An Open-label, Active-Controlled, Safety, and Efficacy Study of Oral Baricitinib in Patients From 2 Years to Less Than 18 Years Old With Active Juvenile Idiopathic Arthritis-Associated Uveitis or Chronic Anterior Antinuclear Antibody-Positive Uveitis
Phase: PHASE3
Conditions: Uveitis
Sponsor: Eli Lilly and Company

 
 
 
Protocol I4V-MC-JAHW(e) 
 
 
Open-label, Active-Controlled, Safety, and Efficacy Study of Oral Baricitinib in Patients from 2 
Years to Less Than 18 Years Old with Active Juvenile Idiopathic Arthritis-Associated Uveitis or 
Chronic Anterior Antinuclear Antibody-Positive Uveitis 
 
NCT04088409 
 
Approval Date: 14-Jun-2023 
 
 
 
 
 
 

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Protocol I4V-MC-JAHW(e) 
An Open-label, Active-Controlled, Safety, and Efficacy Study 
of Oral Baricitinib in Patients from 2 Years to Less Than 
18 Years Old with Active Juvenile Idiopathic 
Arthritis-Associated Uveitis or Chronic Anterior Antinuclear 
Antibody-Positive Uveitis  
EudraCT: 2019-000119-10 
EU trial number: 2023-505811-18-00 
 
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 
baricitinib (LY3009104), unless such persons are bound by a confidentiality agreement with 
Eli Lilly and Company or its subsidiaries. 
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries. 
Baricitinib (LY3009104) 
Eli Lilly and Company 
Indianapolis, Indiana USA 46285 
Approval Date: Protocol Amendment (e) Electronically Signed and Approved by Lilly on date 
provided below.  
Document ID: VV-CLIN-080417 
 
 
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Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
 
Document 
Date 
Amendment (d) 
07-Nov-2020 
Amendment (c) 
14-Aug-2020 
Amendment (b) 
31-May-2019 
Amendment (a) 
05-Apr-2019 
Original Protocol 
05-Mar-2019 
 
Amendment [e] 
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 rights of the study participants  
 reliability and robustness of the data generated in the clinical study, and  
 the quality or safety of any investigational medicinal product used in the trial.  
Overall Rationale for the Amendment:  
The primary purpose of this amendment is to update the protocol to reflect recent modifications 
to the EU Paediatric Investigation Plan (PIP) endorsed by the European Medicines Agency 
Paediatric Committee EMEA-001220-PIP01-11-M08.  Because of the agreement to the original 
PIP, the standard of care for the treatment of patients with JIA-associated uveitis (JIAU) has 
changed substantially.  For contemporary management of JIAU, adalimumab has emerged as the 
preferred treatment for patients developing inadequate response with methotrexate (Constantin 
et al. 2018; Quartier 2021).  During a recent consensus meeting, an expert panel of international 
pediatric rheumatologists and ophthalmologists unanimously recommended adalimumab as the 
first-line therapy in children with JIAU and idiopathic chronic anterior uveitis (CAU) who are 
methotrexate-inadequate responders (MTX-IR) (Foeldvari et al. 2022).  The need to minimize 
unnecessary delays in the initiation of alternative therapy following the failure of conventional 
systemic treatments, such as methotrexate, is important as persistent uveitis predisposes patients 
to higher risk of ocular complications and blindness (Cassidy et al. 2006; Foeldvari et al. 2022). 
As a result of this approved PIP modification, the secondary outcomes for Part A and Part B 
have been updated, and exploratory objectives have been removed to be consistent with the PIP.  
This amendment also updates the number of participants involved in the study.  Patients 
currently assigned to baricitinib who have completed the primary endpoint as a responder will 
continue receiving baricitinib until the end of study or discontinuation from the study, as stated 
in the Paediatric Committee acceptance of a modification of an agreed PIP.  The number of 
participants in the adalimumab arm has been updated. 
A secondary purpose of this amendment is to harmonize trial procedures across EU countries, as 
described by the Clinical Trial Facilitation Group “Best Practice Guide for sponsors of 
multinational clinical trials with different protocol versions approved in different Member States 
under Directive 2001/20/EC that will transition to Regulation (EU) No. 536/2014.” 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1. Synopsis 
Objective(s)/Endpoints 
Deleted time to treatment response in the 
Endpoints column in the Secondary 
objectives for Part A 
Removed time to inactive anterior uveitis 
disease in each affected eye in the 
Endpoints column in the Secondary 
objectives for Part B 
Modified “proportion” to “number” in the 
Endpoints column in the Secondary 
objectives for Part B, description of 
inactive anterior uveitis including time to 
inactive anterior uveitis disease (using 
SUN definition) 
PediACR 30/50/70/90/100 response rate 
statement removed from the endpoint in 
secondary for Part B objectives 
As per PIP 
Section 1. Synopsis 
Title of Study 
Regulatory Agency Identifier numbers 
added 
Elaboration of 
information needed 
according to CTR 
Section 1. Synopsis  
Study Population 
Added a summary of study population 
Added as a subsection 
of the synopsis, as 
needed according to 
CTR 
Section 1. Synopsis 
Number of Patients 
Updated the total number of participants to 
be enrolled 
As per PIP 
Section 1. Synopsis  
Statistical Analysis 
Updated the number of patients 
As per PIP 
Section 1. Synopsis  
Ethical Consideration of 
Benefit/Risk 
Information about ethical considerations of 
benefit/risk added 
To add the 
benefit/risk 
information to the 
synopsis, as needed 
according to CTR 
Section 2. Schedule of Activities 
Included measurements of external tibial 
length at specific weeks 
X-rays have been updated to imaging. 
Visits for imaging  of wrist, hand, finger, 
and knee updated 
Questionnaires for CHAQ, CHQ PF 50, 
morning stiffness duration, SPARCC 
enthesitis index, clinical sacroiliitis, black 
mobility, and PASI removed from Part B 
Occipital frontal circumference 
measurement and joint assessment removed 
from Part B 
Footnotes updated for external tibial length 
and modified the footnote for imaging 
As per Protocol 
Addendum 3.1 to 
harmonize trial 
procedures and as per 
PIP 
 
 
 
 
 
 
 
 
 
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Footnotes added for procedures specific to 
Germany sites 
Abbreviations updated to reflect the current 
changes for tanner scale and external tibial 
length 
Tanner stage scale description updated for 
Part A, footnote updated  for the same for 
both Parts A and B 
 
 
 
 
For robust safety 
assessment 
Section 4. Objectives and 
Endpoints 
Deleted Exploratory objectives 
Updated Endpoints column for Part A and 
Part B Deleted time to response statement 
in endpoint of secondary objectives for Part 
A 
Proportion updated to the number of 
responders in the endpoints for Part B 
secondary objectives. The week number 
has been specified for the responders in 
Part B secondary objectives. 
Added description of inactive anterior 
uveitis including time to inactive anterior 
uveitis disease (using SUN definition) 
Deleted proportion of patients with inactive 
anterior uveitis and time to inactive anterior 
uveitis disease (using SUN definition) from 
endpoints under part B secondary 
objectives 
Deleted exploratory objectives 
As per PIP and to 
maintain consistency 
across all the sections 
of protocol 
Section 5.1. Overall Design 
Updated the total number of participants 
for baricitinib and adalimumab arms 
Study design updated figure added with 
number of participants and duration 
Information about overall design added for 
better clarity 
Statement added about the current 
amendment following the updated study 
design and a footnote added to reference to 
Section 5.1.3 
As per PIP and for 
maintaining 
consistency across all 
the sections of the 
protocol 
Section 5.1.3. Open-Label 
Treatment Period-Part B 
Information about patient randomization to 
adalimumab arm updated 
Information added about patients on 
baricitinib and continuation of treatment in 
Part B 
As per PIP 
Section 5.2. Number of 
Participants  
Updated the number of participants to be 
evaluated for the primary endpoint 
As per PIP 
Section 7.1. Treatments 
Administered 
Updated the note for oral suspension dose 
for participants with hereditary fructose 
tolerance 
 
 
 
Incorporated from 
Protocol 
Addendum 2.1 
for consolidation 
 
 
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Table on treatment regimens updated with 
authorization status of medications 
information added 
To comply 
with CTR requirement 
Section 7.1.1. Packaging and 
Labelling 
Statement added about sponsor (or its 
designee) will supply the investigational 
products as per Good Manufacturing 
Practice and study interventions will be 
labelled according to country requirements 
To comply with CTR 
requirement 
Section 7.2. Method of Treatment 
Assignment 
Updated the number of participants to be 
randomly assigned to baricitinib and 
adalimumab arms 
As per PIP 
Section 7.4 Dosage Modification 
Statement about dose increase for Part B 
patients in adalimumab removed 
As per PIP 
Section 7.8.2. Special Treatment 
Considerations 
Statement about rescue therapy removed 
As per PIP 
Section 8.1.3. Discontinuation of 
Inadvertently Enrolled Patients 
Clarified discontinuation rules for sites in 
France 
Incorporated from 
Protocol 
Addendum 2.1 for 
consolidation 
Section 9.1.2. Secondary Efficacy 
Assessments 
Updated statement for time to treatment 
response 
For clarification 
Section 9.1.4. Exploratory 
Efficacy Assessments 
Deleted section 
Removed exploratory 
assessments 
Section 9.2.1.1. Suspected 
Unexpected Serious Adverse 
Reactions 
European regulation added 
Information added about sponsor having 
the legal responsibility to notify regulatory 
agencies 
Elaboration of 
information needed 
according to CTR 
Section 9.4.6.2. Growth 
Monitoring 
Included details related to the MRI of the 
knee and external tibial length 
measurement 
For consistency across 
all the sections of the 
protocol 
Section 10.1. Sample Size 
Determination 
Updated number of participants for sample 
size determination 
As per PIP 
Section 10.3.1. General Statistical 
Considerations 
Statement about handling of missing, 
unused, and spurious data added. 
 
Changed the method to impute missing 
data in Part A. 
Information about Nonresponder 
Imputation (NRI) added. 
As per PIP 
Section 10.3.3.2. Secondary 
Analyses 
Modified table of secondary endpoint 
analyses for Part A 
For consistency across 
all the sections of the 
protocol 
Section 10.3.3.3. Exploratory 
Analyses 
Deleted the description of exploratory 
analyses 
For consistency across 
all the sections of the 
protocol 
Section 10.3.6. Health Outcomes 
Section removed and subsequent sections 
renumbered 
As per PIP 
Section 10.3.7. Interim Analyses 
Information about the study continuing for 
baricitinib treated patients removed 
Information about additional analyses and 
As per PIP 
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snapshots of study data added 
Section 11. References 
Included reference for European Medicines 
Agency 
 
Included references for PIP modification 
Incorporated from 
Protocol Addendum 
2.1 for consolidation 
As per PIP 
Appendix 3. Study Governance 
Considerations 
Appendix 3.1.1. Informed Consent 
 
 
Appendix 3.2.1. Data Protection 
and Data Capture System 
 
 
 
 
 
Appendix 3.4 Publication Policy 
and Dissemination of Clinical 
Study Data 
Statement added about reporting to sponsor 
or designee about significant issues related 
to participant 
 
 
Information about participants being 
provided a unique identifier, personal 
study-related data, informed consent, 
information security, and transfer of 
personal data information added 
 
 
Information about sponsor’s disclosure of 
summary of study information added 
Elaboration of 
information needed 
according to CTR 
Appendix 10. Protocol 
Amendment History 
Changes for amendment (d) added 
As per harmonized 
protocol template 
Throughout the document 
Minor edits 
For clarity 
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Table of Contents  
Section 
Page  
Protocol I4V-MC-JAHW(e) An Open-label, Active-Controlled, Safety, 
and Efficacy Study of Oral Baricitinib in Patients from 2 Years to 
Less Than 18 Years Old with Active Juvenile Idiopathic 
Arthritis-Associated Uveitis or Chronic Anterior Antinuclear 
Antibody-Positive Uveitis .......................................................................................................1 
Table of Contents .............................................................................................................................7 
1. 
Synopsis .................................................................................................................................14 
2. 
Schedule of Activities ............................................................................................................20 
3. 
Introduction ...........................................................................................................................35 
3.1. 
Study Rationale ................................................................................................................35 
3.2. 
Background.......................................................................................................................38 
3.3. 
Benefit/Risk Assessment ..................................................................................................40 
4. 
Objectives and Endpoints ......................................................................................................43 
5. 
Study Design .........................................................................................................................46 
5.1. 
Overall Design ..................................................................................................................46 
5.1.1. 
Screening and Baseline Periods ...............................................................................48 
5.1.2. 
Open-Label Treatment Period – Part A ...................................................................49 
5.1.3. 
Open-Label Treatment Period – Part B ....................................................................49 
5.1.4. 
Post-Treatment Follow-Up Period ...........................................................................49 
5.2. 
Number of Participants .....................................................................................................50 
5.3. 
End of Study Definition....................................................................................................50 
5.4. 
Scientific Rationale for Study Design ..............................................................................50 
5.5. 
Justification for Dose ........................................................................................................50 
6. 
Study Population ...................................................................................................................53 
6.1. 
Inclusion Criteria ..............................................................................................................53 
6.2. 
Exclusion Criteria .............................................................................................................54 
6.2.1. 
Rationale for Exclusion of Certain Study Candidates .............................................60 
6.3. 
Screen Failures .................................................................................................................60 
7. 
Treatments .............................................................................................................................61 
7.1. 
Treatments Administered .................................................................................................61 
7.1.1. 
Packaging and Labeling ...........................................................................................62 
7.2. 
Method of Treatment Assignment ....................................................................................62 
7.2.1. 
Selection and Timing of Doses ................................................................................63 
7.3. 
Blinding ............................................................................................................................63 
7.4. 
Dosage Modification ........................................................................................................63 
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7.5. 
Preparation/Handling/Storage/Accountability .................................................................63 
7.6. 
Treatment Compliance .....................................................................................................64 
7.7. 
Concomitant Therapy .......................................................................................................64 
7.8. 
Treatment after the End of the Study ...............................................................................69 
7.8.1. 
Treatment after Study Completion ...........................................................................69 
7.8.2. 
Special Treatment Considerations ...........................................................................69 
8. 
Discontinuation Criteria ........................................................................................................70 
8.1. 
Discontinuation from Study Treatment ............................................................................70 
8.1.1. 
Temporary Interruption of Investigational Product .................................................70 
8.1.2. 
Permanent Discontinuation from Investigational Product .......................................71 
8.1.3. 
Discontinuation of Inadvertently Enrolled Patients .................................................72 
8.2. 
Discontinuation from the Study ........................................................................................72 
8.3. 
Lost to Follow-Up ............................................................................................................73 
9. 
Study Assessments and Procedures .......................................................................................74 
9.1. 
Efficacy Assessments .......................................................................................................74 
9.1.1. 
Primary Efficacy Assessment ..................................................................................74 
9.1.2. 
Secondary Efficacy Assessments .............................................................................74 
9.1.2.1. 
Ophthalmic Assessments ....................................................................................75 
9.1.2.1.1. 
SUN Cell-Activity Score ..............................................................................75 
9.1.2.1.2. 
Anterior Chamber Flare ...............................................................................76 
9.1.2.1.3. 
Visual Acuity ................................................................................................76 
9.1.2.1.4. 
Vitritis ...........................................................................................................76 
9.1.2.2. 
Uveitis Disease Activity .....................................................................................76 
9.1.2.3. 
PediACR30/50/70/90/100 Assessments .............................................................76 
9.1.2.4. 
Physician’s Global Assessment of Disease Activity ..........................................77 
9.1.3. 
Health Outcomes ......................................................................................................77 
9.1.4. 
Exploratory Efficacy Assessments ...........................................................................79 
9.1.5. Immunological Measurements ....................................................................................79 
9.1.6. Appropriateness of Assessments....................................................................................79 
9.2. 
Adverse Events .................................................................................................................80 
9.2.1. 
Serious Adverse Events ...........................................................................................80 
9.2.1.1. 
Suspected Unexpected Serious Adverse Reactions ...........................................82 
9.2.2. 
Adverse Events of Special Interest ..........................................................................82 
9.2.3. 
Complaint Handling .................................................................................................82 
9.3. 
Treatment of Overdose .....................................................................................................82 
9.4. 
Safety ................................................................................................................................83 
9.4.1. 
Electrocardiograms ..................................................................................................83 
9.4.2. 
Vital Signs ................................................................................................................83 
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9.4.3. 
Laboratory Tests ......................................................................................................83 
9.4.4. 
Hepatitis B Virus DNA Monitoring .........................................................................83 
9.4.5. 
Hepatic Safety Monitoring and Data Collection ......................................................84 
9.4.6. 
Safety Monitoring ....................................................................................................85 
9.4.6.1. 
Venous Thromboembolic Event Assessment .....................................................85 
9.4.6.2. 
Growth Monitoring ............................................................................................85 
9.4.6.3. 
Tanner Stage Scale .............................................................................................87 
9.4.7. 
Vision-Related Safety Monitoring ...........................................................................87 
9.4.7.1. 
Fundoscopy ........................................................................................................87 
9.4.7.2. 
Optical Coherence Tomography ........................................................................87 
9.4.7.3. 
Cataract Scoring .................................................................................................87 
9.4.7.4. 
Intraocular Pressure ............................................................................................87 
9.4.7.5. 
Other Structural or Vision-Related Complications ............................................87 
9.5. 
Pharmacokinetics ..............................................................................................................88 
9.6. 
Pharmacodynamics ...........................................................................................................88 
9.6.1. 
Pharmacogenetics .....................................................................................................88 
9.6.1.1. 
Whole Blood Sample for Pharmacogenetic Research ........................................88 
9.7. 
Biomarkers .......................................................................................................................88 
9.8. 
Medical Resource Utilization and Health Economics ......................................................89 
10. Statistical Considerations ......................................................................................................90 
10.1. Sample Size Determination ..............................................................................................90 
10.2. Populations for Analyses ..................................................................................................90 
10.3. Statistical Analyses ...........................................................................................................91 
10.3.1. 
General Statistical Considerations ...........................................................................91 
10.3.2. 
Treatment Group Comparability ..............................................................................92 
10.3.2.1. 
Patient Disposition .............................................................................................92 
10.3.2.2. 
Patient Characteristics ........................................................................................93 
10.3.2.3. 
Concomitant Therapy .........................................................................................93 
10.3.2.4. 
Treatment Compliance .......................................................................................93 
10.3.3. 
Efficacy Analyses ....................................................................................................93 
10.3.3.1. 
Primary Analyses ...............................................................................................93 
10.3.3.2. 
Secondary Analyses ...........................................................................................94 
10.3.3.3. 
Exploratory Analyses .........................................................................................96 
10.3.4. 
Safety Analyses ........................................................................................................96 
10.3.4.1. 
Adverse Events ...................................................................................................96 
10.3.4.2. 
Clinical Laboratory Tests ...................................................................................97 
10.3.4.3. 
Vital Signs, Physical Findings, and Other Safety 
Evaluations .........................................................................................................97 
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10.3.5. 
Evaluation of Immunological Measures ..................................................................97 
10.3.6. 
Other Analyses .........................................................................................................97 
10.3.6.1. 
Subgroup Analyses .............................................................................................97 
10.3.7. 
Interim Analyses ......................................................................................................98 
10.3.7.1. 
Adjudication Committee ....................................................................................99 
11. References ...........................................................................................................................100 
12. Appendices ..........................................................................................................................105 
 
 
 
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List of Tables 
Table 
Page 
Table JAHW.1. Schedule of Activities .......................................................................................21 
Table JAHW.2. Schedule of Activities for Patients Participating in Long-Term 
Extension Period................................................................................................29 
Table JAHW.3. Summary of Baricitinib Phase 3 Clinical Studies in Rheumatoid .....................36 
Table JAHW.4. Summary of Primary and Major (Gated) Secondary Endpoints for 
Baricitinib Phase 3 Rheumatoid Arthritis Studies .............................................37 
Table JAHW.5. Objectives and Endpoints ..................................................................................43 
Table JAHW.6. Treatment Regimens ..........................................................................................61 
Table JAHW.7. Concomitant JIA Therapies ...............................................................................68 
Table JAHW.8. Criteria for Temporary Interruption of Investigational Product ........................70 
Table JAHW.9. SUN Grading Scheme for Anterior Chamber Cells ..........................................75 
Table JAHW.10. SUN Grading Scheme for Anterior Chamber Flare ..........................................76 
Table JAHW.11. Uveitis Disease Activity Terminology ..............................................................76 
Table JAHW.12. Secondary Efficacy Endpoint Analyses for Part A ...........................................95 
 
 
 
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List of Figures 
Figure 
Page 
Figure JAHW.1. Study design for Clinical Protocol I4V-MC-JAHW (d). ..................................47 
Figure JAHW.2. Study design for Clinical Protocol I4V-MC-JAHW (e). ...................................48 
Figure JAHW.3. Comparison of predicted steady-state concentrations of baricitinib in 
pediatric (solid lines) versus adults (gray dots) receiving 4-mg QD. ................51 
 
 
 
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List of Appendices 
Appendix 
Page 
Appendix 1. 
Abbreviations and Definitions .........................................................................106 
Appendix 2. 
Clinical Laboratory Tests ................................................................................112 
Appendix 3. 
Study Governance Considerations ..................................................................114 
Appendix 4. 
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ..................119 
Appendix 5. 
Monitoring Tests for Confirmed VTE .............................................................121 
Appendix 6. 
LOCS II Standards for Grading Cataracts .......................................................122 
Appendix 7. 
Weight-Based Prioritization Chart for Blood Sampling .................................123 
Appendix 8. 
Data-based Dosing Cohorts .............................................................................124 
Appendix 9. 
Provisions for Changes in Study Conduct During Exceptional 
Circumstances .................................................................................................126 
Appendix 10. 
Protocol Amendment History ..........................................................................130 
 
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1. Synopsis  
Title of Study 
An Open-label, Active-Controlled, Safety, and Efficacy Study of Oral Baricitinib in Patients 
from 2 Years to Less Than 18 Years Old with Active Juvenile Idiopathic Arthritis-Associated 
Uveitis or Chronic Anterior Antinuclear Antibody-Positive Uveitis. 
Regulatory Agency Identifier Numbers: 
EudraCT: 2019-000119-10 
EU trial number: 2023-505811-18-00 
Rationale 
Juvenile idiopathic arthritis (JIA)-associated uveitis (JIA-U) is the most common extra-articular 
manifestation of JIA.  It involves chronic inflammation of the uveal components of the eye, that 
is, the iris, choroid, and retina.  If inadequately treated, patients with JIA-U can develop 
glaucoma, cataracts, visual impairment, and blindness (Sen and Ramanan 2017). 
Uveitis usually occurs within 3 years following the onset of arthritis in patients with JIA 
(Verazza et al. 2008).  However, in a small proportion of patients, CAU may occur in the 
absence of any detectable systemic manifestations of JIA (Sen and Ramanan 2017).  Owing to 
the similarity of the conditions, it is recommended that patients with anterior antinuclear 
antibody (ANA)-positive CAU, in the absence of systemic symptoms, should be treated in the 
same manner as patients with JIA-U (Heiligenhaus et al. 2012). 
The etiology and pathogenesis of JIA-U and ANA-positive uveitis are still poorly understood; 
however, the aqueous humor of these patients contains elevated levels of a number of cytokines, 
including interleukin (IL)-2, IL-6, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α 
(Agrawal et al. 2014; Sijssens et al. 2007).  Therefore, pharmacologic interventions that reduce 
the activity of such cytokines may prove to be novel therapies for these conditions. 
Baricitinib belongs to the pharmacological class of Janus kinase (JAK) inhibitors.  Janus kinases 
are a family of 4 protein tyrosine kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]) 
that play an important role in cytokine signal transduction.  Baricitinib is a JAK1/JAK2 inhibitor 
demonstrating selectivity for and inhibition of JAK1 and JAK2 with lower potency towards 
inhibition of JAK3 or TYK2 (Fridman et al. 2010). 
In isolated enzyme assays, baricitinib inhibited the activities of JAK1, JAK2, TYK2, and JAK3 
with half-maximal inhibitory concentration values of 5.9, 5.7, 53, and >400 nM, respectively 
(Fridman et al. 2010).  Janus kinases are enzymes that transduce intracellular signals from cell 
surface receptors for a number of cytokines and growth factors involved in hematopoiesis, 
inflammation, and immune function (e.g., IL-2, IL-6, IL-12, IL-15, IL-23, INFs, and 
granulocyte-macrophage colony-stimulating factor signal through the JAK family) (O’Shea et al. 
2015).  Within the intracellular signaling pathway, JAKs phosphorylate and activate signal 
transducers and activators of transcription (STATs), which activate gene expression within the 
cell.  Baricitinib modulates these signaling pathways by partially inhibiting JAK1 and JAK2 
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LY3009104 
enzymatic activity, then reducing the phosphorylation and activation of STATs and thereby 
reducing inflammation, cellular activation, and proliferation of key immune cells (O’Shea et al. 
2013). 
This activity profile suggests that baricitinib may inhibit cytokines implicated in JIA and JIA-U, 
including IL-6 and IFN-γ (O’Shea et al. 2013), as well as other cytokines that may have a role in 
JIA-U including IL-2 and TNF-α.  Therefore, there is a compelling rationale to evaluate 
baricitinib for the treatment of these autoimmune diseases. 
The aim of this study is to evaluate the efficacy and safety of oral baricitinib when administered 
once daily (QD) to pediatric patients with JIA-U or ANA-positive uveitis without systemic 
features despite prior treatment with adequate doses of topical steroids and methotrexate (MTX).  
The safety and tolerability data from this study will establish an understanding of the benefit/risk 
relationship for baricitinib in these patients. 
Adalimumab, an injectable TNF inhibitor therapy, was recently shown to be an effective 
treatment for JIA-U (Ramanan et al. 2017), and is now approved for this indication.  As 
adalimumab is the only approved therapy for JIA-U, adalimumab is included in this study to 
provide an active comparator arm. 
 
 
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Objective(s)/Endpoints: 
Objectives 
Endpoints 
Primary 
 
To evaluate the efficacy of baricitinib in 
children with juvenile idiopathic arthritis-
associated uveitis (JIA-U) or anterior 
antinuclear antibody (ANA)-positive uveitis 
 
 
Proportion of responders at Week 24.  Response is defined 
according to the Standardization of Uveitis Nomenclature 
(SUN) criteria as a 2-step decrease in the level of 
inflammation (anterior chamber cells) or decrease to zero 
through Week 24, in the eye most severely affected at 
baseline. 
Secondary for Part A 
 
To evaluate the efficacy of baricitinib in 
children with JIA-U or ANA-positive 
uveitis in the most severely affected eye and 
less affected eye 
 
 
To evaluate the efficacy of adalimumab in 
children with JIA-U or ANA-positive 
uveitis in the most severely affected eye and 
less affected eye 
 
 
Change in SUN grade of cells in the anterior chamber 
through Week 24 in the most severely affected eye. 
 
Change in SUN grade of cells in the anterior chamber 
through Week 24 in the less severely affected eye (if 
applicable). 
 
In patients with bilateral uveitis disease at baseline:  
Proportion of responders at Week 24, defined according to 
the SUN criteria as a 2-step decrease in the level of 
anterior chamber cells in the most severely affected eye at 
baseline (or both eyes if the inflammation grade is the 
same in both eyes) and a 1-step decrease in the level of 
anterior chamber cells in the less severely affected eye at 
baselinea. 
 
Change in visual acuity measured by age-appropriate 
LogMAR test through Week 24. 
 
Change in vitreous haze through Week 24 in each affected 
eye. 
 
Change in grade of flare in the anterior chamber through 
Week 24 in each affected eye. 
 
