulation, 
symptothermal, post ovulation methods, and withdrawal are not acceptable 
methods of contraception. 
Otherwise, participants and their partners of childbearing potential must 
agree to use 2 effective methods of contraception, where at least 1 form is 
highly effective for the entirety of the study and for at least 12 weeks 
following the last dose of ixekizumab. Participants and their partners of 
childbearing potential must agree to use contraception for 5 months after the 
last dose of adalimumab. 
The following contraception methods are considered acceptable (the 
participant, and their partner, should choose 2, and 1 must be highly 
effective [defined as less than 1% failure rate per year when used 
consistently and correctly]): 
 Highly effective birth control methods: 
o Combined (estrogen- and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation: oral, intravaginal, or transdermal 
o Progestogen-only hormonal contraception associated with inhibition 
of ovulation: oral, intravaginal, or implantable 
o Intrauterine device/intrauterine hormone releasing system 
o Vasectomized partner (with appropriate post 
vasectomy documentation of the absence of sperm in 
the ejaculate). 
 Effective birth control methods: 
o Male or female condom with spermicide. It should be noted that 
the use of male and female condoms as a double barrier method is 
not considered acceptable due to the high failure rate when these 
methods are combined. 
o Diaphragm with spermicide 
o Cervical sponge 
o Cervical cap with spermicide 
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Note: When local guidelines concerning highly effective or effective 
methods of birth control differ from the above, the local guidelines must be 
followed. 
Adolescent females who have started menses (even 1 cycle and any amount of 
spotting) are considered to be of childbearing potential. 
Women of nonchildbearing potential are not required to use birth control and 
they are defined as: 
 Women who are infertile due to surgical sterilization (hysterectomy, 
bilateral oophorectomy, or tubal ligation) and congenital anomaly such as 
Müllerian agenesis. 
[6] 
All immunizations (live vaccines) are up-to-date in agreement with 
current immunization guidelines as noted by country specific pediatric 
authorities. 
Informed Consent  
[7] 
Both the child or adolescent and a parent or legal guardian are able to 
understand and fully participate in the activities of the clinical study and 
sign their assent and consent, respectively, in accordance to local 
guidelines. 
 
6.2. Exclusion Criteria  
Participants will be excluded from study enrollment if they meet any of the following criteria 
at enrollment: 
Medical Conditions  
[8] Fulfill the ILAR classification criteria for any other JIA category than ERA or JPsA. 
[9] Have active or a history of IBD or history of IBD in a first degree relative: Crohn’s 
disease, ulcerative colitis or undifferentiated IBD. 
[10] Have evidence of active uveitis within 4 weeks prior to baseline. 
Note: These participants may be rescreened only one time ≥4 weeks after 
resolution of acute symptoms. 
[11] Have active fibromyalgia or other chronic pain condition or musculoskeletal 
disease that, in the investigator’s opinion, would make it difficult to appropriately 
assess disease activity for the purposes of this study. 
[12] Had a serious infection (e.g., pneumonia, cellulitis), have been hospitalized, have 
received intravenous antibiotics for an infection within 12 weeks prior to baseline 
(Week 0; Visit 2), had a serious bone or joint infection within 24 weeks prior to 
baseline, have ever had an infection of an artificial joint, or are 
immunocompromised to an extent that participation in the study would pose an 
unacceptable risk to the participant. 
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[13] Have or had herpes zoster or other clinically apparent varicella-zoster virus 
infection within 12 weeks prior to baseline. 
[14] Have a positive test for HBV at screening defined as: 
 positive for HBsAg or 
 positive for HBcAb and positive for HBV DNA 
Note: Participants who are HBsAg-, and HBcAb+ and HBV DNA negative 
may be enrolled in the study. Participants who meet these criteria at screening 
will be identified by the central laboratory and monitored during the study as 
detailed in Section 9.4.11.2. 
[15] Have HCV infection (hepatitis C antibody-positive and confirmed presence of 
HCV RNA. 
[16] Have or had an infection typical of an immunocompromised host and/or that 
occurs with increased incidence in an immunocompromised host (including but 
not 
limited 
to 
Pneumocystis 
jiroveci 
pneumonia, 
histoplasmosis, 
or 
coccidioidomycosis) or have a known immunodeficiency. 
[17] Have had household contact with a person with active TB and did not 
receive appropriate and documented prophylaxis for TB. 
[18] Have evidence of active TB or latent TB. 
[19] Major surgery within 8 weeks prior to screening or requiring major surgery during 
the study that in the opinion of the investigator in consultation with Lilly or its 
designee would pose an unacceptable risk to the participant. 
[20] Have had surgical treatment of a joint within 8 weeks prior to randomization or 
will require such up to Week 16. 
[21] History or presence of cardiovascular, respiratory, hepatic, gastrointestinal, 
endocrine, hematological, neurological, or neuropsychiatric disorders or any other 
serious and/or unstable illness that, in the opinion of the investigator, could 
constitute an unacceptable risk when taking investigational product or interfere 
with the interpretation of data. Participants with moderate to severe heart failure 
(New York Heart Association class III/IV) are not eligible for the study. 
[22] Largely or wholly incapacitated, such as being bedridden. 
[23] History of lymphoproliferative disease, or have signs or symptoms of 
lymphoproliferative disease, within 5 years prior to baseline; or have active or 
history of malignant disease within 5 years prior to baseline. 
[24] History of chronic alcohol abuse, intravenous drug abuse, or other illicit drug 
abuse within the 2 years prior to screening. 
[25] Presence of significant uncontrolled neuropsychiatric disorder that, in the opinion 
of the investigator, poses an unacceptable risk to the participant if participating in 
the study or of interfering with the interpretation of data; are, in the judgment of 
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the investigator, actively suicidal and therefore deemed to be at significant risk 
for suicide. 
[26] Have answered “yes” to either Question 4 or Question 5 on the “Suicidal Ideation” 
portion of the Columbia Suicide Severity Rating Scale (C-SSRS) or have 
answered “yes” to any of the suicide-related behaviors on the “suicidal behavior” 
portion of the C-SSRS, and the ideation or behavior occurred within the past 
month. 
[27] History of hypogammaglobulinemia or a serum Ig (IgG, IgM, or IgA) 
concentration less than the lower limit of normal of the reference range. 
[28] Body temperature ≥38°C (100.5°F) at baseline. 
[29] Have a known allergy or hypersensitivity to any biologic therapy (active substance 
or excipients) that would pose an unacceptable risk to the participant if 
participating in this study. 
Prior/Concomitant Therapy  
[30] Have used or is using any therapeutic agent targeted at reducing IL-17. 
[31] Have initiated concomitant csDMARDs (such as, but not limited to, MTX, 
sulfasalazine (SSZ), and leflunomide) within 12 weeks prior to baseline or changed 
the dose within 8 weeks prior to baseline. The dose of csDMARDs is expected to 
remain stable throughout the OLT period and may only be adjusted for safety 
reasons. 
[32] Concurrent use of any biologic agent (bDMARD) including: adalimumab <28 
days, anakinra and etanercept within <14 days; abatacept <90 days; infliximab, 
certolizumab pegol, or alefacept <60 days; golimumab <90 days; rituximab 
<12 months; or any other biologic agent or small molecule (targeted synthetic 
DMARD) <5 half-lives prior to baseline (Week 0; Visit 2). 
[33] MTX use at doses of >0.65 mg/kg/week or sulfasalazine at doses >30 mg/kg/day. 
[34] Are currently receiving concomitant treatment with a combination of ≥2 
csDMARDs (including MTX). 
[35] Prior treatment with analgesics, including NSAIDs, on an unstable dose 
within 1 week of baseline. 
[36] Prior treatment with any parenteral corticosteroid administered by intra-
articular, intramuscular, or intravenous injection within 4 weeks of baseline. 
[37] Oral corticosteroid use at average daily doses of greater than 10 mg/day or 
0.2 mg/kg/day prednisone equivalent, whichever is less, or have done so within 
2 weeks prior to screening. If continuing oral corticosteroids, must be on stable 
dose for 4 weeks prior to baseline. 
[38] Had a live vaccination within 12 weeks prior to baseline (Week 0, Visit 2), 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 
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within 12 weeks prior to baseline. 
Prior/Concurrent Clinical Trial Experience  
[39] Currently enrolled in any other clinical study involving an investigational product 
or any other type of medical research judged not to be scientifically or medically 
compatible with this study. 
[40] Discontinued within 30 days of study entry from any other clinical study involving 
an investigational product or any other type of medical research judged not to be 
scientifically or medically compatible with this study. 
[41] If the previous investigational product has a long half-life, 5 half-lives or 30 
days (whichever is longer) should have passed. 
[42] Previously completed or withdrawn from this study or any other study 
investigating ixekizumab. 
Laboratory Assessments  
[43] Have any of the following specific abnormalities on screening 
laboratory tests: 
 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2 
× upper limit of normal (ULN) 
 Total bilirubin level (TBL) ≥1.5 × ULN 
 Alkaline phosphatase (ALP) ≥2 × ULN 
 Hemoglobin <10.0 g/dL (100.0 g/L) 
 Total white blood cell (WBC) count <3000 cells/L (<3.00 × 103/L or 
<3.00 billion/L) 
 Neutropenia (absolute neutrophil count [ANC] <1500 cells/L) (<1.50 
× 103/L or <1.50 billion/L) 
 Lymphopenia (lymphocyte count <1000 cells/L) (<1.00 × 103/L or 
<1.00 billion/L) 
 Thrombocytopenia (platelet count <100,000/L) (<100 × 103/L or 
<100 billion/L) 
In the case of any of the aforementioned laboratory abnormality, the test may 
be repeated once during screening, and values resulting from repeat testing 
may be accepted for enrollment eligibility if they meet the eligibility criterion. 
[44] Screening laboratory test values outside the reference range for the population or 
investigative site that, in the opinion of the investigator, pose an unacceptable risk 
for the participant’s participation in the study. 
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Other Exclusions  
[45] Donated blood, bone marrow or stem cells within 4 weeks prior to screening or 
intend to donate during the course of the study. 
[46] Are immediate family of investigator or site personnel directly affiliated with 
this study. Immediate family is defined as a spouse, parent, child or sibling, 
whether biological or legally adopted. 
[47] Are Lilly employee’s immediate family. Immediate family is defined as a 
spouse, parent, child or sibling, whether biological or legally adopted. 
[48] Are unwilling or unable to comply with the use of a data collection instrument 
to directly record data from the participant and/or legal guardian. 
 
6.2.1. Rationale for Exclusion of Certain Study Candidates  
The rationale for the exclusion criteria is as follows: 
Exclusion Criteria [8] to [11] exclude individuals with conditions that may confound safety or 
efficacy analyses. 
Exclusion Criteria [12] to [18] exclude individuals who are at an increased risk for infections 
or infectious complications. 
Exclusion Criteria [19] to [29] exclude individuals with previous or concomitant 
medical conditions that increase the risk for their participation in the study. 
Exclusion Criteria [30] to [38] exclude individuals who are taking or who may take JIA 
medications or treatments that may interfere with the ability to assess the safety and efficacy 
of ixekizumab. 
Exclusion Criteria [39] to [42] exclude individuals whose participation in the study may 
introduce bias. 
Exclusion Criteria [43] to [44] exclude individuals with laboratory parameters that may 
increase the risk for their participation in the study. 
Exclusion Criteria [45] to [48] exclude individuals whose participation in the study may 
introduce bias. 
6.3. Lifestyle Restrictions  
Not applicable. 
 
6.4. Screen Failures  
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
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eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be re-screened. Re-screened participants should be assigned a new participant number. 
When re-screening, the screening tests and procedures should be repeated. Those who test 
positive for latent TB at screening or who have a documented history of a positive TB test 
but no documented history of at least 4 weeks of appropriate latent TB treatment, may be 
re-screened following appropriate treatment. Other reasons for re-screening must be 
discussed, approved, and documented by the Lilly Medical Team (Clinical Research 
Scientist [CRS]/Clinical Research Physician). 
Individuals may be rescreened 1 time. The interval between rescreenings should be at 
least 4 weeks. Individuals who are to be rescreened must first sign a new ICF/assent 
form as applicable (Appendix 3). Such individuals will be assigned a new participant 
number. 
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7. Treatments  
 
7.1. Treatments Administered  
Study treatment is defined as any medicinal product(s) or medical device(s) intended to be administered to or used by a study 
participant according to the study protocol. 
This study involves administration of ixekizumab by SC injection Q4W or adalimumab by SC injection Q2W. The ixekizumab and 
adalimumab doses in this study are based on weight (Table RHCG.7.1). 
Table RHCG.7.1. 
Treatment Regimens 
 
Regimen 
Dos
e 
We
ek 0 
Dose 
Open-Label 
Treatment Period 
(Week 2 to Week 
14) 
Dose 
Open-Label Extension 
Treatment Period 
(Week 16 to Week 104) 
Dose 
Long Term 
Extension 
Treatment 
Period (Week 
104 to Week 264) 
Authorized as 
defined by EU 
Clinical Trial 
Regulation 
Ixekizumab 
 
 
 SC 
injections) 
 Q4W SC 
injection 
 Q4W SC 
injection 
 Q4W SC 
injection 
Authorized and 
not used 
according to EU 
marketing 
authorization 
Ixekizumab 
 
 SC 
injection 
 Q4W SC 
injection 
 Q4W SC 
injection 
 Q4W SC 
injection 
Authorized and 
not used 
according to EU 
marketing 
authorization 
Ixekizumab 
 
 SC 
injection 
 Q4W SC 
injection 
 Q4W SC 
injection 
 Q4W SC 
injection 
Authorized and 
not used 
according to EU 
marketing 
authorization 
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Adalimumab 
 
 SC 
injection 
 Q2W SC 
injection 
Respondera: Adalimumab 
 Q2W 
SC injection 
Non-responders or 
participants opting to switch 
to ixekizumaba: Appropriate 
dose according to weight 
Q4W (without a 
starting dose). 
All adalimumab 
participants will switch 
to ixekizumab. 
Appropriate dose 
according to weight 
Q4W (without a starting 
dose). Participants who 
are not switching to 
ixekizumab will undergo 
ETV at Visit 29 (Week 
104). 
Authorized and not used 
according to EU 
marketing authorization 
Adalimumab 
 
 
 SC 
injection 
 Q2W SC 
injection 
Respondersa: Adalimumab 
 Q2W 
SC injection 
Non-responders or 
participants opting to switch 
to ixekizumaba: Appropriate 
dose according to weight 
Q4W (without a starting
 
dose). 
Adalimumab 
 
Authorized and not used 
according to EU 
marketing authorization 
 
Abbreviations: ACR 30 = 30% improvement in American College of Rheumatology criteria; JIA = juvenile idiopathic arthritis; OLE = open-label 
extension; OLT = open-label treatment; Q2W = every 2 weeks; Q4W = every 4 weeks; SC = subcutaneous. 
a Participants receiving adalimumab during the OLT period who did NOT attain a JIA ACR 30 response at Week 16 will be switched to ixekizumab in the OLE 
period. Participants receiving adalimumab during the OLT period who did attain a JIA ACR 30 response at Week 16 will be given the option to switch or 
not to switch to ixekizumab in the OLE period. The decision to switch for participants who achieved a JIA ACR 30 response will be left to the 
participant/participant’s caregiver and investigator. A switch from adalimumab to ixekizumab during the OLE period may also occur at any other visit after 
Week 16 based on the participant/patent’s caregiver and investigator’s decision. 
Note: When switching from adalimumab to ixekizumab, the participant will not receive the ixekizumab starting dose, but will receive the appropriate 
ixekizumab dose per the participant’s weight. The minimum required period between the last dose of adalimumab and first dose of ixekizumab is 2 weeks. 
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This study involves administration of ixekizumab and adalimumab (as a reference arm) 
by SC injection. 
Ixekizumab doses will be prepared by study site personnel. All doses will be 
administered on site. The study drug should be at room temperature when injected. 
Possible injection sites include the abdomen, thigh, and upper arm (using the arm 
contralateral for blood samples for PK). The injection site should not be in a psoriatic 
lesion and should be rotated to another area for subsequent doses at the same visit as well 
as the next visit. 
Dosing  
The selected ixekizumab doses are: 
1) 
 Q4W 
 
2) 
 Q4W 
 
3) 
 Q4W 
 
 
Post-Administration Observation  
Participants should remain under observation for at least 1 hour after the first dose to 
monitor for safety. Following the first injection, and if no problems occur with that 
injection, participants will be observed for 30 minutes following injection at all other 
study visits. 
 
Participants initiating treatment with ixekizumab at Week 0 (Visit 2) will receive the 
starting dose. The participants switching from adalimumab to ixekizumab during the 
study (starting at Week 16) will not receive the starting dose but will receive the 
appropriate regular dose according to their weight at each visit. Switching participants 
from the adalimumab to ixekizumab dosing treatment regimen should follow the post-
administration observation guidelines. 
Participants requiring the starting dose of 
 of ixekizumab will receive 
 
SC injections. Participants requiring the starting doses of 
 of 
ixekizumab will receive 1 SC injection, except for participants with a body weight of 
 who will receive the starting dose of 40 mg in 
 
 These 2 injections will be separated by a minimum of 60 minutes. As per 
previous instructions in the protocol, the second 
 of ixekizumab will 
require a 30-minute observation period after the administration. 
Participants requiring a lower dose of ixekizumab will have the dose prepared by 
 
 
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The selected adalimumab doses are: 
1) 
 Q2W for 
 
2) 
 Q2W for 
 
For training purposes, the proper procedures for the administration of the initial injection 
of adalimumab will be performed by clinical staff at Week 0 (Visit 2). Each participant or 
participant’s caregiver must return to the clinical site for all injections and to be trained to 
inject adalimumab under the supervision of the investigator staff until the investigator 
judges the participant or participant’s caregiver sufficiently competent to perform the 
injections independently. After this time, the participant or the participant’s caregiver will 
be allowed to inject adalimumab at home. 
 
 
The investigator or his/her designee is responsible for the following: 
 explaining the correct use of the investigational agent(s) to the participant or 
participant’s caregiver; 
 verifying that instructions are followed properly; 
 maintaining accurate records of investigational product dispensing and collection; and 
 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. 
 
7.1.1. Packaging and Labelling  
The study drug will be supplied by the sponsor in accordance with current good 
manufacturing practices (cGMP). 
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. Participants weighing >25 kg to <50.0 kg can opt 
for at-home administration when 40 mg prefilled syringe is available for the trial. 
Adalimumab (originator or biosimilar) will be supplied by the sponsor or its designee 
in accordance with cGMP. Adalimumab will be supplied in 2 presentations to be 
administered based on participant’s weight: 
 20 mg in a single-use prefilled syringe, or 
 40 mg in a single-use prefilled syringe. 
Syringes will be supplied in cartons, with the appropriate quantity of syringes specific to 
the planned dispensing schedule of the study drug. Clinical study materials will be 
labeled according to the country’s regulatory requirements. All study drugs will be 
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stored, inventoried, reconciled, and destroyed according to applicable regulations. 
7.2. Method of Treatment Assignment  
Participants who meet all criteria for enrollment will be randomized or assigned, as 
appropriate, to treatment at Visit 2. Participants who are bDMARD-naive will be 
randomized to ixekizumab or adalimumab in a 1:1 ratio. At least 20 participants will be 
randomized to ixekizumab and 20 participants to adalimumab. Randomization will be 
stratified based on the category of JIA (ERA or JPsA). The remaining participants 
(approximately 60 participants) who are bDMARD-naive or bDMARD-IR will be 
assigned to ixekizumab. In practice, this will be accomplished by randomizing the first 40 
bDMARD-naive participants entering the study according to the ratio and stratification 
described above, with all the subsequent bDMARD-naive participants being assigned to 
ixekizumab. 
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 cartons containing investigational product to each participant. Site personnel will 
confirm that they have located the correct cartons by entering a confirmation number 
found on the cartons into the IWRS before dispensing to participants. 
In the OLE period, all participants who were receiving ixekizumab in the OLT period 
will continue to receive ixekizumab for approximately 88 weeks. 
Participants receiving adalimumab during the OLT period who did NOT attain a JIA 
ACR 30 response at Week 16 will be switched to ixekizumab in the OLE period. 
Participants receiving adalimumab during the OLT period who did attain a JIA ACR 30 
response at Week 16 will be given the option to switch or not to switch to ixekizumab 
in the OLE period. The decision to switch for participants who achieved a JIA ACR 30 
response will be left to the participant/participant’s caregiver and investigator. A switch 
from adalimumab to ixekizumab during the OLE period may also occur at any other 
visit after Week 16 based on the participant/participant’s caregiver and investigator’s 
judgment. All participants who enter into the LTE will receive ixekizumab. 
7.2.1. Selection and Timing of Doses  
Participants will be randomized to treatment or will receive their assigned study drug as 
outlined in Sections 7.1 and 7.2. 
The doses will be administered at approximately the same time on each day. For 
injections that are missed and not administered on the scheduled day of the week, the 
missed dose should be administered within 5 days of the originally scheduled day. Dates 
of subsequent study visits should not be modified according to the delay of the injection 
of the missed scheduled dose. 
The actual time of all dose administrations will be recorded in the participant’s case report 
form (CRF). 
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7.3. Blinding  
This is an open-label study. 
7.4. Dosage Modification  
During the OLT period, participants will receive either ixekizumab or adalimumab based 
on their Week 0 (Visit 2) weight category and are not allowed to modify the treatment 
regimen up to Week 16. During the OLE period, all participants will receive ixekizumab or 
adalimumab based on each visit weight, which means that the dose will be adjusted 
according to weight category throughout the period as needed. 
During the LTE period, all participants will receive ixekizumab based on their weight 
at each visit, which means that the dose will be adjusted according to weight category 
throughout the period as needed. No other modifications of dose are permitted. 
7.5. Preparation/Handling/Storage/Accountability  
Study drug will be supplied by Lilly or its representative in accordance with cGMP and 
will be supplied with lot numbers, expiration dates, and certificates of analysis, as 
applicable. 
The study drug should be stored as stated on the label. Sites will be required to 
monitor temperature of the on-site storage conditions for the study drug. 
 The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
 Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labelled storage 
conditions with access limited to the investigator and authorized site staff. 
 The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study intervention accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 
 Further guidance and information for the final disposition of unused study 
interventions are provided in the Pharmacy Manual. 
Instructions for the administration of adalimumab will be provided by the sponsor. 
 
