Clinical trial NCT03773978
Conditions: Juvenile Idiopathic Arthritis
Keywords: Polyarticular JIA Oligoarthritis Juvenile psoriatic arthritis (JPsA) Enthesitis-related juvenile idiopathic arthritis (ERA)
Sponsor: Eli Lilly and Company
Start date: 2018-12-17; Completion date: 2022-01-26
Enrollment: 220 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The reason for this study is to see if the study drug baricitinib given orally is safe and effective in participants with JIA from 2 years to less than 18 years old.

Detailed description:

Arms: arm 1: Baricitinib was administered QD (once daily) as a 4-mg oral tablet for adolescent participants (12 to \<18 years of age) and children ≥9 years of age; and 2 mg for children \<9 years of age. Participants \<6 years of age received an oral suspension. Participants ≥6 to \<12 years old had the option of receiving an oral suspension. Participants \>12 years old were supplied tablets. The oral suspension dose was administered as 4-mg, 2-mg, 1-mg, and 0.5-mg as needed. arm 2: Placebo matched to baricitinib was administered to participants during the DBW period.
Interventions: intervention 1: Baricitinib intervention 2: Placebo
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered orally.

Protocol documents:
Prot_000.pdf: 
 
 
 
JAHV 05 Clinical Protocol (d) 
 
 
A Randomized, Double-Blind, Placebo-Controlled, Withdrawal, Safety and Efficacy Study of 
Oral Baricitinib in Patients From 2 Years to Less Than 18 Years Old With Juvenile Idiopathic 
Arthritis (JIA) 
  
NCT03773978 
Approval Date: 07-Nov-2020 
 
 


I4V-MC-JAHV(d) Clinical Protocol
Page 1
Protocol I4V-MC-JAHV(d)
A Randomized, Double-Blind, Placebo-Controlled, 
Withdrawal, Safety and Efficacy Study of Oral Baricitinib in 
Patients from 2 Years to Less Than 18 Years Old with 
Juvenile Idiopathic Arthritis (JIA)
EUDRA CTA 2017-004518-24
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
Protocol Electronically Signed and Approved by Lilly on 05 July 2018
Amendment (a) Electronically Signed and Approved by Lilly on 14 March 2019
Amendment (b) Electronically Signed and Approved by Lilly on 15 April 2019.
Amendment (c) Electronically Signed and Approved by Lilly on 15 August 2020.
Amendment (d) Electronically Signed and Approved by Lilly on approval date provided 
below
LY3009104
Approval Date: 07-Nov-2020 GMT