Change in overall uveitis-related disability: 
o 
Change in Patient Uveitis-related Disease Activity 
through Week 24. 
o 
Change in Patient Uveitis-related Improvement at 
Week 12 and Week 24. 
o 
Change in Patient Arthritis Disease Activity through 
Week 24. 
o 
Change in Patient Arthritis Improvement at Week 12 
and Week 24. 
o 
Change in Ophthalmologist Uveitis-related Disease 
Activity through Week 24. 
o 
Change in Ophthalmologist Uveitis-related 
Improvement at Week 12 and Week 24. 
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I4V-MC-JAHW(e) Clinical Protocol 
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Objectives 
Endpoints 
 
Proportion of patients with inactive anterior uveitis (using 
SUN definition) in each affected eye through Week 24. 
 
Time to inactive anterior uveitis disease (using SUN 
definition) in each affected eye. 
 
Proportion of patients who are able to taper concomitant 
topical corticosteroids to <2 drops per day and to 0 drops 
per day. 
 
PediACR30/50/70/90/100 response rates (for patients with 
JIA-U). 
 
To evaluate the safety of baricitinib in 
children with JIA-U or ANA-positive 
uveitis 
 
Adverse events (AEs) including serious adverse events. 
 
Permanent discontinuation of investigational product due 
to AE. 
 
Temporary interruption of investigational product. 
Secondary for Part B (open-label extension) 
 
To describe the efficacy of baricitinib in 
children with JIA-U or ANA-positive 
uveitis in the most severely affected eye and 
less affected eye (among the responders at 
Week 24) 
 
 
Number of responders through Week 284. Response is 
defined according to the SUN criteria as a 2-step decrease 
in the level of inflammation (anterior chamber cells) or 
decrease to zero through Week 284, in the eye most 
severely affected at baseline. 
 
Change in SUN grade of cells in the anterior chamber 
through Week 284 in the most severely affected eye. 
 
Change in SUN grade of cells in the anterior chamber 
through Week 284 in the less severely affected eye (if 
applicable). 
 
In patients with bilateral uveitis disease at baseline: 
Number of responders through Week 284, defined 
according to the SUN criteria as a 2-step decrease in the 
level of anterior chamber cells in the most severely 
affected eye at baseline (or both eyes if the inflammation 
grade is the same in both eyes) and a 1-step decrease in 
the level of anterior chamber cells in the less severely 
affected eye at baseline. 
 
Change in grade of flare in the anterior chamber through 
Week 284 in each affected eye. 
 
Description of inactive anterior uveitis including time to 
inactive anterior uveitis disease (using SUN definition) in 
each affected eye through Week 284. 
 
Number of patients who are able to taper concomitant 
topical corticosteroids to <2 drops per day and to 0 drops 
per day. Number of patients who are able to taper 
concomitant oral corticosteroids to <5 mg per day and to 0 
mg per day. 
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I4V-MC-JAHW(e) Clinical Protocol 
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Objectives 
Endpoints 
 
To evaluate the safety of baricitinib in 
children with JIA-U or ANA-positive 
uveitis 
 
Adverse events including serious adverse events. 
 
Permanent discontinuation of investigational product due 
to AE. 
 
Temporary interruption of investigational product. 
Abbreviations:  AE = adverse event; LogMAR = logarithm of the minimum angle of resolution; 
PediACR = Pediatric American College of Rheumatology; SUN = Standardization of Uveitis Nomenclature. 
a Response is defined according to the SUN criteria as a 2-step decrease in the level of inflammation (anterior 
chamber cells) or decrease to 0 through Week 24 in the eye most severely affected at baseline. 
Summary of Study Design 
Study I4V-MC-JAHW (JAHW) is a multicenter, open-label, active-controlled Phase 3 study in 
patients with active JIA-U or chronic ANA-positive uveitis without systemic features despite 
prior treatment with adequate doses of topical steroid therapy and MTX. 
Treatment Arms and Duration 
The study consists of 2 arms.  Patients in the baricitinib arm will receive oral baricitinib at least 
QD at a fixed dose by age group.  Patients in the adalimumab (active control) arm will receive 
adalimumab as a subcutaneous injection every 2 weeks.  The dose will be based on body weight 
(adalimumab Summary of Product Characteristics [SmPC]).  
Study JAHW will be conducted in 2 parts: 
 Treatment Period Part A:  24 weeks 
 Treatment Period Part B:  260 weeks. 
Patients who complete Part A may be eligible to continue to Part B, the open-label extension 
(OLE) period of the study.  Patients on adalimumab will be discontinued after Week 24. Patients 
who do not continue in the OLE will have a follow-up visit (Visit 801) approximately 28 days 
after the last dose of the investigational product. 
Study Population 
This study includes patients from 2 years to less than 18 years old with active JIA-U or chronic 
ANA-positive uveitis without systemic features despite prior treatment with adequate doses of 
topical steroid therapy and MTX. 
Number of Patients 
 Baricitinib arm:  At least 20 patients (MTX-IR and/or bDMARD-IR) evaluable for 
primary endpoint. 
 Adalimumab arm:  At least 4 patients evaluable for the primary endpoint. 
Statistical Analysis 
A Bayesian analysis will determine if the study should be considered a positive study or a 
negative study.  The study will be considered positive if the posterior probability is at least 80% 
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I4V-MC-JAHW(e) Clinical Protocol 
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LY3009104 
that the baricitinib treatment response is greater than 57%, otherwise the study will be considered 
negative. 
Efficacy and health outcome endpoints will be summarized using descriptive statistics.  The 
last-observation-carried-forward approach will be used to impute missing data. 
Categorical data will be summarized as frequency counts and percentages.  The proportions and 
95% confidence interval will be reported.  Missing data will be imputed using the modified 
nonresponder imputation method. 
Two interim analyses will be performed to determine if the study should be stopped for futility 
when 10 and 20 baricitinib-treated patients have completed 24 weeks of treatment.  At each 
interim analysis, the posterior probability of the treatment response rate being lower than 40% 
will be calculated, and the study will be stopped if this probability is greater than 75% (otherwise 
the study will continue).   
Descriptive response rates will be evaluated in adalimumab-treated patients. 
An analysis will evaluate response rates in MTX-IR adalimumab-treated patients and MTX-IR 
baricitinib-treated patients. 
All safety data will be descriptively summarized using corresponding populations. 
Ethical Considerations of Benefit/Risk  
Based on the efficacy of baricitinib demonstrated in the Phase 3 RA program and the observed 
safety profile, the probability of a positive benefit/risk warrants this study to be conducted, given 
the unmet need in patients with JIA-U and ANA-positive uveitis. 
 
 
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2. Schedule of Activities  
The Schedule of Activities described below should be followed for all participants enrolled in 
Study JAHW.  In the event participation in this study is affected by exceptional circumstances 
(such as pandemics or natural disasters), please refer to Appendix 9 and consult with the 
sponsor’s representative for additional guidance. 
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Table JAHW.1. 
Schedule of Activities  
 
Screening 
Treatment Period Part A 
Early Termination 
Post-Treatment Follow-Up 
Visit # 
V1 
V1a 
V2a 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
ETVb 
V801c 
Study Week 
 
 
W0 
W4 W8 W12 W16 W20 W2
4 
Any Week 
 
Study Day 
(Approximately) 
-42 to -1 
 
0 
28 
56 
84 
112 
140 168 
Any Day 
28 ± 5 Days after Last Dose 
Visit Window (Days) 
 
 
 
±4 
 
 
Informed consent and 
assent
d 
X 
 
 
 
 
 
 
 
 
 
 
Complete medical history 
X 
 
 
 
 
 
 
 
 
 
 
Immunization record 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Physical examinatione 
X 
 
 
 
 
 
 
 
 
 
 
Tanner Stage Scalez  
 
 
X 
 
 
 
 
 
 
 
 
Symptom-directed physical 
examinatione 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Habits:  tobacco and 
caffeine 
 
 
X 
 
 
 
 
 
 
 
 
Height 
X 
 
X 
 
 
X 
 
 
X 
X 
 
Weight  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Imaging of wrist, hand, 
finger, and kneef 
 
 
Xf 
 
 
Occipital frontal 
circumference 
measurement in children 
up to 3 years of age 
 
 
X 
Xg 
X 
X 
Vital signs (blood pressure, 
pulse, temperature) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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I4V-MC-JAHW(e) Clinical Protocol 
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LY3009104 
 
Screening 
Treatment Period Part A 
Early Termination 
Post-Treatment Follow-Up 
Visit # 
V1 
V1a 
V2a 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
ETVb 
V801c 
Study Week 
 
 
W0 
W4 W8 W12 W16 W20 W2
4 
Any Week 
 
Study Day 
(Approximately) 
-42 to -1 
 
0 
28 
56 
84 
112 
140 168 
Any Day 
28 ± 5 Days after Last Dose 
Visit Window (Days) 
 
 
 
±4 
 
 
Inclusion/exclusion criteria 
review 
X 
 
X 
 
 
 
 
 
 
 
 
Preexisting conditions 
X 
 
 
 
 
 
 
 
 
 
 
JIA diagnosis 
(ILAR criteria) 
X 
 
 
 
 
 
 
 
 
 
 
Previous JIA and uveitis 
therapy 
X 
 
 
 
 
 
 
 
 
 
 
Visual acuity (LogMAR) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit-lamp examination of 
the retina and optic disc 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Optical coherence 
tomography 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit-lamp examination for 
anterior chamber cells and 
flare assessment 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit-lamp examination for 
assessment of vitritis and 
vitreous haze 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cataract scoringh 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IOP using I-Care 
tonometry, Goldmann 
tonometry, or Tono-Pen 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Log in IWRS 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
Dispense study drug 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
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I4V-MC-JAHW(e) Clinical Protocol 
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LY3009104 
 
Screening 
Treatment Period Part A 
Early Termination 
Post-Treatment Follow-Up 
Visit # 
V1 
V1a 
V2a 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
ETVb 
V801c 
Study Week 
 
 
W0 
W4 W8 W12 W16 W20 W2
4 
Any Week 
 
Study Day 
(Approximately) 
-42 to -1 
 
0 
28 
56 
84 
112 
140 168 
Any Day 
28 ± 5 Days after Last Dose 
Visit Window (Days) 
 
 
 
±4 
 
 
Investigational product 
returned and compliance 
assessedi 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Joint assessment 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
External tibial length 
measurementy 
 
 
X 
 
 
X 
 
 
X 
 
 
Physician’s Global 
Assessment of Disease 
Activity 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Uveitis-related 
Disease Activityj 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Uveitis-related 
Improvementj  
 
 
 
 
 
X 
 
 
X 
X 
X 
Patient Arthritis Disease 
Activityj 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Arthritis 
Improvementj 
 
 
 
 
 
X 
 
 
X 
X 
X 
Ophthalmologist Uveitis-
related Disease Activity 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmologist Uveitis-
related Improvement 
 
 
 
 
 
X 
 
 
X 
X 
X 
CHAQk 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CHQ-PF50k 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Morning stiffness durationj 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SPARCC Enthesitis Indexl 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical sacroiliitisl 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Back mobility 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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I4V-MC-JAHW(e) Clinical Protocol 
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LY3009104 
 
Screening 
Treatment Period Part A 
Early Termination 
Post-Treatment Follow-Up 
Visit # 
V1 
V1a 
V2a 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
ETVb 
V801c 
Study Week 
 
 
W0 
W4 W8 W12 W16 W20 W2
4 
Any Week 
 
Study Day 
(Approximately) 
-42 to -1 
 
0 
28 
56 
84 
112 
140 168 
Any Day 
28 ± 5 Days after Last Dose 
Visit Window (Days) 
 
 
 
±4 
 
 
(Schober’s test)l 
PASIm 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest x-rayn 
X 
 
 
 
 
 
 
 
 
 
 
Administer PPD/ 
QuantiFERON®-TB 
Gold/T-SPOT® TB
o 
X 
 
 
 
 
 
 
 
 
 
 
Read PPD
o 
 
X 
 
 
 
 
 
 
 
 
 
ECGp 
X 
 
 
 
 
 
 
 
 
 
 
hsCRP 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ESRq 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HLA-B27 
 
 
 
 
X 
 
 
 
 
 
 
RF and ACPA 
X 
 
 
 
 
 
 
 
 
 
 
Antinuclear antibodies 
 
 
X 
 
 
 
 
 
X 
X 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
HIV/HCVr 
X 
 
 
 
 
 
 
 
 
 
 
HBV (HBsAg, HBcAb, 
HBsAb) 
X 
 
 
 
 
 
 
 
 
 
 
HBV DNAs 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
Serum pregnancy test
t 
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test
t 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistryu 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
Iron studies (iron, TIBC, 
and ferritin) 
 
 
X 
 
 
X 
 
 
X 
X 
X 
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I4V-MC-JAHW(e) Clinical Protocol 
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LY3009104 
 
Screening 
Treatment Period Part A 
Early Termination 
Post-Treatment Follow-Up 
Visit # 
V1 
V1a 
V2a 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
ETVb 
V801c 
Study Week 
 
 
W0 
W4 W8 W12 W16 W20 W2
4 
Any Week 
 
Study Day 
(Approximately) 
-42 to -1 
 
0 
28 
56 
84 
112 
140 168 
Any Day 
28 ± 5 Days after Last Dose 
Visit Window (Days) 
 
 
 
±4 
 
 
Fasting lipid panelv 
 
 
X 
 
 
X 
 
 
X 
X 
X 
IgA, IgG, IgM 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Lymphocyte subsets (T, B, 
NK, and T-cell subsets) 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Antipneumococcal IgG 
multianalyte Ab assayw 
 
 
 
At relevant visits for prevaccination, 4 weeks post vaccination, 
and 12 weeks postvaccination based on the vaccination schedule 
of each patient 
 
Anti-tetanus toxoid IgG, 
anti-diphtheria toxoid, and 
anti-pertussis toxoid Ab 
assayw 
 
 
 
At relevant visits for prevaccination, 4 weeks post vaccination, 
and 12 weeks postvaccination based on the vaccination schedule 
of each patient 
 
IGF-1 and IGFBP-3 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Gonadal hormonex 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Exploratory storage 
samples (RNA, serum, and 
plasma) 
 
 
X 
 
 
X 
 
 
X 
 
 
Pharmacogenetic (DNA) 
collection 
 
 
 
 
X 
 
 
 
 
 
 
 
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I4V-MC-JAHW(e) Clinical Protocol 
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Abbreviations:  Ab = antibody; ACPA = anti-citrullinated protein antibodies; CHAQ = Childhood Health Assessment Questionnaire; CHQ-PF50 = Child Health 
Questionnaire-Parent Form 50; CRP = C-reactive protein; DNA = deoxyribonucleic acid; ECG = electrocardiogram; eCOA = electronic Clinical Outcome 
Assessment; eGFR = estimated glomerular filtration rate; ESR = erythrocyte sedimentation rate; ETV = early termination visit; 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; IgA = immunoglobulin A; 
IgG = immunoglobulin G; IgM = immunoglobulin M; IGF-1 = insulin-like growth factor-1; IGFBP-3 = insulin-like growth factor-binding protein-3; 
ILAR = International League of Associations for Rheumatology; IOP = intraocular pressure; IWRS = interactive web-response system; JIA = juvenile 
idiopathic arthritis; JPsA = juvenile psoriatic arthritis; LogMAR = logarithm of the minimum angle of resolution; NK = natural killer; PASI = Psoriasis Area 
and Severity Index; PPD = purified protein derivative; RF = rheumatoid factor; RNA = ribonucleic acid; SPARCC = Spondyloarthritis Research Consortium 
of Canada; TB = tuberculosis; TIBC = total iron-binding capacity; TSH = thyroid-stimulating hormone; V = visit. 
a Baseline laboratory samples should be taken before administration of investigational product. 
b Early termination visit (ETV) occurs if the patient terminates participation early.  If the 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. 
c Patients who complete the study or discontinue early from the study will have a post-treatment safety follow-up visit (V801) approximately 28 days after the 
last dose of investigational product. 
d The parent or legal guardian will sign the informed consent form (ICF) and the patient will sign the assent form (as appropriate) per local requirements prior 
to any study assessments, examinations, or procedures being performed. 
e One complete physical examination (excluding pelvic and rectal examinations) will be performed at Visit 1.  All subsequent physical examinations may be 
symptom-directed.  A complete physical examination may be repeated at the investigator’s discretion at any time.  Must include an assessment of serositis, 
splenomegaly, hepatomegaly, or generalized lymphadenopathy attributable to JIA. 
f 
Semiannual wrist, hand, finger, and knee radiographs to monitor bone age and long bone growth.  Imaging will be required until skeletal maturity is attained 
and this should be determined by a qualified physician at the site.  For patients already enrolled in JAHW at the time of Amendment (d), the x-ray procedures 
will be optional.  For these ongoing patients that consent to the x-ray procedures, x-rays must be completed within 30 days from time of consent/assent and 
every 6 months ±30 days thereafter. For patients from Germany, MRI should be utilized for knee imaging. If MRI is not available, X-rays can be used as an 
alternative. 
g Occipital frontal circumference measurement is required every 3 months for patients under 3 years of age, but is no longer required once the patient reaches 3 
years of age.   
h Only for patients with cataracts at baseline, or who develop cataracts during the study. 
i 
Patients will return all investigational products for drug accountability. 
j 
Patient-reported and caregiver-reported questionnaires will be administered on paper at the site and are recommended to be completed prior to any clinical 
examinations. 
k Caregiver-reported questionnaires (CHAQ and CHQ-PF50) will be administered via an on-site eCOA device and are recommended to be completed prior to 
any clinical assessments. 
l 
Only for patients with enthesitis-related juvenile idiopathic arthritis (ERA) or juvenile psoriatic arthritis (JPsA). 
m Only for patients with JPsA. 
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I4V-MC-JAHW(e) Clinical Protocol 
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n Only for patients with a history of active or latent TB with documented evidence of appropriate treatment and patients with a positive or repeated not-negative 
TB test(s) (either PPD, QuantiFERON®-TB Gold, and/or T-SPOT®).  A chest x-ray (posterior-anterior view) will be performed at screening unless one has 
been performed within the past 6 months and the x-ray and reports are available for review. 
o TB tests include PPD, QuantiFERON®-TB Gold, and T SPOT®.  In countries where the QuantiFERON-TB Gold test or T-SPOT is available, either test may 
be used instead of the PPD TB test.  The QuantiFERON-TB Gold test may be performed locally or centrally; the T-SPOT must be performed locally.  PPD 
tests must be read 48 to 72 hours after screening.  (Exception:  Patients with a history of active or latent TB who have documented evidence of appropriate 
treatment, have no history of re-exposure since their treatment was completed, and have a screening chest x-ray with no evidence of active TB may be 
enrolled if other entry criteria are met.  Such patients would not be required to undergo the protocol-specific TB testing but must have a chest x-ray at 
screening.) 
p The ECG will be collected and read locally (no central over read).  An ECG performed within 1 year prior to screening may be used. 
q Performed locally. To be drawn prior to dosing early in the visit. 
r For patients who are positive for HCV antibody, a follow-up test for HCV RNA is required.  Patients 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.  Patients who are positive for HCV 
antibody and negative for HCV RNA may be enrolled. 
s For patients who are positive for HBcAb, a follow-up test for HBV DNA is required.  Patients with a positive 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 patient who is HBcAb positive, regardless 
of HBsAb status or level, must undergo HBV DNA testing per the schedule of activities. 
t 
Pregnancy tests prior to first dose of investigational product for females ≥10 years of age (<10 years at investigator discretion) if menarche reached or if there 
is reason to believe the patient is sexually active.  Pregnancy test results from baseline must be known prior to first dose of investigational product. 
u Clinical chemistry will include eGFR (calculated by Bedside Schwartz 2009 formula). 
v Fasting lipid profile:  Patients should not eat or drink anything except water for 4-12 hours depending on weight and age as specified below.  If a patient 
attends these visits in a nonfasting state, this will not be considered a protocol violation.  Recommended fasting times by age and weight are as follows: 
 
Patients ≥12 years:  fast for 12 hours prior to laboratory test 
 
Patients 8 to <12 years and weighing >50 kg:  fast for 12 hours prior to laboratory test 
 
Patients 8 to <12 years and weighing ≤50 kg:  fast for 8 hours prior to laboratory test 
 
Children <8 years and weighing 25 to ≤50 kg:  fast for 8 hours prior to laboratory test 
 
Children <8 years and weighing 10 to <25 kg:  fast for 6 hours prior to laboratory test 
 
Children <8 years and weighing <10 kg:  fast for 4 hours prior to laboratory test 
w If patients are eligible for vaccination with tetanus, diphtheria, and pertussis (TDaP) and/or pneumococcal conjugate vaccine according to local recommended 
schedule of vaccination, IgG titers for eligible vaccine will be evaluated at prevaccination, 4 weeks postvaccination, and 12 weeks post vaccination. 
x Estradiol (for females) or testosterone (for males) will be collected for the assessment of pubertal development in patients aged 8 to <18 years. 
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I4V-MC-JAHW(e) Clinical Protocol 
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y For sites in Germany only.  This will be collected at baseline and every 3 months during study participation.  Guidance on measuring external tibial length 
will be provided by the sponsor. 
z Participants 8 years and older will be assessing their sexual maturity. Once the participant reaches the score 5 in the scale, no further assessments are needed. 
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 (Appendix 7). 
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I4V-MC-JAHW(e) Clinical Protocol 
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Table JAHW.2. 
Schedule of Activities for Patients Participating in Long-Term Extension Period  
 
Treatment Period Part B 
Early 
Termination 
Post-
Treatment 
Follow-Up 
Visit # 
V9 V10 V11 V12 V13 V14 V15 V16 V17 V18 V19 V20 V21 
V22 
V23 V24 V25 V26 V27 V28 V29 V3
0 
ETVa 
V801b 
Study Week 
W36 W48 W6
0 
W72 W84 W96 W108 W120 W132 W144 W156 W168 W180 W192 W204 W216 W228 W240 W25
2 
W26
4 
W27
6 
W2
84 Any Week 
 
Study Day 
(Approximately) 252 336 420 504 588 672 756 
840 
924 1008 1092 1176 1260 
1344 
1428 1512 1596 1680 1764 1848 1932 198
8 
Any Day 
28 ± 5 
Days after 
Last Dose 
Visit Window 
(Days) 
±7 
 
 
Symptom-directed 
physical 
examinationc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Imaging of wrist, 
hand, finger, and 
kneed 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Vital signs (blood 
pressure, pulse, 
temperature) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visual acuity 
(LogMAR) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit lamp 
examination of the 
retina and optic 
disc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Optical coherence 
tomography 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit lamp 
examination for 
anterior chamber 
cells and flare 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Approved on 14 Jun 2023 GMT

I4V-MC-JAHW(e) Clinical Protocol 
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LY3009104 
 
Treatment Period Part B 
Early 
Termination 
Post-
Treatment 
Follow-Up 
Visit # 
V9 V10 V11 V12 V13 V14 V15 V16 V17 V18 V19 V20 V21 
V22 
V23 V24 V25 V26 V27 V28 V29 V3
0 
ETVa 
V801b 
Study Week 
W36 W48 W6
0 
W72 W84 W96 W108 W120 W132 W144 W156 W168 W180 W192 W204 W216 W228 W240 W25
2 
W26
4 
W27
6 
W2
84 Any Week 
 
Study Day 
(Approximately) 252 336 420 504 588 672 756 
840 
924 1008 1092 1176 1260 
1344 
1428 1512 1596 1680 1764 1848 1932 198
8 
Any Day 
28 ± 5 
Days after 
Last Dose 
Visit Window 
(Days) 
±7 
 
 
Slit-lamp 
examination for 
assessment of 
vitritis and 
vitreous haze 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cataract scoringf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IOP using I-Care 
tonometry, 
Goldmann 
tonometry, or 
Tono-Pen 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Log in IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study 
drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Approved on 14 Jun 2023 GMT

I4V-MC-JAHW(e) Clinical Protocol 
Page 31 
LY3009104 
 
Treatment Period Part B 
Early 
Termination 
Post-
Treatment 
Follow-Up 
Visit # 
V9 V10 V11 V12 V13 V14 V15 V16 V17 V18 V19 V20 V21 
V22 
V23 V24 V25 V26 V27 V28 V29 V3
0 
ETVa 
V801b 
Study Week 
W36 W48 W6
0 
W72 W84 W96 W108 W120 W132 W144 W156 W168 W180 W192 W204 W216 W228 W240 W25
2 
W26
4 
W27
6 
W2
84 Any Week 
 
Study Day 
(Approximately) 252 336 420 504 588 672 756 
840 
924 1008 1092 1176 1260 
1344 
1428 1512 1596 1680 1764 1848 1932 198
8 
Any Day 
28 ± 5 
Days after 
Last Dose 
Visit Window 
(Days) 
±7 
 
 
Investigational 
product returned 
and compliance 
assessedg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
External tibial 
length 
measurementh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physician’s 
Global 
Assessment of 
Disease Activity 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tanner Stage 
Scaler 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
hsCRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ESRk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Antinuclear 
antibodies 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
RF and ACPA 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
HBV DNAl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy 
test
m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical 
chemistryn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Approved on 14 Jun 2023 GMT

I4V-MC-JAHW(e) Clinical Protocol 
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LY3009104 
 
Treatment Period Part B 
Early 
Termination 
Post-
Treatment 
Follow-Up 
Visit # 
V9 V10 V11 V12 V13 V14 V15 V16 V17 V18 V19 V20 V21 
V22 
V23 V24 V25 V26 V27 V28 V29 V3
0 
ETVa 
V801b 
Study Week 
W36 W48 W6
0 
W72 W84 W96 W108 W120 W132 W144 W156 W168 W180 W192 W204 W216 W228 W240 W25
2 
W26
4 
W27
6 
W2
84 Any Week 
 
Study Day 
(Approximately) 252 336 420 504 588 672 756 
840 
924 1008 1092 1176 1260 
1344 
1428 1512 1596 1680 1764 1848 1932 198
8 
Any Day 
28 ± 5 
Days after 
Last Dose 
Visit Window 
(Days) 
±7 
 
 
Urinalysis 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Iron studies (iron, 
TIBC and ferritin) 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Fasting lipid 
panelo 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
IgA, IgG, IgM 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Lymphocyte 
subsets (T, B, NK, 
and T-cell subsets) 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Antipneumococca
l IgG multianalyte 
Ab assayp 
At relevant visits for prevaccination, 4 weeks postvaccination, and 12 weeks postvaccination based on the vaccination 
schedule of each patient 
 
 
Anti-tetanus toxoid 
IgG, anti-
diphtheria toxoid, 
and anti-pertussis 
toxoid Ab assayp 
At relevant visits for prevaccination, 4 weeks postvaccination, and 12 weeks postvaccination based on the vaccination 
schedule of each patient 
 