7.6. Treatment Compliance  
Every attempt will be made to select participants/caregivers who have the ability to 
understand and comply with instructions. The investigator is responsible for discussing 
methods with the participant and caregiver before randomization to ensure high 
treatment compliance. 
Ixekizumab: Throughout the study, site personnel will record information about injections 
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in the Study Drug Administration Logs, including the date, time, and anatomical location 
of administration of study drug (for treatment compliance); syringe number; who prepared 
and administered the study drug; and the reason if study drug was not fully administered. 
Adalimumab: The participant or caregiver will record information in a Study Drug 
Administration Log, including the date, time, and anatomical location of administration 
of adalimumab (for treatment compliance); carton number; who administered the 
investigational product; and the reason if investigational product was not fully 
administered. 
Participant compliance with the study drug will be assessed at each visit. Compliance will 
be assessed by the number of injections needed versus the number of injections 
administered to the participants. Deviation(s) from the prescribed dosage regimen should 
be recorded in the CRF. 
7.7. Concomitant Therapy  
All concomitant medication taken during the study must be recorded on the 
Concomitant Medication electronic case report form (eCRF). 
Participants will be instructed to consult the investigator or other appropriate study 
personnel at the site before taking any new medications or supplements during the study. 
Additional drugs are to be avoided unless required to treat AEs or for the treatment of an 
ongoing medical condition. If the need for concomitant medication arises for an AE or 
for appropriate medical management, the investigator should base decisions on the 
participant and clinical factors. Any additional medication, whether prescription or over-
the-counter, used at baseline (Week 0; Visit 2) and/or during the course of the study, 
must be documented with the start and stop dates on the Concomitant Medications eCRF 
(Section 9.4). 
Treatment with concomitant JIA therapies during the study is permitted only as described 
below. The dosages of concomitant treatment may be adjusted during the OLT period only 
for safety reasons. After the completion of OLT, the concomitant medications may be 
adjusted based on the discretion of the investigator. 
 Chronic stable use of oral corticosteroids is permitted and defined as daily doses of 
10 mg/day or 0.2 mg/kg/day prednisone equivalent, whichever is less. 
Participants must be on a stable dose for at least 2 weeks prior to screening and 4 
weeks prior to baseline and remain on the same dose throughout the OLT period 
study. Participants should not receive other systemic corticosteroids during the 
study including intra- muscular or intra-articular corticosteroids. Topical, 
intranasal, intra-ocular, and inhaled corticosteroids are permitted. 
 Chronic stable use of MTX or SSZ is permitted and defined as MTX dose of 
≤0.65 mg/kg/week (with a maximum dose of 25 mg/week) or SSZ dose of 
≤30 mg/kg/day (with a maximum dose of 3 g/day). Participants must initiate MTX or 
SSZ at least 
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12 weeks prior to baseline and remain on the same dose at least 8 weeks prior to 
baseline and throughout the OLT period study. The dose may only be adjusted for 
safety reasons. Local standard of care should be followed for concomitant 
administration of folic acid. 
 Chronic stable usage of csDMARDs (other than MTX or SSZ) is permitted if 
initiated at least 12 weeks prior to baseline and unchanged within 8 weeks prior to 
baseline. 
 Concomitant usage of 2 or more csDMARDs (including MTX) is not allowed. 
 Chronic stable use of NSAIDs and analgesics is permitted. Participants must be on 
a stable dose for at least 1 week prior to baseline and throughout the OLT period; 
dose reductions and/or termination of NSAIDs and analgesics are permitted for 
safety reasons. 
 Beginning with Week 20/Visit 8, intra-articular joint and bursal corticosteroid 
injections may be given at doses and intervals at the investigator’s discretion. 
Injected joints will be considered active joints for the remainder of the study and 
for efficacy assessments. 
The following therapies will not be permitted during the course of the study as specified 
in the exclusion criteria (Section 6.2): 
 bDMARDs 
 Targeted synthetic DMARDs or small molecules, including but not limited to 
janus kinase (JAK) inhibitors and apremilast 
 Live vaccines are not recommended within 12 weeks prior to baseline or during 
the course of the study. The investigator may base any decisions about live 
vaccinations on a benefit-risk assessment. Use of nonlive seasonal vaccinations 
and/or emergency vaccinations (such as rabies or tetanus vaccinations) is allowed. 
Note: With the exception of live vaccines, no adjustment to the vaccination 
schedule is required. 
Only for participants who discontinued study treatment and have entered the PTFU 
period, JIA therapy with another agent previously excluded during the treatment period 
of the study may be allowed, as determined appropriate by the investigator and approved 
by Lilly medical. 
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Table RHCG.7.2. Concomitant JIA Therapies 
 
Drug Class 
As Needed 
Chronic Use 
Conditions for Use 
MTXa 
No 
Yes 
If on MTX, must be on a stable average dose of 
0.65 mg/kg/week (maximum dose 25 mg/week) for 
12 weeks prior to baseline and unchanged dose within 
8 weeks prior to baseline and throughout OLT period 
(until Week 16)b. 
SSZa 
No 
Yes 
If on SSZ, must be on a stable average dose of 
≤30 mg/kg/day (maximum dose 3 g/day) for 12 weeks 
prior to baseline and unchanged dose within 8 weeks prior 
to baseline and throughout OLT period (until Week 16)b. 
csDMARDs other than 
MTX or SSZa 
No 
Yes 
If receiving csDMARDs (other than MTX or SSZ), must 
be on a stable dose for 12 weeks prior to baseline and 
unchanged dose within 8 weeks prior to baseline and 
throughout OLT period (until Week 16)b. 
Oral corticosteroids 
No 
Yes 
If receiving oral corticosteroids, daily dose must be 
10 mg/day or 0.2 mg/kg/day prednisone equivalent, 
whichever is less. Must be on stable dose for at least 
2 weeks prior to screening and 4 weeks prior to baseline 
and throughout OLT period (until Week 16)b. 
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Drug Class 
As Needed 
Chronic Use 
Conditions for Use 
NSAIDs including 
cyclooxygenase-2 
inhibitors 
No 
Yes 
Must be on stable dose at least 1 week prior to baseline 
and throughout OLT period (until Week 16)b. 
Analgesics 
No 
Yes 
Must be on stable dose at least 1 week prior to baseline 
and throughout OLT period (until Week 16)b. 
Permitted analgesics include: 
 
acetaminophen 
 
opioids (e.g., tramadol, codeine, or morphine) 
 
local anesthetics (e.g., lidocaine), and 
 
topical anesthetics 
Abbreviations: csDMARD = conventional synthetic disease-modifying antirheumatic drug; MTX = 
methotrexate; NSAID = nonsteroidal anti-inflammatory drug; OLT = open-label treatment; SSZ = 
sulfasalazine. 
a Concomitant use of ≥2 of any csDMARDs is not allowed. 
b Dose adjustments may only be made for safety reasons during OLT period (until Week 16). 
7.8. Treatment After the End of the Study  
7.8.1. Study Extensions  
Participants who complete the OLT and OLE periods of this study will be eligible to 
participate in the open-label LTE part of this study. 
7.8.2. Treatment After Study Completion  
Ixekizumab will not be made available to participants after conclusion of the study. 
Adalimumab will be made available to participants until Week 104. After Week 104, 
all adalimumab participants will be assigned to ixekizumab or will end participation in 
the study. 
7.9. Special Treatment Considerations  
Participants will be screened for eligibility in the study as described in Sections 6.1 and 
6.2  will be informed of the study-specific restrictions and requirements of the study. 
Participants/ caregivers who are not willing to comply with the study restrictions and 
requirements of the study will not be eligible for enrollment. 
All biologic agents carry the risk of systemic allergic/hypersensitivity 
reactions. Clinical manifestations of these reactions may include, but are 
not limited to: 
 skin rash, 
 pruritus (itching), 
 urticaria (hives), 
 angioedema (e.g., swelling of the lips and/or tongue), and 
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 anaphylactic reaction. 
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data describing each symptom should be 
provided to the sponsor in the eCRF. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study drug. It is recommended that 
participants who experience a systemic hypersensitivity reaction be treated per the local 
standard of care. 
For an event judged by the investigator to be a potential systemic allergic/hypersensitivity 
reaction, a blood sample is to be drawn as soon as possible to test for antidrug antibodies 
(ADAs) (Section 9.6.1). 
This study involves administration of ixekizumab and adalimumab (as a reference arm) by 
SC injection. During the OLT period, bDMARD-naive participants will receive either 
ixekizumab or adalimumab based on their Week 0 (Visit 2) weight category. Due to 
ixekizumab and adalimumab dosing guidance for the pediatric population, participants 
must have a weight ≥10.0 kg at baseline. 
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8. Discontinuation Criteria  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 3. 
8.1. Discontinuation from Study Treatment  
When necessary, a participant may be permanently discontinued from study intervention. 
If so, the participant will remain in the study to complete procedures for an early 
discontinuation visit and PTFU, if applicable. 
8.1.1. Permanent Discontinuation from Study Treatment  
Possible reasons leading to permanent discontinuation of investigational product: 
 Participant decision: 
o the participant or the participant’s designee, for example parents or legal 
guardian, requests to discontinue investigational product. 
 Discontinuation due to a hepatic event or liver test abnormality. Participants who 
are discontinued from investigational product due to a hepatic event or liver test 
abnormality should have additional hepatic safety data collected via the hepatic 
safety eCRF. 
 Discontinuation of the investigational product for abnormal liver tests should be 
considered by the investigator when a participant meets one of the following 
conditions after consultation with Lilly Medical. 
 In study participants with normal or near normal baseline liver tests (ALT, AST, ALP 
<1.5 × ULN), the study drug should be interrupted and close hepatic monitoring 
initiate (see Appendix 4) if one or more of these conditions occur: 
 
Elevation 
Exception 
ALT or AST >8 × ULN 
ALT or AST >5 × ULN for more than 2 weeks 
ALT or AST >3 × ULN and either TBL >2 × ULN or INR >1.5 
For participants with Gilbert’s syndrome: 
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2 × ULN. 
ALT or AST >3 × ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
ALP >3 × ULN, when the source of increased ALP is the liver 
ALP >2.5 × ULN and TBL >2 × ULN 
For participants with Gilbert’s syndrome: 
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL>2 × ULN. 
ALP >2.5 × ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
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Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; INR = international normalized ratio; TBL = total bilirubin level; ULN = upper 
limit of normal. 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 
  and other consensus guidelines, with minor modifications. 
 
 
 
Interrupting study drug based on elevated liver tests in participants with abnormal baseline 
liver tests  
o In study participants with abnormal baseline liver tests (ALT, AST, ALP 
≥1.5 × ULN), the study drug should be interrupted if one or more of 
these conditions occur: 
 
Elevation 
Exception 
ALT or AST >4 × baseline 
ALT or AST >3 × baseline for more than 2 weeks 
ALT or AST >2 × baseline and either TBL >2 × ULN or 
INR >1.5 
For participants with Gilbert’s syndrome: 
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2 × ULN. 
ALT or AST >2 × baseline with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (>5%) 
ALP >2.5 × baseline, when the source of increased ALP is the 
liver 
ALP >2 × baseline and TBL >2 × ULN 
For participants with Gilbert’s syndrome: 
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2 × ULN. 
ALP >2 × baseline with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = 
aspartate aminotransferase; TBL = total bilirubin level; ULN = upper limit of 
normal. 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 
  2009 and other consensus guidelines, with minor modifications. 
 
 
 
Resuming study drug after elevated liver tests  
o Resumption of the study drug can be considered only in consultation with 
the Lilly-designated medical monitor and only if the liver test results return 
to baseline and if a self-limited nondrug etiology is identified. Otherwise, 
the study drug should be discontinued. 
In addition, patients will be discontinued from the study drug under the following 
circumstances: 
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 Neutrophil (segmented) counts: 
o <500 cells/L 
o ≥500 and <1000 cells/L (based on 2 test results; the second test performed 
within 1 week from knowledge of the initial result) 
o ≥1000 and <1500 cells/L (based on 3 test results) and an infection that is 
not fully resolved 
o white blood cell count <1000 cells/L (1.00 × 103/L or 1.00 billion/L) 
o lymphocyte count <200 cells/L (0.20 × 103/L or 0.20 billion/L) 
o platelet count <50,000 cells/μL 
Note: Temporary interruption rules (see Section 8.1.2) must be followed where 
applicable. For laboratory values that meet permanent discontinuation thresholds, 
investigational product should be discontinued. However, if in the opinion of the 
investigator the laboratory abnormality is due to intercurrent illness such as 
cholelithiasis or another identified factor, laboratory tests may be repeated. Only 
when the laboratory value meets resumption thresholds following the resolution of 
the intercurrent illness or other identified factor may the investigator restart 
investigational product after consultation with Lilly Medical. 
In addition, participants will be discontinued from the investigational product 
in the following circumstances: 
 The participant experiences a severe AE or SAE or has a clinically significant 
change in a laboratory value that, in the opinion of the investigator, merits 
discontinuation of the study drug and appropriate measures being taken. This 
includes evidence of active viral hepatitis or active TB. In such cases, Lilly or its 
designee is to be notified immediately. 
 Clinically significant systemic hypersensitivity reaction following SC 
administration of study drug that does not respond to symptomatic medication or 
results in clinical sequelae. 
 The participant becomes pregnant. 
 The participant develops malignancy. 
 The participant has a positive TB test using QuantiFERON®-TB Gold or T-Spot 
or PPD and is assessed as having latent TB infection (see Section 9.4.5), and/or 
develops symptoms or signs of tuberculosis. 
 The participant develops IBD. 
 The participant 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. 
 Note: It is recommended that the participant be assessed by an appropriately 
trained professional (e.g., psychiatrist, clinical psychologist, social worker 
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etc.) to assist in deciding whether the participant is to be discontinued from 
the study. 
 If the investigator, after consultation with Lilly Medical, determines that a 
systemic hypersensitivity reaction has occurred related to study drug 
administration, the participant should be permanently discontinued from the 
investigational drug. 
Participants discontinuing from the investigational product prematurely for any reason 
should complete adverse event and other follow-up procedures per Section 2 (Schedule 
of Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety) of this protocol. 
8.1.2. Temporary Discontinuation from Study Treatment  
In some circumstances, participants may need to temporarily interrupt treatment as a 
result of AEs or abnormal laboratory values that may have an unclear relationship to 
investigational product. See Section 9.4.5 for details regarding managing participants 
who test positive for TB at any time during the study. 
Participants 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, and resume administration of the investigational product only after complete 
wound healing. 
8.2. Discontinuation from the Study  
A participant may withdraw from the study: 
 at any time at his/her own request 
 at the request of his/her designee (for example, parents or legal guardian) 
 at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons 
 if the participant becomes pregnant during the study 
 if enrollment in any other clinical study 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) 
 if the participant, 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 
Discontinuation is expected to be uncommon. 
At the time of discontinuing from the study, if possible, an early discontinuation visit 
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should be conducted, as shown in the Schedule of Activities (Section 2). See Schedule of 
Activities for data to be collected at the time of study discontinuation and follow-up and 
for any further evaluations that need to be completed. The participant will be 
permanently discontinued both from the study intervention and from the study at that 
time. 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. If a 
participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
8.3. Lost to Follow-Up  
A participant 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 participants who fail to return for a 
scheduled visit or were otherwise unable to be followed up by the site. 
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including 
those who did not get investigational product. Public sources may be searched for vital 
status information. If vital status is determined, this will be documented, and the 
participant will not be considered lost to follow-up. 
Lilly personnel will not be involved in any attempts to collect vital status information. 
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9. Study Assessments and Procedures  
Section 2 lists the Schedule of Activities, with the study procedures and their timing 
(including tolerance limits for timing). 
Appendix 2 lists the laboratory tests that will be performed for this study. The joint 
assessor (or designee) should be a rheumatologist or skilled joint assessor and will be 
responsible for completing the joint counts for swelling, tenderness, and limited range of 
motion. Additionally, the assessor will perform the following assessments: Physician’s 
Global Assessment of Disease Activity, PASI, BSA, Enthesitis and Dactylitis assessment, 
Clinical Sacroiliitis, Back Mobility (Schober’s test), and Uveitis Evaluation. To ensure 
consistent joint evaluation throughout the study, individual participants should be 
evaluated by the same assessor for all study visits whenever possible. 
Investigators or relevant clinical staff will provide age-appropriate explanations to all 
children prior to any assessment or procedure. 
Staff trained or experienced in pediatric phlebotomy should perform blood draws at the 
clinic. Blood draws should be consolidated, and the number of attempts should be kept to 
the minimum number required. The number of sampling attempts should be minimized, in 
keeping with local guidelines and procedures. For example, it is recommended that after 
one unsuccessful attempt, another experienced person should take over the procedure. 
9.1. Efficacy Assessments  
9.1.1. Primary Efficacy Assessment  
The primary efficacy endpoint is the percentage of ixekizumab treated participants 
meeting JIA ACR 30 response criteria at Week 16. A JIA ACR 30 response is defined as 
at least 30% improvement from baseline in 3 of any 6 variables in the core set, with no 
more than 1 of the remaining variables worsening by >30%. 
9.1.1.1. 
JIA ACR 30 Core Set Variables  
The JIA ACR 30 core set variables are defined as follows: 
 number of active joints in 73 joints (active joint defined as a joint that is swollen, 
or in the absence of swelling, has loss of passive motion accompanied by either 
pain on motion or joint tenderness) 
 number of joints with limited range of motion in 69 joints 
 Physician’s Global Assessment of Disease Activity (21-circle Visual Analogue 
Scale [VAS]) (Section 9.1.1.1.1. Physician’s Global Assessment of Disease 
Activity)  
 Parent’s Global Assessment of Well-Being 
 Physical function as assessed by the Childhood Health Assessment 
Questionnaire (CHAQ) (Section 9.1.3.1) 
 Erythrocyte sedimentation rate [ESR]) 
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9.1.1.1.1. Physician’s Global Assessment of Disease Activity  
The Physician’s Global Assessment of Disease Activity is used to assess the participant’s 
current disease activity as it relates to their signs and symptoms. The instrument uses a 21-
circle VAS ranging from 0 to 10 (using 0.5 increments) where 0 = “no activity” and 10 = 
“maximum activity” (Filocamo et al. 2010). 
9.1.2. Secondary Efficacy Assessments  
The secondary efficacy outcomes assessed at each regular visit for all participants are as 
follows: 
 percentage of participants meeting JIA ACR 30/50/70/90/100 response criteria, 
 changes from baseline in each of the 6 individual components of the JIA ACR 
core set variables, and 
 proportion of participants with disease flare (flare defined as worsening of ≥30% 
from baseline in at least 3 of the 6 JIA ACR core criteria for JIA and an 
improvement of ≥30% in no more than 1 of the criteria). 
In addition, for JPsA participants with plaque psoriasis (at least 3% BSA at baseline), 
the following secondary efficacy endpoint will be assessed at each regular visit: 
 change from baseline in PASI. 
In addition, for participants with enthesitis at baseline, the following secondary efficacy 
endpoint will be assessed at each regular visit: 
 change from baseline in Leeds Enthesitis Index (LEI). 
9.1.2.1. JIA ACR 50, 70, 90, and 100  
JIA ACR 50, JIA ACR 70, JIA ACR 90, and JIA ACR 100 responses are secondary 
efficacy endpoints and are improvements of at least 50%, at least 70%, at least 90% and 
at least 100%, respectively, in the JIA ACR criteria set. The JIA ACR 50, JIA ACR 70, 
JIA ACR 90 and JIA ACR 100 are calculated similarly to JIA ACR 30, as described in 
Section 9.1.1.1. 
9.1.2.1.1. 
Percentage of Body Surface Area (BSA)  
The joint assessor (or designee) will evaluate the percentage involvement of psoriasis on 
each participant’s BSA on a continuous scale from 0% (no involvement) to 100% (full 
involvement), in which 1% corresponds to the size of the participant’s hand (including 
the palm, fingers, and thumb) (NPF 2009). 
9.1.2.1.2. 
Psoriasis Area and Severity Index (PASI)  
The PASI will be used to assess plaque psoriasis. The PASI combines assessments of the 
extent of body surface involvement in 4 anatomical regions (head, trunk, arms, and legs). 
It also assesses the severity of erythema (redness), plaque induration/infiltration 
(thickness), and desquamation (scaling) in each region, yielding an overall score of 0 (no 
psoriasis) to 72 (most severe disease [Fredriksson and Pettersson 1978]). 
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The head, upper extremities, lower extremities, and trunk are assessed separately and then 
combined, using weighting based on the surface area represented by each area (head = 0.1, 
upper extremities = 0.2, trunk = 0.3, and lower extremities = 0.4). The degree of erythema, 
induration, and scale in each area is judged on a 0 to 4 scale, the sum of which represents 
disease severity. The area of involvement of each area is graded from 0 to 6, depending on 
the estimated percentage of lesional area (0 = 0%, 1 = 1% to 9%, 2 = 10% to 29%, 3 = 
30% to 49%, 4 = 50% to 69%, 5 = 70% to 89%, and 6 = 90% to 100%). These body scores 
are multiplied by the disease severity score and the weighting for each body area, yielding 
a score between 0 and 72. The PASI score will be program-generated. 
Further practical details help the assessment: (1) the neck is assessed as part of the head; 
(2) the axillae and groin are assessed as part of the trunk; (3) the buttocks are assessed as 
part of the lower limbs; (4) when scoring the severity of erythema, scales should not be 
removed. 
9.1.2.1.3. 
Enthesitis Assessment  
Active enthesitis will be assessed in 2 ways: LEI as a separate outcome measure, and 
active enthesitis count as a component of the Juvenile Spondyloarthritis Disease 
Activity Index (JSpADA). 
LEI measures enthesitis at 3 bilateral sites (lateral epicondyle, left and right; medial 
femoral condyle, left and right; and Achilles tendon insertion, left and right). Each of the 
6 sites 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) (Healy and Helliwell 2008; Mease 2011). 
The Active Enthesitis Count includes any tender enthesis to a maximum of 10 (Weiss et 
al. 2014). For the purposes of this study, assessment of the Active Enthesitis Count will 
include the 6 entheseal sites of the LEI plus 4 additional sites: greater trochanter on the 
femur- hip flexor insertion (left and right), and inferior pole of the patella - infrapatellar 
insertion (left and right). The Active Enthesitis Count will be assessed based on 10 
entheseal sites. There is no weighing of particular entheses, the scoring is as follows: 0 
entheses = score 0; 1 to 2 entheses = score 0.5; >2 entheses = score 1 (Weiss et al. 2014). 
The LEI and Active Enthesitis Count are to be assessed by the investigator or 
health care provider who meets study qualifications for study assessments. 
9.1.3. Health Outcomes Measures  
The self-reported questionnaires will be administered according to the Schedule of 
Activities (Section 2) in countries where the questionnaires have been translated into the 
native language of the region and linguistically validated. 
9.1.3.1. 
Childhood Health Assessment Questionnaire (CHAQ)  
The CHAQ assesses health status and physical function in children with juvenile arthritis 
over the past week, which the parent or legal guardian completes, regardless of the age of 
the participant. 
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The CHAQ has 2 indices – the Disability Index and the Discomfort Index. 
The Disability Index contains 30 items grouped into the following 8 domains (not 
including assistive devices/aids questions): physical function, dressing, and grooming 
(4 items); arising (2 items); eating (3 items); walking (2 items); hygiene (5 items); 
reach (4 items); grip (5 items); and activities (5 items). Each item is scored from 0 to 3 
(0 = no difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do or not 
applicable) (Singh et al. 1994). 
The Discomfort Index of the CHAQ includes (Ruperto et al. 2001): 
 Parent’s Global Assessment of Well-being 
o This is a component of the JIA ACR 30 core response set 
o The instrument uses a 0 to 100 mm VAS where 0 = “very well” and 100 = 
“very poor” 
 Pain assessment due to illness 
o The question uses a 0 to 100 mm VAS where 0 = “no pain” and 100 = “very 
severe 
pain” 
The questionnaires will be administered according to the Schedule of Activities (Section 2). 
Note: For all participants, the CHAQ will be provided to the parent/guardian of the 
participant through Visit 7/Week 16 of the study. Starting with Visit 8, any participant ≥14 
years of age will complete the “CHAQ” of well-being form administered for the remainder 
of the research program. 
9.1.4. Exploratory Efficacy Assessments  
9.1.4.1. 
Total and Tender Dactylitic Digit Count  
Dactylitis is defined as swelling of a digit that extends beyond the joint margin (Petty et 
al. 2004). The assessor will first assess the participant for the presence of dactylitis and 
will record the total number of dactylitic digits in the participant’s hands and feet 
(dactylitic digit count range 0 to 20). Tenderness will be assessed, and the number of 
tender dactylitic digits will be recorded (tender dactylitic digit count range 0 to 20) 
(Helliwell et al. 2005). 
9.1.4.2. 
Juvenile Arthritis Disease Activity Score-27 (JADAS-27)  
The Juvenile Arthritis Disease Activity Score-27 (JADAS-27) score is a validated 
composite disease activity measure for JIA (Consolaro et al. 2012). Recently, the 
scoring system was adapted to use the 27-joint count (Bazso et al. 2009), and high-
sensitivity C-reactive protein (hsCRP) or ESR for the inflammatory marker component 
(Nordal et al. 2012). The JADAS-27 includes the following joints: cervical spine, 
elbows, wrists, metacarpophalangeal joints (from first to third), proximal 
interphalangeal joints, hips, knees, and ankles. 
 