I4V-MC-JAHV(d) Clinical Protocol
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Table of Contents
6HFWLRQ
3DJH
Protocol I4V-MC-JAHV(d) A Randomized, Double-Blind, Placebo-
Controlled, Withdrawal, Safety and Efficacy Study of Oral 
Baricitinib in Patients from 2 Years to Less Than 18 Years Old with 
Juvenile Idiopathic Arthritis (JIA).......................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................15
3.
Introduction ......................................................................................................................28
3.1.
Study Rationale............................................................................................................28
3.2.
Background..................................................................................................................29
3.3.
Benefit/Risk Assessment..............................................................................................31
4.
Objectives and Endpoints..................................................................................................34
5.
Study Design.....................................................................................................................37
5.1.
Overall Design .............................................................................................................37
5.1.1.
Screening and Baseline Periods............................................................................39
5.1.2.
Safety/PK Assessment..........................................................................................40
5.1.3.
Open-Label Lead-In Period..................................................................................40
5.1.4.
Double-Blind Withdrawal Period .........................................................................40
5.1.5.
Post-Treatment Follow-Up Period........................................................................41
5.2.
Number of Participants.................................................................................................41
5.3.
End of Study Definition ...............................................................................................41
5.4.
Scientific Rationale for Study Design...........................................................................42
5.5.
Justification for Dose ...................................................................................................42
6.
Study Population...............................................................................................................44
6.1.
Inclusion Criteria..........................................................................................................44
6.2.
Exclusion Criteria ........................................................................................................46
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................51
6.3.
Screen Failures.............................................................................................................51
7.
Treatments........................................................................................................................52
7.1.
Treatments Administered .............................................................................................52
7.1.1.
Packaging and Labeling .......................................................................................53
7.2.
Method of Treatment Assignment ................................................................................53
7.2.1.
Selection and Timing of Doses.............................................................................54
7.3.
Blinding .......................................................................................................................54
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7.4.
Dosage Modification....................................................................................................55
7.5.
Preparation/Handling/Storage/Accountability...............................................................55
7.6.
Treatment Compliance .................................................................................................55
7.7.
Concomitant Therapy...................................................................................................56
7.8.
Treatment after the End of the Study............................................................................58
7.8.1.
Study Extensions..................................................................................................58
7.8.2.
Special Treatment Considerations ........................................................................58
7.9.
Continued Access.........................................................................................................59
8.
Discontinuation Criteria ....................................................................................................60
8.1.
Discontinuation from Study Treatment.........................................................................60
8.1.1.
Temporary Interruption of Investigational Product ...............................................60
8.1.2.
Permanent Discontinuation from Investigational Product .....................................61
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................62
8.2.
Discontinuation from the Study....................................................................................62
8.3.
Lost to Follow-Up........................................................................................................63
9.
Study Assessments and Procedures ...................................................................................64
9.1.
Efficacy Assessments...................................................................................................65
9.1.1.
Primary Efficacy Assessments .............................................................................65
9.1.2.
Secondary Efficacy Assessments..........................................................................65
9.1.2.1.
PedACR30/50/70/90/100 Assessments ...........................................................66
9.1.2.2.
Juvenile Arthritis Disease Activity Score-27...................................................66
9.1.2.3.
Disease Activity .............................................................................................67
9.1.2.4.
Psoriasis Area and Severity Index...................................................................67
9.1.2.5.
Spondyloarthritis Research Consortium of Canada 
Enthesitis Index..............................................................................................68
9.1.2.6.
Juvenile Spondyloarthritis Disease Activity Index ..........................................68
9.1.2.7.
Physician’s Global Assessment of Disease Activity........................................68
9.1.3.
Exploratory Efficacy Assessment.........................................................................68
9.1.4.
Immunological Measurements..............................................................................69
9.1.5.
Health Outcomes..................................................................................................69
9.1.6.
Appropriateness of Assessments ..........................................................................71
9.2.
Adverse Events ............................................................................................................71