 
IGF-1 and IGFBP-
3 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
Gonadal 
hormoneq 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
Exploratory 
storage samples 
(RNA, serum, and 
plasma) 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
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I4V-MC-JAHW(e) Clinical Protocol 
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LY3009104 
Abbreviations:  Ab = antibody; ACPA = anti-citrullinated protein antibodies; DNA = deoxyribonucleic acid; eCOA = electronic Clinical Outcome Assessment; 
eGFR = estimated glomerular filtration rate; ESR = erythrocyte sedimentation rate; ETV = early termination visit; HBcAb = hepatitis B core antibody; 
HBsAb = hepatitis B surface antibody; HBV = hepatitis B virus; HCV = hepatitis C virus; hsCRP = high-sensitivity C-reactive protein; 
IgA = immunoglobulin A; IgG = immunoglobulin G; IgM = immunoglobulin M; IGF-1 = insulin-like growth factor-1; IGFBP-3 = insulin-like growth 
factor-binding protein-3; IOP = intraocular pressure; IWRS = interactive web-response system; JIA = juvenile idiopathic arthritis; LogMAR = logarithm of 
the minimum angle of resolution; NK =  natural killer; RF = rheumatoid factor; RNA = ribonucleic acid; TB = tuberculosis; TIBC = total iron-binding 
capacity; V = visit. 
a Early termination visit occurs if the patient terminates participation early.  If the 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. 
b Patients who complete the study or discontinue early from the study will have a post-treatment safety follow-up visit (V801) approximately 28 days after the 
last dose of investigational product. 
c All physical examinations in Part B may be symptom-directed; however, a complete physical examination may be repeated at the investigator’s discretion at 
any time.  Must include an assessment of serositis, splenomegaly, hepatomegaly, or generalized lymphadenopathy attributable to JIA. 
d Semiannual wrist, hand, finger, and knee radiographs to monitor bone age and long-bone growth.  These x-rays are mandatory for all patients enrolled in this 
study.  Imaging will be required until skeletal maturity is attained as determined by a qualified physician (either study investigator or as noted in radiology 
report).  X-rays will be completed approximately every 6 months.  If a patient had imaging conducted ≤4 months previously in the Schedule of Activities Part 
A, the patient should not undergo imaging until next defined imaging visit. For patients from Germany, MRI should be utilized for knee imaging. If MRI is 
not available, x-rays can be used as an alternative. 
f Only for patients with cataracts at baseline, or who develop cataracts during the study. 
g Patients will return all investigational products for drug accountability. 
h Applicable for sites in Germany only. 
k Performed locally. To be drawn prior to dosing early in the visit. 
l 
For patients who are positive for HBcAb, a follow-up test for HBV DNA is required.  Patients with a positive 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 patient who is HBcAb positive, regardless 
of HBsAb status or level, must undergo HBV DNA testing per the schedule of activities. 
m Urine pregnancy tests are required for females ≥10 years of age (<10 years at investigator discretion) if menarche reached or if there is reason to believe the 
patient is sexually active. 
n Clinical chemistry will include eGFR (calculated by Bedside Schwartz 2009 formula). 
o Fasting lipid profile:  Patients should not eat or drink anything except water for 4-12 hours depending on weight and age as specified below.  If a patient 
attends these visits in a nonfasting state, this will not be considered a protocol violation.  Recommended fasting times by age and weight are as follows: 
 
Patients ≥12 years:  fast for 12 hours prior to laboratory test 
 
Patients 8 to <12 years and weighing >50 kg:  fast for 12 hours prior to laboratory test 
 
Patients 8 to <12 years and weighing ≤50 kg:  fast for 8 hours prior to laboratory test 
 
Children <8 years and weighing 25 to ≤50 kg:  fast for 8 hours prior to laboratory test 
 
Children <8 years and weighing 10 to <25 kg:  fast for 6 hours prior to laboratory test 
 
Children <8 years and weighing <10 kg:  fast for 4 hours prior to laboratory test 
Approved on 14 Jun 2023 GMT

I4V-MC-JAHW(e) Clinical Protocol 
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LY3009104 
p If patients are eligible for vaccination with tetanus, diphtheria, and pertussis (TDaP) and/or pneumococcal conjugate vaccine according to local recommended 
schedule of vaccination, IgG titers for eligible vaccine will be evaluated at prevaccination, 4 weeks postvaccination, and 12 weeks postvaccination. 
q Estradiol (for females) or testosterone (for males) will be collected for the assessment of pubertal development in patients aged 8 to <18 years. 
r 
Participants 8 years and older will be assessing their sexual maturity. Once the participant reaches the score 5 in the scale, no further assessments are needed. 
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 (Appendix 7). 
Approved on 14 Jun 2023 GMT

I4V-MC-JAHW(e) Clinical Protocol 
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LY3009104 
3. Introduction  
3.1. Study Rationale  
Baricitinib belongs to the pharmacological class of Janus kinase (JAK) inhibitors.  Janus kinases 
are a family of 4 protein tyrosine kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]) 
that play an important role in cytokine signal transduction.  Baricitinib is a JAK1/JAK2 inhibitor 
demonstrating selectivity for and inhibition of JAK1 and JAK2 with lower potency towards 
inhibition of JAK3 or TYK2 (Fridman et al. 2010). 
In isolated enzyme assays, baricitinib inhibited the activities of JAK1, JAK2, TYK2, and JAK3 
with half-maximal inhibitory concentration values of 5.9, 5.7, 53, and >400 nM, respectively 
(Fridman et al. 2010).  Janus kinases are enzymes that transduce intracellular signals from cell 
surface receptors for a number of cytokines and growth factors involved in hematopoiesis, 
inflammation, and immune function (e.g., interleukin [IL]-2, IL-6, IL-12, IL-15, IL-23, 
interferons, and granulocyte-macrophage colony-stimulating factor signal through the JAK 
family) (O’Shea et al. 2015).  Within the intracellular signaling pathway, JAKs phosphorylate 
and activate signal transducers and activators of transcription (STATs), which activate gene 
expression within the cell.  Baricitinib modulates these signaling pathways by partially inhibiting 
JAK1 and JAK2 enzymatic activity, then reducing the phosphorylation and activation of STATs 
and thereby reducing inflammation, cellular activation, and proliferation of key immune cells 
(O’Shea et al. 2013). 
The etiology and pathogenesis of juvenile idiopathic arthritis (JIA), JIA-associated uveitis 
(JIA-U) and antinuclear antibody (ANA)-positive uveitis are still poorly understood, but the 
diseases share several immunological abnormalities identified in rheumatoid arthritis (RA) 
(Ravelli and Martini 2007).  The inflammatory synovitis in JIA is similar to that observed in RA.  
The synovium in JIA shows pronounced hyperplasia of the lining layer and an infiltration of the 
sublining layer with mononuclear cells, including T cells, B cells, macrophages, dendritic cells, 
and plasma cells, as observed in RA.  Similarly, B- and T-lymphocytes appear to be involved in 
the pathogenesis of JIA-U; eye biopsies from patients with JIA-U were found to contain a 
predominance of CD4+ T cells and plasma cells, along with B cells (Kalinina Ayuso et al. 2014). 
Some studies have shown that levels of inflammatory cytokines elevated in adults with RA, such 
as IL-6 and tumor necrosis factor-alpha (TNF-α), are also elevated in the synovial fluid and 
serum of patients with JIA, as well as the aqueous humor of patients with JIA-U (Sijssens et al. 
2007).  Inflammatory cytokines, such as IL-6, which transduces cell signaling through the 
JAK/STAT pathway (Rawlings et al. 2004), and TNF, whose expression is reduced by inhibition 
of JAK1 and JAK2, are considered to be associated with the pathology of JIA-U and 
ANA-positive uveitis (Sijssens et al. 2007; Agrawal et al. 2014).  Therefore, inhibition of 
JAK-STAT signaling by baricitinib can target multiple cytokine pathways associated with JIA-U 
and ANA-positive uveitis, and may provide novel therapeutic approaches to disease 
management. 
Biologic DMARDs, in particular the recently approved anti–TNF-α monoclonal antibody 
adalimumab, have led to significant improvements in JIA-U treatment.  However, many patients 
Approved on 14 Jun 2023 GMT

I4V-MC-JAHW(e) Clinical Protocol 
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LY3009104 
fail to respond to or do not achieve long-lasting remission with these medications.  For example, 
during a 2-year treatment period, 40% of JIA-U patients receiving adalimumab and 79.7% 
receiving infliximab did not achieve clinical remission (Cecchin et al. 2018). 
Baricitinib has demonstrated clinical safety and efficacy in adult patients with moderately to 
severely active RA in 4 completed Phase 3 studies (Genovese et al. 2016; Dougados et al. 2017; 
Fleischmann et al. 2017; Taylor et al. 2017).  These studies are summarized in Table JAHW.3. 
Table JAHW.3. 
Summary of Baricitinib Phase 3 Clinical Studies in Rheumatoid  
Arthritis 
 
Se 
I4V-MC-JADZ 
(RA-BEGIN) 
I4V-MC-JADV 
(RA-BEAM) 
I4V-MC-JADX 
(RA-BUILD) 
I4V-MC-JADW 
(RA-BEACON) 
Length of Study 
52 weeks 
52 weeks 
24 weeks 
24 weeks 
Patient Population 
Limited or no 
prior DMARD 
exposure 
Inadequate 
response to MTX 
and 
bDMARD-naive 
csDMARD-IR 
and 
bDMARD-naive 
IR to ≥1 TNF-α 
inhibitor; No limit 
on number or 
nature of other 
prior bDMARDs. 
Treatment Arms (N) 
 MTX QW 
(210) 
 BARI 4-mg 
QD (159) 
 BARI 4-mg 
QD plus MTX 
QW (215) 
 Placebo QD for 
24 weeks, 
followed by 
switch to BARI 
4-mg QD from 
Week 24 to 
Week 52 (488) 
 BARI 4-mg QD 
(487) 
 Adalimumab 
40-mg Q2W 
(330) 
 Placebo QD 
(228) 
 BARI 2-mg 
(229) 
 BARI 4-mg 
(227) 
 Placebo QD 
(176) 
 BARI 2-mg 
(174) 
 BARI 4-mg 
(177) 
 
Primary Endpoint 
ACR20 at W24 
ACR20 at W12 
ACR20 at W12 
ACR20 at W12 
Response Rate 
 
 BARI:  77% 
 MTX:  62% 
(p≤0.01) 
 BARI:  70% 
 Placebo:  40% 
(p≤0.001)a 
 Adalimumab: 
61% (p = 0.014)a 
 BARI:  62% 
 Placebo:  39% 
(p≤0.001) 
 BARI:  55% 
 Placebo:  27% 
(p≤0.001) 
Reference 
Fleischman et al. 
2017 
Taylor et al. 2017 
Dougados et al. 
2017 
Genovese et al. 
2016 
Approved on 14 Jun 2023 GMT

I4V-MC-JAHW(e) Clinical Protocol 
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LY3009104 
Abbreviations:  ACR = American College of Rheumatology; BARI = baricitinib; bDMARD = biologic 
disease-modifying antirheumatic drug; csDMARD = conventional synthetic disease-modifying antirheumatic 
drug; DMARD = disease-modifying antirheumatic drug; IR = inadequate response or intolerance; 
MTX = methotrexate; N = number of patients; QD = once daily; QW = once weekly; Q2W = every 2 weeks; 
TNF-α = tumor necrosis factor-alpha; W = week. 
a p-value from comparison with baricitinib. 
 
Table JAHW.4 summarizes the efficacy findings from the Phase 3 studies in adult RA by 
displaying the results of the primary and secondary endpoints, which were controlled for 
multiplicity.  Baricitinib 4 mg was efficacious across domains of efficacy that included signs and 
symptoms, physical function, reduction of radiographic progression, and other patient-reported 
outcomes, such as pain and morning joint stiffness. 
Table JAHW.4. 
Summary of Primary and Major (Gated) Secondary Endpoints for 
Baricitinib Phase 3 Rheumatoid Arthritis Studies  
 
Endpointa 
JADZa 
JADV 
JADX 
JADW 
BARI 
4-mg 
vs.  
MTX 
BARI  
4-mg + MTX 
vs.  
MTX 
BARI 
4-mg  
vs.  
PBO 
BARI 
4-mg 
vs. 
ADA 
BARI 
4-mg 
vs. 
PBO 
BARI 
2-mg 
vs. 
PBO 
BARI 
4-mg 
vs. 
PBO 
BARI 
2-mg 
vs. 
PBO 
ACR20 at primary 
time pointa 
≤0.01b 
≤0.001 
≤0.001 
≤0.05b 
≤0.001 
≤0.001 
≤0.001 
≤0.001 
ΔHAQ-DI at W12 
≤0.001 
≤0.001 
≤0.001 
ng 
≤0.001 
≤0.001 
≤0.001 
≤0.001 
ΔmTSS at W24 
NS 
≤0.05 
≤0.001 
ng 
ng 
ng 
n/a 
n/a 
ΔDAS28-hsCRP at 
W12 
≤0.001 
≤0.001 
≤0.001 
≤0.001 
≤0.001 
≤0.001 
≤0.001 
≤0.001 
SDAI remission 
(≤3.3) at W12 
≤0.01 
≤0.001 
≤0.001 
ng 
≤0.001 
≤0.001 
NS 
NSc 
MJS Duration at 
W12 
n/a 
n/a 
≤0.001 
ng 
≤0.001 
ng 
n/a 
n/a 
MJS Severity at 
W12 
n/a 
n/a 
≤0.001 
ng 
≤0.001 
ng 
n/a 
n/a 
Worst Tiredness at 
W12 
n/a 
n/a 
≤0.001 
ng 
≤0.05 
ng 
n/a 
n/a 
Worst Joint Pain at 
W12 
n/a 
n/a 
≤0.001 
ng 
≤0.001 
ng 
n/a 
n/a 
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I4V-MC-JAHW(e) Clinical Protocol 
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LY3009104 
Abbreviations: ∆ = change from baseline; ACR20 = American College of Rheumatology 20% response rate; 
ADA = adalimumab; BARI = baricitinib; DAS28 = Disease Activity Score modified to include the 28 
diarthrodial joint count; HAQ-DI = Health Assessment Questionnaire–Disability Index; MJS = morning joint 
stiffness; mTSS = van der Heijde modified Total Sharp Score; MTX = methotrexate; n/a = not applicable; 
ng = not gated (i.e., not a gated secondary objective); NS = not statistically significant; PBO = placebo; 
SDAI = Simplified Disease Activity Index; vs. = versus; W = week. 
Note:  ≤0.05 = p≤0.05; ≤0.01 = p≤0.01; ≤0.001 = p≤0.001. 
a The primary time point was 24 weeks in Study JADZ, and 12 weeks in Studies JADV, JADX, and JADW. 
b The primary evaluation in Study JADZ was for noninferiority; the gated comparison of baricitinib 4-mg vs. ADA 
in Study JADV was for noninferiority.  Once noninferiority was shown, superiority was tested; p-values shown 
are for superiority. 
c Baricitinib 4-mg was not statistically significantly superior to placebo in the proportion of patients who achieved 
an SDAI score ≤3.3 at Week 12; therefore, progression through the gated endpoints stopped with this hypothesis, 
and hypotheses regarding baricitinib 2-mg versus placebo were not evaluated within the context of this method of 
strong control for multiplicity. 
 
Baricitinib is now approved in the European Union, the United States, Japan, and other regions 
for the treatment of adult patients with moderate-to-severe RA.  Given the promising results 
already observed with baricitinib in patients with RA, benefits in efficacy are expected for 
pediatric patients with JIA-U and ANA-positive uveitis. 
The aim of the current study is to evaluate the efficacy and safety of baricitinib when 
administered once daily (QD) to pediatric patients with JIA-U or ANA-positive uveitis who have 
had an inadequate response to topical steroids and methotrexate (MTX) or biologic 
disease-modifying antirheumatic drugs (bDMARDs).  The inclusion of patients with an 
inadequate response or intolerance to MTX treatment (MTX-IR patients) was driven by 
physician and patient preference for an alternative oral therapeutic option for pediatric patients 
with JIA-U who are MTX-IR (Batchelor and Marriott 2015).  The currently approved therapy for 
JIA-U, adalimumab, is only available in injectable form.  An orally ingested product such as 
baricitinib may be preferable to injectable bDMARDs for both patients and caregivers/legal 
guardians.  The inclusion of bDMARD-IR patients was driven by the unmet need in patients who 
have tried and had inadequate response to such therapies, including adalimumab. 
3.2. Background  
Juvenile idiopathic arthritis is a disease distinct from RA and is defined as arthritis that has an 
onset in patients prior to 16 years of age, persisting for more than 6 weeks, and of unknown 
etiology.  Juvenile idiopathic arthritis belongs to a heterogeneous group of autoimmune diseases 
that represent the most common rheumatic condition of childhood and is estimated to affect 1 in 
1000 children (Ravelli and Martini 2007).  The International League of Associations for 
Rheumatology (ILAR) classification of JIA identifies the following 7 mutually exclusive 
categories (Petty et al. 2004): 
 systemic arthritis 
 oligoarthritis (persistent or extended) 
 rheumatoid factor (RF) negative polyarthritis 
 RF positive polyarthritis 
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 juvenile psoriatic arthritis (JPsA) 
 enthesitis-related juvenile idiopathic arthritis (ERA), and 
 undifferentiated arthritis. 
Juvenile idiopathic arthritis accounts for approximately 75% of all pediatric anterior uveitis 
cases, and is the most common systemic disorder associated with uveitis in childhood.  Uveitis is 
reported to occur in about 30% of patients with JIA who are ANA-positive, regardless of the 
type of arthritis present.  These patients typically develop chronic, bilateral, nongranulomatous, 
and asymptomatic anterior uveitis (Thorne et al. 2007).  Despite current screening and treatment 
options, up to 15% of children with JIA-U develop visual impairment in both eyes, and may be 
certified as legally blind (Ramanan et al. 2017). 
The SYCAMORE study, a double-blind, randomized, placebo-controlled study that assessed the 
efficacy, safety, and cost-effectiveness of adalimumab plus MTX in JIA-U, was completed in 
2017.  SYCAMORE was stopped early for efficacy after 90 of the planned 114 patients had been 
randomized (Ramanan et al. 2017).  Analysis of the primary endpoint (time to treatment failure) 
showed a positive treatment effect in favor of adalimumab (hazard ratio [HR] 0.25 [95% 
confidence interval {CI} 0.12 to 0.49]; p<0.0001). 
Results of the SYCAMORE study now make a placebo-controlled study ethically and 
logistically challenging.  Eli Lilly and Company (Lilly) has, therefore, planned this uveitis study 
with an alternative design to study baricitinib as a treatment for JIA-U. 
Methotrexate is well established as the immunosuppressive therapy of choice for patients with 
JIA-U who have not responded adequately to topical corticosteroid therapy.  Biologic DMARDs 
are not usually initiated until after classic immunosuppressives have been tried.  If uveitis 
persists despite a regimen of adequate topical corticosteroid and immunosuppressive therapy 
(usually MTX), anti-inflammatory treatment is intensified by addition of a TNF inhibitor or 
cyclosporine A to the previous treatment (Heiligenhaus et al. 2012).  The patient population to be 
enrolled into this study comprises patients eligible for intensification of anti-inflammatory 
treatment through the introduction of bDMARD therapy; namely, patients who have been treated 
with adequate doses of topical steroids for at least 4 weeks and MTX for at least 12 weeks, or 
patients with intolerance to MTX.  Concomitant treatment with MTX is not required in the study, 
to allow for the inclusion of MTX-IR or intolerant patients. 
Children with chronic ANA-positive uveitis without systemic features have a similar clinical 
course and treatment response to children with a diagnosis of JIA-U.  In keeping with 
recommendations from an EU Regulatory Ophthalmology Workshop, children with chronic 
anterior ANA-positive uveitis without systemic features will be included in the trial because of 
the similarity of the condition to JIA-U (EMA/450332/2012). 
The choice of primary and secondary endpoints arise from work started in 2005, when the 
Standardization of Uveitis Nomenclature (SUN) Working Group provided a standardized 
nomenclature for uveitis, inflammation grading, and outcome measures (Jabs et al. 2005).  This 
nomenclature has been reviewed by a working group of ophthalmologists and pediatric 
rheumatologists to create recommendations for reporting clinical outcomes in JIA-U clinical 
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studies (Heiligenhaus et al. 2012).  The primary endpoint is the proportion of patients with 
response at Week 24.  Response is defined as a 2-step decrease in the level of inflammation 
(anterior chamber cells) or decrease to 0, and this matches the SUN definition of improved 
activity for uveitis (Jabs et al. 2005).  In the SYCAMORE study, significantly more patients 
treated with adalimumab showed response at 3 months compared with patients treated with 
placebo (57% versus 17%, respectively; p = 0.004; 95% CI = 0.4 to 0.74).  The time to treatment 
response during the SYCAMORE study informed selection of 24 weeks as the time point for the 
primary endpoint in this baricitinib study. 
The primary endpoint will be supported by key secondary outcomes to assess age-appropriate 
visual acuity, change in vitreous haze, grade of flare in the anterior chamber, length of time to 
inactive disease (as defined by SUN criteria), tapering of concomitant steroids, pediatric clinical 
outcomes assessments and patient-reported outcomes, and overall uveitis-related disability.  
Change in grade of cells in the anterior chamber from baseline to Week 12 will also be assessed.  
Visual acuity is also considered to be particularly important for demonstrating clinical benefit.  
However, assessment of visual acuity has been included as a secondary (rather than as a 
co-primary) endpoint, as intraocular inflammation and visual function may improve without a 
discernible change in acuity measurements, particularly in the presence of prior structural 
damage (such as cataracts and macular scars).  Such damage can limit improvement in acuity 
even if inflammation is controlled. 
3.3. Benefit/Risk Assessment  
As summarized in Section 3.1, baricitinib showed clear efficacy in adults with RA, with 
improvements in signs and symptoms, physical function, radiographic progression of structural 
joint damage, and patient-reported outcomes, including pain, stiffness, tiredness, and 
health-related quality of life (HRQOL).  Baricitinib is approved in multiple geographic regions 
for the treatment of adult patients with moderate-to-severe RA.  Juvenile idiopathic arthritis, 
JIA-U, and ANA-positive uveitis share several immunological abnormalities identified in RA, 
such as overproduction of proinflammatory cytokines.  Inhibition of the JAK1 and JAK2 
signalling pathway reduces the activity of proinflammatory cytokines, including IL-6 and 
TNF-α, and provides evidence for potential efficacy for baricitinib in JIA-U and ANA-positive 
uveitis.  Given the results observed in completed baricitinib clinical studies in adult RA 
populations and the nature of the pathophysiology of JIA, JIA-U, and ANA-positive uveitis, 
treating patients with these diseases with baricitinib is expected to provide beneficial and 
therapeutic outcomes for this population. 
Section 9.2.2 describes adverse events (AEs) of special interest in this protocol.  Risk mitigation 
measures added to the protocol to address the important potential risks include appropriate 
inclusion and exclusion criteria, safety monitoring, study drug interruption, and permanent 
discontinuation criteria. 
Although infections were observed in about half of the study population exposed to baricitinib in 
the RA program, only 3.6% of patients reported a serious treatment-emergent infection, and rates 
were similar in both baricitinib- and placebo-treated patients.  The nonserious infections noted in 
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the RA program (upper respiratory tract infections, herpes zoster, herpes simplex) are readily 
diagnosed, manageable, and typically resolve without long-term sequelae.  Prior to receiving 
baricitinib, the vaccination status of patients must be up to date with all immunizations, and 
follow the local requirements for vaccination guidelines for immunosuppressed patients.  
Exclusion criteria have been added to the protocol to limit enrollment of patients who are at 
increased risk of infection. 
Hepatotoxicity has not been identified with baricitinib use, but increases in alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin have occurred in 
patients with RA treated with baricitinib.  Most increases improved with continued use or 
temporary discontinuation of baricitinib with no long-term effects.  In addition to criteria to 
exclude patients with liver failure or increased liver analytes, appropriate monitoring of hepatic 
analytes and discontinuation criteria have been included in the protocol. 
Effects of baricitinib on human fetal development are not known.  The JAK/STAT pathway has 
been shown to be involved in cell adhesion and cell polarity, which can affect early embryonic 
development.  Based on the mechanism of action and findings of maternal and embryo-fetal 
toxicities, including skeletal anomalies in animals dosed in excess of the maximum human 
exposure, baricitinib should only be used during pregnancy if the potential benefit justifies the 
potential risk to the fetus. 
The study protocol excludes pregnant patients and contraceptive use is required for patients who 
may become pregnant.  In clinical pharmacology studies, coadministration of baricitinib with the 
cytochrome (CYP3A) substrates ethinyl estradiol or levonorgestrel resulted in no clinically 
meaningful changes in the pharmacokinetics (PK) of these medicinal products. 
Venous thromboembolic events (VTE; deep vein thrombosis [DVT] or pulmonary embolism 
[PE]) have been determined to be an important potential risk for baricitinib.  There was a 
numerical imbalance in reports of VTEs in the 24-week placebo-controlled period of the Phase 3 
studies of adult patients with RA.  Available evidence does not establish a causal association.  
The exposure-adjusted incidence rate of VTE for baricitinib-treated RA patients over long-term 
exposures was similar to the background rates published in the literature for the target 
population.  There was no pattern of increased or decreased risk during long-term exposures, and 
cases observed with baricitinib were confounded by 1 or more recognized risk factors for VTE.  
Venous thromboembolic event risk can be managed through risk-mitigation strategies.  
Exclusion and discontinuation criteria have been added to the protocol to limit participation of 
patients who are at increased risk of VTE. 
Baricitinib is being used to treat pediatric patients participating in an expanded access program 
(protocol I4V-MC-JAGA [JAGA]:  Compassionate Use Protocol for the Treatment of 
Autoinflammatory Syndromes), which has been ongoing since 2011 (Kim et al. 2018; Sanchez et 
al. 2018).  More than 30 patients ages 2 months to <18 years have been enrolled in the program 
as of June 2018.  Safety information from the expanded access program has not identified any 
new safety signals for baricitinib beyond those identified in the Phase 3 studies in adult patients 
with RA for the range of doses tested (1- to 12-mg/day).  As children generally have fewer 
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age-related comorbidities, such as diabetes and heart disease, they are expected to be at a lower 
risk for some of the AEs related to comorbidities observed in RA studies, and are not anticipated 
to be at any higher risk of AEs potentially associated with baricitinib. 
Therefore, based on the efficacy of baricitinib demonstrated in the Phase 3 RA program and the 
observed safety profile, the probability of a positive benefit/risk warrants this study to be 
conducted, given the unmet need in patients with JIA-U and ANA-positive uveitis. 
More information about the known and expected benefits, risks, serious AEs (SAEs) and 
reasonably anticipated AEs of baricitinib is found in the Investigator’s Brochure (IB). 
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4. Objectives and Endpoints  
Table JAHW.5 shows the objectives and endpoints of the study. 
Table JAHW.5. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
 
To evaluate the efficacy of baricitinib in 
children with JIA-U or ANA-positive 
uveitis 
 
 
Proportion of responders at Week 24.  Response is defined 
according to the SUN criteria as a 2-step decrease in the 
level of inflammation (anterior chamber cells) or decrease 
to zero through Week 24, in the eye most severely affected 
at baseline. 
Secondary for Part A 
 
To evaluate the efficacy of baricitinib in 
children with JIA-U or ANA-positive 
uveitis in the most severely affected eye 
and less affected eye 
 
 
To evaluate the efficacy of adalimumab in 
children with JIA-U or ANA-positive 
uveitis in the most severely affected eye 
and less affected eye 
 
 
Change in SUN grade of cells in the anterior chamber 
through Week 24 in the most severely affected eye. 
 
Change in SUN grade of cells in the anterior chamber 
through Week 24 in the less severely affected eye (if 
applicable). 
 
In patients with bilateral uveitis disease at baseline:  
Proportion of responders at Week 24, defined according to 
the SUN criteria as a 2-step decrease in the level of anterior 
chamber cells in the most severely affected eye at baseline 
(or both eyes if the inflammation grade is the same in both 
eyes) and a 1-step decrease in the level of anterior chamber 
cells in the less severely affected eye at baselinea. 
 
Change in visual acuity measured by age-appropriate 
LogMAR test through Week 24. 
 
Change in vitreous haze through Week 24 in each affected 
eye. 
 
Change in grade of flare in the anterior chamber through 
Week 24 in each affected eye. 
 
Change in overall uveitis-related disability: 
o Change in Patient Uveitis-related Disease Activity 
through Week 24. 
o Change in Patient Uveitis-related Improvement at 
Week 12 and Week 24. 
o Change in Patient Arthritis Disease Activity through 
Week 24. 
o Change in Patient Arthritis Improvement at Week 12 
and Week 24. 
o Change in Ophthalmologist Uveitis-related Disease 
Activity through Week 24. 
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Objectives 
Endpoints 
o Change in Ophthalmologist Uveitis-related 
Improvement at Week 12 and Week 24. 
 
Proportion of patients with inactive anterior uveitis (using 
SUN definition) in each affected eye through Week 24. 
 
Time to inactive anterior uveitis disease (using SUN 
definition) in each affected eye. 
 
Proportion of patients who are able to taper concomitant 
topical corticosteroids to <2 drops per day and to 0 drops 
per day. 
 