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JADAS-27 score will be determined based on 4 components:  
 Physician’s Global Assessment of Disease Activity (Section 9.1.1.1.1. Physician’s 
Global Assessment of Disease Activity), 
 Parent’s Global Assessment of Well-Being (from CHAQ; Section 9.1.3), 
 Number of joints with active disease (27-joint assessment), and 
 hsCRP or ESR, as applicable. 
9.1.4.3. 
EuroQol-Five Dimensions-Youth (EQ-5D-Y)  
The European Quality of Life EuroQol-Five 5 Dimensions-Youth (EQ-5D-Y) is a 
widely used, generic questionnaire that assesses health status “today” (The EuroQol 
Group 2014). It is completed by parents or caregiver (proxy) for children aged 4 to 7 
years; for children aged 8 years and older, the EQ-5D-Y will be self-completed (children 
aged <4 years will not complete this assessment per developer recommendation); 
respondents will continue with the version of the instrument they begin the study with 
even if their age changes during the course of the study. Children who attain age 4 
during the course of the study will not be included in this assessment due to a 
nonexistent baseline assessment. The questionnaire consists of 2 parts: the first part 
assesses 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression) that have 3 possible levels of response (no problems, some problems, 
or a lot of problems). This part of the EQ-5D-Y can be used to generate a health state 
index score, which is often used to compute quality-adjusted life years for utilization in 
health economic analyses. The health state index score is calculated based on the 
responses to the 3 dimensions, providing a single value on a scale from less than 0 
(where zero is a health state equivalent to death; negative values are valued as worse 
than dead) to 1 (perfect health), with higher scores indicating better health utility. 
The second part of the questionnaire consists of a VAS on which the participant rates 
their perceived health state from 0 (“the worst health you can imagine”) to 100 (“the best 
health you can imagine”). Published studies by EuroQol Group members showed 
preliminary evidence of the instrument’s feasibility, reliability, and validity (Ravens-
Sieberer et al. 2010). The scale will be given to the parent or caregiver/participant by the 
site investigator and self-completed by the parent or caregiver/participant while they are 
at the site. The investigator will be responsible for checking for missing responses. 
9.1.4.4. 
Juvenile Spondyloarthritis Disease Activity Index (JSpADA)  
The JSpADA is a validated composite disease activity measure for juvenile SpA (JSpA). 
The JSpADA includes 8 items that measure arthritis, enthesitis, sacroiliitis, morning 
stiffness, pain, uveitis, back mobility, and laboratory inflammatory markers. Each item is 
considered to be of equal importance and is assigned a maximum score of 1 without 
weighting. The range of possible JSpADA scores is 0 to 8, where higher scores indicate 
more disease activity (Weiss et al. 2014). 
JSpADA score will be determined as follows: 
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 active joint count: 0 joints = 0, 1 to 2 joints = 0.5, >2 joints = 1 
 active enthesitis count:  0 entheses = 0, 1 to 2 entheses = 0.5, >2 entheses =1 
 pain over the past week as assessed using a 0 to 10 Numeric Rating Scale (0 = 
no pain; 10 = pain as bad as your child can imagine: 0 = 0, 1 to 4 = 0.5, 5 to 10 
= 1) 
 hsCRP level related to JSpA activity: normal = 0, 1 to 2 times normal = 0.5, 
>2 times normal = 1 
 morning stiffness >15 minutes: Absent = 0, Present = 1 
 clinical sacroiliitis (defined as the presence of ≥2 of the following: tenderness on 
examination; positive Patrick’s test or flexion, abduction and external rotation 
(FABER) test; and inflammatory back pain): Absent = 0, Present = 1 
 uveitis (any uveitis including acute/symptomatic and chronic/asymptomatic 
disease): Absent = 0, Present =1 
 back mobility (abnormal back mobility defined as modified Schober’s test 
<20 cm): Normal = 0, Abnormal = 1 
The JSpADA score is obtained by summing the total for each item (maximum total per 
item = 1; JSpADA range is 0 to 8). 
9.1.4.5. 
Morning Joint Stiffness Duration  
As one of the assessments to determine the JSpADA score, the parent/caregiver will 
indicate if the duration of their child’s morning joint stiffness was >15 minutes since the 
previous visit. Responses are yes/no. 
Note: For all participants, morning stiffness will be assessed by the parent/guardian of the 
participant through Visit 7/Week 16 of the study. Starting with Visit 8, any participant ≥14 
years of age will complete the morning stiffness assessment form administered for the 
remainder of the research program. 
9.1.5. Appropriateness of Assessments  
All assessments utilized in this study are standard, widely used, and generally recognized 
as reliable, accurate, and relevant. 
9.2. Adverse Events  
Adverse events will be reported by the study participant or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative. 
The investigator and qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE (Appendix 5) and remain 
responsible for follow-up of AEs that are serious, considered related to the study 
intervention or study procedures, or that caused the participant to discontinue the study 
(see Section 8). 
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Investigators are responsible for monitoring the safety of participants 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 
participant. 
The investigator is responsible for the appropriate medical care of participants during the 
study. 
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 participant to discontinue the 
investigational product before completing the study. The participant 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 ICF and Assent Form (as applicable) are signed, study site personnel will 
record via electronic data entry the occurrence and nature of each participant’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 and/or investigational 
product, via electronic data entry. 
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 participant’s investigational product is discontinued as a result of an AE, study site 
personnel must report this to Lilly or its designee via electronic data entry, clarifying if 
possible, the circumstances leading to any dosage modifications, or discontinuations of 
treatment. 
9.2.1. Timing and Mechanism for Collecting Events  
This table describes the timing, deadlines, and mechanism for collecting events. 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
SAE and SAE 
updates – after 
start of study 
intervention 
Start of 
intervention 
Participation 
in study has 
ended 
Within 24 hours of 
awareness 
SAE CRF 
SAE paper 
form 
SAE* – after 
participant’s 
study 
participation has 
ended and the 
investigator 
becomes aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
Pregnancy 
Pregnancy in 
female 
participants and 
female partners 
of male 
participants 
receiving 
ixekizumab 
After the 
start of study 
intervention 
At least 
5 terminal 
half-lives 
after the last 
dose 
Within 24 hours (see 
Section 9.4.5) 
SAE CRF 
SAE paper 
form 
Product Complaints 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 24 hours of 
awareness 
PC form 
N/A 
Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
Adverse Event 
AE 
Signing of 
the informed 
consent form 
(ICF) 
Participation 
in study has 
ended 
As soon as possible 
upon site awareness 
AE case report form 
(CRF) 
N/A 
Serious Adverse Event 
SAE and SAE 
updates – prior 
to start of study 
intervention and 
deemed 
reasonably 
possibly related 
to study 
procedures 
Signing of 
the ICF 
Start of 
intervention 
Within 24 hours of 
awareness 
SAE CRF 
SAE paper 
form 
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PC not 
associated with 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
PC form 
N/A 
Updated PC 
information 
— 
— 
As soon as possible 
upon site awareness 
Originally 
completed PC form 
with all changes 
signed and dated by 
the investigator 
N/A 
PC (if 
investigator 
becomes aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
PC form 
Abbreviations: AE = adverse event; N/A = not applicable; PC = product complaint; SAE = serious adverse event. 
* Serious adverse events should not be reported unless the investigator deems them to be possibly related 
to study treatment or study participation. 
 
9.2.2. Serious Adverse Events  
An SAE is any AE from this study that results in one of the following outcomes: 
 death 
 initial or prolonged in-participant hospitalization 
 a life-threatening experience (that is, immediate risk of dying) 
 persistent or significant disability/incapacity 
 congenital anomaly/birth defect 
 important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the participant or may require 
intervention to prevent one of the other outcomes listed in the definition above. 
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in in- participant hospitalization, or the 
development of drug dependency or drug abuse. 
All SAEs will be collected from the signing of the ICF until the follow-up visit at the time 
points specified in the Schedule of Activities. 
All AEs will be collected from the signing of the ICF until participation in study has ended. 
Medical occurrences that begin before the start of study intervention but after signing of 
the ICF will be recorded on the Adverse Event CRF. 
All AEs occurring after signing the ICF and Assent Form (as applicable) are recorded by 
the site in the CRF/electronic data entry and assessed for serious criteria. The SAE 
reporting to the sponsor begins after the participant 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. 
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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. Participants with a serious hepatic AE 
should have additional data collected using the electronic data entry. 
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 participants once they have 
discontinued and/or completed the study (the participant disposition CRF has been 
completed). However, if the investigator learns of any SAE, including a death, at any time 
after a participant 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. 
9.2.2.1. 
Suspected Unexpected Serious Adverse Reactions  
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not 
listed in the IB and that the investigator identifies as related to investigational product or 
procedure. United States 21 CFR 312.32 and European Union Clinical Trial Directive 
2001/20/EC and the associated detailed guidance or national regulatory requirements in 
participating countries require the reporting of SUSARs. Lilly has procedures that will be 
followed for the identification, recording, and expedited reporting of SUSARs that are 
consistent with global regulations and the associated detailed guidance. 
9.2.2.2. 
Pregnancy  
Collection of pregnancy information: Male participants with partners who become 
pregnant 
 The investigator will attempt to collect pregnancy information on a male 
participant’s female partner who becomes pregnant while the male participant is 
in this study. This applies only to male participants who receive ixekizumab. 
 After obtaining the necessary signed informed consent and/or assent from the 
pregnant female partner directly, 
o the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor 
o within 24 hours of learning of the partner’s pregnancy. The female partner 
will also be followed up to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date. Any termination of the pregnancy 
will be reported regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
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Female participants who become pregnant  
 The investigator will collect pregnancy information on any female 
participant who becomes pregnant while participating in this study. The 
initial information will be recorded on the appropriate form and submitted 
to the sponsor within 24 hours of learning of a participant’s pregnancy. 
 The participant will be followed up to determine the outcome of the pregnancy. 
The investigator will collect follow-up information on the participant and the 
neonate, and the information will be forwarded to the sponsor. Generally, follow-
up will not be required for longer than 6 to 8 weeks beyond the estimated delivery 
date. Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
 A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and will be 
reported as such. 
 Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Appendix 5. While the investigator is not obligated to actively seek this information in 
former study participants, the investigator may learn of an SAE through spontaneous 
reporting. 
See Section 8.2 about the discontinuation of participants who become pregnant. 
9.2.2.3. 
Adverse Events of Special Interest  
The following adverse events of special interest (AESIs) will be evaluated 
specifically to determine the safety and tolerability of ixekizumab over the range of 
doses selected for this clinical study. 
AESIs for ixekizumab are: 
 cytopenias (leukopenia, neutropenia, and thrombocytopenia), 
 liver biochemical test changes/enzyme elevations (ALT, AST, bilirubin, and ALP), 
 infections, 
 immunogenicity, 
 injection-site reactions, 
 allergic reactions/hypersensitivities, 
 cerebrocardiovascular events, 
 malignancies, 
 depression, 
 inflammatory bowel disease, and 
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 interstitial lung disease. 
If infections, injection-site reactions, or allergic/hypersensitivity reactions are reported, 
study sites will provide details on these events as instructed on the eCRF. Investigators 
will also educate participants and/or caregivers about the symptoms of 
allergic/hypersensitivity reactions and will provide instructions on dealing with these 
reactions. A blood sample will be collected when possible for any participant who 
experiences an AE of allergic reactions/hypersensitivities during the study. 
In the case of suspected IBD, the participant should be referred to a gastroenterologist 
(preferably pediatric gastroenterologist) for evaluation and management. Data on 
suspected IBD, as identified by events possibly indicative of ulcerative colitis or Crohn’s 
disease will be collected, and the events will be adjudicated by an external Clinical Events 
Committee (CEC) composed of gastroenterologists with expertise in IBD. The role of the 
CEC is to adjudicate defined clinical events in a consistent, and unbiased manner 
throughout a study. The importance of the CEC is to ensure that all events that have been 
reported are evaluated uniformly by a single group. 
9.2.3. Complaint Handling  
Lilly collects product complaints on investigational products and drug delivery systems 
used in clinical studies in order to ensure the safety of study participants, monitor 
quality, and to facilitate process and product improvements. 
Participants will be instructed to contact the investigator as soon as possible if he or 
she has a complaint or problem with the investigational product so that the situation 
can be assessed. 
9.3. Treatment of Overdose  
For this study, any dose of ixekizumab greater than 80 mg within a 24-hour time period 
will be considered an overdose. Any dose of adalimumab greater than 40 mg within a 24-
hour time period will be considered an overdose. 
The sponsor does not recommend specific treatment for an overdose. In the event of an 
overdose, the investigator/treating physician should: 
● Contact the medical monitor immediately 
● For adalimumab patients, please reference the product label for 
additional information 
● Evaluate the participant to determine, in consultation with the medical 
monitor, whether study intervention should be interrupted or whether the 
dose should be reduced 
● Closely monitor the participant for any AE/SAE and laboratory abnormalities 
● For ixekizumab participants only, obtain a plasma sample for PK 
analysis if requested by the medical monitor (determined on a case-
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by-case basis) 
 Document the quantity of the excess dose as well as the duration of the 
overdose in the CRF 
 
9.4. Safety  
Any clinically significant findings from physical examination, vital signs measurements, 
or laboratory measurements that result in a diagnosis and that occur after the participant 
receives the first dose of investigational product should be reported to Lilly or its 
designee as an AE via eCRF. These events will also be considered as an AE if the event 
does not result in a diagnosis but is considered clinically significant by the investigator. 
9.4.1. Physical Examination  
The complete physical examination (excluding pelvic, rectal, and breast examinations) 
will be performed according to the Schedule of Activities (Section 2). This examination 
will determine whether the participant 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 adverse event (TEAE) assessment. All 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. 
9.4.2. Tanner Stage Scale  
The Tanner Stage Scales are a series of line drawings that are designed to aid the participant or 
caregiver in appropriately assessing the sexual maturity of the participant at the time of the 
visit (Chavarro et al. 2017). Participants 8 years and older will be assessing their sexual 
maturity according to the Schedule of Activities (Section 2). 
Once the participant reaches the score 5 in the scale, no further assessments are needed. 
 