9.2.1.
Serious Adverse Events........................................................................................72
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................73
9.2.2.
Adverse Events of Special Interest .......................................................................73
9.2.3.
Complaint Handling.............................................................................................73
9.3.
Treatment of Overdose.................................................................................................74
9.4.
Safety...........................................................................................................................74
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9.4.1.
Electrocardiograms ..............................................................................................74
9.4.2.
Vital Signs ...........................................................................................................74
9.4.3.
Laboratory Tests ..................................................................................................74
9.4.4.
Hepatitis B Virus DNA Monitoring......................................................................75
9.4.5.
Hepatic Safety Monitoring and Data Collection....................................................75
9.4.6.
Safety Monitoring ................................................................................................76
9.4.6.1.
Venous Thromboembolic Event Assessment ..................................................76
9.4.6.2.
Growth Monitoring.........................................................................................77
9.4.6.3.
Tanner Stage Scale .........................................................................................77
9.5.
Pharmacokinetics .........................................................................................................77
9.5.1.
Pharmacokinetic Strategy.....................................................................................77
9.5.2.
Safety/PK Assessment Lead-in Period..................................................................78
9.5.3.
OLLI Assessment Period......................................................................................79
9.6.
Pharmacodynamics ......................................................................................................80
9.6.1.
Pharmacogenetics ................................................................................................80
9.6.1.1.
Whole Blood Sample for Pharmacogenetic Research......................................80
9.7.
Biomarkers...................................................................................................................80
9.8.
Medical Resource Utilization and Health Economics ...................................................80
10.
Statistical Considerations ..................................................................................................81
10.1. Sample Size Determination ..........................................................................................81
10.2. Populations for Analyses..............................................................................................81
10.3. Statistical Analyses ......................................................................................................82
10.3.1.
General Statistical Considerations ........................................................................82
10.3.2.
Treatment Group Comparability...........................................................................83
10.3.2.1.
Patient Disposition..........................................................................................83
10.3.2.2.
Patient Characteristics ....................................................................................83
10.3.2.3.
Concomitant Therapy .....................................................................................83
10.3.2.4.
Treatment Compliance....................................................................................83
10.3.3.
Efficacy Analyses ................................................................................................84
10.3.3.1.
Primary Analyses ...........................................................................................84
10.3.3.2.
Secondary Analyses........................................................................................84
10.3.4.
Safety Analyses....................................................................................................85
10.3.4.1.
Adverse Events...............................................................................................86
10.3.4.2.
Clinical Laboratory Tests................................................................................87
10.3.4.3.
Vital Signs, Physical Findings, and Other Safety 
Evaluations.....................................................................................................87
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................87
10.3.6.
Evaluation of Immunological Measures ...............................................................87
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10.3.7.
Health Outcomes..................................................................................................88
10.3.8.
Product Acceptability and Palatability..................................................................88
10.3.9.
Subgroup Analyses ..............................................................................................88
10.3.10. Exploratory Analysis............................................................................................88
10.3.11. Interim Analyses..................................................................................................88
10.3.11.1. Adjudication Committee.................................................................................89
11.
References ........................................................................................................................90
12.
Appendices .......................................................................................................................95
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List of Tables
Table
Page
Table JAHV.1.
Schedule of Activities for the Safety/PK Cohort ............................................16
Table JAHV.2.
Schedule of Activities....................................................................................21
Table JAHV.3.
Summary of Primary and Major (Gated) Secondary Endpoints for 
Baricitinib Phase 3 Rheumatoid Arthritis Studies...........................................31
Table JAHV.4.
Objectives and Endpoints...............................................................................34
Table JAHV.5.
Treatment Regimens......................................................................................52
Table JAHV.6.
Concomitant JIA Therapies............................................................................58
Table JAHV.7.
Criteria for Temporary Interruption of Investigational Product.......................60
Table JAHV.8.
Secondary Efficacy Endpoint Analyses..........................................................85
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List of Figures
Figure
Page
Figure JAHV.1. Study design for Clinical Protocol I4V-MC-JAHV. .......................................38