PediACR30/50/70/90/100 response rates (for patients with 
JIA-U). 
 
 
 
To evaluate the safety of baricitinib in 
children with JIA-U or ANA-positive 
uveitis 
 
 
Adverse events including serious adverse events. 
 
Permanent discontinuation of investigational product due to 
AE. 
 
Temporary interruption of investigational product. 
Secondary for Part B (OLE) 
 
To describe the efficacy of baricitinib in 
children with JIA-U or ANA-positive 
uveitis in the most severely affected eye 
and less affected eye (among the 
responders at Week 24) 
 
 
Number of responders through Week 284.  Response is 
defined according to the SUN criteria as a 2-step decrease 
in the level of inflammation (anterior chamber cells) or 
decrease to zero through Week 284, in the eye most 
severely affected at baseline. 
 
Change in SUN grade of cells in the anterior chamber 
through Week 284 in the most severely affected eye. 
 
Change in SUN grade of cells in the anterior chamber 
through Week 284 in the less severely affected eye (if 
applicable). 
 
In patients with bilateral uveitis disease at baseline:  
Number of responders through Week 284, defined 
according to the SUN criteria as a 2-step decrease in the 
level of anterior chamber cells in the most severely affected 
eye at baseline (or both eyes if the inflammation grade is 
the same in both eyes) and a 1-step decrease in the level of 
anterior chamber cells in the less severely affected eye at 
baseline. 
 
Change in grade of flare in the anterior chamber through 
Week 284 in each affected eye. 
 
Description of inactive anterior uveitis including time to 
inactive anterior uveitis disease (using SUN definition) in 
each affected eye through Week 284. 
 
Number of patients who are able to taper concomitant 
topical corticosteroids to <2 drops per day and to 0 drops 
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Objectives 
Endpoints 
per day.  Number of patients who are able to taper 
concomitant oral corticosteroids to <5 mg per day and to 0 
mg per day. 
 
To evaluate the safety of baricitinib in 
children with JIA-U or ANA-positive 
uveitis 
 
Adverse events including serious adverse events. 
 
Permanent discontinuation of investigational product due to 
AE. 
 
Temporary interruption of investigational product. 
Abbreviations:  AE = adverse event; ANA = antinuclear antibody; JIA = juvenile idiopathic arthritis; 
LogMAR = logarithm of the minimum angle of resolution; OLE = open-label extension; PediACR = Pediatric 
American College of Rheumatology; PK = pharmacokinetic(s); SUN = Standardization of Uveitis Nomenclature. 
a Response is defined according to the SUN criteria as a 2-step decrease in the level of inflammation (anterior 
chamber cells) or decrease to 0 through Week 24 in the eye most severely affected at baseline. 
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5. Study Design  
5.1. Overall Design  
Study JAHW is a multicenter, open‑label, active‑controlled Phase 3 study in patients with active 
JIA‑U or chronic ANA‑positive uveitis without systemic features, despite prior treatment with 
topical steroid therapy and MTX.  The study will be conducted in 2 parts.  Part A will include the 
screening period and treatment period that includes open‑label treatment with baricitinib and 
adalimumab up to Week 24.  Part B will provide an open label extension period for up to 5 years 
after Part A.  
In the original study design (Figure JAHW.1), patients receiving baricitinib during Part A 
continued to receive baricitinib during Part B.  Patients receiving adalimumab during Part A 
continued to receive adalimumab for an additional 96 weeks and were then switched to 
baricitinib for the remaining 164 weeks of Part B. 
Since then, the protocol and study design have been modified (Figure JAHW.2). Patients 
currently assigned to baricitinib who have completed the primary endpoint as a responder will 
continue receiving baricitinib until the end of study or discontinuation from the study. 
Investigator may consult the study team for guidance on study continuation in the event the 
patient is a nonresponder at the primary endpoint, but demonstrates clinically meaningful benefit 
from baricitinib. Patients on adalimumab will discontinue the study after Week 24. 
Interim analyses are described in Section 10.3.7 .  Interim analyses will occur during Part A and 
when Part A is complete (Week 24). 
The study will enroll at least  20 and up to  40 patients who have had an inadequate response or 
intolerance to MTX (MTX‑IR) and/or bDMARDs (bDMARD‑IR) as follows: 
Baricitinib arm: At least 20 patients (MTX-IR and/or bDMARD-IR) evaluable for primary 
endpoint. 
Adalimumab arm: At least 4  patients evaluable for the primary endpoint. 
This study will be conducted at centers offering combined pediatric 
rheumatology/ophthalmology service. 
Figure JAHW.1 illustrates the study design from the previous Amendment (d). 
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Abbreviations: bDMARD = biologic disease-modifying antirheumatic drug; 
IR = inadequate response or intolerance to; MTX = methotrexate; OLE = open-label 
extension. 
a 
Patients ≥6 to <12 years old assigned to baricitinib have the option of receiving 
the oral suspension or tablets. Patients >12 years old assigned to baricitinib will receive 
tablets. Patients assigned to adalimumab weighing <30 kg will receive 20 mg, and those 
≥30 kg will receive 40 mg. 
b 
Patients receiving adalimumab who experience a treatment failure after at least 
24 weeks of treatment may receive rescue therapy with baricitinib. Rescued patients 
will receive baricitinib for the remainder of the study. 
Figure JAHW.1. 
Study design for Clinical Protocol I4V-MC-JAHW (d).  
 Figure JAHW.2 illustrates the modified study design for Amendment (e). 
 
Screening
Treatment Period Part B (OLE)
Same age-based dosesa
Age-based dosesa
1-6 weeks
Post-Treatment 
Follow-Up
Follow-Up Visit 801
Treatment Period Part A
164 weeks
28 days
24 weeks
Adalimumab, n = 10
Baricitinib (MTX-IR or bDMARD-IR), n = 20
Baricitinib, n = 10
Continue Baricitinib
Continue Baricitinib
Continue 
Adalimumab
Switch to Baricitinib
Switch to Baricitinib (Rescue)b
Randomization
MTX-IR, n = 20
72 weeks
Screening
Treatment Period Part B (OLE)
Same age-based dosesa
Age-based dosesa
1-6 weeks
Post-Treatment 
Follow-Up
Follow-Up Visit 801
Treatment Period Part A
28 days
24 weeks
Adalimumab, n = 4
Baricitinib (MTX-IR  and/or bDMARD-IR), up to n = 20
Baricitinib, n = 6
Continue Baricitinib if responder*
Randomization
MTX-IR, up to n = 
20
284 weeks
Discontinue study
Continue Baricitinib if responder*
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Abbreviations:  bDMARD = biologic disease-modifying antirheumatic drug; 
IR = inadequate response or intolerance to; MTX = methotrexate; OLE = open-label 
extension. 
a 
Patients ≥6 to <12 years old assigned to baricitinib have the option of receiving 
the oral suspension or tablets.  Patients >12 years old assigned to baricitinib will receive 
tablets.  Patients assigned to adalimumab weighing <30 kg will receive 20 mg, and 
those ≥30 kg will receive 40 mg.  
* 
Please refer to Section 5.1.3 for details. 
 
Figure JAHW.2. 
Study design for Clinical Protocol I4V-MC-JAHW (e).  
The study allows for treatment with background conventional synthetic DMARDs 
(csDMARDs), corticosteroids, and/or nonsteroidal anti-inflammatory drugs (NSAIDs) at a stable 
dose (refer to Section 7.7). 
Study governance considerations are described in detail in Appendix 3. 
5.1.1. Screening and Baseline Periods  
The Screening Period is up to 42 days prior to baseline.  At screening, the parent or legal 
guardian will sign the informed consent form (ICF) and the patient 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). 
Patients who receive a purified protein derivative (PPD) skin test at screening must return within 
48 to 72 hours to read the skin test.  Treatment with concomitant JIA therapies and topical 
corticosteroids during the study is permitted only as described in Section 7.7.  Patients will 
remain on background MTX, other csDMARDs, and oral, topical or ophthalmic corticosteroids 
if patients are on stable doses of these treatments at screening (see Sections 6.2 and 7.7 for 
details).  Patients who have previously been treated with bDMARDs are eligible for the study.  
However, treatment must have been discontinued 1 week prior to screening for anakinra, 
4 weeks prior to screening for TNF inhibitors, other IL-1 inhibitors, IL-6 inhibitors, or abatacept 
and 6 months prior to screening for rituximab. 
Investigators should review the vaccination status of their patients and ensure that patients are up 
to date with all immunizations, and follow the local requirements for vaccination guidelines and 
schedule for immunosuppressed patients.  If a patient received a live vaccine within 28 days 
prior to baseline or intends to receive a live vaccine (except booster immunization with 
attenuated vaccine for measles, mumps, and rubella [MMR] or varicella zoster virus [VZV]) 
during the course of the study or up to 28 days after the last dose of investigational product, the 
patient is not eligible for the study.  Considering the European League Against Rheumatism 
(EULAR) recommendations (Heijstek et al. 2011) and accumulated evidence (Groot et al. 2015; 
Sousa et al. 2017), booster vaccination for MMR or VZV may be considered if it is essential 
based on the local guideline and/or in the opinion of the investigator.  If a patient becomes 
eligible for vaccination with tetanus, diphtheria, and pertussis (TDaP) and/or pneumococcal 
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conjugate vaccine during the study period according to local recommended schedule of 
vaccination, antibody titres to the vaccine will be evaluated pre-immunization and at 4 and 
12 weeks post immunization.  A primary immune response will be assessed in patients who have 
never received TdaP or pneumococcal conjugate vaccines previously, and secondary/booster 
responses will be assessed if the patients have previously received the vaccines. 
Patients who meet all of the inclusion and none of the exclusion criteria (Section 6) will continue 
to baseline. 
At baseline, study eligibility for each patient will be reviewed, based on all inclusion and 
exclusion criteria (Section 6), and laboratory test results.  Patients who meet all criteria will 
proceed to the subsequent period.  Laboratory samples will be collected at baseline and all 
assessments should be completed before the patient takes the first dose of investigational 
product.  Owing to blood volume restrictions, some laboratory tests may not be collected.  
Laboratory samples are recommended to be collected as described in a sponsor-provided 
weight-based prioritization chart. 
5.1.2. Open-Label Treatment Period – Part A  
Part A is an open-label treatment period.   Up to 10 MTX-IR (but not bDMARD-IR) patients will 
be randomly assigned to receive either oral baricitinib once-daily or subcutaneous adalimumab 
every other week for approximately 24 weeks.  Approximately 20 additional patients who are 
MTX-IR and/or bDMARD-IR will receive oral baricitinib once daily for approximately 24 
weeks. 
5.1.3. Open-Label Treatment Period – Part B  
Part B is an open-label extension period. In the previous study design (amendment d or prior), all 
patients who were receiving baricitinib in Part A received oral baricitinib once daily for 
approximately 260 weeks.  Patients who were randomized to adalimumab treatment in Part A 
continued to receive adalimumab for approximately 96 weeks in Part B and were then switched 
to baricitinib for the remaining weeks.  The first dose of baricitinib was given approximately 
2 weeks after the last injection of adalimumab. 
Since then, the protocol and study design has been modified (Amendment e). Patients receiving 
adalimumab will be discontinued from the study after Week 24. 
Patients currently assigned to baricitinib who have completed the primary endpoint as a 
responder will continue receiving baricitinib until the end of study or discontinuation from the 
study.  Investigator may consult the study team for guidance on study continuation in the event 
the patient is a nonresponder at the primary endpoint, but demonstrates clinically meaningful 
benefit from baricitinib. 
5.1.4. Post-Treatment Follow-Up Period  
Patients who complete the study or discontinue early from the study will return for the 
post-treatment safety follow-up visit (Visit 801) approximately 28 days after the last dose of 
investigational product. 
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Patients who have received at least 1 dose of investigational product and terminate participation 
early must have an early termination visit (ETV). 
Patients who have discontinued investigational product but remain in the study for more than 
28 days without investigational product will have an ETV if they choose to withdraw from the 
study; however, a separate follow-up visit (Visit 801) is not required. 
Patients should not initiate new treatment during the post-treatment follow-up period.  However, 
if patients or investigators must initiate a new treatment, patients should complete a Visit 801 
prior to the first dose of the new therapy (if possible). 
5.2. Number of Participants  
• 
Baricitinib arm:  At least 20 patients (MTX-IR and/or bDMARD-IR) evaluable for 
primary endpoint. 
• 
Adalimumab arm:  At least  4  patients evaluable for the primary endpoint. 
5.3. End of Study Definition  
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient in the 28-day follow-up period. 
5.4. Scientific Rationale for Study Design  
Randomized withdrawal designs have worked well in many studies of patients with polyarticular 
arthritis as well as in some studies of patients with systemic JIA.  However, the randomized 
withdrawal design is likely to be particularly problematic for a JIA-U trial due to the variable 
nature of the disease and the limited understanding of the long-term disease course.  Randomized 
placebo-controlled withdrawal designs for JIA-associated uveitis were debated at a European 
Medicines Agency (EMA) regulatory workshop on ophthalmology (EMA/450332/2012) and 
concern was raised that the natural history of uveitis was unknown, which could affect this 
design. 
This open-label Study JAHW of baricitinib in children with JIA-U or ANA-positive uveitis is 
similar in design to the APTITUDE study of tocilizumab conducted in 22 patients with JIA-U 
refractory to anti-TNF therapy (EudraCT 2015-001323-23).  Study JAHW will incorporate 
Bayesian analysis techniques, which are more suitable for clinical trials in rare conditions such 
as JIA-U.  Bayesian analysis techniques are potentially more useful for assessing treatment 
options than conventional frequentist analysis methods when limited available data do not allow 
conclusive inferences to be made (Hampson et al. 2014; Bayarri and Berger 2004). 
5.5. Justification for Dose  
The dose selection for baricitinib in this patient population is informed by the Phases 2 and 3 
data in adults with RA, which demonstrated a positive benefit/risk profile for the 4-mg QD dose.  
The PK of baricitinib in pediatric patients with JIA will be investigated in Study I4V-MC-JAHV 
(JAHV), and the doses selected in this study will also be used in Study JAHW (see Appendix 8 
for updated dosing based on the current JAHV data). 
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Predicted concentration-versus-time data in patients with RA were simulated using 
physiologically based pharmacokinetic (PBPK) modeling.  The modeling predicted that 
baricitinib concentrations in adolescents 12 to <18 years old and in children 9 to <12 years old 
would be expected to be similar to those in adults (Figure JAHW.3); therefore, these patients will 
initially receive the 4-mg QD dose in Study JAHV.  Conversely, concentrations in children aged 
<9 years would be expected to be toward the higher end of the range observed in adults; 
therefore, these patients will initially receive a lower 2-mg QD dose. 
 
These graphs are overlay plots comparing model-predicted mean concentration–time 
curves in pediatric age groups to model-predicted plasma concentrations in adults.  
Solid lines are model-predicted mean concentrations in age groups 2 to <6 years (top 
line), 6 to <12 years (middle line), and 12 to <18 years (bottom line).  These lines were 
developed using a physiologically-based pharmacokinetic (PK) model implemented 
with Simcyp®, based on adult data with adjustment for age.  The gray dots indicate 
individual concentrations derived from simulations of the final population PK model 
for baricitinib in adult patients with rheumatoid arthritis. 
Figure JAHW.3. 
Comparison of predicted steady-state concentrations of baricitinib 
in pediatric (solid lines) versus adults (gray dots) receiving 4-mg 
QD.  
The PK assessment period of Study JAHV will determine if baricitinib exposure in pediatric 
patients with JIA is consistent with baricitinib 4-mg exposure in adults with RA.  The baricitinib 
dose will be adjusted as necessary if baricitinib exposure is not consistent between these patient 
populations.  The final age-based dose selected in the PK assessment period of Study JAHV will 
be used in Study JAHW.  Therefore, enrollment in Study JAHW may be restricted to the age 
cohorts for which PK data are available from Study JAHV. 
Due to the overlap between the conditions, JIA and JIA-U are typically treated with the same 
therapies and doses.  For example, the same dose of adalimumab is approved for JIA and JIA-U 
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(adalimumab SmPC), and similar doses of MTX are recommended for both indications (Ferrara 
et al. 2018).  Therefore, the same dose of baricitinib should be appropriate for patients with JIA 
and JIA-U. 
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6. Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
6.1. Inclusion Criteria  
Patients are eligible to enroll in the study only if they meet all of the following criteria at 
screening and at baseline: 
Patient and Disease Characteristics 
[1] 
Are at least 2 years and less than 18 years of age; full date of birth will be 
collected except in countries in which it is not allowed. 
[2] 
Have a diagnosis of JIA-U or chronic ANA-positive uveitis without systemic 
features. 
[3] 
Have active anterior uveitis, defined as cellular infiltrate in the anterior chamber of 
SUN criteria grade ≥1+ at Visit 1 (screening) and Visit 2 (potential randomization), 
despite prior treatment with adequate doses of topical steroid therapy and MTX. 
[4] 
Have an inadequate response or intolerance to MTX (minimum dose of 
10 mg/m2/week, with a maximum dose of 25 mg/m2/week).  Patients considered to 
have inadequate response must have received MTX for at least 12 weeks before an 
inadequate response may be determined, and must have been on a stable dose for at 
least 4 weeks prior to screening if continuing MTX therapy during the study. 
[5] 
Are receiving topical corticosteroid eye drops at a stable dose for at least 2 weeks 
prior to screening (maximum of 4 drops/day per eye at screening). 
Informed Consent 
[6] 
Both a parent or legal guardian and the patient (as appropriate) are able to 
understand and fully participate in the activities of the study and sign their consent 
and assent, respectively, in accordance to local guidelines. 
Contraception 
[7] 
Male or nonpregnant, nonbreastfeeding female patients 
Patients of child-bearing potential who are abstinent (if this is complete 
abstinence, as their preferred and usual lifestyle) must agree to remain 
abstinent. 
Total abstinence is defined as refraining from intercourse during the entirety 
of the study and for at least 1 week following the last dose of investigational 
product.  Periodic abstinence such as calendar, ovulation, symptothermal, 
postovulation methods and withdrawal are not acceptable methods of 
contraception. 
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Otherwise, patients and their partners of child-bearing 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 1 week following the 
last dose of investigational product. 
The following contraception methods are considered acceptable (the patient, 
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 
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 child-bearing potential. 
Women of nonchild-bearing 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 mullerian agenesis. 
6.2. Exclusion Criteria  
Patients will be excluded from study enrollment if they meet any of the following criteria: 
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Medical Conditions 
[8] 
Have uveitis without a diagnosis of JIA or CAU without positive ANA. 
[9] 
Have a history or presence of any autoimmune inflammatory condition other than 
JIA, such as Crohn’s disease or ulcerative colitis. 
[10] Have any contraindications to adalimumab as addressed in local product labeling or 
local clinical practice that would preclude the patient from participating in this 
study. 
Exception:  Patients who are bDMARD-IR with a contraindication to adalimumab 
may be enrolled, as they will be assigned to baricitinib. 
[11] Have increased intraocular pressure ≥25 mm Hg or that required treatment, 
including increases in medications, surgery, or hospitalization, within 4 weeks prior 
to baseline that, in the opinion of the investigator, would pose an unacceptable risk 
to the patient if participating in the study. 
[12] Have had intraocular surgery within the 3 months prior to screening (such as for 
cataract(s), glaucoma or vitrectomy). 
[13] Are pregnant or breastfeeding.  Prior to initiation of treatment, female patients of 
child-bearing potential must have a negative serum pregnancy test at the central 
laboratory during screening and a negative urine pregnancy test at Visit 2. 
[14] Have a current or recent (<4 weeks prior to baseline) clinically serious viral, 
bacterial, fungal, or parasitic infection or any other active or recent infection that, in 
the opinion of the investigator, would pose an unacceptable risk to the patient if 
participating in the study. 
Note:  For example, a recent viral upper respiratory tract infection or 
uncomplicated urinary tract infection need not be considered 
clinically serious. 
[15] Have had an infection of bone or joint within 6 months prior to screening. 
[16] Have symptomatic herpes simplex at baseline. 
[17] Have had symptomatic herpes zoster infection within 12 weeks prior to baseline. 
[18] Have a history of multidermatomal herpes zoster, or complicated herpes zoster 
(e.g., ocular or motor nerve involvement or disseminated herpes zoster such as 
systemic infection). 
[19] Have a positive test for hepatitis B virus (HBV) at screening defined as: 
a. 
positive for hepatitis B surface antigen (HBsAg), or 
b. 
positive for hepatitis B core antibody (HBcAb) and positive for HBV 
deoxyribonucleic acid (DNA) 
Note:  Patients who are HBcAb-positive and HBV DNA-negative may be 
enrolled in the study but will require additional HBV DNA 
monitoring during the study. 
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[20] Have hepatitis C virus (HCV) infection (hepatitis C antibody-positive and 
confirmed presence of HCV ribonucleic acid [RNA]). 
Note:  Patients who have documented anti-HCV treatment for a past HCV 
infection AND are HCV RNA-negative may be enrolled in the 
study. 
[21] Have evidence of human immunodeficiency virus (HIV) infection and/or positive 
HIV antibodies. 
[22] Have had household contact with a person with active tuberculosis (TB) and did 
not receive appropriate and documented prophylaxis for TB. 
[23] Have evidence of active TB or untreated/inadequately/inappropriately treated latent 
TB 
a. 
Have evidence of active TB, defined in this study as the following: 
 
Positive PPD test (≥5 mm induration between approximately 48 and 
72 hours after application, regardless of vaccination history), medical 
history, and clinical features. 
 
QuantiFERON®-TB Gold test or T-SPOT®.TB test (as available and 
if compliant with local TB guidelines) may be used instead of the 
PPD test.  Patients are excluded from the study if the test is not 
negative and there is clinical evidence of active TB. 
Exception:  Patients with a history of active TB who have documented 
evidence of appropriate treatment, have no history of re-exposure since 
their treatment was completed, have no clinical features of active TB, and 
have had a screening chest x-ray within the prior 6 months with no 
evidence of active TB may be enrolled if other entry criteria are met.  
Such patients would not be required to undergo the protocol-specific TB 
testing for PPD, QuantiFERON®-TB Gold test, or T-SPOT®.TB test, but 
must have had a screening chest x-ray within the prior 6 months. 
b. 
Have evidence of untreated/inadequately or inappropriately treated latent 
TB, defined in this study as the following: 
 
Positive PPD test, no clinical features consistent with active TB, and a 
chest x-ray with no evidence of active TB at screening; or  
 
If the PPD test is positive and the patient has no medical history or 
chest x-ray findings consistent with active TB, the patient may have a 
QuantiFERON®-TB Gold test or T-SPOT®.TB test (as available and 
if compliant with local TB guidelines).  If the test results are not 
negative, the patient will be considered to have latent TB (for 
purposes of this study); or  
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 
QuantiFERON®-TB Gold test or T-SPOT®.TB test (as available and 
if compliant with local TB guidelines) may be used instead of the 
PPD test.  If the test results are positive, the patient will be considered 
to have latent TB.  If the test is not negative, the test may be repeated 
once within approximately 2 weeks of the initial value.  If the repeat 
test results are again not negative, the patient will be considered to 
have latent TB (for purposes of this study). 
Exception:  Patients who have evidence of latent TB may be enrolled if at 
least 4 weeks of appropriate treatment is completed prior to Visit 2 and the 
remainder of treatment will be completed while in the study. 
Exception:  Patients with a history of latent TB who have documented 
evidence of appropriate treatment, have no history of re-exposure since 
their treatment was completed, have no clinical features of active TB, and 
have had a screening chest x-ray within the prior 6 months with no 
evidence of active TB may be enrolled if other entry criteria are met.  
Such patients would not be required to undergo the protocol-specific TB 
testing for PPD, QuantiFERON®-TB Gold test, or T-SPOT®.TB test, but 
must have had a screening chest x-ray within the prior 6 months. 
[24] Had major surgery within 8 weeks prior to screening or will require 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 patient. 
[25] Have a 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. 
[26] Have a history of a VTE or are considered at high risk of VTE as deemed by the 
investigator. 
[27] Are largely or wholly incapacitated, such as being bedridden. 
[28] Have a history of lymphoproliferative disease; have signs or symptoms suggestive 
of possible lymphoproliferative disease, including lymphadenopathy or 
splenomegaly; have active primary or recurrent malignant disease; or have been in 
remission from clinically significant malignancy for <5 years prior to Visit 2. 
The following may be exempted: 
a. 
Patients with cervical carcinoma in situ that has been resected with no 
evidence of recurrence or metastatic disease for at least 3 years may 
participate in the study. 
b. Patients with nonmelanoma skin cancers (basal cell or squamous epithelial 
skin cancers) that have been completely resected with no evidence of 
recurrence for at least 3 years may participate in the study. 
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[29] Have body temperature ≥38°C (100.5°F) at baseline (Visit 2). 
Prior/Concomitant Therapy 
[30] Have initiated or changed dosage of concomitant mycophenolate mofetil or 
csDMARDs (other than MTX) within 4 weeks prior to screening (such as, but not 
limited to, hydroxychloroquine, sulfasalazine, gold salts, cyclosporine, or 
azathioprine). 
[31] Are currently receiving concomitant treatment with combination of >2 csDMARDs 
(including MTX). 
[32] Have received prior bDMARDs for any indication less than 1 week prior to 
screening for anakinra, less than 4 weeks prior to screening for TNF inhibitors 
(e.g., etanercept, infliximab, certolizumab, adalimumab, golimumab), other IL-1 
inhibitors, IL-6 inhibitors (e.g., tocilizumab), or abatacept, and less than 6 months 
prior to screening for rituximab. 
[33] Have received an unstable dose of analgesics, including NSAIDs, within 1 week 
prior to Visit 2. 
[34] Have received treatment with any parenteral corticosteroid administered by 
intra-articular, intramuscular, or intravenous injection within 4 weeks prior to Visit 
2. 
[35] Are using oral corticosteroids 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 (see Section 7.7). 
[36] Have received a depot peri-ocular, peri-ocular or intraocular corticosteroid injection 
within 30 days prior to Visit 2. 
[37] Have received an intraocular steroid implant within 6 months (e.g., Ozurdex) or 
18 months (e.g., Iluvien) prior to Visit 2. 
[38] Have received intraocular disease-modifying agents, including anti-vascular 
endothelial growth factor (VEGF) injections, for 30 days prior to Visit 2. 
[39] Are being treated with a strong organic anion transporter 3 (OAT3) inhibitor, such 
as probenecid, that cannot be discontinued for the duration of the study. 
[40] Have received a live vaccine within 28 days prior to baseline or intend to receive a 
live vaccine (except booster immunization with attenuated vaccine for measles, 
mumps, and rubella [MMR] or varicella-zoster virus [VZV]) during the course of 
the study or up to 28 days after the last dose of investigational product.  Booster 
vaccination for MMR or VZV may be considered if it is essential based on the local 
guideline and/or in the opinion of the investigator. 
[41] Have been treated with a JAK inhibitor. 
[42] Have experienced hypersensitivity to the active substance or to any of the 
excipients. 
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[43] Have been treated with interferon therapy (such as Roferon-A, Intron-A, Rebetron, 
Alferon-N, Peg-Intron, Avonex, Betaseron, Infergen, Actimmune, Pegasys) within 
4 weeks prior to study entry or are anticipated to require interferon therapy during 
the study. 
[44] Have commenced thyroxine therapy or changed dosage within 12 weeks prior to 
baseline, or have thyroid-stimulating hormone (TSH) levels outside the 
laboratory’s reference range. 
Exception:  Patients who are receiving stable thyroxine replacement therapy for 
≥12 weeks prior to baseline who have TSH marginally outside the laboratory’s 
normal reference range may participate if the treating physician has documented 
that the thyroxine replacement therapy is adequate for the patient. 
Diagnostic Assessments 
[45] Have any of the following specific abnormalities on screening laboratory tests:  
 AST or ALT ≥2 x upper limit of normal (ULN) 
 Total bilirubin level (TBL) ≥1.5 x ULN 
 Alkaline phosphatase (ALP) ≥2 x ULN 
 Hemoglobin <10.0 g/dL (100.0 g/L) 
 Total white blood cell count <3000 cells/L (<3.00 x 103/L or 
<3.00 billion/L) 
 Neutropenia (absolute neutrophil count [ANC] <1500 cells/L) 
(<1.50 x 103/L or <1.50 billion/L) 
 Lymphopenia (lymphocyte count <1000 cells/L) (<1.00 x 103/L or 
<1.00 billion/L) 
 Thrombocytopenia (platelets <100,000/L) (<100 x 103/L or 
<100 billion/L) 
 eGFR <40 mL/min/1.73 m2 (Bedside Schwartz formula 2009) 
 
In the case of any of the aforementioned laboratory abnormalities, the tests 
may be repeated once during screening and values resulting from repeat 
testing may be accepted for enrollment eligibility if they meet the 
eligibility criterion. 
 