9.4.3. Vital Signs  
For each participant, vital sign measurements should be conducted according to the 
Schedule of Activities (Section 2). 
Any clinically significant findings from vital signs measurement that result in a 
diagnosis and that occur after the participant receives the first dose of study treatment 
should be reported to Lilly or its designee as an AE via electronic data entry. 
9.4.4. Laboratory Tests  
For each participant, laboratory tests detailed in Appendix 2 should be conducted 
according to the Schedule of Activities (Section 2). 
Blood volume restrictions are anticipated to be applicable for participants 2 to <8 years 
old and particularly for participants 10.0 to <20.0 kg in body weight; however, it may be 
used for older participants if local regulations require restrictions on blood volumes. The 
Blood Volume Prioritization Tool is provided in Appendix 7. 
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Due to blood volume restrictions, some laboratory samples may not be collected (for 
example, cell flow cytometry in case needed to reduce blood volumes of a certain visit). 
Laboratory samples should be collected as described in a sponsor-provided weight-based 
prioritization chart. 
Additional allowances to accommodate blood volume restrictions may include, but 
are not limited to the following: 
 Blood draws for Visit 1 and Visit 2 may be divided over 2 days if the 24-hour 
blood volume limit is exceeded. 
 Hepatitis B virus DNA will be collected as a reflex test prior to Visit 2 and 
is only required for participants who are positive for HBcAb. 
 Hepatitis C virus RNA will be collected as a reflex test prior to Visit 2 and 
is only required for participants who are positive for HCV antibody. 
Use of local anesthetics or devices consistent with local prescribing information is 
permitted during the study visit to ease discomfort associated with venipunctures. Lilly or 
its designee will provide the investigator with the results of laboratory tests analyzed by a 
central vendor, if a central vendor is used for the clinical study. 
Any clinically significant findings from laboratory tests that result in a diagnosis and that 
occur after the participant receives the first dose of investigational product should be 
reported to Lilly or its designee as AE via electronic data entry. 
The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE section 
of the CRF. The laboratory reports must be filed with the source documents. 
9.4.5. Pregnancy Testing  
See the Schedule of Activities (Section 2) for frequency of pregnancy testing and 
Appendix 2 and Appendix 6 for additional details about these tests. As per Clinical Trial 
Facilitation Group (CTFG) recommendation: In each case of delayed menstrual period 
(over 1 month between menstruations), confirmation of absence of pregnancy is strongly 
recommended. This recommendation also applies to women of childbearing potential 
(WOCBP) with infrequent or irregular menstrual cycles. 
At Screening  
Serum pregnancy tests will be given prior to the first dose of the study intervention for females 
≥10 years of age (<10 years at investigator discretion) if menarche has been reached or if 
there is reason to believe the participant is sexually active. Pregnancy test results at 
screening must be known prior to first dose of the study intervention. 
Open-Label Treatment, Open-Label Extension Treatment, and Long-Term Extension 
Periods  
Female participants of childbearing potential (age 10 and older if menarche has been 
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reached or if there is reason to believe the participant is sexually active, or younger 
participants per investigator assessment of sexual maturity) will undergo a urine 
pregnancy test at the clinic on a monthly basis during scheduled visits through Week 264 
or the ETV. Additional urine pregnancy testing may be performed at the investigator’s 
discretion. Participants determined to be pregnant will be discontinued from treatment and 
will no longer be administered study intervention (see Section 8.1.1). 
During the Post-Treatment Follow-Up Period  
As indicated in the Schedule of Activities, urine pregnancy tests will be collected during 
each of the post-treatment follow-up visits. 
9.4.6. Chest X-Ray and Tuberculosis Testing  
A posterior-anterior view chest x-ray will be obtained, unless the x-ray or results from a chest 
x-ray obtained within 6 months prior to the study are available or the results from the TB 
testing (QuantiFERON® TB Gold, T-Spot or PPD) if aligned with local practice. 
The chest x-ray or results will be reviewed by the investigator or designee and considered 
along with the participant’s medical history, assessment of risk factor for M. tuberculosis 
infection and physical examination to exclude participants with active TB infection. 
Participants will be tested as indicated in the Schedule of Activities (Section 2) for evidence of 
M. tuberculosis infection. 
TB testing - QuantiFERON® TB Gold will be the preferred testing option for TB. The 
QuantiFERON® TB Gold test may be performed locally or centrally. If the 
QuantiFERON®-TB Gold test is indeterminate (not negative), 1 retest is allowed. If the 
retest for the QuantiFERON®-TB Gold test is indeterminate (not negative), the 
participant is excluded from enrollment in the study. 
In countries where the QuantiFERON®-TB Gold test is not available or due to 
investigator’s judgement (e.g., need to reduce the volume of blood collected), the T-Spot 
or PPD test may be used. In the case of selecting the PPD test, the participant must return 
within 48 to 72 hours to read the skin test. 
A positive PPD skin test response for this study is defined as ≥5-mm induration between 
48 and 72 hours after PPD application, regardless of Bacillus Calmette-Guérin vaccination 
history. 
Participants with documentation of a negative QuantiFERON®-TB Gold test or T-Spot 
result or PPD result within 3 months prior to baseline (Week 0; Visit 2) are not required to 
have a TB test at Visit 1 unless medical history, including assessment for TB infection risk 
factors, chest x-ray, or physical examination indicate that testing should be done. 
Documentation of this test result must include a record of the size of the induration 
response (<5-mm induration) or the laboratory report of the QuantiFERON®-TB Gold test 
or T-Spot result. A PPD test recorded as negative without documenting the size of 
induration will require a retest. 
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Participants with a PPD skin test ≥5 mm induration or a positive QuantiFERON®-TB 
Gold or T-Spot test but no evidence of active TB, and participants who have a 
documented history of a positive TB test but no documented history of completion of a 
full, appropriate latent TB treatment course, who are assessed as having latent TB 
infection may be re-screened 1 time and may be enrolled without repeating a 
QuantiFERON®-TB Gold, T-Spot or PPD test if the following conditions are met: 
 after receiving at least 4 weeks of appropriate latent TB infection therapy with 
no evidence of hepatotoxicity (ALT/AST must remain ≤2 × ULN) upon retesting 
of serum ALT/AST prior to randomization, 
 commitment by the participant and the caregiver for the participant to 
complete a full course of standard prophylaxis for TB, and 
 meet all other inclusion/exclusion criteria for participation. 
Such participants must complete appropriate latent TB infection therapy to remain 
eligible for continued study participation. If rescreening occurs within 6 months of the 
screening chest x-ray, a repeat of chest x-ray for considering enrollment is not required. 
If a participant with a positive QuantiFERON®-TB Gold or T-Spot or PPD is fully 
assessed by the investigator and the investigator determines that the participant has no risk 
factors for and no symptoms or signs of M. tuberculosis infection, the investigator may 
contact Lilly Medical to discuss the possibility of a false-positive test result. 
Participants with positive TB test results on file: Participants with a documented prior 
history of a positive TB test and participants who have a documented history of completion 
of an appropriate TB treatment regimen for latent or active TB should not have a TB test 
performed at Visit 1. Such participants with no history of re-exposure to TB since their 
treatment was completed and no evidence of active TB are eligible to participate in the 
study. Participants who have had household contact with a person with active TB are 
excluded unless an appropriate and documented course of prophylaxis for TB was 
completed. 
Participants are to be monitored on a regular basis for any symptoms or signs of active TB 
and for any new risk factors for TB infection, with full medical evaluation including TB 
testing when medically indicated. Participants that exhibit symptoms of active TB should 
be referred to a specialist in the care of participants with TB. 
Any clinically significant findings from chest x-rays and/or TB testing that result in a 
diagnosis and that occur after the participant signs the ICF should be reported to Lilly or 
its designee as an AE via eCRF. 
9.4.7. Uveitis Evaluation  
At each study visit, the investigator will ask the participant/caregiver whether they 
developed uveitis since the last visit and evaluate the participant for any symptoms of 
acute anterior uveitis since the last visit as specified in the Schedule of Activities (Section 
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2). If the participant has no prior ophthalmologist-diagnosed uveitis and develops eye pain 
or discomfort, eye redness, blurring of vision, or any other symptoms suggestive of acute 
anterior uveitis, the participant must be evaluated by an ophthalmologist. It is expected 
that all children with JIA will be on screening and regular evaluation with 
ophthalmologists based on local/regional/national guidelines. 
9.4.8. Children’s Depression Inventory 2 Short Form (CDI-2)  
The Children's Depression Inventory-2 (CDI-2) short form is modeled after the Beck 
Depression Inventory and is a 12-item self-reported scale designed to measure depressive 
symptoms in children and adolescents (ages 7 years and older) (Helsel and Matson 1984; 
Kovacs 1992; Ahlen and Ghaderi 2017). The instrument has a recall period of the past 2 
weeks and responses use a 3- item Likert scale. A higher score indicates more clinically 
severe depression. 
9.4.9. Columbia–Suicide Severity Rating Scale (C-SSRS)  
The C-SSRS is a scale that captures the occurrence, severity, and frequency of suicidal 
ideation and behavior during the assessment period via a questionnaire. The scale was 
developed by the National Institute of Mental Health (NIMH) trial group Treatment of 
Adolescent Suicide Attempters (TASA) for the purpose of being counterpart to the 
Columbia Classification Algorithm of Suicide Assessment (C-CASA) categorization of 
suicidal events and is administered by the clinician. 
The instrument is validated for use in children ages 7 to 11 (using the Children C-SSRS) 
as well as adults ages 12 and older (using the Adult C-SSRS form). The instrument is a 
composite instrument with responses being a mixture of Yes/No, ordinal and nominal 
scales. Higher scores indicate higher suicidal ideation and behavior. 
The sites will use the appropriate version according to the age. Respondents will 
continue with the version of the instrument they begin the study with even if their age 
changes during the course of the study. 
9.4.10. Self-Harm Supplement Form  
The Self-Harm Supplement Form is part of the C-SSRS instrument. It consists of 1 
question and is completed at any visit, including baseline visits by the clinician. The 
question asks for the number of suicidal or non-suicidal self-injurious behaviors the 
participant experienced since last assessment. 
For each unique event identified, a questionnaire (Self-Harm Follow-Up Form), which 
collects supplemental information on the self-injurious behavior, must be completed. This 
information is then documented in the eCRF. 
9.4.11. Safety Monitoring  
Lilly will periodically review evolving aggregate safety data within the study by 
appropriate methods. 
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Refer to Interim Analyses Section 10.3.8) for information about additional analyses of the 
safety data. 
9.4.11.1. Hepatic Safety Monitoring  
Close hepatic monitoringa 
Laboratory tests (Appendix 4), including ALT, AST, ALP, TBL, direct bilirubin, gamma- 
glutamyl transferase (GGT), and creatine kinase (CK), should be repeated within 48 to 72 
hours to confirm the abnormality and to determine if it is increasing or decreasing, if 1 or 
more of these conditions occur: 
 
If a participant with baseline results 
of... 
develops the following elevations: 
ALT or AST <1.5 × ULN 
ALT or AST ≥3 × ULN 
ALP <1.5 × ULN 
ALP ≥2 × ULN 
TBL <1.5 × ULN 
TBL ≥2 × ULN, except for patients with Gilbert’s 
syndrome 
ALT or AST ≥1.5 × ULN 
ALT or AST ≥2 × baseline 
ALP ≥1.5 × ULN 
ALP ≥2 × baseline 
TBL ≥1.5 × ULN 
TBL ≥1.5 × baseline, except for patients with Gilbert’s 
syndrome 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; TBL = total bilirubin; ULN = upper limit of normal. 
a All ULN values should be age adjusted (AAULN) for participants <18 years of age. 
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation 
for possible causes of abnormal liver tests should be initiated by the investigator in 
consultation with the Lilly-designated medical monitor. At a minimum, this evaluation 
should include physical examination and a thorough medical history, including symptoms, 
recent illnesses (for example, heart failure, systemic infection, hypotension, or seizures), 
recent travel, history of concomitant medications (including over-the-counter), herbal and 
dietary supplements, history of alcohol drinking, and other substance abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a 
frequency of 1 to 3 times weekly, based on the participant’s clinical condition and hepatic 
biochemical tests. Subsequently, the frequency of monitoring may be lowered to once 
every 1 to 2 weeks, if the participant’s clinical condition and lab results stabilize. 
Monitoring of ALT, AST, ALP, and TBL should continue until levels normalize or return 
to approximate baseline levels. Special care should be taken to minimize the volume of 
blood taken during hepatic monitoring. 
Comprehensive hepatic evaluationa  
A comprehensive evaluation should be performed to search for possible causes of liver 
injury if 1 or more of these conditions occur: 
 
If a participant with baseline results 
of... 
develops the following elevations: 
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ALT or AST <1.5 × ULN 
ALT or AST ≥3 × ULN with hepatic signs/symptomsb, or 
ALT or AST ≥5 × ULN 
ALP <1.5 × ULN 
ALP ≥3 × ULN 
TBL <1.5 × ULN 
TBL ≥2 × ULN (except for participants with Gilbert’s 
syndrome) 
ALT or AST ≥1.5 × ULN 
ALT or AST ≥2 × baseline with hepatic signs/symptomsb, or 
ALT or AST ≥3 × baseline 
ALP ≥1.5 × ULN 
ALP ≥2 × baseline 
TBL ≥1.5 × ULN 
TBL ≥1.5 × baseline (except for participants with Gilbert’s 
syndrome) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; TBL = total bilirubin; ULN = upper limit of normal. 
a 
All ULN values should be age adjusted (AAULN) for participants <18 years of age. 
b Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, 
fever, rash, and/or eosinophilia >5%. 
At a minimum, this evaluation should include physical examination and a thorough 
medical history, as outlined above, as well as tests for PT-INR and direct bilirubin, if 
TBL was elevated, tests for viral hepatitis A, B, C, or E; tests for autoimmune hepatitis; 
and an abdominal imaging study (for example, ultrasound or computed tomography [CT] 
scan). 
Based on the participant’s age, medical history, and initial results, further testing 
should be considered in consultation with the Lilly-designated medical monitor, 
including tests for viral hepatitis A, B, C, E; autoimmune hepatitis; or an abdominal 
imaging study (for example, ultrasound, MRI, or CT scan). Consider additional tests, 
based on the medical history and clinical picture, including tests for hepatitis D virus, 
cytomegalovirus, Epstein-Barr virus, acetaminophen levels, acetaminophen protein 
adducts, urine toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl 
glucuronide, and blood phosphatidylethanol. Special care should be taken to prioritize 
more pertinent blood tests and minimize the volume of blood taken during hepatic 
evaluation. Based on the circumstances and the investigator’s assessment of the 
participant’s clinical condition, the investigator should consider referring the 
participant for a pediatric hepatologist or gastroenterologist consultation, magnetic 
resonance cholangiopancreatography, endoscopic retrograde 
cholangiopancreatography, cardiac echocardiogram, or a liver biopsy as deemed 
appropriate for the clinical condition and participant’s age. 
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study  
Additional hepatic safety data collection in hepatic safety CRF should be performed in 
study participants who meet 1 or more of the following 5 conditions:a 
1. Elevation of serum ALT to ≥5 × ULN on 2 or more consecutive blood tests (if 
baseline ALT <1.5 × ULN) 
o In participants with baseline ALT ≥1.5 × ULN, the threshold is 
ALT ≥3 × baseline on 2 or more consecutive tests 
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2. Elevated TBL to ≥2 × ULN (if baseline TBL <1.5 × ULN) (except for cases of known 
Gilbert’s syndrome) 
o In participants with baseline TBL ≥1.5 × ULN, the threshold should be 
TBL ≥2 × baseline 
3. Elevation of serum ALP to ≥2 × ULN on 2 or more consecutive blood tests (if 
baseline ALP <1.5 × ULN) 
o In participants with baseline ALP ≥1.5 × ULN, the threshold is ALP ≥2 × 
baseline on 2 or more consecutive blood tests 
4. Hepatic event considered to be a SAE 
5. Discontinuation of study drug due to a hepatic event 
Note: the interval between the two consecutive blood tests should be at least 2 days. 
a 
All ULN values should be age adjusted 
9.4.11.1.1. Hepatic Safety Data Collection  
Additional safety data should be collected via the electronic data entry if 1 or more of 
the following conditions occur: 
 elevation of serum ALT to ≥5 × ULN on 2 or more consecutive blood tests, 
 elevated serum TBL to ≥2 × ULN (except for cases of known Gilbert’s syndrome), 
 elevation of serum ALP to ≥2 × ULN on 2 or more consecutive blood tests, 
 participant discontinued from treatment due to a hepatic event or abnormality 
of liver tests, or 
 hepatic event considered to be an SAE. 
9.4.11.2. Hepatitis B Monitoring  
Participants who are HBsAg- and HBcAb+ at screening, regardless of other hepatitis B 
testing results, will have a plasma HBV DNA specimen obtained to be analyzed by the 
central laboratory. Such participants 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. 
Participants who are found to be HBV DNA positive (detectable) at screening will be 
excluded from the trial. 
Any enrolled participant 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 participants 
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. 
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Upon discontinuation from investigational product, the participant should be 
discontinued from the study. Any participant who discontinues the study for any reason 
will complete the ETV before entering the PTFU. 
9.4.11.3. Growth Monitoring  
Height and weight will be measured at baseline and postbaseline for the assessment of 
physical growth according to the Schedule of Activities (Section 2). Occipital frontal 
circumference will be collected in participants up to 3 years of age. Height, weight and 
occipital frontal circumference changes in pediatric participants (both at an individual 
and group level) will be reviewed by the data monitoring committee (DMC). 
9.5. Pharmacokinetics  
At the visits and times specified in the Schedule of Activities (Section 2), venous samples of 
approximately 2 mL each will be collected to determine the serum concentrations of 
ixekizumab. 
A maximum of 3 samples may be collected at additional time points during the study if 
warranted and agreed upon between both the investigator and sponsor. Instructions for 
the collection and handling of blood samples will be provided by the sponsor. The 
actual date and 24-hour clock time of each sampling will be recorded. 
Pharmacokinetic samples will be retained for a maximum of 1 year following last 
participant visit for the study. During this time, samples remaining after the 
bioanalyses may be used for exploratory analyses such as metabolism work, 
bioanalytical validation, and/or bioanalytical method cross-validation. 
9.6. Pharmacodynamics  
9.6.1. Immunogenicity Assessments  
At the visits and times specified in the Schedule of Activities (Section 2), venous blood 
samples will be collected to determine antibody production against ixekizumab. 
Antibodies may be further characterized for their ability to neutralize the activity of 
ixekizumab. To interpret the results of immunogenicity, a venous blood sample will be 
collected at the same time points to determine the serum concentrations of ixekizumab. All 
samples for immunogenicity should be taken pre-dose when applicable and possible. 
Treatment-emergent antidrug antibodies (TE-ADAs) are defined in Section 10.3.6. If the 
immunogenicity sample at the last scheduled assessment or discontinuation visit is TE-
ADA positive, additional samples may be taken every 3 months for up to 1 year from last 
dose or until the ADA titer returns to baseline (i.e., no longer TE-ADA positive). 
Samples will be retained for a maximum of 15 years after the last participant visit, or for 
a shorter period if local regulations and Ethical Review Boards allow, at a facility 
selected by the sponsor. The duration allows the sponsor to respond to future regulatory 
requests related to ixekizumab. Any samples remaining after 15 years will be destroyed. 
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9.7. Pharmacogenomics  
Not applicable 
 
9.8. Biomarkers  
Not applicable 
 
9.9. Medical Resource Utilization and Health Economics  
Health economics and medical resource utilization parameters will not be evaluated in this 
study. 
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10. Statistical Considerations  
10.1. Sample Size Determination  
The Bayesian methodology results in a posterior distribution which rigorously quantifies 
the uncertainty around the estimate of the JIA ACR 30 response. The primary objective of 
this study is to detect a JIA ACR 30 response rate of at least 50% for ixekizumab-treated 
participants at Week 16. 
A sample size of at least 80 participants assigned to ixekizumab has been shown via 
simulation to have reasonable operating characteristics as follows: 
 a study success rate greater than 80% if the true JIA ACR 30 response is at 60% 
 a false-positive rate of less than 1% if the true JIA ACR 30 response is placebo-
like at 35% 
These rates are derived from the Bayesian decision criterion, but are similar to a 
traditional power calculation. 
Overall, approximately 100 participants will be assigned to therapy in this study. 
Of the 80 ixekizumab-treated participants in this study, 20 bDMARD-naive participants 
will be randomized to ixekizumab. An additional 20 participants will be randomized to 
adalimumab (1:1 randomization to ixekizumab or adalimumab). The remaining 60 
participants who are either bDMARD-naive or bDMARD-IR will be assigned to 
ixekizumab in the OLT period. 
The above sample size and power estimates are based on Fixed and Adaptive Clinical 
Trials Simulator version 6.0 (FACTS™). 
10.2. Populations for Analyses  
For analysis purposes, populations are defined based on the different treatment 
period in Table RHCG.10.1. 
Table RHCG.10.1. 
Populations Based on Treatment Period 
 
Population 
Description 
Enrolled 
All participants who sign informed consent. 
ITT population 
All participants, even if the participant does not take the 
assigned treatment, does not receive the correct treatment, or 
otherwise does not follow the protocol. Unless otherwise 
specified, efficacy and health outcomes analyses will be 
conducted on the ITT Population during the OLT period. 
Participants will be analyzed according to the treatment to 
which they were assigned. 
OLE period population 
All participants who receive at least 1 dose of either treatment 
in OLE. 
OLE period adalimumab switchers (switchers) 
Participants initially randomized to adalimumab who switch 
  
to ixekizumab in the OLE period 
 
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  Populations Based on Treatment Period 
 
 
Population 
Description 
OLT safety population 
LTE safety population 
All participants who received at least 1 dose of either 
treatment product in OLT. 
All participants who received at least 1 dose of ixekizumab in 
the LTE period. 
PTFU period population 
Safety analyses for the Post-Treatment Follow-Up Period will 
be conducted on the Post-Treatment Follow-Up Period 
population, defined as all randomized participants who 
received at least 1 dose of study treatment at any time during 
the study period, and have entered the Post-Treatment Follow- 
Up Period. Participants will be analyzed according to the 
treatment in which they were assigned. 
Abbreviations: ITT=intend-to-treat; LTE = long-term extension; OLE = open-label extension; OLT = 
open-label treatment; PTFU = post-treatment follow-up. 
 