[46] Have screening laboratory test values, including TSH, outside the reference range 
for the population or investigative site that, in the opinion of the investigator, pose 
an unacceptable risk for the patient’s participation in the study. 
Prior/Concurrent Clinical Study Experience 
[47] Are 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. 
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[48] 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. 
If the previous investigational product has a long half-life, 5 half-lives or 30 days 
(whichever is longer) should have passed. 
[49] Previously completed or withdrew from this study or any other study investigating 
baricitinib. 
Other Exclusions 
[50] Donated blood within 4 weeks prior to screening or intend to donate blood during 
the course of the study. 
[51] Are immediate family of investigator or site personnel directly affiliated with this 
study.  Immediate family is defined as a child, or sibling, whether biological or 
legally adopted. 
[52] Are Lilly or Incyte employees or immediate family. 
[53] Are unwilling or unable to comply with the use of a data collection instrument to 
directly record data from the patient. 
6.2.1. Rationale for Exclusion of Certain Study Candidates  
The rationale for the exclusion criteria is as follows: 
 Exclusion Criteria [8] to [13] exclude individuals with conditions that may confound 
safety or efficacy analyses. 
 Exclusion Criteria [14] to [23] exclude individuals who are at an increased risk for 
infections or infectious complications. 
 Exclusion Criteria [24] to [29] exclude individuals with previous or concomitant medical 
conditions that increase the risk for their participation in the study. 
 Exclusion Criteria [30] to [44] exclude individuals who are taking or who may take JIA 
or JIA-U medications or treatments that interfere with the ability to assess the safety and 
efficacy of baricitinib. 
 Exclusion Criteria [45] to [46] exclude individuals with laboratory parameters that may 
increase the risk for their participation in the study. 
 Exclusion Criteria [47] to [53] exclude individuals whose participation in the study may 
introduce bias. 
6.3. Screen Failures  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened up to 2 times.  The interval between rescreenings should be at least 4 weeks.  Each 
time rescreening is performed the legal representative must sign a new ICF and the child must 
sign an assent, as applicable.  The individual will be assigned a new identification number. 
 
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7. Treatments  
7.1. Treatments Administered  
The dose selection for baricitinib in this patient population is informed by the Phases 2 and 3 
data in adults with RA, which demonstrated a positive benefit/risk profile for the 4-mg QD dose.  
The PK of baricitinib in pediatric patients with JIA will be investigated in Study I4V-MC-JAHV 
(JAHV), and the doses selected in this study will also be used in Study JAHW (see Appendix 8 
for updated dosing based on the current JAHV data). 
Adalimumab will be administered as a subcutaneous injection.  The first dose of adalimumab 
will be administered by the research team.  All participants or a family member/caregiver will be 
invited to (self-)administer adalimumab after the first dose, and taught to do this under the 
procedures in place within each participating center.  The first dose they administer may also be 
under the supervision of the clinical team, who will ensure the appropriateness and accuracy of 
the technique.  If the patient, family member or caregiver do not want to (self-)administer 
adalimumab, then arrangements will be put in place on an individual basis to ensure that trial 
medication is administered as prescribed. 
Table JAHW.6 shows the treatment regimens. 
Table JAHW.6. 
Treatment Regimens  
Treatment 
Group 
Treatments Administered (Intervention 
name, dosage level, and route of 
administration) 
Authorized as defined by EU Clinical Trial 
Regulations 
Baricitinib 4-mg Baricitinib 4-mg oral tablet 
 
Baricitinib 2-mg/mL oral suspension 
Authorized in EU and not used according to 
authorization 
Not authorized in EU 
Baricitinib 2-mg Baricitinib 2-mg oral tablet 
 
Baricitinib 2-mg/mL oral suspension 
Authorized in EU and not used according to 
authorization 
Not authorized in EU 
Baricitinib 1-mg Baricitinib 1-mg oral tabletBaricitinib 
2-mg/mL oral suspension 
Not authorized in the EU  
Not authorized in the EU 
Adalimumab 
Adalimumab 20 mg in those weighing <30 kg 
or 40 mg in those  ≥30 kg 
Authorized and used according to authorization 
Note:  The oral suspension dose may be administered as 4-mg, 2-mg, 1-mg, and 0.5-mg as needed. The oral 
suspension contains sorbitol solution (70% sorbitol) at a concentration of 150 mg/mL, which is equivalent to 
105 mg of sorbitol per mL.  Patients with hereditary fructose intolerance should not exceed 5 mg/kg/day of 
sorbitol, according to the guideline on “Excipients in the labelling and package leaflet of medicinal products for 
human use (EMA/CHMP/302620/2017; EMA [WWW]).”  
Note:  Patients with renal impairment or renal immaturity (defined as eGFR <60 mL/min/1.73 m2) at baseline will 
have their baricitinib dose reduced by 50%.  Patients with renal impairment or renal immaturity who would have 
received the 2-mg or 1-mg dose will be dose-reduced to 1-mg or 0.5-mg, respectively, using the oral suspension. 
The investigator or appointed designee is responsible for the following: 
 Explaining the correct use of the investigational agent(s) to the parent or legal 
guardian 
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 Verifying that instructions are followed properly 
 Maintaining accurate records of investigational product dispensing and collection 
 At the end of the study returning all unused medication to Lilly, or its designee, 
unless the sponsor and sites have agreed all unused medication is to be destroyed 
by the site, as allowed by local law. 
7.1.1. Packaging and Labeling  
The sponsor (or its designee) will supply the following investigational products in accordance 
with current Good Manufacturing Practice: 
 Tablets containing 4-mg of baricitinib 
 Tablets containing 2-mg of baricitinib 
 Tablets containing 1-mg of baricitinib 
 Suspension containing 2-mg/mL of baricitinib 
 Vials or syringes of adalimumab for injection 
Each tablet has a distinctive shape and color:  4-mg versus 2-mg versus 1-mg.  Baricitinib oral 
suspension (containing 2 mg/mL baricitinib) will be supplied as a ready-to-use oral suspension.  
Baricitinib oral suspension will be provided in a bottle and doses will be delivered to the patient 
using a standard oral syringe. 
Study interventions will be labeled as appropriate for country requirements. 
7.2. Method of Treatment Assignment  
Patients will receive the final age-based dose of baricitinib selected in the PK assessment period 
of Study JAHV (Section 7.2.1).  Pharmacokinetic data from Study JAHV will be provided by 
age cohort (12 to <18 years, 9 to <12 years, 6 to <9 years, and 2 to <6 years; see Appendix 8 for 
updated dosing based on the current data).  Enrollment in Study JAHW may be restricted to 
patients represented in the age cohorts for which PK data are available from Study JAHV, until 
JAHV PK data become available for other age groups. 
All patients <6 years of age will receive oral suspension.  Patients ≥6 to <12 years of age have 
the option of receiving the oral suspension.  Patients >12 years will be supplied tablets only. 
 Baricitinib arm:  At least 20 patients (MTX-IR and/or bDMARD-IR) evaluable for 
primary endpoint. 
 Adalimumab arm:  At least 4 patients evaluable for the primary endpoint. 
Assignment to treatment groups will be determined by a computer-generated random sequence 
using an interactive web-response system (IWRS).  The IWRS will be used to assign 
investigational product to each patient.   
Site personnel will confirm that they have located the correct packages by entering a 
confirmation number found on the packages into the IWRS before dispensing to the patient. 
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7.2.1. Selection and Timing of Doses  
Baricitinib: 
Baricitinib should be administered at approximately the same time each day.  Patients will 
receive the final age-based dose of baricitinib selected in the PK assessment period of Study 
JAHV.  Based on PBPK modeling, this is expected to be 4-mg for patients ≥9 to <18 years of 
age and 2-mg for patients <9 years of age, in order to produce exposures similar to those in 
adults after 4-mg QD administration; see Appendix 8 for updated dosing based on the current 
data.  Refer to Section 5.5 for additional information. 
Adalimumab: 
Adalimumab will be administered as a subcutaneous injection once every 2 weeks.  The dose 
will be based on body weight:  20 mg every 2 weeks for participants weighing <30 kg, or 40 mg 
every 2 weeks for patients weighing ≥30 kg (adalimumab SmPC). 
7.3. Blinding  
This is an open-label study. 
7.4. Dosage Modification  
Baricitinib: 
The baricitinib dose and formulation for an individual patient will not change during Part A of 
this study.  During Part B, as patients age over 9 years old, they will receive baricitinib 4 mg at 
their next scheduled visit, and as patients age over 6 years old, they will have the option of 
receiving tablets instead of suspension.  For patients who progress to the ≥18 years age group, 
their current dose will be maintained. 
The baricitinib dose will be reduced by 50% in patients with renal impairment (defined as eGFR 
<60 mL/min/1.73 m2) at baseline. 
Adalimumab: 
The adalimumab dose will be based on body weight (20 mg for patients weighing <30 kg or 
40 mg for patients weighing ≥30 kg; adalimumab SmPC).  Dose modifications are NOT 
permitted in patients whose body weight changes from less than 30 kg to greater than 30 kg or 
from greater than 30 kg to less than 30 kg during Part A.   
7.5. Preparation/Handling/Storage/Accountability  
All investigational products (used and partially used) will be returned to the sponsor or destroyed 
at site level with the sponsor’s written approval.  In some cases, sites may destroy the material if, 
during the investigative site selection, the evaluator has verified and documented that the site has 
appropriate facilities and written procedures to dispose of clinical study materials. 
Investigators and site personnel will follow storage and handling instructions on the 
investigational product packaging. 
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Only participants enrolled in the study, or their parent or legal guardian, may receive 
investigational product and only authorized site staff may supply investigational product.  All 
investigational products should be stored in an environmentally controlled and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff. 
The investigator is responsible for investigational product accountability, reconciliation, and 
record maintenance (such as receipt, reconciliation, and final disposition records). 
7.6. Treatment Compliance  
Patient compliance with study medication will be assessed during the treatment period of Part A 
and Part B per the Schedule of Activities. 
Patients treated with baricitinib or adalimumab will be considered noncompliant if they miss 
≥20% of the prescribed doses during the study (unless the patient’s investigational product was 
withheld by the investigator for safety reasons).  For adalimumab, a patient will be considered 
significantly noncompliant if his or her study medication compliance rate is <80% or if there are 
any consecutive missed injections, unless the patient’s investigational product was withheld by 
the investigator for safety reasons. 
Similarly, patients will be considered noncompliant if they are judged by the investigator to have 
intentionally or repeatedly taken more than the prescribed amount of study medication.  Patients 
found to be noncompliant with the investigational product should be assessed to determine the 
reason for noncompliance and educated and/or managed as deemed appropriate by the 
investigator to improve compliance. 
Patients will be counseled by study staff on the importance of taking the investigational product 
as prescribed, as appropriate. 
Patient compliance will be further defined in the statistical analysis plan (SAP). 
7.7. Concomitant Therapy  
All concomitant medication taken during the study must be recorded on the Concomitant 
Medication electronic case report form (eCRF). 
Patients 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 other concomitant medications arises, discontinuation 
of the patient from the investigational product or the study will be at the discretion of the 
investigator in consultation with Lilly or its designee (Section 8.2). 
Treatment with concomitant therapies during the study is permitted only as described below and 
in Table JAHW.7.  During Part A, the dosages of concomitant treatment may only be adjusted 
for safety reasons, with the exception of topical corticosteroid eye drops. 
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Methotrexate, mycophenolate mofetil, and csDMARDs: 
 Chronic stable use of MTX is permitted up to a maximum dose of 25 mg/m2/week 
throughout the study. 
 Patients must be on a stable dose of MTX for at least 4 weeks prior to screening, 
and remain on the same dose throughout Part A. 
 During Part B, MTX may be initiated or the dose increased, decreased, or 
discontinued, at the discretion of the investigator, and according to local clinical 
practice. 
 Local standard of care should be followed for concomitant administration of folic 
acid. 
 Chronic stable use of csDMARDs (other than MTX) and mycophenolate mofetil is 
permitted.  Patients must be on a stable dose for at least 4 weeks prior to screening. 
 During Part A, initiation of new csDMARDs and/or increases in dose are not 
permitted. 
 During Part B, other csDMARDs or mycophenolate mofetil may be initiated, or the 
dose increased, decreased, or discontinued, at the discretion of the investigator, and 
according to local clinical practice. 
 Concomitant use of >2 csDMARDs (including MTX) is not allowed. 
 
Topical steroid eye drops: 
 Topical steroid eye drops, with a maximum of 4 drops/day per eye at screening, are 
permitted as background therapy during the study.  The dose must have been stable 
for at least 2 weeks prior to screening. 
 Steroid drop tapering is recommended as shown in the following table: 
 
Study Interval 
Dose Reduction 
Week 0–Week 4 
No dose changes permitted 
Week 4–Week 8 
Reduce drops to a maximum of 3 drops/day per eye 
Week 8–Week 20 
Reduce drops to a maximum of 2 drops/day per eye 
Week 20–Week 24 
No dose changes permitted 
Week 24 onward (Part B) 
Reduce drops at the discretion of the treating clinician to any dose, including zero 
 
 If tapering is not tolerated during Part A or Part B, the number of drops can be 
increased up to the number received at screening. 
 The topical steroid eye drop formulation (Maxidex, Predforte, or equivalent) should 
remain the same as that used at screening and will not change for individual patients 
throughout Part A, unless required for safety or supply issues; the formulation may 
be changed during Part B. 
 
Oral corticosteroids: 
 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. 
 Patients 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 Part A, except for 
treatment of an AE. 
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 During Part B, oral corticosteroids may be initiated, or the dose increased, 
decreased, or discontinued, at the discretion of the investigator. 
 
Intra-articular corticosteroid joint injections: 
 A maximum of 8 injections are permitted per year. 
 No more than 2 injections are permitted in a single session. 
 No injections are permitted within 4 weeks prior to Visit 2. 
 
 
Intraocular corticosteroid injections: 
 Depot peri-ocular, peri-ocular or intraocular corticosteroid injections are not 
permitted within 30 days prior to Visit 2 or during Part A. 
 Intraocular or peri-ocular corticosteroid injections are permitted during Part B at the 
discretion of the investigator. 
 
Other corticosteroids 
 With the exception of oral and intra-articular corticosteroids, patients should not 
receive other systemic corticosteroids during Part A, including intramuscular 
corticosteroids. 
 During Part B, other systemic steroids may be administered; however, the daily dose 
should be 10 mg/day or 0.2 mg/kg/day prednisone equivalent, whichever is less. 
 Topical, intranasal, and inhaled corticosteroids are permitted. 
 
Analgesics and NSAIDs 
 Chronic stable use of NSAIDs and analgesics is permitted.  Patients must be on a 
stable dose for at least 1 week prior to Visit 2.  
 Increases in dose and/or introduction of new NSAIDs and analgesics are not 
permitted during Part A, except for treatment of an AE. 
 During Part B, other analgesics or NSAIDs may be initiated or dose may be 
increased at the discretion of the investigator. 
 Dose reductions and/or termination of NSAIDs and analgesics are permitted. 
 
Permitted analgesics include 
o acetaminophen 
o NSAIDs, e.g. ibuprofen 
o cyclooxygenase-2 inhibitors, e.g. celecoxib 
o opioids, e.g. tramadol, codeine, or morphine 
o local anaesthetics, e.g. lidocaine, and 
o topical anaesthetics, e.g. EMLA cream. 
 
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The following therapies will not be permitted during the course of the study as specified in the 
exclusion criteria (Section 6.2): 
 bDMARDs 
 Intraocular steroid implants 
 Intraocular disease modifying agents, including anti-VEGF injections 
 Strong OAT3 inhibitors, e.g. probenecid 
 Interferon therapy 
 Live vaccine within 28 days prior to baseline or expect to need/receive live vaccine 
during the course of the study (except booster immunization with attenuated vaccine for 
MMR or VZV).  Booster vaccination with attenuated vaccine for MMR or VZV may be 
considered if it is essential based on the local guideline and/or in the opinion of the 
investigator. 
 
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Table JAHW.7. 
Concomitant JIA Therapies  
Drug Class 
As 
Needed 
Chronic 
Use 
Conditions for Use During Part A 
MTXa 
No 
Yes 
 Maximum of 25 mg/m2/week. 
 Stable dose is required for at least 4 weeks prior to screening. 
 Must continue on same dose throughout Part A. 
 May initiate, increase or decrease the dose, or discontinue during Part B. 
csDMARDs 
other than MTXa 
No 
Yes 
 Stable dose is required for at least 4 weeks prior to screening. 
 Must continue on same dose throughout Part A. 
 May initiate, increase or decrease dose, or discontinue during Part B. 
 Maximum of 2 concomitant csDMARDs (including MTX). 
Mycophenolate 
mofetil 
No 
Yes 
 Stable dose is required for at least 4 weeks prior to screening. 
 Must continue on same dose throughout Part A. 
 May initiate, increase or decrease the dose, or discontinue during Part B. 
Topical steroid 
eye drops 
No 
Yes 
 Maximum of 4 drops/day per eye at screening. 
 Stable dose is required for at least 2 weeks prior to screening. 
 In Part A, drops may be tapered between Week 4 through Week 20. 
 In Part B, drops may be tapered after Week 24 to any dose, including 
zero. 
 Formulation may not change during Part A, but may change during 
Part B. 
Oral 
corticosteroids 
No 
Yes 
 Maximum dose of 10 mg/day or 0.2 mg/kg/day prednisone equivalent, 
whichever is less. 
 Stable dose is required for at least 2 weeks prior to screening and 
4 weeks prior to baseline. 
 Must continue on same dose throughout Part A, except for treatment of 
an AE. 
 May initiate, increase or decrease dose, or discontinue during Part B. 
Intra-articular 
corticosteroid 
joint injections 
No 
No 
 Maximum of 8 injections per year. 
 Maximum of 2 injections in a single session. 
 Not permitted within 4 weeks prior to Visit 2. 
Intraocular 
corticosteroid 
injections 
No 
No 
 Not permitted within 30 days prior to Visit 2. 
 Not permitted during Part A. 
 Permitted during Part B. 
Systemic 
corticosteroids 
(other than oral 
and 
intra-articular) 
No 
Yes 
 Not permitted during Part A. 
 Permitted during Part B at a maximum dose of 10 mg/day or 
0.2 mg/kg/day prednisone equivalent, whichever is less. 
Analgesics & 
NSAIDs 
No 
Yes 
 Stable dose is required for at least 1 week prior to Visit 2. 
 Must continue on same dose throughout Part A, except for treatment of 
an AE. 
 May initiate, increase or decrease dose, or discontinue during Part B. 
Abbreviations:  csDMARD = conventional synthetic disease-modifying antirheumatic drug; MTX = methotrexate; 
NSAID = nonsteroidal anti-inflammatory drug. 
a Concomitant use of >2 of any csDMARDs (including MTX) is not allowed. 
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7.8. Treatment after the End of the Study  
7.8.1. Treatment after Study Completion  
After the conclusion of the study, continued access to baricitinib will not be provided. 
7.8.2. Special Treatment Considerations  
Patients receiving baricitinib who experience a treatment failure after at least 24 weeks of 
treatment can have concomitant medication altered (as described in Section 7.7), but should also 
be considered for discontinuation from the study (see Section 8.2). 
Treatment failure is defined by the presence of 1 or more of the following: 
 A 2-step increase in SUN cell-activity score (anterior chamber cells) over 2 consecutive 
readings for patients with a baseline grade of 1+ or 2+. 
 Sustained non-improvement in SUN cell-activity score for 2 consecutive readings for 
patients with a baseline grade of 3+ or greater. 
 Only partial improvement of other ocular co-morbidity for 2 consecutive assessments. 
o Ocular co-morbidities are defined as: 
▪ Disc swelling and/or cystoid macular edema, as gauged clinically and 
confirmed by optical coherence tomography (OCT) evidence 
▪ Sustained raised intraocular pressure (>25 mm Hg) for more than 1 month, not 
responding to topical anti-hypertensives 
▪ Sustained hypotony (<6 mm Hg) for more than 1 month 
▪ Reduction in vision (LogMAR test) of 15 letters, secondary to active uveitis 
(excluding cataract) 
o Note:  Patients can remain in the study in the event of cataract. 
 No improvement in SUN cell-activity score over 2 consecutive readings after 6 months of 
therapy. 
 Worsening of existing (on enrollment) ocular co-morbidity (as defined above) after 
12 weeks of therapy. 
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8. Discontinuation Criteria  
8.1. Discontinuation from Study Treatment  
8.1.1. Temporary Interruption of Investigational Product  
In some circumstances, patients may need to temporarily interrupt treatment as a result of AEs or 
abnormal laboratory values that may have an unclear relationship to investigational product.  
Except in cases of emergency, it is recommended that the investigator consult with Lilly (or its 
designee) before temporarily interrupting therapy for reasons other than those defined in Table 
JAHW.8. 
For the abnormal laboratory findings and clinical events (regardless of relatedness) listed in 
Table JAHW.8, specific guidance is provided for temporarily interrupting treatment and when 
treatment may be restarted.  Retest frequency and timing of follow-up laboratory tests to monitor 
the abnormal finding is at the discretion of the investigator.  Investigational product that was 
temporarily interrupted because of an AE or abnormal laboratory value not specifically covered 
in Table JAHW.8 may be restarted at the discretion of the investigator. 
Table JAHW.8. 
Criteria for Temporary Interruption of Investigational Product  
Hold Investigational Product if the Following Laboratory 
Test Results or Clinical Events Occur: 
Investigational Product May be Resumed When: 
WBC count <2000 cells/L 
(<2.00 x 103/L or <2.00 billion/L) 
WBC count 3000 cells/L 
(≥3.00 x 103/L or ≥3.00 billion/L) 
ANC <1000 cells/L 
(<1.00 x 103/L or <1.00 billion/L) 
ANC ≥1500 cells/L 
(≥1.50 x 103/L or ≥1.50 billion/L) 
Lymphocyte count <500 cells/L 
(<0.50 x 103/L or <0.50 billion/L) 
Lymphocyte count 1000 cells/L 
(≥1.00 x 103/L or ≥1.00 billion/L) 
Platelet count <75,000/L 
(<75 x 103/L or <75 billion/L) 
Platelet count 100,000/L 
(≥100 x 103/L or ≥100 billion/L) 
eGFR <40 mL/min/1.73 m2 (from serum creatinine) for 
patients with screening eGFR ≥60 mL/min/1.73 m2 
eGFR 50 mL/min/1.73 m2 
eGFR <30 mL/min/1.73 m2 (from serum creatinine) for 
patients with screening eGFR ≥40 to <60 mL/min/1.73 m2 
eGFR 40 mL/min/1.73 m2 
ALT or AST >5 x ULN 
ALT and AST return to <2 x ULN, and IP is not 
considered to be the cause of enzyme elevation 
Hemoglobin <8 g/dL (<80.0 g/L) 
Hemoglobin 10 g/dL (≥100.0 g/L) 
Symptomatic herpes zoster 
All skin lesions have crusted and are resolving 
Infection that, in the opinion of the investigator, merits the IP 
being interrupted 
Resolution of infection that, in the opinion of the 
investigator, merits the IP being restarted 
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Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; eGFR = estimated glomerular filtration rate; IP = investigational product; ULN = upper limit 
of normal; WBC = white blood cell. 
8.1.2. Permanent Discontinuation from Investigational Product  
Investigational product must be permanently discontinued if the patient or the patient’s designee 
requests to discontinue investigational product. 
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator after consultation with the Lilly-designated medical monitor when a patient 
meets 1 of the following conditions: 
 ALT or AST >8 x ULN 
 ALT or AST >5 x ULN for more than 2 weeks after temporary interruption of 
investigational product 
 ALT or AST >3 x ULN and TBL >2 x ULN or international normalized ratio (INR) >1.5 
 ALT or AST >3 x ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
 ALP >3 x ULN that is deemed to be of liver origin and drug-related 
 ALP >2.5 x ULN and TBL >2 x ULN 
 ALP >2.5 x ULN with the appearance of fatigue, nausea, vomiting, right upper-quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
Note:  Patients 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. 
Investigational product should be permanently discontinued if any of the following laboratory 
abnormalities are observed: 
 White blood cell count <1000 cells/L (1.00 x 103/L or 1.00 billion/L) 
 ANC <500 cells/L (0.50 x 103/L or 0.50 billion/L) 
 Lymphocyte count <200 cells/L (0.20 x 103/L or 0.20 billion/L) 
 Hemoglobin <6.5 g/dL (<65.0 g/L) 
Note:  Temporary interruption rules (see Section 8.1.1) 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 (Table JAHW.8) 
following the resolution of the intercurrent illness or other identified factor may the investigator 
restart investigational product after consultation with the Lilly-designated medical monitor. 
Use of analgesics “as needed” must lead to a thorough diagnostic assessment of all potential 
underlying causes and, if lack of efficacy cannot be ruled out, to considering permanent 
discontinuation of the investigational product. 
 
 
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In addition, patients will be discontinued from investigational product in the following 
circumstances: 
 Pregnancy 
 Malignancy 
 HBV DNA detected with a value above the limit of quantitation (see Section 9.4.4) 
 Development of a VTE (DVT/PE) during the study  
Patients discontinuing from the investigational product prematurely for any reason should 
complete follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety). 
8.1.3. Discontinuation of Inadvertently Enrolled Patients  
The following paragraph is retained and applicable to sites in France. 
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, then the participant should be discontinued from study treatment and 
safety follow-up should be performed as outlined in Section 2 (Schedule of Activities), 
Section 9.2 (Adverse Events), and Section 9.4 (Safety). 
The following paragraph is not applicable to sites in France. 
If the investigator and the sponsor-designated medical monitor agree that it is medically 
appropriate to continue, the investigator must obtain documented approval from the sponsor-
designated medical monitor to allow the inadvertently enrolled patient to continue in the study 
with or without treatment with investigational product where locally permitted. 
8.2. Discontinuation from the Study  
Patients may choose to withdraw from the study for any reason at any time; the reason for early 
withdrawal will be documented. 
Possible reasons that may lead to permanent discontinuation include the following: 
 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. 
 Determination that clinically meaningful adverse trends in patient growth (either at an 
individual or at an age-group level) are observed. 
 Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP). 
 Investigator decision 
o The investigator decides that the patient should be discontinued from the 
study.  If this decision is made because of an intolerable AE or a clinically 
significant laboratory value, appropriate measures are to be taken. 
o If the patient, for any reason, requires treatment with a therapeutic agent 
excluded per the criteria described in Section 7.7, discontinuation from the 
study occurs prior to introduction of the new agent. 
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 Patient decision 
o The patient or the patient’s designee (e.g., parent or legal guardian) 
requests to be withdrawn from the study. 
Patients discontinuing from the study prematurely for any reason should complete AE and other 
safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety). 
8.3. Lost to Follow-Up  
Patients will be considered lost to follow-up if they repeatedly fail to return for scheduled visits 
and are unable to be contacted by the study site.  Site personnel are expected to make diligent 
attempts to contact patients/legal representatives who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site. 
Lilly personnel will not be involved in any attempts to collect vital status information. 
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9. Study Assessments and Procedures  
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing). 
Appendix 2 lists the laboratory tests that will be performed for this study. 
Unless otherwise stated in the following subsections, all samples collected for specified 
laboratory tests will be destroyed within 60 days of receipt of confirmed test results.  Certain 
samples may be retained for a longer period, if necessary, to comply with applicable laws, 
regulations, or laboratory certification standards. 
Investigators or relevant clinical staff will provide age-appropriate explanations to all children, 
prior to any assessment or procedure.  Investigators should assess and monitor physical pain and 
distress at each visit. 
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 accordance 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 assessment is to determine the proportion of patients with a 2-step decrease 
in the level of inflammation (anterior chamber cells) or decrease to zero through Week 24 in the 
eye most severely affected at baseline. 
In order to reduce the confounding effects of variations in disease activity and time, it is optimal 
to perform the ophthalmologic and rheumatologic examinations on the same day, although a 
separation of up to 3 days is acceptable. 
9.1.2. Secondary Efficacy Assessments  
Secondary endpoints (assessed at each visit) are as follows: 
 Change in SUN grade of cells in the anterior chamber through Week 24 (Part A) and 
through Week 284 (Part B) in the most severely affected eye. 
 Change in SUN grade of cells in the anterior chamber through Week 24 and Week 284 in 
the less severely affected eye (if applicable). 
 In patients with bilateral uveitis disease at baseline:  proportion of responders at Weeks 
24 and 284, defined according to the SUN criteria as a 2-step decrease in the level of 
anterior chamber cells in the most severely affected eye at baseline (or both eyes if the 
inflammation grade is the same in both eyes) and a 1-step decrease in the level of anterior 
chamber cells in the less severely affected eye at baseline. 
 Change in visual acuity measured by age-appropriate LogMAR test through Week 24. 
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 Change in vitreous haze through Week 24 in each affected eye. 
 Change in grade of flare in the anterior chamber through Week 24 and Week 284 in each 
affected eye. 
 Change in overall uveitis-related disability: 
o Change in Patient Uveitis-related Disease Activity through Week 24. 
o Change in Patient Uveitis-related Improvement at Week 12 and Week 24. 
o Change in Patient Arthritis Disease Activity through Week 24. 
o Change in Patient Arthritis Improvement at Week 12 and Week 24. 
o Change in Ophthalmologist Uveitis-related Disease Activity through 
Week 24. 
o Change in Ophthalmologist Uveitis-related Improvement at Week 12 and 
Week 24. 
 Proportion of patients with inactive anterior uveitis (using SUN definition) in each 
affected eye through Week 24 and Week 284. 
 Time to inactive anterior uveitis disease (using SUN definition) in each affected eye. 
 Proportion of patients who are able to taper concomitant corticosteroids. 
 Time to treatment response:  response is defined by a 2-step decrease in the level of 
inflammation (anterior chamber cells) or decrease to zero in the eye most severely 
affected at baseline. 
 Proportion of responders at Week 284. 
 Pediatric American College of Rheumatology (PediACR)30/50/70/90/100 response rates 
(for patients with JIA-U). 
 Safety variables: 
o AEs, including SAEs 
o Permanent discontinuation of investigational product due to AE, and 
o Temporary interruption of investigational product. 
9.1.2.1. Ophthalmic Assessments  
9.1.2.1.1. SUN Cell-Activity Score  
Anterior chamber cells will be examined using a slit-lamp, and graded using the SUN grading 
scheme (Table JAHW.9).  This is a quantitative assessment of cell number in the anterior 
chamber, which is graded 0-4 (Jabs et al. 2005). 
Table JAHW.9. 
SUN Grading Scheme for Anterior Chamber Cells  
Grade 
Cells in Fielda 
0 
<1 
0.5+ 
1-5 
1.0+ 
6-15 
2.0+ 
16-25 
3.0+ 
26-50 
4.0+ 
>50 
Abbreviation:  SUN = Standardization of Uveitis Nomenclature. 
a Field size is a 1 mm by 1 mm slit beam. 
 
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9.1.2.1.2. Anterior Chamber Flare  
Flare will be assessed using a slit-lamp, and graded using the SUN grading scheme (Table 
JAHW.10; Jabs et al. 2005). 
Table JAHW.10. 
SUN Grading Scheme for Anterior Chamber Flare  
Grade 
Description 
0 
None 
1+ 
Faint 
2+ 
Moderate (iris and lens details clear) 
3+ 
Marked (iris and lens details hazy) 
4+ 
Intense (fibrin or plastic aqueous) 
Abbreviation:  SUN = Standardization of Uveitis Nomenclature. 
9.1.2.1.3. Visual Acuity  
Visual acuity will be assessed in both eyes using an age-appropriate LogMAR test (Kay picture 
and crowded LogMAR test). 
9.1.2.1.4. Vitritis  
Binocular indirect ophthalmoscopy score will be used to grade vitritis and vitreous haze in each 
affected eye (Nussenblatt et al. 1985). 
9.1.2.2. Uveitis Disease Activity  
The definition of uveitis disease activity used in this study is based on the SUN Working Group 
criteria (Table JAHW.11; Jabs et al. 2005).  Inactive disease is defined as the presence of 0 
anterior chamber cells upon slit-lamp examination. 
Table JAHW.11. 
Uveitis Disease Activity Terminology  
Term 
Definition 
Inactive 
Grade 0 cellsa 
Worsening activity 
2-step increase in level of inflammation (e.g., anterior chamber cells, vitreous haze) or 
increase from grade 3+ to 4+ 
Improved activity 
2-step decrease in level of inflammation (e.g., anterior chamber cells, vitreous haze) or 
decrease to grade 0 
Remission 
Inactive disease for ≥3 months 
a Applies to anterior chamber inflammation. 
9.1.2.3. PediACR30/50/70/90/100 Assessments  
The PediACR30 consists of the 6 core criteria listed below.  The definition of improvement is 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%. 
 Number of active joints (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) in 
73 joints 
 Number of joints with limited range of motion in 69 joints 
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 Physician’s Global Assessment of Disease Activity (21-circle visual analogue scale 
[VAS]) (Section 9.1.2.4) 
 Parent’s Global Assessment of Well-Being (Section 9.1.3) 
 Physical function as assessed by the Childhood Health Assessment Questionnaire 
(CHAQ) (Section 9.1.3) 
 Acute-phase reactant (high-sensitivity C-reactive protein [hsCRP] and erythrocyte 
sedimentation rate [ESR]) 
PediACR50/70/90/100 responses are efficacy measures that are calculated as improvements of at 
least 50%, 70%, 90% and 100%, respectively, in the PediACR Core Set values listed above. 
9.1.2.4. Physician’s Global Assessment of Disease Activity  
The Physician’s Global Assessment of Disease Activity is used by the physician to assess the 
patient’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). 
9.1.3. Health Outcomes  
Childhood Health Assessment Questionnaire 
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 patient. 
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):  dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.  
The domains are averaged to calculate the Disability Index (physical function).  Each item is 
scored from 0 to 3 (0 = no difficulty; 1 = some difficulty; 2 = much difficulty; and 3 = unable to 
do or not applicable).  A higher score indicates worse physical function (Singh et al. 1994).  Data 
will be captured on an electronic tablet. 
The Discomfort Index of the CHAQ includes the following (Ruperto et al. 2001): 
 Parent’s Global Assessment of Well-Being 
o This is a component of the PediACR core response set, as well as the Juvenile 
Arthritis Disease Activity Score-27 (JADAS-27). 
o The instrument is a 0-100 mm VAS assessing the current level of well-being, 
where 0 = “Very well” and 100 = “Very poor”. 
 Pain assessment due to illness 
o This instrument is a 0-100 mm VAS that assesses the current level of pain 
severity over the past week, where 0 = “No pain” and 100 = “Very severe pain”. 
Childhood Health Questionnaire-Parent Form 50 
The Childhood Health Questionnaire-Parent Form 50 (CHQ-PF50) is a generic observer-reported 
instrument designed to capture the health-related quality of life of children and adolescents (from 
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5- to 18-years of age), as well as the impact of the child’s disease on the caregivers 
(HealthActCHQ 2013).  The CHQ-PF50 is completed by the caregivers and has been validated 
for use in patients with JIA (Ruperto et al. 2001). 
The CHQ-PF50 consists of 50 questions covering 14 health concepts:  Global Health; Physical 
Functioning; Role/Social Limitations-Physical; Role/Social Limitations-Emotional/Behavioral; 
Bodily Pain/Discomfort; General Behavior; Mental Health; Self-Esteem; General Health 
Perceptions; Change in Health; Parental Impact-Emotion; Parental Impact-Time; 
Family-Activities; and Family-Cohesion. 
Overall means for the individual CHQ scales and items will be scored according to the scoring 
manual.  Scores will be transformed to ensure that all items are positively scored so that a higher 
score indicates better health (HealthActCHQ 2013).  In addition, 2 summary scores, the Physical 
Summary Score (PhS) and Psychosocial Summary Score (PsS), will be evaluated based upon 10 
scales of the CHQ-PF50.  United States norms are available for the CHQ-PF50.  The response 
options for the CHQ-PF50 vary from 4 to 6 levels for the scales.  The majority of the items have 
a recall period of 4 weeks.  Data will be captured on an electronic tablet. 
Morning Joint Stiffness Duration 
As one of the assessments to determine inactive disease, the physician will ask the parent/legal 
guardian if the duration of their child’s morning joint stiffness was >15 minutes since the 
previous visit; inactive disease is ≤15 minutes in duration.  Responses are yes/no. 
Patient Uveitis-related Disease Activity  
The Patient Uveitis-related Disease Activity instrument is a single-item question.  It is completed 
by caregivers/legal guardians (proxy) for children less than 8 years; for children aged 8 years or 
older, this will be self-completed.  The single item asks the respondent to rate their eye problems 
“at this time”.  It uses a 4-item Likert scale (1 = “None”, 2 = “Mild”, 3 = “Moderate”, and 
4 = “Severe”). 
Patient Uveitis-related Improvement 
The Patient Uveitis-related Improvement instrument is a single-item question.  It is completed by 
caregivers/legal guardians (proxy) for children less than 8 years; for children aged 8 years or 
older, this will be self-completed.  The item asks the respondent to rate the overall change in 
their eye problems since they started taking study medication.  It uses a 5-item Likert scale 
(1 = “Much Better”, 2 = “A little Better”, 3 = “No Change”, 4 = “A Little Worse”, and 
5 = “Much Worse”). 
Patient Arthritis Disease Activity 
The Patient Arthritis Disease Activity instrument is a single-item question.  It is completed by 
caregivers/legal guardians (proxy) for children less than 8 years; for children aged 8 years or 
older, this will be self-completed.  The item asks the respondent to rate their arthritis “at this 
time”.  It uses a 4-item Likert scale (1 = “None”, 2 = “Mild”, 3 = “Moderate”, and 4 = “Severe”). 
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Patient Arthritis Improvement  
The Patient Arthritis Improvement instrument is a single-item question.  It is completed by 
caregivers/legal guardians (proxy) for children less than 8 years; for children aged 8 years or 
older, this will be self-completed.  The question asks the respondent to rate the overall change in 
their arthritis since they started taking study medication.  It uses a 5-item Likert scale (1 = “Much 
Better”, 2 = “A little Better”, 3 = “No Change”, 4 = “A Little Worse”, and 5 = “Much Worse”). 
Ophthalmologist Uveitis-related Disease Activity 
The Ophthalmologist Uveitis-related Disease Activity instrument is a single-item question asking 
the ophthalmologist to rate their patients’ disease activity in each eye “at this time”.  It uses a 
4-item Likert scale (1 = “None”, 2 = “Mild”, 3 = “Moderate”, and 4 = “Severe”). 
Ophthalmologist Uveitis-related Improvement  
The Ophthalmologist Uveitis-related Improvement instrument is a single-item question asking 
the ophthalmologist to rate the overall change in their patients’ uveitis in each eye since they 
started taking study medication.  It uses a 5-item Likert scale (1 = “Much Better”, 2 = “A little 
Better”, 3 = “No Change”, 4 = “A Little Worse”, and 5 = “Much Worse”). 
9.1.4. Exploratory Efficacy Assessments  
Efficacy Exploratory Assessments have been removed. 
9.1.5. Immunological Measurements  
Potential effects of baricitinib on the cellular and humoral immune system will be evaluated 
through the analysis of immunoglobulin levels, immunophenotyping (including T and B cells, 
T-cell subsets, and natural killer [NK] cells), white blood cells (WBC), and WBC differential. 
Changes from baseline in immunoglobulin levels and peripheral blood immunophenotyping 
(including T and B cells, T cell subsets, and NK cells) will be assessed at the following weeks: 
 Part A:  Week 12 and Week 24. 
 Part B:  Week 48, Week 96, Week 144, Week 192, Week 240, and Week 284. 
In addition, patients will be immunized with appropriate vaccinations as part of or in the course 
of their usual care according to the local requirement throughout the study period.  When the 
patients become eligible for a TDaP and/or a pneumococcal conjugate vaccine during the study 
period, they will be immunized with the vaccines, and their antibody titres to the antigens will be 
evaluated pre-immunization and at 4 and 12 weeks post-immunization.  A primary immune 
response will be assessed in patients who have never received TDaP or pneumococcal conjugate 
vaccines previously and secondary/booster responses will be assessed if the patients have 
previously received the vaccines. 
9.1.6. Appropriateness of Assessments  
All assessments utilized in this study are standard, widely used, and generally recognized as 
reliable, accurate, and relevant, except for the Uveitis-related Disease Activity and Improvement, 
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and Arthritis Disease Activity and Improvement scales, which are novel instruments developed 
by Lilly. 
9.2. Adverse Events  
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient. 
The investigator is responsible for the appropriate medical care of patients during the study. 
Investigators must document their review of each laboratory safety report. 
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves or until the event 
stabilizes with appropriate diagnostic evaluation.  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 patient’s preexisting conditions, including 
clinically significant signs and symptoms of the disease under treatment in the study.  In 
addition, site personnel will record any change in the condition(s) and any new conditions as 
AEs.  Investigators should record the following via eCRF for each AE:  time of onset, time of 
termination, severity, and their assessment of the potential relatedness of each AE to protocol 
procedure and/or investigational product.  The investigator will record all relevant AE/SAE 
information in the CRF. 
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to investigational product, study device, or a study procedure, taking into 
account the disease, concomitant treatment, or pathologies.  A “reasonable possibility” means 
that there is a cause-and-effect relationship between the investigational product, study device, 
and/or study procedure and the AE.  The investigator answers yes/no when making this 
assessment. 
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study. 
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via electronic data entry, clarifying if possible the 
circumstances leading to discontinuations of treatment. 
9.2.1. Serious Adverse Events  
An SAE is any AE from this study that results in one of the following outcomes: 
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 Death 
 Initial or prolonged inpatient hospitalization 
 Life-threatening experience (i.e., immediate risk of death) 
 Persistent or significant disability/incapacity 
 Congenital anomaly/birth defect 
 Important medical events that may not be immediately life-threatening or result in death 
or hospitalization, but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above. 
All AEs occurring after signing the ICF and Assent Form (as applicable) are recorded in the 
electronic data entry system and assessed for serious criteria.  The SAE reporting to the sponsor 
begins after the parent/legal guardian has signed the ICF, and the patient has signed the Assent 
Form (as applicable) and received investigational product.  However, if an SAE occurs after 
signing the ICF and Assent Form (as applicable), but prior to receiving investigational product, 
the SAE should be reported to the sponsor according to SAE-reporting requirements and 
timelines if it is considered reasonably possibly related to study procedure. 
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via initiation of a SAE eCRF.  Once the SAE eCRF form is initiated, an 
email is automatically triggered to the Sponsor’s global patient safety department.  Investigators 
can contact the Sponsor via telephone at any time using the qualified medical personnel or Lilly 
affiliate medical contact details, which are provided in the site study file.  If alerts are issued via 
telephone, they are to be immediately followed with official notification via completion of the 
SAE eCRF.  If the eCRF is unavailable (for example, for system maintenance) for a period of 
time that would compromise the sites’ ability to report an event within 24 hours of awareness, a 
paper version of the form should be downloaded from the Investigator Space portal, completed 
by the investigator, and submitted via fax to the Sponsor’s global patient safety department.  This 
form includes a fax cover page that is pre-populated with the appropriate fax number.  Serious 
AEs submitted via the paper method are entered into the eCRF once the database is available.  
The 24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.  Patients with a serious hepatic AE should have additional data collected using the 
eCRF. 
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus. 
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient disposition CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discontinued from the study and he or she considers the event reasonably possibly related to 
the study treatment or study participation, the investigator must promptly notify Lilly. 
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9.2.1.1. Suspected Unexpected Serious Adverse Reactions  
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Study Directive 2001/20/EC, and 
European regulation 536/2014 and the associated detailed guidances or national regulatory 
requirements in participating countries require the reporting of SUSARs.  Lilly has procedures 
that will be followed for the identification, recording, and expedited reporting of SUSARs that 
are consistent with global regulations and the associated detailed guidances. 
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, Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), 
and investigators. 
 
9.2.2. Adverse Events of Special Interest  
Adverse events of special interest will include the following: 
 Infections (including TB, herpes zoster, or opportunistic infections) 
 Malignancies 
 Hepatic events (see Section 9.4.5) 
 Major adverse cardiovascular events (MACE) (see Section 9.4.7) 
 Venous thromboembolism (DVT and PE) 
 Arterial thromboembolic events (ATE) 
Investigators will provide details on these AEs as instructed on the eCRF and may be asked for 
additional description by Lilly. 
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 facilitate 
process and product improvements. 
Patients (or parents/legal guardians) will be instructed to contact the investigator as soon as 
possible if they have a complaint or problem with the investigational product so that the situation 
can be assessed. 
9.3. Treatment of Overdose  
Baricitinib single doses up to 40-mg and multiple doses of up to 20-mg daily for 10 days have 
been administered in clinical studies without dose-limiting toxicity.  Pharmacokinetic data of a 
single dose of 40-mg in healthy volunteers indicate that >90% of the administered dose is 
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expected to be eliminated within 24 hours.  In case of an overdose, the patient should be 
monitored for signs and symptoms of adverse reactions.  Patients who develop adverse reactions 
should receive appropriate treatment. 
9.4. Safety  
Any clinically significant findings from electrocardiogram (ECG) testing, physical examination, 
vital signs measurements, or laboratory measurements that result in a diagnosis and that occur 
after the patient receives the first dose of investigational product should be reported to Lilly or its 
designee as an AE via eCRF. 
9.4.1. Electrocardiograms  
A single 12-lead standard ECG will be obtained locally at screening and read by a physician 
qualified to read pediatric ECGs (the investigator or qualified designee) at the site to determine 
whether the patient meets entry criteria.  Electrocardiograms may be obtained at additional times 
when deemed clinically necessary. 
9.4.2. Vital Signs  
For each patient, vital signs 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 patient receives the first dose of study treatment should be reported to Lilly or 
its designee as an AE via electronic data entry. 
9.4.3.  Laboratory Tests  
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).  Use of local anesthetics (e.g., EMLA cream) consistent with 
local prescribing information are permitted during the study visit to ease discomfort associated 
with venipuncture.  Owing to blood volume restrictions, some laboratory tests may not be 
collected.  Laboratory samples are recommended to be collected as described in a 
sponsor-provided weight-based prioritization chart (Appendix 7). 
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 patient receives the first dose of investigational product should be reported to Lilly or its 
designee as an AE via electronic data entry. 
9.4.4. Hepatitis B Virus DNA Monitoring  
Hepatitis B virus DNA testing will be performed in enrolled patients who tested positive for 
HBcAb at screening (refer to the Schedule of Activities [Section 2]). 
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Patients who are HBcAb positive and HBV DNA negative (undetectable) at screening will 
require measurement of HBV DNA as shown in the Schedule of Activities (Section 2) and the 
follow-up visit, regardless of their hepatitis B surface antibody (HBsAb) status. 
The following actions should be taken in response to HBV DNA test results: 
 If a single result is obtained with a value “below limit of quantitation,” the test should be 
repeated within approximately 2 weeks. 
 If the repeat test result is “target not detected,” monitoring will resume according to the 
study schedule. 
 If the patient has 2 or more test results with a value “below limit of quantitation,” HBV 
DNA testing should be performed approximately once per month for the remainder of the 
study and referral to a hepatologist is recommended. 
 If a result is obtained with a value above the limit of quantitation, at any time 
during the study, the patient will be permanently discontinued from 
investigational product (see Section 8.1.2) and should be referred to a hepatology 
specialist. 
o In selected cases, investigators may temporarily continue investigational 
product in accordance with current immunomodulator management in the 
setting of HBV DNA positivity.  This option may be considered in 
consultation with Lilly (or its designee) and evaluation of individual 
patient risks and benefits. 
9.4.5. Hepatic Safety Monitoring and Data Collection  
If a study patient experiences elevated ALT ≥3 x ULN, ALP ≥2 x ULN, or elevated TBL 
≥2 x ULN, liver testing (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, 
ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine phosphokinase to confirm 
the abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator and in 
consultation with the study medical monitor.  Monitoring of ALT, AST, TBL, and ALP should 
continue until levels normalize or return to approximate baseline levels.  Discontinuation criteria 
of investigational products, either temporary interruption or permanent discontinuation, due to 
abnormal ALT, AST, TBL, or ALP, are detailed in Section 8.1. 
Additional safety data should be collected via the hepatic eCRF if 1 or more of the following 
conditions occur: 
 ALT ≥5 x ULN confirmed by repeat testing 
 ALP ≥2 x ULN confirmed by repeat testing 
 TBL ≥2 x ULN confirmed by repeat testing (except for cases of known Gilbert’s 
syndrome) 
 Permanent discontinuation of investigational product due to hepatic event or 
hepatic laboratory abnormality 
 Hepatic SAE 
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Refer to Appendix 4 for a description of hepatic laboratory values that warrant exclusion from 
the study, temporary or permanent discontinuation of investigational product (Section 8.1), or 
additional safety collection via the hepatic eCRF. 
9.4.6. Safety Monitoring  
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods. 
If safety issues are identified, the Data Monitoring Committee (DMC) (refer to Interim Analyses 
section, Section 10.3.7) can request additional analyses of the safety data or request changes to 
the conduct of the study. 
The Lilly clinical research physician/scientist will monitor safety data throughout the course of 
the study.  Lilly will review SAEs within time frames mandated by company procedures.  The 
Lilly clinical research physician will, as is appropriate, consult with the functionally independent 
Global Patient Safety therapeutic area physician or clinical scientist and periodically review 
trends in safety data and laboratory analytes.  Any concerning trends in frequency or severity 
noted by an investigator and/or Lilly (or designee) may require further evaluation. 
All deaths and SAE reports will be reviewed by Lilly during the clinical study.  These reports 
will be reviewed to ensure completeness and accuracy.  If a death or a clinical AE is deemed 
serious, unexpected, and possibly related to investigational product, Lilly Global Patient Safety 
will report the event for regulatory reporting and safety monitoring purposes. 
Investigators will monitor vital signs and review findings that may be associated with 
cardiovascular and venous thrombotic events.  Adverse event reports and vital signs will be 
collected at each study visit.  The cardiovascular monitoring plan includes the following: 
 Regular monitoring of lipid levels 
 Potential MACE (cardiovascular death, myocardial infarction [MI], stroke), other 
cardiovascular events (such as hospitalization for unstable angina, hospitalization 
for heart failure, serious arrhythmia, resuscitated sudden death, cardiogenic shock, 
coronary interventions), ATE, venous thrombotic events, and noncardiovascular 
deaths will be identified by the investigative site or through medical review and 
will be sent to a blinded Clinical Event Committee for adjudication at regular 
intervals. 
9.4.6.1. Venous Thromboembolic Event Assessment  
If a patient develops the clinical features of a DVT or PE, appropriate local laboratory tests and 
imaging is recommended, as necessary, for diagnosis of the event.  For confirmed cases, 
additional laboratory testing should be performed as outlined in Appendix 5.  All suspected VTE 
events will be independently adjudicated by a blinded Clinical Event Committee. 
9.4.6.2. Growth Monitoring  
Height and weight will be measured at screening and baseline and postbaseline for the 
assessment of physical growth according to the Schedule of Activities (Section 2).  Height, 
weight, occipital frontal circumference, and growth velocity changes in pediatric patients (both at 
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an individual and group level) will be reviewed by the DMC.  Height measurements will be 
made using a stadiometer.   
Insulin-like growth factor (IGF)-1, the principal mediator of growth hormone, and IGF-binding 
protein-3, the principal carrier protein for IGF-1, will be collected for the assessment of 
growth-related disorders.  Gonadal hormone (estradiol for females or testosterone for males) will 
be collected for the assessment of pubertal development with patients 8 to <18 years of age.  For 
each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). 
A semiannual wrist, hand, finger, and anteroposterior (AP) knee radiographs to monitor bone age 
and long-bone growth is required, with an option to consent to this procedure for patients already 
enrolled in the study. 
If a local addendum is in place that specifies another mode of imaging (e.g., magnetic resonance 
imaging [MRI] instead of x-ray), the local addendum should be followed.  Otherwise, the current 
protocol amendment should be followed. 
Any symptomatic areas of bones/joints will be assessed and investigated as appropriate by study 
investigators.  Any diagnoses made based on symptomatic areas of bones/joints or imaging data 
will be reported as appropriate (e.g. recorded on eCRF). 
For study sites in Germany: 
 MRI of the knee will be collected to monitor bone and cartilage growth and/or 
maturation. 
o MRI of the knee will be collected approximately every 6 months as shown in 
Section 2 . A central vendor will be used for reading of the MRI images.  
o An x-ray of the knee (anteroposterior) may be collected in place of the MRI in 
cases where MRI is not possible (e.g., site does not have MRI access, sedation is 
required, MRI is not medically advisable in the opinion of the investigator, 
parents/patients do not consent).  The clinical site will document the rationale for 
collecting x-rays vs. MRIs.  An appropriate physician at the clinical site will read 
the x-ray image, and if it is determined that the patient does not have growth 
potential (that is, the patient has completed skeletal maturity), then no further 
knee x-rays will be required.  The clinical sites will document the decision that a 
patient has reached skeletal maturity. 
 External tibial length measurement will be collected as an additional assessment of 
growth. 
o External tibial length will be measured approximately every 3 months as shown in 
Section 2. Guidance on measuring external tibial length will be provided by the 
Sponsor. 
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9.4.6.3. Tanner Stage Scale  
The Tanner Stage Scales are a series of line drawings that are designed to assess sexual maturity 
of the patient, and will be included as a baseline assessment.  The line drawings are intended for 
patient self-assessment; however, this assessment may be also conducted by an appropriate 
health care professional if the patient and legal guardian agree (Marshall and Tanner 1969, 1970; 
Tanner and Davis 1985; Chavarro et al. 2017).  Assessment by the health care professional will 
not be completed if the patient and parent do not provide appropriate consent and assent.  The 
self-assessment will only be collected if the appropriate translation of the scale is available for 
use at the time of the baseline assessment. 
9.4.7. Vision-Related Safety Monitoring  
9.4.7.1. Fundoscopy  
Fundoscopy will be used to assess disc swelling, macular edema, and other structural changes in 
macular (epiretinal membrane) and optic nerve (optic disc swelling and glaucomatous 
neuropathy) and retina (neovascularization and retinal detachment).  Fundoscopy will be 
assessed at all visits in each affected eye. 
9.4.7.2. Optical Coherence Tomography  
Optical coherence tomography (at least stratus II) will be used to assess macular edema and 
central macular thickness in each affected eye. 
9.4.7.3. Cataract Scoring  
The Lens Opacities Classification Score (LOCS) II grading will be used for cataract scoring 
(Chylack et al. 1989).  The LOCS II standards for grading cataracts are shown in Appendix 6. 
9.4.7.4. Intraocular Pressure  
Intraocular pressure will be measured in each affected eye by I-Care, Goldmann tonometry or 
Tono-Pen, as deemed appropriate. 
9.4.7.5. Other Structural or Vision-Related Complications  
The following structural changes and vision related complications will be assessed and 
monitored: 
 Band keratopathy 
 Synechiae 
 Iris bombe 
 Glaucoma 
 Neovascularization 
 Cataract 
 Cystoid macular edema  
 Optic neuropathy  
 Ocular hypertension:  >21 mm Hg 
 Ocular hypotony:  <6 mm Hg 
 Glaucomatous field loss and/or glaucomatous optic atrophy 
 Epiretinal membrane formation, and 
 Visual deterioration:  worsening by 0.3 LogMAR in any eye 
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9.5. Pharmacokinetics  
Not applicable. 
9.6. Pharmacodynamics  
Refer to Section 10.3.5. 
9.6.1. Pharmacogenetics  
9.6.1.1. Whole Blood Sample for Pharmacogenetic Research  
A whole blood sample will be collected for pharmacogenetic analysis as specified in the 
Schedule of Activities (Section 2) where local regulations allow. 
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 
etiology, and/or the molecular subtype of the disease being treated.  In the event of an 
unexpected AE, the samples may be genotyped and analysis may be performed to evaluate a 
genetic association with response to baricitinib.  These investigations may be limited to targeted 
exome sequencing approach of known targets involved in drug metabolism or, if appropriate, 
genome-wide association studies may be performed to identify regions of the genome associated 
with the variability observed in drug response.  Samples will be used only for investigations 
related to disease and drug or class of drugs under study in the context of this clinical program. 
9.7. Biomarkers  
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics (PD), mechanism of action, variability of patient response 
(including safety), and clinical outcome.  Sample collection is incorporated into clinical studies 
to enable examination of these questions through measurement of biomolecules including DNA, 
RNA, proteins, lipids, and other cellular elements. 
Blood for nonpharmacogenetic biomarker research will be collected at the times specified in the 
Schedule of Activities (Section 2) where local regulations allow. 
Samples will be used for research on the drug target, disease process, variable response to 
baricitinib, pathways associated with JIA or JIA-U, mechanism of action of baricitinib, and/or 
research method, or in validating diagnostic tools or assay(s) related to JIA or JIA-U. 
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigator or site personnel. 
Samples will be retained at a facility selected by the sponsor for a maximum of 15 years after the 
last patient visit for the study, or for a shorter period if local regulations require and ethical 
review boards impose shorter time limits.  The duration allows the sponsor to respond to future 
regulatory requests related to the investigational product.  Any samples remaining after 15 years 
will be destroyed. 
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9.8. Medical Resource Utilization and Health Economics  
There will be no collection of healthcare resource utilization or calculation of utilities for 
economic modeling in this study. 
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10. Statistical Considerations  
10.1. Sample Size Determination  
The original sample size was determined by the following: 
At least 20 and up to 40 patients will be enrolled. 
 Baricitinib arm:  At least 10 and up to 30 patients (MTX-IR and bDMARD-IR) ; at least 
10 MTX-IR patients 
 Adalimumab arm:  At least 10 MTX-IR patients. 
At least 20 MTX-IR (but not bDMARD-IR) patients will be randomized to baricitinib and 
adalimumab in a 1:1 ratio. 
With a total sample size of 30 in the baricitinib arm, and assuming an observed response rate of 
66.7%, the study will be able to detect a true baricitinib treatment response rate of greater than 
57% with greater than 80% probability.  The observed response rate of 66.7% is based on the 
assumption that 20 out of 30 patients in the baricitinib arm will achieve the primary endpoint.  
The response rate threshold of 57% was chosen to match the response rate observed for 
patients with JIA-associated uveitis treated with adalimumab in the SYCAMORE study 
(Ramanan et al. 2017). 
Since the original sample size was determined, the study enrollment has been updated to the 
following: 
 Baricitinib arm:  At least 20 patients (MTX-IR and/or bDMARD-IR) evaluable for the 
primary endpoint. 
 Adalimumab arm:  At least 4 patients evaluable for the primary endpoint. 
10.2. Populations for Analyses  
Unless otherwise specified, the efficacy and health outcome analyses will be conducted on the 
modified intent-to-treat (mITT) analysis set in Part A.  The mITT set is defined as the patients 
who take at least 1 age-based dose of investigational product in Part A.  Patients will be analyzed 
according to the treatment to which they were assigned.  For the efficacy and health outcomes 
analysis in Part B, the analysis will be conducted on as-observed data, which is defined in 
Section 10.3.1.  Significant protocol violations will be described in the SAP. 
Safety analyses will be carried out on all randomized patients who receive at least 1 dose of 
investigational product and who did not discontinue from the study for the reason “Lost to 
Follow-up” at the first postbaseline visit. 
Further details of other populations will be described in the SAP. 
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10.3. Statistical Analyses  
10.3.1. General Statistical Considerations  
Statistical analysis of this study will be the responsibility of Lilly or its designee.  A detailed 
SAP describing the statistical methodologies will be developed by Lilly or its designee. 
Bayesian analysis will be used as the primary analysis method for the primary endpoint and 
interim analysis.  The posterior probability will be reported and the conclusion will be made 
based on the prespecified success criteria.  The primary endpoint is the proportion of patients 
with response at Week 24.  Response is defined as a 2-step decrease in the level of inflammation 
(anterior chamber cells) or decrease to zero in the eye most severely affected at baseline, 
measured by SUN criteria (Jabs et al. 2005).  If the study is not stopped for futility, the posterior 
probability of the treatment response rate exceeding 57% will be calculated, and the study 
objective will be successfully met (i.e., a positive study) if this probability is at least 80%.  The 
detail of the analyses will be described in the SAP. 
Unless otherwise specified, for the endpoints that may relate to both eyes, such as patients with 
uveitis affecting both eyes, the summary of the data for a given endpoint measure will be based 
on both affected eyes.  The summary statistics may be grouped into “less severely affected eye” 
and “more severely affected eye,” or “right eye” and “left eye” subgroups.  The details will be 
documented in the SAP. 
Efficacy and health outcome endpoints will also be summarized using descriptive statistics for 
the baricitinib arm and adalimumab arm.  No treatment comparison will be conducted. 
Continuous data will be summarized in terms of the mean, standard deviation, minimum, 
maximum, and median.  Categorical data will be summarized as frequency counts and 
percentages. 
All safety data will be descriptively summarized. 
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report.  Additional exploratory analyses of the data will be conducted as 
deemed appropriate.  Complete details of the planned analyses will be documented in the SAP. 
The SAP will be approved before the first patient visit in Study JAHW. 
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. 
 