10.3. Statistical Analyses  
10.3.1. General Statistical Considerations  
Statistical analysis of this study will be the responsibility of Lilly or its designee. A 
detailed statistical analysis plan (SAP) describing the statistical methodologies will be 
developed by Lilly or its designee. 
Continuous data will be summarized in terms of number of observations, mean, standard 
deviation, minimum, maximum, and median. Categorical data will be summarized as 
frequency counts and percentages. The proportions and 95% confidence intervals will be 
reported. 
A futility analysis will be conducted using the JIA ACR 30 response rate observed in 
the first 40 ixekizumab participants who have the opportunity to complete OLT period 
(Week 16). 
Adding an interim analysis for lack of benefit will reduce the risk of unnecessarily 
exposing pediatric participants to a treatment that does not meet the desired efficacy 
threshold. The study will stop for futility if the observed JIA ACR 30 response rate is 
less than 40% among participants who have had opportunity to complete Week 16 at the 
time of the interim analysis. 
All efficacy and safety data will be descriptively summarized in each treatment period 
using corresponding populations, including switchers. No inferential comparisons will 
be made between treatment groups. Continuous vital signs, body weight, growth 
velocity, and other continuous safety variables, including laboratory variables, will be 
summarized. 
Any change to the data analysis methods described in the protocol will require an 
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amendment ONLY if it changes a principal feature of the protocol. Any other change to 
the data analysis methods described in the protocol, and the justification for making the 
change, will be described in the clinical study report. Additional exploratory analyses of 
the data will be conducted as deemed appropriate. Complete details of the planned 
analyses will be documented in the SAP.  
Handling of missing, unused, and spurious data is addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. 
Adjustments to the planned analyses are described in the final CSR. 
10.3.1.1. General Considerations for the OLT Period  
The OLT period starts at the first injection of study treatment at Week 0 (Visit 2) and 
ends prior to the first injection of study treatment at Week 16 (Visit 7) or the ETV 
(between Weeks 0 and 16). Efficacy and health outcomes data collected in the OLT 
period will be summarized for intent-to-treat (ITT) population without inferential 
statistics. 
Efficacy baseline will be defined as the last available value before the first injection for 
efficacy and health outcomes. In most cases, this will be the measure recorded at Week 0 
(Visit 2). For efficacy measures, if the participant does not take any injection, the last 
available value on or prior to randomization date will be used. Change from baseline will 
be calculated as the visit value of interest minus the baseline value. For safety analyses 
using a baseline period, the baseline period is defined as the time from Visit 1 to the 
date/time of the first injection. 
10.3.1.2. General Considerations for the OLE Period  
Unless otherwise specified, the OLE period starts at the first injection of study treatment 
at Week 16 (Visit 7) and ends on the date of Week 104 (Visit 29) or the ETV (between 
Weeks 16 and 104). 
For the efficacy and health outcomes analyses, baseline is defined as the last available 
value before the first injection in the OLT period and, in most cases, will be the value 
recorded at Week 0 (Visit 2). 
Unless otherwise specified, for the safety analyses during the OLE period, baseline is 
defined as the last available value before first injection of either ixekizumab or 
adalimumab in the OLE period. In most cases, this will be the measure recorded at Week 
16 (Visit 7). 
Safety and efficacy data for participants in the OLE period adalimumab switchers 
population will be summarized separately using descriptive statistics without inferential 
statistics. Safety baseline for switchers is defined as the last available value before first 
injection of ixekizumab or adalimumab in the OLE period. 
All efficacy and safety data collected will be summarized using descriptive statistics. 
10.3.1.3. General Considerations for the LTE Period  
The LTE period starts at the first injection of ixekizumab at Week 104 (Visit 29) and 
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ends at Week 264 (Visit 69) or at ETV (between Weeks 104 and 264).  
Note: Participants will be administered ixekizumab only until the treatment period at 
Week 68 (Visit 260). 
All safety data will be descriptively summarized using the LTE safety population. For 
safety analyses using a baseline period, the baseline period is defined as the time from 
Visit 1 to date/time of the first injection in the LTE period. 
Efficacy and health outcomes data collected in the LTE period will be summarized for 
the ITT population who entered the LTE period without inferential statistics. 
All safety data will be descriptively summarized using the LTE safety population, defined as 
ITT participants who receive at least 1 dose of ixekizumab in the LTE period. 
 
10.3.1.4. General Considerations for the Post-Treatment Follow-up (PTFU) 
Period  
For the safety analyses during the PTFU period, baseline is defined as the last non-missing 
assessment on or prior to entering the PTFU period, that is, on or prior to Week 104 (Visit 
29), or ETV. 
Safety data will be summarized using descriptive statistics without inferential statistics 
by the study treatment the participant was receiving prior to entering PTFU period. 
Safety baseline is defined as the last available value immediately before entering PTFU 
period. 
10.3.1.5. Missing Data Imputation Methods  
10.3.1.5.1. Non-responder Imputation for Clinical Response  
Summaries for all categorical efficacy and health outcomes variables will include a 
summary that uses a nonresponder imputation (NRI) approach. In this approach, 
participants will be considered a non-responder if they do not meet the clinical response 
criteria at any specified analysis time point. Participants without at least 1 observation on 
study treatment will also be defined as a non-responder for the NRI analysis. All 
participants who discontinue the study treatment will be defined as non-responders for 
the NRI analysis for categorical variables, such as JIA ACR 30/50/70/90/100, from the 
time of discontinuation and onward. 
10.3.1.5.2. Modified Baseline Observation Carried Forward  
Summaries for all continuous efficacy and health outcomes variables will include a 
summary that uses a modified baseline observation carried forward (mBOCF) approach. 
In this approach, the baseline observation will be carried forward to the corresponding 
endpoint for evaluation for participants who discontinue study treatment due to an AE. 
10.3.1.5.3. Last Observation Carried Forward  
The last non-missing observation before discontinuation of study treatment will be carried 
forward (LOCF) to the corresponding endpoint for evaluation of participants who 
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discontinue study treatment for any reason other than due to an AE. Participants without at 
least 1 post baseline observation will not be included for evaluation, except for 
participants who discontinue study treatment due to an AE. 
10.3.2. Treatment Group Comparability  
10.3.2.1. Participant Disposition  
The number of participants along with enrolled, ITT, OLE, LTE, PTFU, and switchers 
populations will be summarized. Frequency counts and percentages will be presented. 
All participants who discontinue from the study will be identified, and the extent of 
their participation in the study will be reported along with their reason for 
discontinuation. Reasons for discontinuation from the study will be summarized. 
10.3.2.2. Participant Characteristics  
Participant characteristics and baseline clinical measures will be summarized by treatment 
group. Baseline characteristics will include gender, age, height, weight, body mass index 
(BMI), race, geographic region, and subtype of JIA (ERA, JPsA). Baseline clinical 
measurements may include the following: 
 previous DMARD experience (bDMARD, csDMARD), 
 concurrent csDMARDs use (in total and by individual csDMARDs such as 
MTX and SSZ), 
 JIA ACR core set 
 PASI 
 BSA 
 LEI 
 total and tender dactylitic digit count. 
10.3.2.3. Concomitant Therapy  
Previous and concomitant medications will be summarized for participants who enter 
each treatment period and presented by World Health Organization (WHO) Anatomic 
Therapeutic Class Level 1 and generic name. 
10.3.2.4. Treatment Compliance  
Treatment compliance with investigational product will be summarized for each 
treatment period. Participant compliance with investigational product will be assessed 
at each visit. Participants will be considered compliant for each study period if they 
miss <20% of the expected doses, do not miss 2 consecutive doses, and do not 
overdose. Proportions of participants compliance will be summarized. Participant 
compliance will be further defined in the SAP. 
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10.3.3. Efficacy Analyses  
10.3.3.1. Primary Analyses  
The primary efficacy endpoint is the percentage of ixekizumab treated participants 
meeting JIA ACR 30 response criteria at Week 16, as defined in Section 9.1.1. A 
Bayesian analysis will be utilized to assess the primary endpoint of JIA ACR 30 response 
rate at Week 16. A positive study will satisfy at least 80% posterior probability that the 
JIA ACR 30 response rate in ixekizumab-treated participants is greater than 50%. The 
posterior distribution will be computed using the relatively noninformative Jeffreys’ prior, 
Beta (0.5, 0.5). 
10.3.3.2. Secondary Analyses  
Secondary efficacy and health outcomes analyses will be based on study periods and 
study populations as outlined in Table RHCG.10.2. 
Table RHCG.10.2. 
Secondary Efficacy and Health Outcomes 
Analyses OLT, OLE, and LTE Periods 
 
Abbreviations: ITT = intent-to-treat; LTE = long-term extension; OLE = open-label extension; OLT = 
open-label treatment. 
 
For the OLT period, summary statistics will be performed for endpoints at each participant 
visit as outlined in Table RHCG.10.3. 
Table RHCG.10.3. 
Summary Statistics OLT Period 
 
Efficacy Measure 
Population 
JIA ACR 30/50/70/90/100 response from baseline 
ITT Population 
Change from baseline for individual JIA ACR 
components 
ITT Population 
Proportion of participants with disease flare 
ITT Population 
Change from baseline in PASI 
ITT Population – Participants with plaque psoriasis 
(at least 3% BSA) at baseline 
Change from baseline in LEI 
ITT Population – Participants with enthesitis at 
baseline 
Abbreviations: ACR = American College of Rheumatology; BSA = body surface area; ITT = intent-to-
treat; JIA = juvenile idiopathic arthritis; LEI = Leeds Enthesitis Index; OLT = open-label treatment; 
PASI = Psoriasis Area and Severity Index. 
 
Study Period 
Analysis Population 
OLT period 
ITT population 
OLE period 
OLE period population 
OLE period 
Adalimumab switcher 
LTE period 
LTE period population 
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For the OLE period, summary statistics will be performed for the endpoints at each 
participant visit as outlined in Table RHCG.10.4: 
Table RHCG.10.4. 
Summary Statistics OLE Period 
 
Efficacy Measure 
Population 
JIA ACR 30/50/70/90/100 response from baseline 
OLE period population 
Change from baseline for individual JIA ACR 
components 
OLE period population 
Proportion of participants with disease flare 
OLE period population 
Change from baseline in PASI 
OLE period population – participants with plaque 
psoriasis (at least 3% BSA) at baseline 
Change from baseline in LEI 
OLE period population – participants with enthesitis 
at baseline 
Abbreviations: ACR = American College of Rheumatology; BSA = body surface area; JIA = juvenile 
idiopathic arthritis; LEI = Leeds Enthesitis Index; OLE = open-label extension; PASI = Psoriasis Area 
and Severity Index. 
 
Analyses for the PTFU period will be described in the SAP. 
Table RHCG.10.5 
Summary Statistics: Long-Term Extension Period 
 
Efficacy Measure 
Population 
JIA ACR 30/50/70/90/100 response from baselinea 
LTE population 
Change from baseline for individual JIA ACR 
components 
LTE population 
Change from baseline in PASI 
LTE population – Participants with plaque psoriasis (at 
least 3% BSA) at baseline 
Change from baseline in LEI 
LTE population – Participants with enthesitis at 
baseline 
Abbreviations: ACR = American College of Rheumatology; BSA = body surface area; JIA = juvenile 
idiopathic arthritis; LEI = Leeds Enthesitis Index; LTE = long-term extension; PASI = Psoriasis Area 
and Severity Index. 
a 
Baseline for all the measures in this table = baseline of the originating study. 
 
 
Analyses for the PTFU period will be described in the SAP. 
10.3.3.3. Exploratory Analyses  
Analyses will be conducted for the exploratory efficacy objectives as defined in 
Section 4. Complete details will be described in the SAP. 
10.3.4. Safety Analyses  
Safety, including the following but not limited to, will be summarized: 
 infections, 
 injection-site reactions, 
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 B-, T-, and natural killer (NK)-cell levels 
 AEs, treatment emergent AEs (TEAEs) 
 SAEs, 
 AEs that lead to discontinuation, 
 Other AESIs, 
 WBC count and RBC count, 
 Laboratory analytes (including hematology and chemistry [including ALT and 
AST], neutrophil counts and immunogenicity), 
 Exposure to study drug, 
 CDI-2 score 
 C-SSRS 
 self-harm, 
 vital signs, and 
 growth and maturation (including growth velocity). 
Immunization history will be summarized at baseline, and any unexpected outcomes or 
effects related to standard-of-care vaccination will be summarized. 
Primary safety analyses will be summarized and analyzed by treatment groups 
(ixekizumab and adalimumab) as described in Section 10.3.1.1 for the OLT safety 
population in the OLT period and Section 10.3.1.2 for the OLE period population in the 
OLE period. 
Summaries of safety data collected during the PTFU period will be presented for the 
PTFU period population. 
10.3.4.1. Adverse Events  
Adverse events are considered TEAEs if they first occur or worsen after the start of 
treatment during a study period. In the case of a missing onset date for an AE, an AE with 
a start date equal to or greater than the dosing date will be considered a TEAE. For each 
TEAE, the severity is recorded according to the participant’s or physician’s perceived 
severity of the event (mild, moderate, or severe). 
Treatment-emergent adverse events, SAEs including deaths, AEs that lead to 
investigational product discontinuation, and AEs by maximum severity and relationship 
to investigational product will be summarized by the Medical Dictionary for Regulatory 
Activities System Organ Class (SOC) and Preferred Term (PT). Treatment-emergent 
adverse events will also be summarized by PT sorted by decreasing frequency within 
SOC for all TEAEs, TEAEs by maximum severity, and TEAEs considered possibly 
related to study drug. For events that are gender specific, the denominator and 
computation of the percentage will include only participants from the given gender. 
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Medical Dictionary for Regulatory Activities groupings of PTs will be used to 
investigate AESIs. 
Adverse events of special interest will also be presented by severity. Adverse events of 
special interest will include cytopenias, liver function test changes/enzyme elevations, 
infections, immunogenicity, injection site reactions, allergic/hypersensitivity reactions, 
cerebrocardiovascular events, malignancies, depression, IBD, and interstitial lung 
disease. 
10.3.4.2. Clinical Laboratory Tests  
Laboratory assessments will be presented as mean changes from baseline and as 
incidence of treatment-emergent abnormal, high, or low laboratory values. 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: 
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 presented as mean changes from baseline and as incidence of 
abnormal values. 
CDI-2 total scores will be summarized as mean changes from baseline. Columbia 
Suicide Severity Rating Scale responses will be listed by participants and visit. Only 
participants that show suicidal ideation/behavior or self-injurious behavior with suicidal 
intent will be displayed (i.e., if a participant answers are all “no” for the C-SSRS, then 
that participant will not be displayed). Self-Harm Follow-Up Form will be listed. 
Other data, including body weight and height will be summarized. Weight, height, and 
BMI data will be merged to the Centers for Disease Control and Prevention standard 
growth data by age and gender to compare participants’ growth with the standard. 
Further analyses may be performed. 
 
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses  
Observed ixekizumab serum trough concentrations will be summarized by time point 
across the study. Data may also be summarized by weight category, disease, and age as 
deemed appropriate. 
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In addition, the clearance of ixekizumab in this participant population may be determined 
using population PK methods. If this analysis is conducted, then the data from this study 
may be combined with data from prior studies to aid in model development. 
The exposure-response relationship will be investigated between steady-state trough 
concentrations of ixekizumab and JIA ACR 30 response using graphical methods and, 
if appropriate, modeling methods. Evaluation of additional time points or endpoints 
may also be considered. 
If applicable, the potential impact of immunogenicity on ixekizumab exposure may be 
evaluated by graphical assessments, as appropriate, to compare drug exposure between 
antidrug antibodies (ADA-) negative and TE-ADA-positive participants at corresponding 
visits. 
Additional analyses may be performed upon receipt of the data. 
Details about the analyses to be conducted will be contained in the PK/PD analysis plan. 
 
10.3.6. Evaluation of Immunogenicity  
Treatment-emergent antidrug antibody is defined as any occurrence of a 4-fold (2-
dilution) increase in titer over the pretreatment baseline titer. In the case of a negative 
result at baseline, treatment-emergent immunogenicity is defined as an increase in titer 
to ≥1:10. 
The analyses of TE-ADA effects will be conducted on all evaluable participants within the 
defined safety population. Evaluable participants will be identified as positive, negative, or 
inconclusive for TE-ADA and neutralizing antidrug antibody (NAb), as well as low, 
moderate, or high titer (as defined in the SAP). The incidence of participants with positive, 
negative, or inconclusive TE-ADA and NAb and low, moderate, or high titer at baseline 
and postbaseline will be summarized by treatment group. 
10.3.7. Other Analyses  
10.3.7.1. Subgroup Analyses  
For both treatments (ixekizumab and adalimumab), summary statistical analyses will 
be conducted for JIA ACR 30 at each regular visit for the following subset of 
participants: ERA and JPsA. Additional subgroups may be described in the SAP. 
10.3.7.2. Exploratory Analysis  
Analyses will be conducted for the exploratory efficacy objectives as defined in Section 
4. Complete details will be described in the SAP. 
10.3.8. Interim Analyses  
An interim analysis may be performed at the time (that is, a cut-off date) the last 
participant completes the OLT period. 
An interim analysis will be performed to determine if the study should be stopped for 
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futility when 40 ixekizumab-treated participants have completed 16 weeks of treatment. If 
the observed JIA ACR 30 response rate is less than 40% at interim, futility will be 
declared, and the study will be terminated, after the applicable required regulatory 
agreements are obtained. Due to the open-label feature, and because there is no stopping 
rule for early efficacy, there will be no adjustment for multiple testing in the interim 
analysis or final Bayesian primary analyses. 
A DMC will oversee the conduct of Study RHCG. The DMC will consist of members 
external to Lilly. This DMC will follow the rules defined in the DMC charter, focusing 
on potential and identified risks for this molecule and for this class of compounds. The 
DMC will review and evaluate planned interim analyses. 
Data that the DMC will review include, but is not limited to, study discontinuation data, 
AEs including SAEs, clinical laboratory data, vital signs data, and growth. The DMC 
may recommend continuation of the study as designed, temporary suspension of 
enrollment, or discontinuation of a particular dose regimen or discontinuation of the 
entire study. The DMC may request to review efficacy data to investigate the benefit/risk 
relationship in the context of safety observations for ongoing participants in the study. 
Details of the DMC and interim safety analyses will be documented in a DMC charter 
and DMC analysis plan. 
Additional analyses and snapshots of study data may be performed after the planned 
interim analysis to inform the need for an additional interim analysis, and after all 
participants complete OLT period (Week 16) to fulfill the need for regulatory interactions 
or publication purposes. 
10.3.9. Adjudication Committee 
Data on suspected IBD as identified by events possibly indicative of ulcerative colitis or 
Crohn’s disease will be collected, and the events will be adjudicated by an external CEC 
composed of gastroenterologists with expertise in IBD. 
Details of membership, operations, recommendations from the Committee, and the 
communication plan will be documented in the CEC charter. 
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Nordal EB, Zak M, Aalto K, Berntson L, Fasth A, Herlin T, Lahdenne P, Nielsen S, 
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Paller AS, Seyger MMB, Magariños GA, Bagel J, Pinter A, Cather J, Keller S, 
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Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, He X, 
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12. Appendices  
 
 
Appendix 1. 
Abbreviations  
 
 
Term 
Definition 
abuse 
use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
ACR 
American College of Rheumatology 
ACR 30 
30% improvement in American College of Rheumatology criteria 
active joint 
Joint that is swollen, or in the absence of swelling, has loss of passive motion 
accompanied by either pain on motion or joint tenderness 
ADA 
antidrug antibodies 
AE 
adverse event: Any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
(new or exacerbated) temporally associated with the use of a study intervention. 
AESI 
adverse events of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AS 
ankylosing spondylitis 
assent 
Affirmative agreement of a child to participate in research or to undergo a medical 
intervention. Lack or absence of expression of dissent or objection must not be 
interpreted as assent. When obtaining child assent, relevant elements of informed 
consent should be provided appropriate to the child’s capability to understand 
(ICH 2016). 
AST 
aspartate aminotransferase 
axSpA 
axial spondyloarthritis 
bDMARD 
biologic disease-modifying antirheumatic drug 
bDMARD-IR 
inadequate response or intolerance to at least one prior bDMARD 
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blinding/masking 
A single-blind study is one in which investigators and/or staff are aware of the 
treatment but the participant is not, or vice versa, or when the sponsor is aware of the 
treatment but investigators and/or staff and the participant are not. A double-blind 
study is one in which neither the participant nor any of the investigators or sponsor 
staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received. 
BMI 
body mass index 
BSA 
body surface area 
C-CASA 
Columbia Classification Algorithm of Suicide Assessment 
CDI-2 
Children’s Depression Inventory 2 Short Form 
CEC 
Clinical Events Committee 
cGMP 
good manufacturing practices 
CHAQ 
Childhood Health Assessment Questionnaire 
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. 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
case report form 
CRP 
C-reactive protein 
CRS 
Clinical Research Scientist 
C-SSRS 
Columbia Suicide Severity Rating Scale 
csDMARD 
conventional synthetic disease-modifying antirheumatic drug 
CT 
computed tomography 
CTFG 
Clinical Trial Facilitation Group 
disease flare 
Worsening of 30% or more in at least 3 of the 6 JIA ACR core criteria for JIA and an 
improvement of 30% or more in no more than 1 of the criteria 
DMARD 
disease-modifying antirheumatic drug 
DMC 
data monitoring committee 
eCRF 
electronic case report form 
enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
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enter 
Participants entered into a study are those who sign the informed consent form 
directly or through their legally acceptable representatives. 
EQ-5D-Y 
European Quality of Life-Five Dimensions–Youth 
ERA 
enthesitis-related arthritis 
ESR 
erythrocyte sedimentation rate 
ETV 
early termination visit 
FABER 
flexion, abduction and external rotation 
FACTS™ 
Fixed and Adaptive Clinical Trials Simulator version 6.0 
FDA 
Food and Drug Administration 
GDPR 
EU General Data Protection Regulation 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B virus surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HLA-B27 
human leukocyte antigen-B27 
hsCRP 
high-sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
IBD 
inflammatory bowel disease 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
Ig 
Immunoglobulin 
IgG4 
immunoglobulin G subclass 4 
IL 
Interleukin 
ILAR 
International League of Associations for Rheumatology 
IMP 
Investigational Medicinal Product (see also “investigational product”) 
A medicinal product which is being tested or used as a reference, including as a 
placebo, in a clinical trial. 
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investigational product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical study, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. 
IR 
inadequate response 
IRB 
Institutional Review Board 
ITT 
intent-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 participant (that is, 
the planned treatment regimen) rather than the actual treatment given. It has the 
consequence that participants allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to 
the planned course of treatment. 
IWRS 
interactive web-response system 
JADAS-27 
Juvenile Arthritis Disease Activity Score-27 
JAK 
Janus kinase 
JIA 
juvenile idiopathic arthritis 
JIA ACR 30 
30% improvement in American College of Rheumatology criteria 
JoAS 
juvenile onset ankylosing spondylitis 
JPsA 
juvenile psoriatic arthritis 
JSpA 
juvenile spondyloarthritis 
JSpADA 
Juvenile Spondyloarthritis Disease Activity Index 
LEI 
Leeds Enthesitis Index 
LOCF 
last non-missing observation carried forward 
LTE 
long-term extension 
mBOCF 
modified baseline observation carried forward 
medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
Informed consent 
A process by which a participant voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study 
that are relevant to the participant’s decision to participate. Informed consent is 
documented by means of a written, signed and dated informed consent form. 
INR 
international normalized ratio 
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. 
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error leads to an AE. Medication error generally involve a failure to uphold 1 or more 
of the 5 “rights” of medication use: the right participant, the right drug, the right dose, 
right route, at the right time. 
In addition to the core 5 rights, the following may also represent medication errors:  
• dose omission associated with an AE or a product complaint 
• dispensing or use of expired medication 
• use of medication past the recommended in-use date 
• dispensing or use of an improperly stored medication 
• use of an adulterated dosage form or administration technique inconsistent with the 
medication’s labeling (for example, Summary of Product Characteristics, IB, local 
label, protocol), or 
• shared use of cartridges, prefilled pens, or both. 
misuse 
Use of a study intervention for self-treatment that either is inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a prescription 
MRI 
magnetic resonance imaging 
MTX 
Methotrexate 
NAb 
neutralizing antidrug antibody 
NIMH 
National Institute of Mental Health 
NRI 
nonresponder imputation 
NSAID 
nonsteroidal anti-inflammatory drug 
OLE 
open-label extension 
OLT 
open-label treatment 
PASI 
Psoriasis Area and Severity Index 
PC 
product complaint 
PD 
Pharmacodynamic 
PIP 
Paediatric Investigation Plan 
PK 
pharmacokinetic(s) 
PPD 
purified protein derivative 
PsA 
psoriatic arthritis 
PT 
Preferred Term 
PTFU 
post-treatment follow-up 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
RA 
rheumatoid arthritis 
r-axSPA 
radiographic axial spondyloarthritis 
RF 
rheumatoid factor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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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. 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SpA 
Spondyloarthritis 
SSZ 
Sulfasalazine 
SUSAR 
suspected unexpected serious adverse reaction 
Refers to an adverse event that occurs in a clinical trial participant, which is assessed 
by the sponsor and or study investigator as being unexpected, serious and as having a 
reasonable possibility of a causal relationship with the study intervention. 
TASA 
Treatment of Adolescent Suicide Attempters 
TB 
Tuberculosis 
TBL 
total bilirubin level 
TE-ADA 
treatment-emergent antidrug antibody 
TEAE 
treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment. 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
USPI 
US package insert 
VAS 
Visual Analogue Scale 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
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Appendix 2. 
Clinical Laboratory Tests  
 
 
The tests detailed in the table below will be performed by the central laboratory. 
● In circumstances where the sponsor approves local laboratory testing in 
lieu of central laboratory testing (in the table below), the local 
laboratory must be qualified in accordance with applicable local 
regulations. 
● Protocol-specific requirements for inclusion or exclusion of 
participants are detailed in Section 6 of the protocol. 
● Additional tests may be performed at any time during the study as 
determined necessary by the investigator or required by local 
regulations. 
● Investigators must document their review of the laboratory safety results. 
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  Clinical Laboratory Tests 
 
Hematologya,b,c 
Clinical Chemistrya,b,c 
Hemoglobin 
Serum Concentrations of: 
Hematocrit 
Sodium 
Erythrocyte count (RBC) 
Potassium 
Mean cell volume 
Total bilirubin 
Mean cell hemoglobin concentration 
Direct bilirubin 
Leukocytes (WBC) 
Alkaline phosphatase 
Neutrophils, segmented 
Neutrophils, juvenile (bands) 
Alanine aminotransferase (ALT) 
Lymphocytes 
Aspartate aminotransferase (AST) 
Monocytes 
Blood urea nitrogen (BUN) 
Eosinophils 
Creatinine 
Basophils 
Uric acid 
Platelets 
Calcium 
Glucose 
Urinalysisa,b,c,d 
Albumin 
Specific gravity 
Cholesterol 
pH 
Creatine kinase (CK) 
Protein 
Glucose 
Pregnancy Test (females only)c,e 
Ketones 
Serum pregnancy test 
Urine pregnancy test 
Blood 
Urine leukocyte esterase 
Other Tests 
Human immunodeficiency virus antibodyf 
Hepatitis B surface antigen (HBsAg)f 
Cell Flow Cytometry 
Hepatitis B surface antibodyf 
(B cells, T cells, CD4+T cells, CD8+T cells, 
Hepatitis B core antibodyf 
and NK cells) 
Hepatitis C virus antibodyf,g 
Hepatitis B virus DNAh 
High sensitivity C-reactive protein (hsCRP)i 
HLA-B27 
QuantiFERON®-TB Gold or T-Spot or PPDj 
Acute phase reactant (ESR)k 
Pharmacokinetic sample 
 
Abbreviations: ESR = erythrocyte sedimentation rate; HLA-B27 = human leukocyte antigen-B27; NK = 
natural killer; PPD = purified protein derivative; RBC = red blood cells; TB = tuberculosis; WBC = 
white blood cells. 
a Assayed by Lilly-designated laboratory. 
b Results will be confirmed by the central lab at the time of initial testing. 
c Unscheduled or repeat blood chemistry, hematology, and urinalysis panels may be performed at the 
discretion of the investigator, as needed. 
d Microscopic examination of sediment performed only if abnormalities are noted on the routine urinalysis. 
e Serum pregnancy test will be performed centrally at screening only, prior to the first dose of the study 
intervention, for all females aged ≥10 years (<10 years at investigator’s discretion) if menarche is 
reached or if there is reason to believe that the participant is sexually active. After screening, urine 
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pregnancy test will be performed locally for females of childbearing potential. As per Clinical Trial 
Facilitation Group (CTFG) recommendation: In each case of delayed menstrual period (over 1 month 
between menstruations), confirmation of absence of pregnancy is strongly recommended. This 
recommendation also applies to women of childbearing potential with infrequent or irregular menstrual 
cycles. 
f Test required at Visit 1 only to determine eligibility of participant for the study. 
g A positive hepatitis C antibody result will be confirmed with presence of HCV RNA. 
h HBV DNA testing will be done on those participants who are HBcAb+ at screening. For participants 
who are positive for HBcAb, a follow-up test for HBV DNA is required. Participants with a positive 
HBcAb will return to the site and have HBV DNA samples drawn, which will be processed centrally. 
Any enrolled participant who is HBcAb positive, regardless of HBsAb status or level, must undergo 
HBV DNA testing per the schedule. 
i Test results of hsCRP and lymphocyte subsets will be blinded after Week 16 and the test results will not 
be sent to the study sites. 
j 
As stated in the Schedule of Activities (Section 2), TB testing is required only based on clinical 
assessment of TB risk and according to local regulations and/or local standard of care (Section 9.4.5). For 
countries where the QuantiFERON®-TB Gold test is not available the T-Spot or PPD test may be used.T-
Spot or PPD to be performed/read locally. 
k Sponsor-provided; assayed by clinical study site. 
Recommended Laboratory Testing for Hypersensitivity Events  
Lab testing should be performed at the time of a Systemic Hypersensitivity Event. 
Important information about why, when, and what to test for are provided below. The 
management of the adverse event may warrant lab testing beyond that described below 
and should be performed as clinically indicated. 
Laboratory testing during a Systemic Hypersensitivity Event is not performed for 
diagnostic purposes. Its intent is several fold: 
 To help characterize and classify systemic hypersensitivity reactions 
 To meet regulatory expectations 
 To improve subsequent clinical management by helping to distinguish 
between the various mechanistic bases of anaphylaxis 
When should labs be obtained? 
 In the presence of generalized urticaria or if anaphylaxis is suspected* 
 After the participant has been stabilized, obtain a sample within 1 to 2 hours of the 
event, however, samples may be obtained as late as 12 hours after the event as 
analytes can remain altered for an extended period of time. Record the time at 
which the sample was collected. 
 Obtain a follow-up sample at the next regularly scheduled visit or after 4 
weeks, whichever is later. 
What labs should be obtained? 
 tryptase* 
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
antidrug antibody (ADA) and LY2439821 (LY) concentration (pharmacokinetic)
o
ADA testing should include drug-specific immunoglobulin E (IgE)
o
If a drug-specific IgE assay isn’t available, a commercially available
alternative test that can indicate the presence of drug specific IgE in
serum is the basophil activation test (BAT)#.

complement
o
C3a and C5a

cytokines
o
Interleukin (IL)‐6, IL‐1β, IL‐10 (or any cytokine panel that includes
these 3 cytokines)
*If a tryptase sample is obtained more than 2 hours after the event (that is, within 2-12
hours), or is not obtained because more than 12 hours have lapsed since the event, obtain
urine for N- methylhistamine (NMH) testing. Note that for tryptase serum samples
obtained within 2 to 12 hours of the event, urine NMH testing is performed in addition to
tryptase testing. Collect the first void urine following the event. Obtain a follow-up urine
for NMH testing at the next regularly scheduled visit or after 4 weeks, whichever is later.
#The BAT is an in vitro cell-based assay that only requires a serum sample. It is a 
surrogate assay for drug-specific IgE but is not specific for IgE. If an in vivo assay is 
called for, the passive cutaneous anaphylaxis (PCA) assay may be performed in rodents 
or NHP, is commercially available, and only requires a serum sample. Skin prick testing 
in humans is a sensitive and specific assay for drug-specific IgE but requires 
qualification of the method in negative controls and participants with documented Type 
I hypersensitivity to the drug. 
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Appendix 3. 
Study Governance Considerations  
 
Regulatory, Ethical, and Study Oversight Conditions  
Regulatory and Ethical Considerations  
 This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
o Applicable ICH Good Clinical Practice (GCP) Guidelines 
o Applicable laws and regulations 
 The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 
 Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants. 
 Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate 
an immediate hazard to study participants. 
 The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and 
adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and 
all other applicable local regulations 
o Reporting to the sponsor or designee significant issues related to 
participant safety, participant rights, or data integrity. 
Financial Disclosure  
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
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Informed Consent Process  
 The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the participant and the participant’s 
legally authorized representative, defined as parent(s) or legal guardian, and 
answer all questions regarding the study. 
 Participants must be informed that their participation is voluntary. Participants 
or their representative, parent(s), or legal guardian will be required to provide a 
statement of informed consent/assent that meets the requirements of 21 Code of 
Federal Regulations 50, local regulations, ICH guidelines, privacy and data 
protection requirements, where applicable, and the IRB/IEC or study center. 
 The medical record must include a statement that legally acceptable representative, 
parent(s), or legal guardian consent and child/adolescent assent (if deemed 
appropriate by local ethics review) was obtained. The medical record should also 
describe how the clinical investigator determined that the person signing the ICF 
was the participant’s legally acceptable representative, parent(s), or legal guardian. 
The acceptable person obtaining the informed consent must also sign the ICF. The 
person obtaining the informed consent must also sign the ICF. 
 Participants and their legally acceptable representative, parent(s), or legal 
guardian must be reconsented and reassented to the most current version of the 
ICF(s) during their participation in the study. 
 Minor participants must be reconsented if they reach the age of majority during the 
study, in order to continue participating. A copy of the ICF(s) must be provided to 
the participant or the participant’s legally acceptable representative, parent(s), or 
legal guardian. 
Data Protection  
 Participants will be assigned a unique identifier by the sponsor to protect the 
participant’s personal data. Any participant information, such as records, datasets, 
or tissue samples that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant 
identifiable will not be transferred. 
 The participant must be informed that the participant’s personal study-related data 
will be used by the sponsor in accordance with local data protection law. The level 
of disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent. This is done 
by the site personnel through the informed consent process. 
 The participant must be informed through the informed consent by the site personnel 
that their medical records may be examined by Clinical Quality Assurance auditors 
or other authorized personnel appointed by the sponsor, by appropriate IRB/IEC 
members, and by inspectors from regulatory authorities. 
 The sponsor has processes in place to ensure information security, data integrity, 
and data protection. These processes address management of data transfer, and 
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prevention and management of unauthorized access, disclosure, dissemination, 
alteration or loss of information or personal data. These processes include 
appropriate contingency plan(s) for appropriate and timely response in the event 
of a data security breach. 
 The transfer of personal data is subject to appropriate safeguards through contractual 
agreements and processes. The sponsor’s processes are compliant with local privacy 
laws and relevant legislations including the General Data Protection Regulation 
(GDPR). 
Rationale for collection of full date of birth  
This study includes participants aged from 2 years to <18 years. Within this vast age 
range, participants’ expected height and weight, as well as normal ranges for laboratory 
tests, vary by both age and sex. Therefore, it is necessary to collect the full date of birth 
(day, month, and year) for all pediatric participants to appropriately analyze and interpret 
changes in growth and laboratory parameters. 
 In countries where local regulations do not permit collection of the full date of 
birth, providing the supporting regulatory/ethics documentation is available, at a 
minimum, the month and year of birth must be collected on the eCRF. 
Dissemination of Clinical Study Data  
Reports 
The sponsor will disclose a summary of study information, including tabular study 
results, on publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or 
regulation. If the study remains ongoing in some countries and a statistical analysis of an 
incomplete data set would result in analyses lacking scientific rigor (for example, 
underpowered) or compromise the integrity of the overall analyses (for example, trial not 
yet unblinded), the summary of results will be submitted within 1 year after the end of the 
study globally or as soon as available, whichever is earlier. 
Data 
The sponsor provides access to all individual participant data collected during the trial, 
after anonymization, with the exception of PK or genetic data. 
Data are available to request 6 months after the indication studied has been approved in 
the European Union and after primary publication acceptance, whichever is later. No 
expiration date of data requests is currently set once data are made available. 
Access is provided after a proposal has been approved by an independent review 
committee identified for this purpose and after receipt of a signed data sharing 
agreement. 
Data and documents, including the study protocol, SAP, clinical study report, and blank 
or annotated case report forms, will be provided in a secure data sharing environment 
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for up to 2 years per proposal. 
For details on submitting a request, see the instructions provided at www.vivli.org. 
Data Quality Assurance  

All participant data relating to the study will be recorded on printed or
electronic CRF unless transmitted to the sponsor or designee electronically (for
example, laboratory data). The investigator is responsible for verifying that
data entries are accurate and correct by physically or electronically signing the
CRF. The investigator must maintain accurate documentation (source data) that
supports the information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/IEC
review, and regulatory agency inspections and provide direct access to
source data documents.

Monitoring details describing strategy (for example, risk-based initiatives in
operations and quality such as Risk Management and Mitigation Strategies and
Analytical Risk- Based Monitoring), methods, responsibilities, and
requirements, including handling of noncompliance issues and monitoring
techniques are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study
including quality checking of the data.

The sponsor assumes accountability for actions delegated to other
individuals (for example, Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that
data transcribed into the CRF by authorized site personnel are accurate,
complete, and verifiable from source documents; that the safety and rights of
participants are being protected; and that the study is being conducted in
accordance with the currently approved protocol and any other study
agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this
study must be retained by the investigator for the time period outlined in the
Clinical Trial Agreement unless local regulations or institutional policies
require a longer retention period. No records may be destroyed during the
retention period without the written approval of the sponsor. No records may be
transferred to another location or party without written notification to the
sponsor.

In addition, Sponsor or its representatives will periodically check a sample of
the participant data recorded against source documents at the study site. The
study may be audited by Sponsor or its representatives, and/or regulatory
agencies at any time. Investigators will be given notice before an audit occurs.
Data Capture System  
The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
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timeliness of the data reported to the sponsor. 
An electronic data capture system (EDC) will be used in this study for the collection of 
CRF data. The investigator maintains a separate source for the data entered by the 
investigator or designee into the sponsor-provided EDC system. The investigator is 
responsible for the identification of any data to be considered source and for the 
confirmation that data reported are accurate and complete by signing the CRF. 
Additionally, clinical outcome assessment (COA) data (participant-focused outcome 
instrument) will be collected via a paper source document and will be transcribed by the 
investigator site personnel into the EDC system. 
Additionally, electronic Clinical Outcome Assessment (eCOA) data (participant-focused 
outcome instrument) will be directly recorded into an instrument per the Schedule of 
Activities (for example, hand-held device). The eCOA data will serve as the source 
documentation and the investigator does not maintain a separate, written or electronic 
record of these data. 
Data collected via the sponsor-provided data capture systems will be stored at third 
parties. The investigator will have continuous access to the data during the study and 
until decommissioning of the data capture systems. Prior to decommissioning, the 
investigator will receive an archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored 
electronically in the central vendor’s database system and reports/electronic transfers 
will be provided to the investigator for review and retention. Data will subsequently be 
transferred from the central vendor to the Sponsor data warehouse. 
Data from complaint forms submitted to Sponsor will be encoded and stored in the 
global product complaint management system. 
Source Documents  
 Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
 Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
 Definition of what constitutes source data can be found in the Data Quality 
Assurance Section above. 
Study and Site Start and Closure  
The sponsor or sponsor’s designee reserves the right to close the study site or terminate the 
study at any time for any reason at the sole discretion of the sponsor. Study sites will be 
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closed upon study completion. A study site is considered closed when all required 
documents and study supplies have been collected and a study-site closure visit has been 
performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For study termination: 

Discontinuation of further study intervention development.
For site termination: 

Failure of the investigator to comply with the protocol, the requirements of the
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment (evaluated after a reasonable amount of time) of
participants by the investigator

Total number of participants included earlier than expected.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The Investigator shall promptly inform the 
participant and should assure appropriate participant therapy and/or follow-up. 
Publication Policy 
In accordance with the sponsor’s publication policy the results of this study will be submitted 
for publication by a peer-reviewed journal. 
Investigator Information 
Physicians with experience in the diagnosis and treatment of rheumatology and 
pediatric rheumatology will participate as investigators in this clinical trial. 
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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 participants in consultation with Lilly, or its 
designee’s, clinical research physician. 
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs - red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs - white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
Lymphocytes 
Creatine kinase (CK) 
Monocytes 
Other Chemistry 
Basophils 
Acetaminophen 
Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl alcohol (EtOH) 
Prothrombin time, INR (PT-INR) 
Haptoglobin 
Serology 
Immunoglobulin A (IgA, quantitative) 
Hepatitis A virus (HAV) testing: 
Immunoglobulin G (IgG, quantitative) 
HAV total antibody 
Immunoglobulin M (IgM, quantitative) 
HAV IgM antibody 
Phosphatidylethanol (PEth) 
Hepatitis B virus (HBV) testing: 
Urine Chemistry 
Hepatitis B surface antigen (HBsAg) 
Drug screen 
Hepatitis B surface antibody (anti-HBs) 
Ethyl glucuronide (EtG) 
Hepatitis B core total antibody (anti-HBc) 
Other Serology 
Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA) 
Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA)a
HBV DNAc
Anti-actin antibodyb
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Hematology 
Clinical Chemistry 
Hepatitis C virus (HCV) testing: 
Epstein-Barr virus (EBV) testing: 
HCV antibody 
EBV antibody 
HCV RNAc 
EBV DNAc 
Hepatitis D virus (HDV) testing: 
Cytomegalovirus (CMV) testing: 
HDV antibody 
CMV antibody 
Hepatitis E virus (HEV) testing: 
CMV DNAc 
HEV IgG antibody 
Herpes simplex virus (HSV) testing: 
HEV IgM antibody 
HSV (Types 1 and 2) antibody 
HEV RNAc 
HSV (Types 1 and 2) DNAc 
Microbiologyd 
Liver kidney microsomal type 1 (LKM-1) antibody 
Culture: 
Blood 
Urine 
Abbreviation: INR = international normalized ratio. 
a Not required if anti-actin antibody is tested. 
b Not required if anti-smooth muscle antibody (ASMA) is tested. 
c Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
d Assayed ONLY by investigator-designated local laboratory; no central testing available. 
 