 
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Missing Data Imputation 
The following methods will be used to impute missing data in Part A: 
Modified nonresponder imputation (mNRI): 
For primary efficacy data, missing data due to lack of efficacy will be imputed as a nonresponder 
under mNRI.  If primary efficacy data are missing for reasons other than this, available 
preceding data from patients with missing data will be reviewed by an independent and external 
Clinical Endpoints Committee (CEC), as outlined in the CEC charter.  The CEC will ensure that 
patients with missing data are evaluated in a consistent manner.  The CEC will consider the 
complete patient history and the reasons for the missing data, in order to determine whether 
responder or nonresponder status is appropriate on a case-by-case basis.  Study sites should send 
any requested source documentation to the CEC in a timely fashion. 
Nonresponder Imputation (NRI): 
A patient is defined as a responder only if (i) they meet the clinical requirements for response at 
the predefined time and (ii) they remain on the assigned study treatment; failing either criteria by 
definition (i) or (ii) makes them a nonresponder. 
Binary efficacy and health-outcome data, excluding the primary outcome data, will be imputed 
using NRI.  Patients will be considered a nonresponder for the NRI analysis if they do not meet 
the clinical response criteria or are entirely missing the visit at the analysis time point.  Patients 
without at least 1 postbaseline observation will also be defined as nonresponders for the NRI 
analysis. 
Last observation carried forward (LOCF): 
The LOCF method will be used for the analysis of continuous endpoints (unless otherwise 
stated).  For patients who discontinue the study, the last nonmissing observation will be carried 
forward to the subsequent time points for evaluation. 
The following method will be used to handle missing data in Part B: 
As-observed analysis: 
A summary based on observed data at each postbaseline visit will be provided.  For “as-observed” 
analysis, only data from completers at the visit are relevant, and therefore, the analysis does not 
need to deal with missing data. 
10.3.2. Treatment Group Comparability  
10.3.2.1. Patient Disposition  
Patient disposition will be summarized for all enrolled patients.  Frequency counts and 
percentages of patients who complete the study treatment visits or discontinue early from the 
study will be summarized by prior treatment group and overall. 
A listing of patient disposition will be provided for all patients, with the extent of their 
participation in the study and the reason for discontinuation. 
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10.3.2.2. Patient Characteristics  
Demographic and baseline characteristics will be summarized descriptively by treatment group.  
Baseline characteristics may include gender, age, height, weight, body mass index (BMI), race, 
geographic region, baseline disease severity, and subtypes of JIA.  Baseline clinical 
measurements may include PediACR core set variables, vision assessment, slit lamp 
examination, number of topical steroid drops taken per day, intraocular pressure, and number of 
study eyes. 
10.3.2.3. Concomitant Therapy  
Concomitant medications will be descriptively summarized for patients who enter each treatment 
period.  The medications will be coded accordingly. 
10.3.2.4. Treatment Compliance  
Treatment compliance with investigational product will be summarized for each treatment 
period.  Patient compliance with investigational product will be assessed at each visit.  Patients 
will be considered compliant for each study period if they miss <20% of the expected doses.  
Proportions of patients compliant will be summarized.  Patient compliance will be further 
defined in the SAP. 
10.3.3. Efficacy Analyses  
10.3.3.1. Primary Analyses  
The primary efficacy endpoint is the proportion of responders at Week 24.  Response is defined 
according to the SUN criteria as a 2-step decrease in the level of inflammation (anterior chamber 
cells) or decrease to zero in the eye most severely affected at baseline. 
A Bayesian posterior probability will be calculated based on the number of observed responders 
who complete or have the opportunity to complete 24 weeks of the study at each stage: 
 Stage 1:  10 baricitinib-treated patients. 
 Stage 2:  20 baricitinib-treated patients. 
 Stage 3:  up to 30 baricitinib-treated patients. 
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The details of the calculation of the posterior probability are as follows: 
𝑋𝑖: 𝑖 𝑡ℎ 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 
𝑋𝑖|𝜃∼𝐵𝑒𝑟𝑛(𝜃) 
𝜃∼𝐵𝑒𝑡𝑎(1,1) 
Then, 
𝑌𝑠𝑡𝑎𝑔𝑒1 = ∑𝑋𝑖
10
𝐼=1
 
𝑌𝑠𝑡𝑎𝑔𝑒2 = ∑𝑋𝑖
20
𝐼=1
 
𝑌𝑠𝑡𝑎𝑔𝑒3 = ∑𝑋𝑖
30
𝐼=1
 
The Bayesian posterior probability for futility at interim 1 (Stage 1) is calculated as 
𝑝𝑟(𝜃< 0.4|𝑌𝑠𝑡𝑎𝑔𝑒1) = Pr(𝑌𝑠𝑡𝑎𝑔𝑒1|𝜃< 0.4) ⋅Pr (𝜃< 0.4)
Pr (𝑌𝑠𝑡𝑎𝑔𝑒1)
 
The Bayesian posterior probability for futility at interim 2 (Stage 2) is calculated as  
𝑝𝑟(𝜃< 0.4|𝑌𝑠𝑡𝑎𝑔𝑒2) = Pr(𝑌𝑠𝑡𝑎𝑔𝑒2|𝜃< 0.4) ⋅Pr (𝜃< 0.4)
Pr (𝑌𝑠𝑡𝑎𝑔𝑒2)
 
 
The Bayesian posterior probability for study success at the end of study (Stage 3) is calculated as 
𝑝𝑟(𝜃> 0.57|𝑌𝑠𝑡𝑎𝑔𝑒3) = Pr(𝑌𝑠𝑡𝑎𝑔𝑒3|𝜃> 0.57) ⋅Pr (𝜃> 0.57)
Pr (𝑌𝑠𝑡𝑎𝑔𝑒3)
 
10.3.3.2. Secondary Analyses  
Secondary efficacy and health outcomes analyses (Table JAHW.12) will be based on all 
participants who take at least 1 age-based dose of investigational product for Part A.  Baseline is 
defined as Week 0. 
The secondary efficacy and health outcomes analysis for Part B will be addressed in the SAP. 
 
 
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Table JAHW.12. 
Secondary Efficacy Endpoint Analyses for Part A  
Measure  
Endpoint  
Analysis Method  
SUN grade of cells in the anterior chamber in the most 
severely affected eye 
Change from baseline 
Summary statistics 
SUN grade of cells in the anterior chamber in the less 
severely affected eye (if applicable) 
Change from baseline 
Summary statistics 
In patients with bilateral uveitis disease at baseline: 
Responders, defined according to the SUN criteria as a 
2-step decrease in the level of anterior chamber cells in 
the most severely affected eye at baseline (or both eyes 
if the inflammation grade is the same in both eyes) and 
a 1-step decrease in the level of anterior chamber cells 
in the less severely affected eye at baseline. 
Proportion of patients 
Summary statistics 
Visual acuity by age-appropriate LogMAR test in each 
eye 
Change from baseline 
Summary statistics 
Vitreous haze in each affected eye 
Change from baseline 
Summary statistics 
Grade of flare in the anterior chamber in each affected 
eye 
Change from baseline 
Summary statistics 
Overall uveitis-related disability: 
o Change in Patient Uveitis-related Disease 
Activity through Week 24. 
o Change in Patient Uveitis-related Improvement 
at Week 12 and Week 24. 
o Change in Patient Arthritis Disease Activity 
through Week 24. 
o Change in Patient Arthritis Improvement at 
Week 12 and Week 24. 
o Change in Ophthalmologist Uveitis-related 
Disease Activity through Week 24. 
o Change in Ophthalmologist Uveitis-related 
Improvement at Week 12 and Week 24. 
Change from baseline 
Shift table 
Proportion of patients with inactive anterior uveitis 
disease status in each affected eye 
Proportion of 
affected eyes 
Summary statistics 
Time to inactive 
disease status 
Summary statistics 
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Measure  
Endpoint  
Analysis Method  
Concomitant topical corticosteroid tapering status, for 
patients eligible for corticosteroid tapering 
Proportion of patients 
Summary statistics 
PediACR 30/50/70/90/100 
Proportion of 
responders 
Summary statistics 
Abbreviations:  PediACR = Pediatric American College of Rheumatology; SUN = Standardization of Uveitis 
Nomenclature. 
10.3.3.3. Exploratory Analyses  
Not Applicable. 
10.3.4. Safety Analyses  
Safety variables will be summarized, which include the following, but are not limited to: 
 Exposure to investigational product 
 AEs 
 SAEs 
 Permanent discontinuation of investigational product 
 Temporary interruption of investigational product 
 AEs leading to discontinuation 
 AEs of special interest 
 Laboratory analytes 
 Vital signs 
Summaries of safety data will be presented for baricitinib and adalimumab.  Further details will 
be described in the SAP. 
10.3.4.1. Adverse Events  
Adverse events are classified based on the Medical Dictionary for Regulatory Activities 
(MedDRA).  Treatment-emergent adverse events (TEAEs) are defined as AEs that first occurred 
or worsened in severity on or after the date of the first dose of investigational product.  The 
number of TEAEs as well as the number and percentage of patients who experienced at least 
1 TEAE will be summarized using MedDRA for each system organ class (or a body system) and 
each preferred term by treatment group.  For events that are gender-specific, the denominator and 
computation of the percentage will only include patients from the given gender. 
Serious adverse events (including deaths), treatment-emergent AEs of special interest, and AEs 
that lead to investigational product discontinuation will also be summarized using MedDRA for 
each system organ class and each preferred term by treatment group.  Potential AEs of special 
interest will be identified by a standardized MedDRA query or a Lilly-defined MedDRA listing.  
Details of the AEs of special interest (including but not limited to those listed in Section 9.2.2) 
and analysis will be documented in the SAP or program SAP.  Adverse events of special interest 
will also be presented by severity.  Adverse events of special interest will include the following: 
 
Infections (including TB, herpes zoster, or opportunistic infections) 
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 
Malignancies 
 
Hepatic events (Section 9.4.5) 
 
MACE as adjudicated by the external Clinical Event Committee (Section 10.3.7.1) 
 
Thrombotic events (such as ATE, deep vein thrombosis and pulmonary embolism) 
Investigators will provide details on these AEs as instructed on the eCRF and may be asked for 
additional description by Lilly. 
10.3.4.2. Clinical Laboratory Tests  
All clinical laboratory results will be descriptively summarized.  Individual results that are 
outside the normal reference ranges will be flagged in data listings.  Quantitative clinical 
hematology, chemistry, and urinalysis variables obtained at the baseline to postbaseline visits 
will be summarized as changes from baseline.  Categorical variables, including the incidence of 
abnormal values and incidence of AEs of special interest, will be summarized by frequency and 
percentage of patients in corresponding categories.  Shift tables will be presented for selected 
measures. 
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.  Other data, including body weight and height data will be summarized.  Weight, height, 
and BMI data will be merged to the Centers for Disease Control standard growth data by age and 
gender to compare subjects’ growth with the standard.  Other measures related to growth 
velocity (e.g., occipital circumference measurement) will be evaluated.  Further analyses may be 
performed. 
10.3.5. Evaluation of Immunological Measures  
Change from baseline in immunoglobulin levels and peripheral blood immunophenotyping 
(including T and B cells, T cell subsets, and NK cells) will be evaluated and summarized using 
descriptive statistics.  Patients who are immunized with TDaP or pneumococcal conjugate vaccines 
will have their IgG antibody titers to the antigens evaluated preimmunization and at 4 and 
12 weeks postimmunization.  A primary immune response will be assessed in patients who have 
never received TDaP or pneumococcal conjugate vaccines previously and secondary/booster 
responses will be assessed if the patients have previously received the vaccines.  More detailed 
analytical methods will be described in the SAP. 
10.3.6. Other Analyses  
10.3.6.1. Subgroup Analyses  
In Part A, efficacy and safety assessments will be summarized and analyzed at Week 24, by 3 
age groups:   
 12 to 17 years old  
 6 to 11 years old, and  
 2 to 5 years old.   
The details will be described in the SAP. 
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Age group efficacy summaries may include:  
 Number and proportion of responders at Week 24 by each age group.   
Response is defined according to the SUN criteria as a 2-step decrease in the level of 
inflammation (anterior chamber cells) or decrease to zero in the eye most severely 
affected at baseline.  
 Change in  
o SUN grade of cells in the anterior chamber 
o visual acuity measured by LogMAR test 
o vitreous haze, and  
o grade of flare  
at Week 24 by each age group, in each affected eye. 
 Number and proportion of patients with inactive anterior uveitis at Week 24 by each age 
group, in each affected eye. 
Age group safety summaries may include 
 AEs, including SAEs 
 permanent discontinuation of investigational product due to AEs, and 
 temporary interruption of investigational product. 
10.3.7. Interim Analyses  
Two interim analyses will be performed to potentially stop the study early due to futility when 10 
and 20 baricitinib-treated patients have completed, or had the opportunity to complete, 24 weeks 
of treatment.  At each interim analysis, the posterior probability of the treatment response rate 
being lower than 40% will be calculated, and the study will be stopped if this probability is 
greater than 75%. 
The above Bayesian decision rules can be translated to correspond to the following: 
 At the first interim analysis, the study will be stopped if 2 or fewer of the 10 
baricitinib-treated patients are responders. 
 If the study continues, at the second interim analysis, the study will be stopped if 6 or 
fewer of the 20 baricitinib-treated patients are responders. 
A DMC will oversee the conduct of all the Phase 3 clinical studies evaluating baricitinib in 
patients with JIA, JIA-U, or ANA-positive uveitis.  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.  Membership to the DMC will 
include, at a minimum, specialists with expertise in pediatrics, rheumatology, statistics, and other 
appropriate specialties.  The DMC will review and evaluate planned interim analyses on an 
approximate semiannual basis.  This DMC will be coordinated with the DMC(s) for other 
ongoing studies of baricitinib in other indications, and this coordination may alter the number 
and timing of the interim analyses. 
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Study sites will receive information about interim results ONLY if they need to know for the 
safety of their patients. 
Data that the DMC will review include, but are 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 patients 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 to fulfill the need for 
regulatory interactions or publication purposes.  
10.3.7.1. Adjudication Committee  
A blinded Clinical Event Committee will adjudicate potential MACE (cardiovascular death, MI, 
stroke), other cardiovascular events (such as hospitalization for unstable angina, hospitalization 
for heart failure, serious arrhythmia, resuscitated sudden death, cardiogenic shock, coronary 
revascularization such as coronary artery bypass graft or percutaneous coronary intervention), 
ATE, VTEs, and noncardiovascular deaths.  Details of membership, operations, 
recommendations from the Committee, and the communication plan will be documented in the 
charter. 
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S, Straume B, Rygg M. Validity and predictive ability of the juvenile arthritis disease activity 
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12. Appendices  
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Appendix 1. 
Abbreviations and Definitions  
Term 
Definition 
ACPA 
anti-citrullinated protein antibodies 
ACR30 
30% improvement in American College of Rheumatology criteria 
active joint 
Joint with swelling or, in the absence of swelling, limitation of motion accompanied 
by pain on motion and/or tenderness 
AE 
Adverse event:  Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not necessarily 
have a causal relationship with this treatment.  An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) 
product. 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANA 
anterior antinuclear antibody 
ANC 
absolute neutrophil count 
APC 
activated protein C 
APTT 
activated partial thromboplastin time 
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 
ATE 
arterial thromboembolic events 
bDMARD 
biologic disease-modifying antirheumatic drug 
blinding/masking 
A single-blind study is one in which investigators and/or staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but investigators and/or staff and the patient are not. 
A double-blind study is one in which neither the patient 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 
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Term 
Definition 
CAP 
College of American Pathologists 
csDMARD 
conventional synthetic disease-modifying antirheumatic drug 
CEC 
clinical endpoints committee 
CHAQ 
Childhood Health Assessment Questionnaire 
CHQ-PF50 
Child Health Questionnaire-Parent Form 50 
CIOMS 
Council for International Organizations of Medical Sciences 
CLIA 
Clinical Laboratory Improvement Amendments 
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. 
CRF 
case report form 
CRP 
C-reactive protein 
CSR 
clinical study report 
DMARD 
disease-modifying antirheumatic drug 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DVT 
deep vein thrombosis 
ECG 
electrocardiogram 
eCOA 
electronic clinical outcome assessment 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
enroll 
The act of assigning a patient to a treatment.  Patients who are enrolled in the study 
are those who have been assigned to a treatment. 
enter 
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives. 
ERA 
enthesitis-related juvenile idiopathic arthritis 
ERB 
ethical review board 
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Term 
Definition 
ESR 
erythrocyte sedimentation rate 
ETV 
early termination visit 
EULAR 
European League Against Rheumatism 
GCP 
good clinical practice 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B virus surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HLA-B27 
human leukocyte antigen-B27 
HRQOL 
health-related quality of life 
hsCRP 
high-sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IFN 
interferon 
Ig 
immunoglobulin 
IGF-1 
insulin-like growth factor-1 
IL 
interleukin 
ILAR 
International League of Associations for Rheumatology 
Informed consent 
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the patient’s decision to participate.  Informed consent is documented by 
means of a written, signed and dated informed consent form. 
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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Term 
Definition 
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. 
IOP 
intraocular pressure 
IR 
inadequate response or intolerance 
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 patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to 
the planned course of treatment. 
IWRS 
interactive web-response system 
JADAS 
Juvenile Arthritis Disease Activity Score 
JAK 
Janus kinase 
JIA 
juvenile idiopathic arthritis 
JIA-U 
juvenile idiopathic arthritis-associated uveitis 
JPsA 
juvenile psoriatic arthritis 
JSpADA 
Juvenile Spondyloarthritis Disease Activity Index 
LOCF 
last observation carried forward 
LOCS 
Lens Opacities Classification Score 
LogMAR 
logarithm of the minimum angle of resolution 
MACE 
major adverse cardiovascular events 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
mITT 
modified intent-to-treat:  patients who take at least 1 age-based dose of 
investigational product in Part A of Study JAHU 
MMR 
measles, mumps, and rubella 
mNRI 
modified nonresponder imputation 
MTX 
methotrexate 
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Term 
Definition 
NK 
natural killer 
NSAID 
nonsteroidal anti-inflammatory drug 
OAT3 
organic anion transporter 3 
OCT 
optical coherence tomography 
OLE 
open-label extension 
PASI 
Psoriasis Area and Severity Index 
PBPK 
physiologically based pharmacokinetic 
PD 
pharmacodynamic(s) 
PE 
pulmonary embolism 
PediACR 
Pediatric American College of Rheumatology 
PhS 
Physical Summary Score 
PIP 
Pediatric Investigation Plan 
PK 
pharmacokinetic(s) 
PPD 
purified protein derivative 
PsS 
Psychosocial Summary Score 
Q2W 
once every 2 weeks 
QD 
once daily 
QW 
once every week 
RA 
rheumatoid arthritis 
RF 
rheumatoid factor 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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 
SPARCC 
Spondyloarthritis Research Consortium of Canada 
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Term 
Definition 
STAT 
signal transducer and activator of transcription 
SUN 
standardization of uveitis nomenclature 
SUSAR 
suspected unexpected serious adverse reaction 
TB 
tuberculosis 
TBL 
total bilirubin level 
TDaP 
tetanus, diphtheria, and pertussis 
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. 
TIBC 
total iron-binding capacity 
TNF 
tumor necrosis factor-alpha 
TSH 
thyroid-stimulating hormone 
TYK2 
tyrosine kinase 2 
ULN 
upper limit of normal 
VAS 
visual analogue scale 
VEGF 
vascular endothelial growth factor 
VTE 
venous thromboembolic events 
VZV 
varicella zoster virus 
WBC 
white blood cell 
 
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Appendix 2. 
Clinical Laboratory Tests 
Hematologya 
Clinical Chemistrya,b 
Hemoglobin 
Serum Concentrations of: 
Hematocrit 
Sodium 
Erythrocyte count (RBC) 
Potassium 
Absolute reticulocyte count 
Total bilirubin 
Mean cell volume 
Direct bilirubin 
Mean cell hemoglobin 
Alkaline phosphatase (ALP) 
Mean cell hemoglobin concentration 
Alanine aminotransferase (ALT) 
Leukocytes (WBC) 
Aspartate aminotransferase (AST) 
Platelets 
Blood urea nitrogen (BUN) 
Mean platelet volume 
Creatinine 
Absolute counts of: 
Uric acid 
Neutrophils, segmented 
Calcium 
Neutrophils, juvenile (bands) 
Glucose 
Lymphocytes 
Albumin 
Monocytes 
Total protein 
Eosinophils 
Estimated glomerular filtration rate (eGFR)c 
Basophils 
Creatine phosphokinase (CPK) 
 
 
Urinalysisa,d 
Other Testsa 
Color 
Hepatitis B Surface antigen (HBsAg)e 
Specific gravity 
Hepatitis B Core antibody (HBcAb)e
pH 
Hepatitis B Surface antibody (HBsAb)e 
Protein 
Hepatitis C antibodye,f  
Glucose 
HBV DNA
g 
Ketones 
Human immunodeficiency virus (HIV)e 
Bilirubin 
HLA-B27 
Urobilinogen 
Thyroid-stimulating hormone (TSH) 
Blood 
Exploratory storage samples (RNA, serum, and plasma) 
Leukocyte esterase 
Pharmacogenetic Sample (DNA) 
Nitrite 
Pregnancy Test (serum)h 
 
Pregnancy Test (urine)h 
Lipidsa,b 
High sensitivity C-reactive protein (hsCRP)  
Total cholesterol 
Rheumatoid factor 
Low-density lipoprotein 
QuantiFERON®-TB Gold or T-SPOT®.TBi 
High-density lipoprotein 
Purified protein derivative (PPD)j 
Triglycerides 
ACPA (Anti-CCP) 
 
ESR (sponsor-provided; assayed by clinical study site) 
 
Iron studies (iron, TIBC and ferritin) 
 
Immunoglobulins (IgG, IgA, and IgM) 
 
Lymphocyte subsets (T, B, NK, and T-cell subsets)j 
 
Antinuclear antibodies 
 
IGF-1 
 
IGFBP-3 
 
Gonadal hormone (estradiol for females aged 8 to <18 years, 
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testosterone for males aged 8 to <18 years) 
Abbreviations:  DNA = deoxyribonucleic acid; ESR = erythrocyte sedimentation rate; HCV = hepatitis C virus; 
HBV = hepatitis B virus; HLA-B27 = human leukocyte antigen-B27; Ig = immunoglobulin; IGF-1 = insulin-like 
growth factor-1; IGFBP-3 = insulin-like growth factor-binding protein-3; RBC = red blood cell; 
RNA = ribonucleic acid; TB = tuberculosis; TIBC = total iron-binding capacity; WBC = white blood cell. 
a Unscheduled or repeat blood chemistry, hematology, and urinalysis panels may be performed at the discretion of 
the investigator, as needed. 
b Fasting laboratory values for lipids will be required as per Schedule of Activities (Section 2).  Patients should not 
eat or drink anything except water for 4-12 hours depending on weight and age as specified below. If a patient 
attends these visits in a nonfasting state, this will not be considered a protocol violation.  Recommended fasting 
times by age and weight are as follows: 
 
Patients ≥12 years: fast for 12 hours prior to laboratory test 
 
Patients 8 to <12 years and weighing >50 kg: fast for 12 hours prior to laboratory test 
 
Patients 8 to <12 years and weighing ≤50 kg: fast for 8 hours prior to laboratory test 
 
Children <8 years and weighing 25 to ≤50 kg: fast for 8 hours prior to laboratory test 
 
Children <8 years and weighing 10 to <25 kg: fast for 6 hours prior to laboratory test 
 
Children <8 years and weighing <10 kg: fast for 4 hours prior to laboratory test 
c eGFR calculated by Bedside Schwartz 2009 formula. 
d Microscopic examination of sediment performed only if abnormalities are noted on the routine urinalysis. 
e Test required at Visit 1 only to determine eligibility of patient for the study. 
f A positive hepatitis C antibody result will be confirmed with presence of HCV RNA. 
g HBV DNA testing will be done in those patients who are HBcAb+ at screening.  For patients who are positive 
for HBcAb, a follow-up test for HBV DNA is required.  Patients with a positive HBcAb will return to the site 
and have HBV DNA samples drawn, which will be processed centrally.  Any enrolled patient who is HBcAb 
positive, regardless of HBsAb status or level, must undergo HBV DNA testing per the schedule. 
h Serum pregnancy test for all females of appropriate age who are of child-bearing potential at screening only and 
will be performed centrally; after screening, urine pregnancy test will be performed locally for females of child-
bearing potential. 
i 
In countries where the QuantiFERON®-TB Gold test or T-SPOT® is available, either test may be used instead of 
the PPD TB test.  The QuantiFERON®-TB Gold test may be performed locally or centrally; the T-SPOT® must 
be performed locally. 
j 
Test results of lymphocyte subsets will be blinded after Week 12, and the test results will not be sent to the study 
sites. 
 