The Lilly-designated central laboratory must complete the analysis of all selected testing 
except for microbiology testing. 
Local testing may be performed in addition to central testing when necessary for 
immediate participant management. 
Results will be reported if a validated test or calculation is available. 
 
 
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Appendix 5. 
Adverse Events: Definitions and Procedures 
for Recording, Evaluating, Follow-Up, and 
Reporting 
 
 The definitions and procedures detailed in this appendix are in 
accordance with International Organization for Standardization (ISO) 
14155. 
 Both the investigator and the sponsor will comply with all local medical device 
reporting requirements. 
 The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices provided for use in the study. See Section 9.2 for the 
list of sponsor medical devices. 
Definition of AE  
 
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product and that does not necessarily have a causal relationship with the study 
intervention. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product. 
 An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory finding) in study participants, users, or other 
persons, whether or not related to the investigational medical device. This definition 
includes events related to the investigational medical device or comparator and events 
related to the procedures involved except for events in users or other persons, which only 
include events related to investigational devices. 
 
 
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is an intentional overdose taken with possible suicidal or self-harming intent. Such 
overdoses should be reported regardless of sequelae. 

Lack of efficacy or failure of expected pharmacological action per se will not be reported as an 
AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs,
symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or
SAE if they fulfil the definition of an AE or SAE.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety
assessments that are associated with the underlying disease, unless judged by the
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the
disease/disorder being studied, unless more severe than expected for the participant’s
condition.

Medical or surgical procedure (for example, endoscopy, appendectomy). Note: The
condition that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital). Anticipated day-to-day fluctuations of pre-
existing diseases or conditions present or detected at the start of the study that do not
worsen.
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. Results in death
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other
safety assessments (for example, ECG, radiological scans, vital signs measurements), including
those that worsen from baseline, considered clinically significant in the medical and scientific
judgment of the investigator (that is, not related to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an increase in
frequency and/or intensity of the condition.

New condition detected or diagnosed after study intervention administration even though it
may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug–drug interaction.

Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical sequelae.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention
or a concomitant medication. Overdose per se will not be reported as an AE or SAE unless it
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b. Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death, if the event were more severe. 
c. Requires in-participant hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to the hospital 
for observation and/or treatment that would not have been appropriate in the physician’s 
office or out-participant setting. Complications that occur during hospitalization are 
AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
 Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
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d. Results in persistent disability/incapacity 
 The term “disability” means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (for example, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
 Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
f. Other situations: 
 Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious.
 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
g. Resulted in medical or surgical intervention to prevent life-threatening illness or injury 
or permanent impairment to a body structure or a body function 
Definition of Product Complaints  
 
Product Complaint 
 A PC is any written, electronic, or oral communication that alleges deficiencies related to 
the identity, quality, durability, reliability, safety, effectiveness, or performance of a 
study intervention. When the ability to use the study intervention safely is impacted, the 
following are also PCs: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 PCs related to study interventions used in clinical trials are collected in order to ensure the 
safety of participants, monitor quality, and to facilitate process and product improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a PC or problem with the study intervention so that the situation can be assessed. 
 An event may meet the definition of both a PC and an AE/SAE. In such cases, it should 
be reported as both a PC and as an AE/SAE. 
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Recording and Follow-up of AE and/or SAE and Product Complaints  
 
AE, SAE, and PC Recording 
 When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (for example, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
 The investigator will then record all relevant AE/SAE information in the participant’s 
medical records, in accordance with the investigator’s normal clinical practice. AE/SAE 
information is reported on the appropriate CRF page and PC information is reported on the 
Product Complaint Form. 
Note: An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a PC and as an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor or designee in lieu of completion of the AE/SAE CRF page for 
AE/SAE and the PC Form for PCs. 
 There may be instances when copies of medical records for certain cases are requested by 
the sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before submission 
to the sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
 
 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
 Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
 Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, not when it is rated as severe. 
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Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 The investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration will be 
considered and investigated. 
 The investigator will also consult the Investigator’s Brochure (IB) in his/her assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor or designee. However, it is very 
important that the investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to Sponsor or designee. 
 The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
 
Follow-Up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested to elucidate the 
nature and/or causality of the AE or SAE as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
health care professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide a copy of any post-mortem findings including 
histopathology. 
 
Reporting of SAEs  
 
SAE Reporting via an Electronic Data Collection Tool 
 The primary mechanism for reporting an SAE to the sponsor or the sponsor’s designee will 
be the electronic data collection tool. 
 If the electronic system is unavailable or if a pregnancy is reported, then the site will use the 
paper SAE or pregnancy data collection tools to report the event within 24 hours. 
 The site will enter SAE data into the electronic system as soon as it becomes available. 
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 After the study is completed at a given site, the electronic data collection tool will be taken 
offline to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated data on 
a previously reported SAE after the electronic data collection tool has been taken offline, 
then the site can report this information on a paper SAE form or to the medical monitor or 
SAE by telephone. 
 Contacts for SAE reporting can be found in the site training documents. 
Reporting of SAEs  
 
SAE Reporting via Paper Form 
 Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the medical monitor or the SAE coordinator. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in the site training documents. 
Regulatory Reporting Requirements  
 
SAE Regulatory Reporting 
 Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities toward the safety of participants and 
the safety of a study intervention under clinical investigation are met. 
● The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under 
clinical investigation. The sponsor will evaluate the reported SAEs, including 
confirmation of relatedness and assessment of expectedness. The sponsor has 
processes for safety reports for identification, recording, and expedited reporting 
of SUSARs according to local regulatory requirements. The sponsor will comply 
with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators. 
● An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (for example, summary or listing of SAEs) from 
the sponsor will review and then file it along with the IB will notify the IRB/IEC, 
if appropriate according to local requirements. 
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Appendix 6. 
Contraceptive Guidance and 
Collection of Pregnancy Information  
 
 
Definitions  
 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry. 
 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
 
3. Postmenopausal female is defined as, women with: 
 At least 6 weeks post-surgical bilateral oophorectomy with or without 
hysterectomy, confirmed by operative note. 
OR 
 With spontaneous amenorrhea for at least 12 months, not induced by a medical 
condition such as anorexia nervosa and not taking medications during the 
amenorrhea (e.g. oral contraceptives, hormones, gonadotropin releasing 
hormone, anti-estrogens, selective estrogen receptor modulators (SERMs), or 
chemotherapy that induced the amenorrhea. And if ≤ age 50, has an FSH of 
≥40 mIU/mL and estradiol of 
≤30 pg/mL. 
Contraception guidance for women of childbearing potential (WOCBP):  
This outlines the rules for WOCBP to ensure they do not become pregnant during the study. 
See guidance for specific patient populations below:  
Women of childbearing potential who are completely abstinent as their preferred and 
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usual lifestyle or in a same-sex relationship as their preferred and usual lifestyle: 
 
Must… 
Must not… 
agree to either 
remain abstinent or 
stay in a same-sex 
relationship without 
sexual relationships 
with males 
 use periodic abstinence methods 
o calendar 
o ovulation 
o symptothermal, or 
o postovulation 
 declare abstinence just for the duration of a trial, or 
 use the withdrawal method 
 
Women of childbearing potential who are NOT completely abstinent as their preferred and 
usual lifestyle, or NOT in a same-sex relationship as their preferred and usual lifestyle, 
must do the following: 
 
Topic 
Condition 
Pregnancy testing 
Have a negative (serum/urine) test result at screening followed by a 
negative (urine/serum) result within 24 hours prior to treatment exposure. 
See the protocol Schedule of Activities for subsequent pregnancy testing 
requirements. 
Contraception 
Agree to use 1 highly effective method of contraception, or a combination 
of 2 effective methods of contraception. 
These forms of contraception must be used for the duration of the study. 
 
Examples of different forms of contraception:  
Methods 
Examples 
Highly effective 
contraception (less than 
1% failure rate) 
 female sterilization 
 combination oral contraceptive pill 
 progestin-only contraceptive pill (mini-pill) 
 implanted contraceptives 
 injectable contraceptives 
 contraceptive patch (only women <198 pounds or 90 kg) 
 total abstinence 
 vasectomy (if only sexual partner) 
 fallopian tube implants (if confirmed by hysterosalpingogram) 
 combined contraceptive vaginal ring, or 
 intrauterine devices 
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Effective contraception 

male or female condoms with spermicide

diaphragms with spermicide or cervical sponges

barrier method with use of a spermicide
o
condom with spermicide
o
diaphragm with spermicide, or
o
female condom with spermicide
Note: The barrier method must include use of a spermicide (that is, 
condom with spermicide, diaphragm with spermicide, or female condom 
with spermicide) to be considered effective. 
Ineffective forms of 
contraception whether 
used alone or in any 
combination 

spermicide alone

periodic abstinence

fertility awareness (calendar method, temperature method,
cervical mucus, or symptothermal)

withdrawal

postcoital douche, or

lactational amenorrhea
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Appendix 7. 
I1F-MC-RHCG Blood Volume Prioritization Tool  
 
 
Due to blood volume restrictions, some laboratory samples may not be collected. 
This appendix (Blood Volume Prioritization Tool) provides guidance on blood 
sample prioritization for participants who will participate in the study. This tool 
includes a separate table for each of the following age groups: 
 
15 years and older (page 173-174) 
 
8 years to <15 years (page 175-176) 
 
2 years to <8 years (page 177-178) 
 
Blood volume calculations (page 179) 
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Abbreviations: ADA = antidrug antibody; ANC = absolute neutrophil count; B-HCG = Beta-Human Chorionic Gonadotropin; Chem = Chemistry; ESR = 
erythrocyte sedimentation rate; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HLA-B27 = human leukocyte 
antigen-B27; hs-CRP = high sensitivity C-reactive protein; Nab = neutralizing antidrug antibody; PK = pharmacokinetic; PPD = purified protein 
derivative; TB = tuberculosis; V = visit. 
 
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Abbreviations: ADA = antidrug antibody; ANC = absolute neutrophil count; B-HCG = Beta-Human Chorionic Gonadotropin; Chem = chemistry; ESR = 
erythrocyte sedimentation rate; ET = early termination; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HLA-
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B27 = human leukocyte antigen-B27; hs-CRP = high sensitivity C-reactive protein; Nab = neutralizing antidrug antibody; PK = pharmacokinetic; PPD = 
purified protein derivative; TB = tuberculosis; V = visit. 
 
 
Abbreviations: ADA = antidrug antibody; ANC = absolute neutrophil count; B-HCG = Beta-Human Chorionic Gonadotropin; Chem = Chemistry; ESR = 
erythrocyte sedimentation rate; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HLA-B27 = human leukocyte 
antigen-B27; hs-CRP = high sensitivity C-reactive protein; Nab = neutralizing antidrug antibody; PK = pharmacokinetic; PPD = purified protein 
derivative; TB = tuberculosis; V = visit. 
 
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Abbreviations: ADA = antidrug antibody; ANC = absolute neutrophil count; B-HCG = Beta-Human Chorionic Gonadotropin; Chem = Chemistry; ESR = 
erythrocyte sedimentation rate; ET = early termination; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HLA-
B27 = human leukocyte antigen-B27; hs-CRP = high sensitivity C-reactive protein; Nab = neutralizing antidrug antibody; PK = pharmacokinetic; PPD = 
purified protein derivative; TB = tuberculosis; V = visit. 
 
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Abbreviations: ADA = antidrug antibody; ANC = absolute neutrophil count; B-HCG = Beta-Human Chorionic Gonadotropin; Chem = Chemistry; ESR = 
erythrocyte sedimentation rate; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HLA-B27 = human leukocyte 
antigen-B27; hs-CRP = high sensitivity C-reactive protein; Nab = neutralizing antidrug antibody; PK = pharmacokinetic; PPD = purified protein 
derivative; V = visit. 
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Abbreviations: ADA = antidrug antibody; ANC = absolute neutrophil count; B-HCG = Beta-Human Chorionic Gonadotropin; Chem = Chemistry; ESR = 
erythrocyte sedimentation rate; ET = early termination; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HLA-
B27 = human leukocyte antigen-B27; hs-CRP = high sensitivity C-reactive protein; Nab = neutralizing antidrug antibody; PK = pharmacokinetic; PPD = 
purified protein derivative; V = visit. 
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Abbreviations: CDC = Centers for Disease Control; WHO = World Health Organization. 
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Appendix 8. Provisions for Changes in Study 
Conduct During Exceptional 
Circumstances  
Implementation of this Appendix 
The changes to procedures described in this appendix are temporary measures 
intended to be used only during specific time periods as directed by the sponsor in 
partnership with the investigator. 
Exceptional Circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the 
study. Examples include pandemics or natural disasters. These disruptions may limit the 
ability of the investigators, participants, or both to attend on-site visits or to conduct planned 
study procedures. 
Implementing Changes under Exceptional Circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites 
may implement changes if permitted by local regulations. 
After approval by local Ethical Review Boards, regulatory bodies, and any other 
relevant local authorities, implementation of these exceptional circumstance changes 
will not typically require additional notification to these groups, unless they have 
specific conditions in which notification is required. To protect the safety of study 
participants, urgent changes may be implemented before approval but need to be 
reported as soon as possible. All approvals must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also 
provide additional written guidance, if needed. 
Considerations for Making a Change 
The prevailing consideration for making a change is ensuring the safety of study 
participants. Additional important considerations for making a change are compliance 
with Good Clinical Practice, enabling participants to continue safely in the study and 
maintaining the integrity of the study. 
Informed Consent 
Additional consent/assent from the participant will be obtained, as applicable, and/or 
as required by Ethical Review Boards and local regulations. Assent will also be 
obtained to the same parameters, with consent for participants reaching the legal age 
for consent during the trial for continued participation, for: 

participation in remote visits, as defined in Section “Remote Visits,”

a change in the location of study intervention administration,
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 alternate delivery of ancillary supplies, and 
 provision of their personal or medical information required prior to 
implementation of these activities. 
Changes in Study Conduct During Exceptional Circumstances  
Changes in study conduct not described in this appendix, or not consistent with 
applicable local regulations, are not allowed. The following changes in study conduct 
will not be considered protocol deviations. 
1. Remote Visits  
In source documents and the CRF, the study site should capture the visit location 
and method, with a specific explanation for any data missing because of missed in-
person site visits. 
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable 
to complete appropriate assessments. Assessments to be completed in this manner 
include, but are not limited to, 
 Immunization record 
 AEs and product complaints 
 Concomitant medications 
 Clinician reported measures except for those assessments or fields that 
require joint manipulation, such as Joint Assessment, Enthesitis 
Assessment, Dactylitic Count, Physician’s Global Assessment of Disease 
Activity, and Clinical Sacroiliitis 
 Participant/Parent administered measures 
Other alternative locations: Other procedures that may be done at an alternate 
location in exceptional circumstances are local draw labs, investigational product 
preparation and administration. This alternative location may count as an “on-
site” visit with regard to the guidance in this appendix. 
In the event that access to the site is not possible, and with approval from Lilly 
Medical, sites will follow the guidance in the table below. 
 
Visit(s) 
Guidance 
V1-V2 
If one of these visits cannot be accomplished at the site, then the visit should 
be postponed. Refer to Section “Screening Period Guidance” in this appendix 
for further screening guideline and Section “Adjustments to Visit Windows” in 
this appendix for visit window adjustments. 
V7 
This visit must be performed at site (Primary Outcome). 
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Participants under Ixekizumab 
Arm 
Participants under Adalimumab Arm 
OLT Visits 
(V3-V6) 
Use a combination of 
telephone/telemedicine with use 
of an acceptable alternative site 
for the safe administration of the 
ixekizumab injection and 
assessments performed by site 
personnel. 
Use a combination of 
telephone/telemedicine with use of an 
acceptable alternative site for assessments 
performed by site personnel. 
OLE Visits: 
Use a combination of 
Use a combination of 
V8, V11, V14, 
V17, V20, 
V23, V26, 
V29 
telephone/telemedicine with use 
of an acceptable alternative site to 
perform the assessments required 
to be done by health care 
professional, and for the 
telephone/telemedicine with use of an 
acceptable alternative site to perform the 
assessments required to be done by health 
care professional and the delivery of 
treatment supplies for the actual visit and 
preparation and safe 
for the next 2 treatment-only visits (e.g., 
administration of the ixekizumab 
V8 + V9, V10). 
injection. 
Tx only visits: Use a combination of 
Telephone/telemedicine for follow up. 
V9, V10, V12, 
telephone/telemedicine for follow 
Participants would have received 
V13, V15, 
up with use of an acceptable 
additional treatment supplies in the 
V16, V18, 
alternative site for the safe 
previous regular visit. 
V19, V21, 
administration of the injection for 
V22, V24, 
participants under ixekizumab 
V25, V27, 
treatment arm. 
V28 
LTE Visits: 
V30, V31, 
Use a combination of 
telephone/telemedicine with use 
of an acceptable alternative site to 
Use a combination of 
telephone/telemedicine with use of an 
acceptable alternative site to perform the 
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Visit(s) 
Guidance 
V33, V36, 
V39, 
V42,V45, 
V48, V51, 
V54, V57, 
V60, V63, 
V66, V69 
perform the assessments required 
to be done by health care 
professionals, and for the 
preparation and safe 
administration of the ixekizumab 
injection. 
assessments required to be done by health 
care professionals and the delivery of 
treatment supplies for the actual visit and 
for the next 2 treatment-only visits (e.g., 
V31 + V32, V34). 
LTE Tx Visits 
Only: 
V32, V34, 
V35, V37, 
V38, V40, 
V41, V43, 
V44, V46, 
V47, V49, 
V50, V52, 
V53, V55, 
V56, V58, 
V59, V61, 
V62, V64, 
V65, V67, 
V68 
Telephone/telemedicine for follow up. 
Participants would have received 
additional treatment supplies in the 
previous regular visit. 
ETV 
Sites may use 
telephone/telemedicine. 
Sites may use telephone/telemedicine. 
Follow-up 
(V801-V803) 
Telephone/telemedicine or use of 
an acceptable alternative site. 
Telephone/telemedicine or use of an 
acceptable alternative site. 
Abbreviations: ETV = early termination visit; LTE = long-term extension; OLE = open-
label extension; OLT = open-label treatment; Tx = treatment; V = visit. 
 
Any required procedures that cannot be conducted at that time should be conducted 
as soon as possible thereafter, using an unscheduled visit if necessary. 
Regardless of the type of remote visits implemented, the protocol requirements 
regarding the reporting of AEs, SAEs, and product complaints remain unchanged. 
Furthermore, every effort should be made to enable participants to return to on-site 
visits as soon as reasonably possible, while ensuring the safety of both the participants 
and the site staff. 
2. Local Laboratory Testing Option  
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Preferred collection of labs is centrally, but if the participant is unable to attend the 
site, labs can be collected locally in lieu of central laboratory testing. For participants 
unable to access investigator sites, laboratory testing will be conducted locally 
approximately every 8 weeks through Week 16, and then approximately every 12 
weeks. Failure to have labs collected within the described ranges above will result in 
participant termination from the study. The local laboratory must be qualified in 
accordance with applicable local regulations. 
When collecting local labs, sites should store/retain records from the labs including 
results, address, certification (College of American Pathologists/Clinical Laboratory 
Improvement Amendments [CAP/CLIA]) status, and reference ranges. The principal 
investigator/subinvestigator should document, sign, and date review of local labs per 
normal process and follow-up with the participant as needed. Local labs may be sent 
to the participant as this is standard process in clinical care. 
These laboratory measures listed below are the minimum required to monitor 
participant safety and determine temporary or permanent discontinuation of 
investigational product. Additionally, investigators should include any symptom-based 
laboratory testing based on their interactions with their participants. As stated in the 
protocol, investigators are responsible for monitoring the overall health of their 
participants. 
Because these participants have already successfully screened into the study (therefore 
have met all study inclusion/exclusion criteria for laboratory values), the investigators 
should request the following laboratory analyses for these select parameters: 
1) ALT, AST, total bilirubin, INR 
2) ALP 
3) WBC 
4) Neutrophil and lymphocyte count 
5) hemoglobin 
6) platelet count 
7) Serum pregnancy tests (where 
applicable) Notes: 
Serum pregnancy is to ensure female participants do not become pregnant while 
participating in the study (in lieu of urine pregnancy testing at the study site). 
Temporary interruption rules (see Protocol RHCG Section 8.1.2) must be followed 
where applicable. For laboratory values that meet permanent discontinuation 
thresholds, investigational product should be discontinued. However, if in the opinion 
of the investigator the laboratory abnormality is due to intercurrent illness such as 
cholelithiasis or another identified factor, laboratory tests may be repeated. Only when 
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the laboratory value meets resumption thresholds following the resolution of the 
intercurrent illness or other identified factor may the investigator restart investigational 
product after consultation with Lilly Medical. 
In some circumstances, participants may need to temporarily interrupt treatment as a 
result of AEs or abnormal laboratory values that may have an unclear relationship to 
investigational product. See Protocol RHCG Section 9.4.5 for details regarding 
managing participants who test positive for TB at any time during the study. 
3. Study Intervention and Ancillary Supplies  
When a participant is unable to go to the site to receive study supplies during normal 
on-site visits, the site should work with the sponsor to determine appropriate actions. 
These actions may include: 
 asking the participant to go to the site and either receive study 
supplies or have injection administration from site staff without 
completion of a full visit, 
 arranging delivery of study supplies, and 
 working with the sponsor to determine how study intervention that is 
typically administered on-site will be administered to the participant at 
an alternate location. 
These requirements must be met before action is taken: 
 Alternate delivery of study intervention should be performed in a manner 
that ensures product integrity. The existing protocol requirements for 
product accountability remain unchanged, including verification of study 
supplies. 
 When delivering supplies to a location other than the study site as an 
alternative site for the safe administration of the ixekizumab injection or 
the supply treatment for adalimumab. The investigator, sponsor, or both 
should ensure oversight of the shipping process to ensure accountability 
and product quality (that is, storage conditions maintained and intact 
packaging upon receipt). 
 Instructions may be provided to the participant or designee on the final 
disposition of any unused or completed study supplies. 
In addition, if study intervention will be administered to the participant at an 
alternate location, these additional requirements must be met: 
 Only authorized study personnel may supply, prepare, or 
administer study intervention. 
 Requirements and instructions for investigational product storage 
and dose preparation will be the same as stated in main protocol, 
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Pharmacy Binder and Ixekizumab Dosing Instructions Manual 
must be followed. 
4. Screening Period Guidance  
To ensure safety of study participants, laboratory values, and other eligibility 
assessments taken at screening visit are valid for a maximum of 42 days. The 
following rules will be applied for active, nonrandomized participants whose 
participation in the study must be paused due to exceptional circumstances: 
 If paused for less than 42 days from screening to randomization visit: The 
participant will proceed to the next study visit per the usual Schedule of 
Activities, provided that randomization visit must be conducted within 7 
days from first screening. 
o The site should conduct the next visit if the participant’s eligibility 
criteria are confirmed, and the site should document the reason for 
delay in the CRF. 
o Due to the pause in screening, sites should also reconfirm the 
impacted participant’s consent and document this 
confirmation in the source documentation. 
 If paused for more than 42 days from screening to randomization visit: 
The participant must be discontinued because of screening interruption 
due to an exceptional circumstance. This is documented as a screen fail in 
the CRF with a reason of exceptional circumstance. This screen fail is 
allowed in addition to the main protocol screen fail. The participant can 
reconsent and be rescreened as a new participant. The screening 
procedures per the usual Schedule of Activities should be followed, 
starting at screening visit to ensure participant eligibility by randomization 
visit. 
5. Adjustments to Visit Windows  
Whenever possible and safe to do so, as determined by the investigator’s discretion, 
participants should complete the usual Schedule of Activities. To maximize the 
possibility that these visits can be conducted as on-site visits, the windows for visits 
may be adjusted, upon further guidance from the sponsor. This minimizes missing data 
and preserves the intended conduct of the study. 
 
This table describes the allowed adjustments to visit windows. 
 
Visit Number 
Tolerance 
Visit 3 through Visit 7 
(OLT) 
Within 14 days before intended date, or up to 14 days after the 
intended date 
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Visit 8 through Visit 29 
(OLE) 
Within 14 days before intended date, or up to 14 days after the 
intended date 
Visit 30 through Visit 69 
(LTE) 
Within 14 days before intended date, or up to 14 days after the 
intended date 
Visit 801 through Visit 802 
(Visit 803) 
Within 14 days before intended date, or up to 14 days after the 
intended date 
Abbreviations: LTE = long-term extension; OLE = open-label extension; OLT = open-label treatment. 
For participants whose visits have extended windows, additional study intervention 
may need to be provided to avoid interruption and maintain overall integrity of the 
study, as well as to prevent dosing administration less than 21 days apart. 
Documentation  
Changes to study conduct will be documented: 
 Sites will identify and document the details of how participants, visits 
types, and conducted activities were affected by exceptional 
circumstances. 
 Dispensing/shipment records of study intervention and relevant 
communications, including delegation, should be filed with site study 
records. 
 Source documents generated at a location other than the study site should 
be part of the investigator’s source documentation and should be 
transferred to the site in a secure and timely manner. 
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Appendix 9. Protocol Amendment History  
 
 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [b]: (21-Sep-2022) 
This amendment is considered to be substantial. 
The amendment is considered to be substantial because it is likely to have a significant impact on 
the 
● safety or the rights of the study participants 
● reliability and robustness of the data generated in the clinical study 
Overall Rationale for the Amendment: 
To include Long Term Extension Study information to determine long term efficacy 
and safety of LY2439821 in children with Juvenile Idiopathic Arthritis Subtypes of 
Enthesitis-related Arthritis (Including Juvenile-Onset Ankylosing Spondylitis) and 
Juvenile Psoriatic Arthritis. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Title Page 
 Adjusted to follow the harmonized 
template. 
 Deleted original title page. 
For alignment of Legacy 
Protocol documents with 
the new harmonized 
template. 
SOC Table 
Protocol Amendment SOC table added. 
For alignment with new 
harmonized template. 
Section 1. 
Synopsis 
LTE period data added. 
For alignment. 
Section 2. 
Schedule of 
Activities 
 LTE tables added, and OLE adjusted. 
 Visit and week numbering adjusted. 
 Weight recording adjusted to 10th of a 
kilogram. 
 Deleted the Self-Harm Follow- up Form 
 Specified that the Global Assessment 
of Well-Being must be completed by a 
caregiver until participant 
≥14 years of age. 
For alignment and 
accuracy. 
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Section # and Name 
Description of Change 
Brief 
Rationale 
Section 3.1 Study Rationale 
Study Rationale for LTE period information added. 
For accuracy. 
Section 3.2 Background 
IXORA-PEDS trial information added. 
For 
alignment. 
Section 4 Objectives and 
Endpoints 
LTE O/E added. 
For accuracy. 
Section 5.1 Overall Design 
 
LTE information added. 
 
LTE treatment period added. 
 
Schema Adjusted to incorporate LTE 
information. 
For 
alignment. 
Section 5.1.3 Open-Label 
Extension Period 
Sentence added to indicate participants switched over 
to ixekizumab will be treated in separate group. 
For accuracy. 
Section 5.1.4 Long-Term 
Extension Period 
New section to depict LTE period of study. 
For 
alignment. 
Section 5.1.5 Post-
Treatment Follow-up 
Period 
LTE post follow up period clarified. 
For 
alignment. 
Section 5.3 End of Study 
Definition 
LTE information added. 
For 
alignment. 
Section 5.4 Scientific 
Rationale for Study Design 
 Added 3-year optionality wording. 
 Rationale for LTE added. 
For accuracy. 
Section 5.5 Justification 
for Dose 
Wording added to clarify LTE dose. 
For accuracy. 
Section 6.1 Inclusion Criteria Screening and baseline wording added to Inclusion 
Criterion #3 
For 
clarification. 
Section 6.4 Screen Failures 
Wording on ICF/assent form added. 
For 
alignment. 
Section 7.1 Treatments 
Administered 
 LTE information added to Table RHCG 
7.1. 
 Wording added to Post- Administration 
Observation. 
For 
alignment. 
Section 7.2 Method of 
Treatment Assignment 
Clarified that all participants who enter LTE will 
receive ixekizumab. 
For 
clarification. 
Section 7.4 Dosage 
Modification 
Clarified dosing during LTE period. 
For 
alignment. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.7 Concomitant 
Therapy 
 Clarified use of concomitant 
therapy in LTE period. 
 Wording on intra-articular joint 
and bursal corticosteroid 
injections changed. 
 For alignment. 
 For clarification. 
Section 7.8.1 Study Extensions 
Changed wording to include LTE in 
RHCG study. 
For accuracy. 
Section 7.8.2 Treatment After 
Study Completion 
Clarified use of adalimumab in LTE 
period. 
For alignment. 
Section 8 Discontinuation 
Criteria 
Sentence added to refer to Appendix 3 
for discontinuation criteria. 
For accuracy. 
Section 8.1 Discontinuation 
from Study Treatment 
Paragraph added to clarify permanent 
discontinuation. 
For accuracy. 
Section 8.1.1 Permanent 
Discontinuation from Study 
Treatment 
Updated hepatic parameters for 
discontinuation and resumption of study 
drug. 
As per updated safety 
requirements. 
Section 8.1.3 Discontinuation 
of Inadvertently Enrolled 
Patients 
Section removed. 
As per new Lilly 
guidelines. 
Section 9.1.3.1 Childhood 
Health Assessment 
Questionnaire (CHAQ) 
Note added to state the CHAQ will be 
provided to participants. 
For alignment. 
Section 9.1.4.5 Morning Joint 
Stiffness Duration 
Note added to state the morning stiffness 
will be assessed by participants. 
For alignment. 
Section 9.2.1 Timing and 
Mechanism, for Collecting 
Events 
Adverse Event collecting events table 
added. 
As per new 
harmonized template 
guidelines. 
Section 9.3 Treatment 
Overdose 
Updated treatment overdose information. 
As per new 
harmonized template 
guidelines. 
Section 9.4.11.1 Hepatic Safety 
Monitoring 
Hepatic Safety information updated. 
As per new safety 
guidelines. 
Section 10.2 Population for 
Analyses 
LTE information added. 
For alignment. 
Section 10.3.1 General 
Statistical Considerations 
Clarified wording for OLT participants. 
For clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.3.1.2 General Considerations for 
OLE Period 
 Visit 8 changed to Visit 7. 
 Adalimumab wording added. 
For accuracy. 
Section 10.3.1.3 General Considerations for 
LTE Period 
New section added to incorporate 
general considerations for the LTE 
period. 
For alignment. 
Section 10.3.2.1 Participant Disposition 
LTE and PTFU wording added. 
For accuracy. 
Section 10.3.3.2 Secondary Analyses 
 Adjusted Table 
RHCG.10.2 to 
incorporate LTE period 
information. 
 New LTE period 
Table RHCG.10.5 added. 
For alignment. 
Appendix 2. Clinical Laboratory Tests 
Updated wording added and 
outdated wording removed. 
As per new 
harmonized 
template 
guidelines. 
Appendix 3. Study Governance 
Considerations 
Updated wording added and 
outdated wording removed. 
As per new 
harmonized 
template 
guidelines. 
Appendix 
4. 
Hepatic 
Monitoring 
Tests 
for 
Treatment-Emergent 
Abnormality 
Hepatic Safety information updated. As per new safety 
guidelines. 
Appendix 5. Adverse Events: Definitions 
and Procedures for Recording, Evaluating, 
Follow- up, and Reporting 
Updated wording added and 
outdated wording removed. 
As per new 
harmonized 
template 
guidelines. 
Appendix 6. Contraceptive Guidance 
and 
Collection 
of 
Pregnancy 
Information 
Updated contraceptive language. 
As per new safety 
guidelines. 
Appendix 7. I1F-MC-RHCG Blood 
Volume Prioritization Tool 
 Pages updated. 
 Blood volumes updated. 
For accuracy. 
Appendix 8 Provisions for Changes in 
Study Conduct During Exceptional 
Circumstances 
Updated language for LTE period 
added. 
To follow new 
guidelines. 
Appendix 9 Protocol Amendment I1F-MC-
RHCG(a) 
 
Title removed. 
 
Approval date added. 
For alignment. 
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Section # and 
Name 
Description of Change 
Brief 
Rationale 
All Sections Minor editorial/formatting made throughout, including changing 
patient wording to participant where applicable. 
For 
accuracy. 
Abbreviations: ICF = informed consent form; LTE = long-term extension; O/E = Objectives/Endpoints; OLE = 
open label extension; OLT = open label treatment; PTFU = post-treatment follow up; SOC = summary of 
changes. 
Amendment [a]: (06-Nov-2020) 
Overview 
Protocol I1F-MC-RHCG, Multicenter, Open-label, Efficacy, Safety, Tolerability, and 
Pharmacokinetic Study of Subcutaneous Ixekizumab with Adalimumab Reference Arm, 
in Children with Juvenile Idiopathic Arthritis Subtypes of Enthesitis-related Arthritis 
(Including Juvenile-Onset Ankylosing Spondylitis) and Juvenile Psoriatic Arthritis, has 
been amended.  
Overall Rationale for the Amendment: 
The overall changes and rationale for changes made to this protocol are described in the 
following table. Note that minor edits have been made throughout the protocol, which 
are not captured in the amendment summary table. 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
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I1F-MC-RHCG(c) Clinical Protocol 
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Amendment Summary for Protocol I1F MC RHCG Amendment (a) 06-Nov-2020 
 
Section # 
Description of Change 
Brief Rationale 
Section 1, 
Synopsis 
Updated status of ixekizumab to approved 
for plaque psoriasis in adult and pediatric 
participants, adult psoriatic arthritis, 
radiographic axial spondyloarthritis (r-
axSpA), and non-radiographic axSpA with 
objective signs of inflammation. 
Removed Week 16 as a timepoint for 
PK analysis and relationship between 
exposure, efficacy, and 
immunogenicity. 
Updated to be consistent with the label. 
Clarification 
Section 2, 
Schedule of 
Activities 
Extended Screening period from -
42 to -14 days to -42 to -7 days. 
Correction to standard minimum 
window for randomization 
For Tanner Stage Scale, added the 
clarification, 
“Once 
the 
participant 
reaches the score of 5 on this scale, no 
further assessments are needed.” 
Clarification 
Clarified reading PPD was to be 
performed locally. 
Minor clarification 
Combined HBV DNA row with 
HBV antibody row. 
Added the word “site” to 
administration of study treatment 
at treatment visits (TV). 
Deleted TB testing after screening 
Added urine pregnancy test at every 
visit starting at Visit 8. Added tests are to 
be performed locally. Added clarification 
for testing during instances of delayed 
menstruation. 
In response to Competent Authority 
request 
Added, “Includes an assessment of 
rash, serositis, splenomegaly, 
hepatomegaly, or generalized 
lymphadenopathy attributable to 
JIA.” to clinical chemistry. 
Clarification 
Added, “V803 is an additional 
follow-up based on neutrophil count 
(Section 5.1.4).” as a clarification. 
Clarification to be consistent with 
other ixekizumab studies. 
Added “or ETV” to LV at each 
follow-up visit. 
Clarification 
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I1F-MC-RHCG(c) Clinical Protocol 
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Section # 
Description of Change 
Brief Rationale 
Section 3.2 
Background 
Updated background information for 
ixekizumab 
Updated to include current study results 
and indications 
Section 4 
Objectives and 
Endpoints 
Removed Week 16 as a PK analysis time point 
Removed Week 16 as an analysis time point 
for the relationship between exposure, efficacy, 
and immunogenicity 
Clarification 
Clarification 
Section 5.1 
Overall Design 
Updated screening period and designation of 
follow-up visits. 
For consistency with revisions made to 
Schedule of Activities 
Section 5.1.3 
Open-Label 
Extension Period 
Added requirements for participants switching 
from adalimumab to ixekizumab. 
A requirement to capture the reasons for 
switching was also added. 
In response to Competent Authority request 
Section 5.5 
Justification for 
Dose 
Added requirements for participants switching 
from adalimumab to ixekizumab. 
In response to Competent Authority request 
Section 6.1 
Inclusion Criteria 
Added statement, “Participants and their 
partners of childbearing potential must agree to 
use contraception for 5 months after the last 
dose of adalimumab.” to criterion [5]. 
In response to Competent Authority request 
Section 6.2 
Exclusion Criteria 
Added statement, “Participants with moderate 
to severe heart failure [NYHA class III/IV] are 
not eligible for the study.” to criterion [21]. 
In response to Competent Authority request 
Section 7.1 
Treatments 
Administered 
Reorganized section by showing the dose level 
table at the beginning and adding subsections 
for Dosing and Post-Administration 
Observation. Added instructions for 
participants with a body weight of 10.0 kg to 
15 kg. 
Clarification 
In response to Competent Authority request 
Section 7.7 
Concomitant 
Therapy 
Corrected the maximum dose of SSZ to be 
3 g/day instead of 3 mg/day. 
Clarified the conditions for stable use of 
concomitant medications extend through the 
OLT period. 
Added footnote: Dose adjustments may only 
be made for safety reasons during OLT period 
(until Week 16). 
Typo error 
Clarification 
Clarification 
Section 8.1.1 
Permanent 
Discontinuation 
Revised consultation with Lilly-designated 
medical monitor to consultation with Lilly 
Medical. 
Clarification on terms 
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Section # 
Description of Change 
Brief Rationale 
from Study 
Treatment 
Removed criterion of hemoglobin <6.5 g/dL 
from discontinuation criteria. 
Corrected typos. 
In response to Competent Authority request 
Section 8.1.3 
Discontinuation of 
Inadvertently 
Enrolled 
Participants 
Revised wording 
To update to the current harmonized 
template language 
Section 9 Study 
Assessments and 
Procedures 
Deleted language about 60-day retention 
period for samples. 
Removed “Investigators should assess and 
monitor physical pain and distress at each 
visit.” 
To update to the current harmonized 
template language 
Statement did not belong in this section and 
it was not specific enough for site staff to 
interpret. 
Section 9.2.1.2 
Adverse Events of 
Special Interest 
Added sentence, “In the case of suspected IBD, 
the participant should be referred to a 
gastroenterologist (preferably pediatric 
gastroenterologist) for evaluation and 
management.” 
In response to Competent Authority request 
Section 9.4 Safety 
Added sentence “These events will also be 
considered as an AE if the event does not result 
in a diagnosis but is considered clinically 
significant by the investigator.” 
In response to Competent Authority 
request. 
Section 9.4.4 
Laboratory Tests 
Added mention of the Blood Volume 
Prioritization Tool as a new appendix. 
In response to Competent Authority request 
Section 9.4.4.1 
Pregnancy Testing 
Added section regarding pregnancy testing 
To update to the current harmonized 
template language 
Section 10.3.5 
Pharmacokinetic/ 
Pharmacodynamic 
Analyses 
Removed Week 16 as an analysis timepoint 
Clarification 
Section 10.3.8 
Interim Analyses 
Removed PK data as an interim analysis 
Clarification 
Section 10.3.9 
Adjudication 
Committee 
Corrected IBD charter to CEC charter 
Terminology update 
Appendix 2. 
Clinical 
Laboratory Tests 
Added Neutrophils, juvenile (bands) 
Added footnote d clarifying urinalysis testing 
Added clarification for testing during instances 
of delayed menstruation to serum pregnancy 
testing footnote. 
Added clarification about when TB testing is 
required and add that it is to be performed 
locally. 
Clarification 
Clarification 
In response to Competent Authority request 
Clarification 
Appendix 3 
Study Governance 
Considerations 
Added for competent authority to approve 
Updated language according to the most 
current template 
In response to Competent Authority request 
Updating per protocol template 
Appendix 7. 
I1F-MC-RHCG 
Blood Volume 
Added new appendix 
In response to Competent Authority request 
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I1F-MC-RHCG(c) Clinical Protocol 
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Section # 
Description of Change 
Brief Rationale 
Prioritization Tool 
Appendix 8. 
Added new appendix 
In response to Competent Authority 
request 
Provisions for 
Changes in Study 
Conduct During 
Exceptional 
Circumstances 
 
Approved on 01 Dec 2023 GMT

Signature Page for VV-CLIN-126448 v2.0
Signature Page for VV-CLIN-126448 v2.0
Approval
Statistician
30-Nov-2023 16:13:47 GMT+0000
Approval
Medical
01-Dec-2023 15:53:21 GMT+0000
Approved on 01 Dec 2023 GMT
PPD
PPD