Note:  Due to blood volume restrictions, some laboratory tests may not be collected.  Laboratory samples are 
recommended to be collected as described in a sponsor-provided weight-based prioritization chart. 
  
 
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Appendix 3. 
Study Governance Considerations  
Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Appendix 3.1.1. 
Informed Consent 
The investigator is responsible for the following: 
 Ensuring that the patient/patient’s legal representative understands the nature of the 
study, the potential risks and benefits of participating in the study, and that their 
participation is voluntary. 
 Ensuring that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the informed consent form 
(ICF) and Assent Form per local requirements prior to the performance of any protocol 
procedures and prior to the administration of investigational product. 
 Answering any questions the patient/patient’s legal representative may have throughout 
the study and sharing in a timely manner any new information that may be relevant to the 
willingness of the patient/patient’s legal representative to continue his or her participation 
in the study. 
 Ensuring that a copy of the ICF and Assent Form is provided to the participant or the 
participant’s legal representative and is kept on file. 
 Ensuring that the medical record includes a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent 
was obtained.  The authorized person obtaining the informed consent must also sign the 
ICF and Assent Form (as applicable). 
 Adequate informed consent for continued participation from pediatric participants once a 
child reaches the age of legal consent. 
 Reporting to the sponsor or designee significant issues related to participant 
safety, participant rights, or data integrity. 
A legal representative must give informed consent for a child to participate in this study.  In 
addition to informed consent given by the legal representative, the child may be required to give 
documented assent, if capable. 
Appendix 3.1.2. 
Recruitment 
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes. 
Appendix 3.1.3. 
Ethical Review 
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Council for Harmonisation (ICH) 
guidelines and other applicable laws and regulations. 
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Documentation of ERB approval of the protocol and the ICF and Assent Form must be provided 
to Lilly before the study may begin at the investigative site(s).  Lilly or its representatives must 
approve the ICF and Assent Form, including any changes made by the ERBs, before it is used at 
the investigative site(s).  All ICFs and Assent Forms must be compliant with the ICH guideline 
on Good Clinical Practice (GCP). 
The study site’s ERB(s) should be provided with the following: 
 protocol and related amendments and addenda, current Investigator’s 
Brochure (IB) and updates during the course of the study 
 Informed Consent Form and Assent Form 
 other relevant documents (e.g., curricula vitae, advertisements) 
Appendix 3.1.4. 
Regulatory Considerations 
This study will be conducted in accordance with the protocol and with the 
 consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines 
 applicable ICH GCP guidelines, and 
 applicable laws and regulations. 
Some of the obligations of the sponsor will be assigned to a third party. 
Appendix 3.1.5. 
Investigator Information 
Physicians with a specialty in pediatric rheumatology and ophthalmology (pediatric 
rheumatologist or other medically qualified physician) will participate as investigators in this 
clinical study. 
Appendix 3.1.6. 
Protocol Signatures 
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study. 
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative. 
Appendix 3.1.7. 
Final Report Signature 
The clinical study report (CSR) coordinating investigator will sign the final CSR for this study, 
indicating agreement that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study. 
Lilly will select a qualified investigator(s) from among investigators participating in the design, 
conduct, and/or analysis of the study to serve as the CSR coordinating investigator.  If this 
investigator is unable to fulfill this function, another investigator will be chosen by Lilly to serve 
as the CSR coordinating investigator. 
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The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of their knowledge, the report accurately describes the conduct 
and results of the study. 
Appendix 3.2. 
Data Quality Assurance 
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following: 
 Provide instructional material to the study sites, as appropriate 
 Provide sponsor start-up training to instruct the investigators and study 
coordinators.  This training will give instruction on the protocol, the completion 
of the CRFs, and study procedures. 
 Make periodic visits to the study site 
 Be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax, and 
 Review and verify data reported to detect potential errors. 
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs. 
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents. 
Appendix 3.2.1. 
Data Protection and Data Capture System 
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. 
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The sponsor has processes in place to ensure information security, data integrity, and data 
protection. These processes address management of data transfer, and 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). 
Data capture system 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
An electronic data capture 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 (questionnaires, scales) will be collected 
by the patient/caregiver/investigator site personnel, via a paper source document and will be 
transcribed by the investigator site personnel into the EDC system. 
Additionally, electronic Clinical Outcome Assessment (eCOA) data (questionnaires, scales) will 
be directly recorded by the patient/caregiver/investigator site personnel into an instrument.  The 
eCOA data will serve as the source documentation and the investigator does not maintain a 
separate written or electronic record of these data. 
Data collected via the sponsor-provided data capture system(s) will be stored at a third-party (at 
third parties).  The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture system(s).  Prior to decommissioning, the investigator will 
receive an archival copy of pertinent data for retention. 
Data managed by a central vendor (e.g., 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 Lilly data warehouse. 
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system. 
Appendix 3.3. 
Study and Site Closure 
Appendix 3.3.1. 
Discontinuation of Study Sites 
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Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP. 
Appendix 3.3.2. 
Discontinuation of the Study 
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP. 
Appendix 3.4. 
Publication Policy and Dissemination of Clinical Study Data 
Publication policy 
The publication policy for Study I4V-MC-JAHW is described in the Clinical Study Agreement. 
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 dataset 
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. 
 
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Appendix 4. 
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality  
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with Lilly, its designee, or the clinical 
research physician. 
Hepatic Monitoring Tests 
Hepatic Hematologya 
Haptoglobina 
Hemoglobin 
 
Hematocrit 
Hepatic Coagulationa 
RBC 
Prothrombin time 
WBC 
Prothrombin time, INR 
Neutrophils, segmented 
 
Lymphocytes 
Hepatic Serologiesa,b 
Monocytes 
Hepatitis A antibody, total 
Eosinophils 
Hepatitis A antibody, IgM 
Basophils 
Hepatitis B surface antigen 
Platelets 
Hepatitis B surface antibody 
 
Hepatitis B Core antibody 
Hepatic Chemistrya 
Hepatitis C antibody 
Total bilirubin 
Hepatitis E antibody, IgG 
Direct bilirubin 
Hepatitis E antibody, IgM 
Alkaline phosphatase 
 
ALT 
Anti-nuclear antibodya 
AST 
 
GGT 
CPK 
Anti-smooth muscle antibody 
 
 
Alkaline phosphatase isoenzymesa 
 
 
Anti-Actina 
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma-glutamyl transferase; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international 
normalized ratio; RBC = red blood cells; WBC = white blood cells. 
a Assayed by Lilly-designated or local laboratory. 
b Reflex/confirmation dependent on regulatory requirements and/or testing availability. 
 
 
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Liver Function Testing and Hepatic Safety Monitoring 
Analyte 
Exclusion 
Criteria 
Additional 
Hepatic 
Testing 
Hepatic eCRF 
Reporting 
Temporary 
Interruption of 
Investigational 
Product 
Permanent Discontinuation 
of Investigational Product 
after Consultation with the 
Lilly Designated Medical 
Monitor 
Protocol 
Section 
Section 6.2 
Section 9.4.5 
Section 9.4.5 
Section 8.1.1 
Section 8.1.2 
ALT/AST 
≥2 x ULN 
ALT ≥3 x 
ULN 
ALT ≥5 x ULN 
on ≥2 
consecutive 
tests 
>5 x ULN 
 
>8 x ULN 
 
>5 x ULN for >2 
weeks after 
temporary 
interruption of 
investigational 
product 
 
>3 x ULN and TBL 
>2 x ULN or INR 
>1.5 
 
>3 x ULN with 
symptomsa 
ALP 
≥2 x ULN 
≥2 x ULN 
≥2 x ULN on 
≥2 consecutive 
tests 
N/A 
 
>3 x ULN 
 
>2.5 x ULN and 
TBL >2 x ULN  
 
>2.5 x ULN with 
symptomsa 
TBL 
≥1.5 x ULN 
≥2 x ULN 
≥2 x ULN on 
≥2 consecutive 
tests (excluding 
Gilbert’s 
syndrome) 
N/A 
 
ALT or AST >3 x 
ULN and TBL >2 x 
ULN 
 
ALP >2.5 x ULN 
and TBL >2 x ULN 
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
eCRF = electronic case report form; INR = international normalized ratio; TBL = total bilirubin level; 
ULN = upper limit of normal. 
a Fatigue, nausea, vomiting, right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
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Appendix 5. 
Monitoring Tests for Confirmed VTE  
Selected tests may be obtained in the event of a confirmed venous thromboembolic event (VTE) 
and may be required in follow-up with patients in consultation with Eli Lilly and Company, its 
designee, or the clinical research physician.  The choice and optimal timing of these tests will be 
directed by the patient’s management and may require ongoing follow-up after study 
discontinuation. 
Protein C Functional 
Protein S Clottable 
Antithrombin III 
APC Resistance 
PT 
APTT 
Fibrinogen 
Cardiolipin Antibodies 
PT Gene 
Factor VIII C Assay 
Hexagonal Phase Phospholipid Neutralization 
C-Reactive Protein 
PTT Incubated Mixing  
Dilute Russell Viper Venom  
Platelet Neutralization  
Factor V Leiden  
MTHFR  
Thrombin Time  
Reptilase  
Fibrinogen Antigen  
Protein C Immunologic  
Protein S Immunologic  
Heparin fXa Inhibition  
Abbreviations:  APC = activated protein C; APTT = activated partial thromboplastin time; MTHFR = methylene 
tetrahydrofolate reductase; PT = prothrombin time; PTT = partial thromboplastin time. 
 
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Appendix 6. LOCS II Standards for Grading Cataracts  
 
 
From Chylack et al. 1989. 
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Appendix 7. 
Weight-Based Prioritization Chart for Blood 
Sampling  
Patients with a body weight lower than 25 kg will have a lower volume of blood taken, as certain 
tests will be excluded.  The weight based prioritization chart shown below is recommended to be 
followed for Study JAHW.  Lilly also recommends that purified protein derivative is used for 
tuberculosis testing instead of Quantiferon Gold or T-Spot in patients whose body weight is <18 
kg. 
Weight-Based Prioritization Chart for Blood Sampling 
Weight 
Excluded Testing – will not be collected 
≥25 kg 
N/A 
≥18 to <25 kg 
 Long-term storage samples at V2, V5, V8, and V30:  RNA, serum, and plasma 
<18 kg 
 Long-term storage samples:  RNA, serum, and plasma 
 Testosterone or estradiol 
 Flow cytometry 
Abbreviations:  N/A = not applicable; RNA = ribonucleic acid; V = visit. 
 
 
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Appendix 8. 
Data-based Dosing Cohorts  
The dose selection for baricitinib in this patient population is informed by the Phases 2 and 3 
data in adults with RA, which demonstrated a positive benefit/risk profile for the 4-mg QD dose.  
The PK of baricitinib in pediatric patients with JIA will be investigated in Study I4V-MC-JAHV 
(JAHV), and the doses selected in this study will also be used in Study JAHW. 
Current JAHV data on age-based cohorts 
Ages 12 to<18 
The PK data from the 8 pediatric patients aged 12 to <18 years support continued dosing with the 
4-mg QD dose of baricitinib in patients with JIA or JIA-uveitis.  These data confirmed the 
recommended baricitinib dose of 4 mg QD for pediatric patients with JIA or JIA-uveitis aged 
12 to <18 years.   
Ages 6 to <12 
The PK and safety data from the 8 pediatric patients aged 9 to <12 years support continued 
dosing with the 4-mg QD dose of baricitinib in patients with JIA, JIA-uveitis, or ANA positive 
uveitis in this age group.  The observed concentrations of baricitinib in the middle age group 
(9 to <12 years old) were consistent with:  
 the anticipated efficacious exposure level in adult patients with RA receiving baricitinib 
4 mg QD, 
 model-predicted mean concentrations in pediatric patients aged 9 to <12 years with JIA 
receiving baricitinib 4 mg QD.  
The population of patients recruited at global investigative sites did not include any patients 6 to 
<9 years of age.  The PBPK prediction suggested that a dose of 2 mg QD is likely to produce 
exposure in this age group more aligned with the mean adult exposure. 
Next Steps for Study JAHW 
An updated summary of dosing for Study JAHW is provided in the table below.  
Lilly has initiated the following for Study JAHV to confirm dosing:  
 Lilly has enrolled the cohort aged 6 to <9 years in the PK cohort in JAHV to receive a 
dose of 2 mg baricitinib in order to conduct a safety/PK analysis and to confirm the dose 
for this age group.  
 Once the PK analysis is completed in the patients aged 6 to <9 years in JAHV, the PBPK 
model will be updated accordingly for the patients aged 2 to <6 years (the youngest age 
cohort) to verify the appropriate starting dose for the safety/PK evaluation.  These 
patients will proceed into the Open-Label Lead-In period after the safety/PK assessment. 
  
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Updated Study JAHW Dosing Summary 
Age Group 
Baricitinib Dose 
12 to <18 years old  
4 mg   
9 to <12 years old  
4 mg  
6 to <9 years old  
2 mg (based on predicted data – to be confirmed with 
observed data)  
2 to <6 years old  
2 mga 
Abbreviations:  OLLI = open-label lead-in; PK = pharmacokinetic; QD = once daily. 
a 
To be confirmed after evaluating data from patients aged 6 to <9 years.  
 
 
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Appendix 9. 
Provisions for Changes in Study Conduct 
During Exceptional Circumstances  
There may be times of exceptional circumstances, such as pandemics or natural disasters, which 
may cause disruptions to the conduct of the study.  Possible disruptions are limitations in the 
ability to conduct study procedures or ability to have on-site visits occur by participants. 
To mitigate the risk of participants missing visits, to allow participants to safely continue in the 
study, and to maintain the data integrity of the study in the case of an exceptional circumstance, 
sites may implement changes to the conduct of the study on a case-by-case basis following 
sponsor’s written approval (if permitted by local regulations).  Good Clinical Practice 
compliance and minimization of risks to study integrity are important considerations.  Ensuring 
the safety of study participants is the prevailing consideration. 
Additional written guidance will be provided by the sponsor in the event written approval is 
granted for changes in study conduct.  
The following changes in study conduct captured in this appendix will not be considered 
protocol deviations.  Missing data will be captured as protocol deviation(s). 
1. Remote visit (telephone/telemedicine) 
Telephone or technology-assisted virtual visits (telemedicine) to complete appropriate 
assessments are acceptable if in-person site visits are not possible.  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 in source document and eCRF.  The site must discuss with the patient and 
ensure consent to the proposed remote operational plan.  This communication should be 
documented in the patient’s records.  
Examples of assessments that may be completed via telephone/telemedicine visit include the 
following: 
 AEs and product complaints  
 concomitant medications  
 review of study participant diary (including study drug compliance)  
2. Remote Assessment and Data Collection 
Patient visit and data collection can be done remotely for treatment period A and treatment 
period B.  The PI/Sub-I is to document all teleconferences/remote visits in the patient’s 
records.  Site facing assessments can be completed on paper (preferably eCOA if the site is able) 
and patient facing assessments will be conducted in interview format with the qualified 
personnel documenting the patient’s responses on paper.  Sponsor will provide guidance for 
performing these assessments (CHQ-PF50, EQ-5D).  For ophthalmology assessments, PI should 
direct patient care based on symptom-directed physical examination.  Ophthalmology 
assessments are required to be completed every 8 weeks. 
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3. Investigational product and ancillary supplies 
In cases when a patient is unable to come to site to receive trial supplies during a normal on-site 
visit, the site should work with the sponsor to determine appropriate actions to receive trial 
supplies.  This may include a participant coming to the site to receive trial supplies only from site 
staff without full completion of a visit, a participant-approved designee coming to the site to 
receive trial supplies on a participant’s behalf, or delivery to a participant’s home.  
The following requirements must be met: 
 sponsor approves the alternative method of delivery, taking local regulatory 
requirements into consideration 
 participant consents to alternate method of delivery as defined by local regulations   
 site confirms the participant’s receipt of the trial supplies 
 site/sponsor confirms appropriate ethics review board notification 
 alternate delivery of IP should be performed in a manner that does not compromise 
treatment blinding and ensures product integrity.  The existing protocol requirements 
for product accountability remain unchanged.  
 when delivering supplies to a patient’s home: 
o participant consent must include provision of any personal information 
o site should ensure oversight of the shipping process to ensure accountability 
and product quality (i.e., storage conditions and intact packaging upon receipt) 
 additional instructions should be provided to the participant on how to return any 
unused or completed trial supplies. 
4. Local laboratory option 
In exceptional circumstances, to ensure patient safety and with the sponsor's prior written 
approval, local laboratory testing may be conducted in lieu of central laboratory testing.  The 
local laboratory must be qualified in accordance with local regulations.  Clinically significant 
laboratory findings must be recorded as an adverse event in the AE eCRF.  
For patients unable to access investigator sites, laboratory testing will be obtained and collected 
at least every 8 weeks in treatment period A and every 12 weeks in treatment period B.  The first 
collection should be 8 weeks or 12 weeks, respectively, from the patient’s last collected central 
laboratory samples.  
When collecting local labs, sites should store records from the labs including results, address, 
certification (College of American Pathologists/Clinical Laboratory Improvement Amendments, 
[CAP/CLIA]) status, and reference ranges.  The PI/Sub-I should sign and date review of local 
labs per normal process and follow-up with the patient as needed.  Local labs may be sent to the 
patient as this is standard process in clinical care.  
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The laboratory measures listed below are the minimum required in order to monitor patient 
safety and determine temporary or permanent discontinuation of IP.  Additionally, investigators 
should include any symptom-based laboratory testing based on their interactions with their 
patients.  As stated in the protocol, investigators are responsible for monitoring the overall health 
of their patients. 
The investigators should request the following laboratory analyses: 
 
WBC 
 
ANC 
 
Lymphocyte count 
 
Platelet count 
 
Hemoglobin 
 
ALT, AST, total bilirubin, INR 
 
ESR 
 
Urine pregnancy  
These laboratory results will allow the investigators to follow both the temporary and permanent 
discontinuation criteria as provided in the protocol (Section 8.1.1, Temporary Interruption of 
Investigational Product and Section 8.1.2, Permanent Discontinuation from Investigational 
Product). 
5. Documentation  
a. Changes to study conduct 
Changes to study conduct will be documented as the following: 
 Sites will need to identify and document the details of how all participants, visits, 
methods, and activities conducted were affected by exceptional circumstances.  All 
dispensing/shipment records of IP and relevant communications, including delegation, 
should be filed with site trial records. 
 The site should document the participant’s consent for having remote visits and 
remote dispensing of IP, ancillaries, and diaries, prior to implementation of these 
activities.  
 Source document(s) that are generated at participant’s home should be part of the 
investigator’s source documentation and should be transferred to the site in a secure 
and timely manner.  
b. Missing data and other protocol deviations  
The study site should capture specific explanations for any missing data and other protocol 
deviations in source documents and eCRF.  While protocol deviations may be unavoidable in an 
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exceptional circumstance, documentation of deviations and missing data will be important for 
data analysis and reporting. 
Details of changes in analyses to specifically accommodate exceptional circumstances will be 
further described in the study SAP. 
6. Informing ethical review boards (ERBs) 
The sponsor and study investigators will notify ERBs as soon as possible to communicate 
implementation of changes in study conduct due to exceptional circumstances.  To protect the 
safety of study participants, urgent changes may be implemented before such communications 
are made, but all changes will be reported as soon as possible following implementation. 
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Appendix 10. Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [d]: 07-Nov-2020 
Overall Rationale for the Amendment 
The overall changes and rationale for the changes made to this protocol are described in the 
following table.  Editorial revisions with no impact on protocol design or implementation were 
also made.  These revisions are not noted in this protocol amendment summary except where 
contained in a section with substantive changes. 
Amendment Summary for Protocol I4V-MC-JAHW Amendment (d) 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1. Synopsis 
Section 4. Objectives and 
Endpoints 
Addition of footnote for endpoints 
in Secondary Part A 
Clarification of response definition for 
Secondary Endpoints related to bilateral 
uveitis disease SUN criteria. 
Section 2. Schedule of Activities 
Appendix 9. Provisions for 
Changes in Study Conduct During 
Exceptional Circumstances 
Addition of provisional language 
for participation in the study during 
exceptional circumstances such as 
the COVID-19 pandemic 
 
 
 
This language and appendix describe the 
types of changes to study conduct that 
will be possible during exceptional 
circumstances.  These changes to study 
conduct will only be implemented with 
approval from the sponsor and if 
permitted by local regulations. 
Section 2. Schedule of Activities 
Section 9.4.6.3. Tanner Stage 
Scale 
Section 11. References 
Addition of baseline Tanner 
Staging Scale 
Baseline assessment of sexual maturity 
(Tanner Staging) was included based on 
feedback from regulatory agencies. 
Section 2. Schedule of Activities 
 
Addition of x-ray procedure 
Imaging procedures were included or 
increased in frequency based on 
feedback from regulatory agencies for 
additional monitoring of bone growth 
and assessment of symptomatic areas of 
bones/joints.  
 
Height measurements were added 
for all study visits 
The additional measurements for height 
were added for additional growth 
monitoring. 
 
 
Height schedule changed 
to Initial Protocol design 
 
Added Weight in V1 
Screening  
 
Adjusted footnote f in 
Table JAWH.1. to include 
imaging requirements and 
specify ± timing for 
 
Error in previous amendment. 
 
 
For Clarity.  
*Only applicable if Amendment (c) is in 
effect. These changes are not present in 
Amendment (b). 
 
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consent/assents  
 
Removed positioning 
wording “AP” for hand 
and knee X-rays in both 
column cell and footnote f  
 
Adjusted footnote d in 
Table JAWH.2. to include 
imaging requirements and 
specify ± timing for 
consent/assents 
 
5.1. Overall Design, 
Figure JAHW.1 
Updated study figure in Treatment 
Period Part B (OLE) with change 
from 96 to 74 weeks for 
adalimumab  
Study figure was updated to clarify 
number of weeks on adalimumab during 
Treatment Period Part B (OLE).  
5.5. Justification of Dose 
Updated Cohorts 
For Clarity.  
*Only applicable if Amendment (c) is in 
effect. These changes are not present in 
Amendment (b). 
5.5. Justification for Dose 
7.1. Treatments Administered 
7.2. Method of Treatment 
Assignment 
7.2.1. Selection and Timing of 
Doses 
Addition of language to reference 
Appendix 8 for dosing guidance 
 
Dosing was updated per protocol 
requirement after PK analysis of study 
JAHV. 
7.2. Method of Treatment 
Assignment 
7.2.1. Selection and Timing of 
Doses 
7.4 Dosage Modification 
Updated Cohorts  
For Clarity.  
*Only applicable if Amendment (c) is in 
effect. These changes are not present in 
Amendment (b). 
8.1.3. Discontinuation of 
Inadvertently Enrolled Patients 
Addition of Lilly template language  
 
Clarification of discontinuation of 
inadvertently enrolled participants and 
safety follow-up.  
*Only applicable if Amendment C is in 
effect. 
9.4.6.2. Growth Monitoring 
 
Addition of language 
related to height 
measurement  
 
Added screening 
 
Specification of stadiometer as 
device to be used for height 
measurement.  
 
Error in previous amendment.  
*Only applicable if Amendment (c) is in 
effect. These changes are not present in 
Amendment (b). 
Addition of language on x-rays and 
country specific addenda 
Guidance on previous country specific 
addenda containing additional imaging. 
Appendix 2. Clinical Laboratory 
Tests 
Removal of footnote in table for 
hsCRP 
Clarification to sites of unblinding of 
test results for hsCRP.   
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Appendix 8. Data-based Dosing 
Cohorts 
 
Addition of Appendix 8 
related to data-based 
dosing cohorts 
 
 
Updated enrollment Status 
 
Dosing was updated per 
protocol requirement after PK 
analysis of study JAHV. 
 
For Clarity.  
*Only applicable if Amendment (c) is in 
effect. These changes are not present in 
Amendment (b). 
Appendix 9. Provisions for 
Changes in Study Conduct During 
Exceptional Circumstances 
 
Added collection period of 
12 weeks 
 
Removed C-SRRS 
assessments 
 
Laboratory collections 
adjusted 
 
For clarity.  
 
Not applicable.  
 
For clarity.  
*Only applicable if Amendment (c) is in 
effect. These changes are not present in 
Amendment (b). 
 
 
 
Approved on 14 Jun 2023 GMT

Signature Page for VV-CLIN-080417 v1.0
Signature Page for VV-CLIN-080417 v1.0
Approval
14-Jun-2023 12:34:20 GMT+0000
Approval
14-Jun-2023 21:33:55 GMT+0000
Approved on 14 Jun 2023 GMT
PPD
PPD