Figure JAHV.2. Comparison of predicted steady-state concentrations of baricitinib in 
pediatric (solid lines) versus adults (gray dots) receiving 4-mg QD................43
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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................96
Appendix 2.
Clinical Laboratory Tests.............................................................................101
Appendix 3.
Study Governance Considerations................................................................103
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality..................107
Appendix 5.
Monitoring Tests for Confirmed VTE..........................................................109
Appendix 6.
Weight-Based Prioritization Chart for Blood Sampling................................110
Appendix 7.
Data-Based Dosing Cohorts.........................................................................111
Appendix 8.
Provisions for Changes in Study Conduct During Exceptional 
Circumstances .............................................................................................113
Appendix 9.
Protocol Amendment I4V-MC-JAHV(d) Summary - A Randomized, 
Double-Blind, Placebo-Controlled, Withdrawal, Safety and Efficacy 
Study of Oral Baricitinib in Patients from 2 Years to Less Than 
18 Years Old with Juvenile Idiopathic Arthritis (JIA) ..................................117
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1. Synopsis
Title of Study
A Randomized, Double-Blind, Placebo-Controlled, Withdrawal, Safety and Efficacy Study of 
Oral Baricitinib in Patients from 2 Years to Less Than 18 Years Old with Juvenile Idiopathic 
Arthritis (JIA).
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, tyrosine kinase 2 [TYK2]) that 
play an important role in cytokine signal transduction. Baricitinib is a JAK1/JAK2 inhibitor 
demonstrating selectivity for and balanced 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) (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 rationale for the current study is to evaluate the efficacy and safety profile of oral baricitinib
when administered once daily (QD) to pediatric patients with JIA who have had an insufficient 
response or intolerance to treatment with at least 1 other conventional or biologic disease-
modifying antirheumatic drug (DMARD).  This includes patients with polyarticular JIA 
(rheumatoid factor positive or rheumatoid factor negative), extended oligoarticular course JIA, 
enthesitis-related JIA (ERA), and juvenile psoriatic arthritis (JPsA) as defined by the 
International League of Associations for Rheumatology (ILAR) criteria.  The safety and 
tolerability data from this study are intended to establish an understanding of the benefit/risk 
relationship for baricitinib in patients with nonsystemic JIA.
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Objective(s)/Endpoints:
Objectives
Endpoints
Primary
•
To evaluate the efficacy of baricitinib 
compared to placebo in children with 
JIA
•
Time to disease flare (flare defined as worsening of ≥30% in 
at least 3 of the 6 PedACR core criteria for JIA and an 
improvement of ≥30% in no more than 1 of the criteria) from 
the beginning of the double-blind withdrawal (DBW) period 
to the end of the DBW period
Secondary
•
To evaluate the efficacy of baricitinib in 
children with JIA
During the open-label lead-in (OLLI) period:
•
PedACR30/50/70/90/100 response rates
•
Changes from baseline in each of the 6 individual
components of the PedACR Core Set variables as follows:
o
Number of active joints
o
Number of joints with limited range of motion
o
Physician’s Global Assessment of Disease Activity
o
Parent’s Global Assessment of Well-Being
o
Physical function as measured by the Childhood Health 
Assessment Questionnaire (CHAQ)
o
Acute-phase reactant (high-sensitivity c-reactive protein 
[hsCRP]) and erythrocyte sedimentation rate (ESR)
•
Proportion of patients with inactive disease (as defined by 
Wallace et al. 2011)
•
Proportion of patients with minimal disease activity (as 
defined by Consolaro et al. 2012)
•
Change from baseline in the Physical Summary Score (PhS) 
and Psychosocial Summary Score (PsS) of the Child Health 
Questionnaire-Parent Form 50 (CHQ-PF50)
•
Change from baseline in caregiver burden as measured by the 
Parental Impact-Time and Parental Impact-Emotion scales of 
the CHQ-PF50
•
Change from baseline in Juvenile Arthritis Disease Activity 
Score-27 (JADAS-27)
•
Change from baseline in arthritis-related pain severity as 
measured by the CHAQ pain severity Visual Analogue Scale 
(VAS) item
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Objectives
Endpoints
•
To evaluate the efficacy of baricitinib 
compared to placebo in children with 
JIA
During the DBW period:
•
Proportion of patients with disease flare
•
PedACR30/50/70/90/100 response rates
•
Changes from baseline in each of the 6 individual 
components of the PedACR Core Set variables to the end of 
the DBW period (due to disease flare or completion) as 
follows:
o
Number of active joints
o
Number of joints with limited range of motion
o
Physician’s Global Assessment of Disease Activity
o
Parent’s Global Assessment of Well-Being
o
Physical function as measured by the CHAQ
o
Acute-phase reactant (hsCRP) and ESR
•
Proportion of patients with inactive disease (as defined by 
Wallace et al. 2011)
•
Proportion of patients with minimal disease activity (as 
defined by Consolaro et al. 2012)
•
Proportion of patients in remission (as defined by Wallace 
et al. 2012)
•
Change from baseline in JADAS-27
•
Change from baseline in the PhS and PsS of the CHQ-PF50
•
Change from baseline in caregiver burden as measured by the 
Parental Impact-Time and Parental Impact-Emotion scales of 
the CHQ-PF50
•
Change from baseline in arthritis-related pain severity as 
measured by the CHAQ pain severity VAS item
•
To assess the efficacy of baricitinib in 
children with JPsA
•
Change in Psoriasis Area and Severity Index (PASI) score 
during the OLLI period
•
To assess the efficacy of baricitinib
compared to placebo in children with 
JPsA
•
Change from baseline in PASI score during the DBW period
•
To assess the efficacy of baricitinib in 
children with ERA or JPsA
•
Change in Spondyloarthritis Research Consortium of Canada 
(SPARCC) enthesitis index during the OLLI period
•
Change in Juvenile Spondyloarthritis Disease Activity Index 
(JSpADA) during the OLLI period
•
To assess the efficacy of baricitinib 
compared to placebo in children with 
ERA or JPsA
•
Change from baseline in SPARCC enthesitis index during the 
DBW period.
•
Change from baseline in JSpADA during the DBW period
•
To evaluate the potential effects of 
baricitinib on the cellular and humoral 
immune system
•
Change in immunoglobulin levels and peripheral blood 
immunophenotyping (including T and B cells, T cell subsets, 
and NK cells) from baseline and at Week 4, Week 12, and 
Week 44.
•
Change of IgG titers from pre-vaccination to 4 weeks and 
12 weeks post vaccination in patients eligible for vaccination 
with tetanus, diphtheria, and pertussis (tDaP) and/or 
pneumococcal conjugate vaccine according to local guidelines.
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Objectives
Endpoints
•
To characterize baricitinib PK in the JIA 
population and explore relationships 
between baricitinib exposure and study 
endpoints
•
Population PK of baricitinib in patients with JIA
•
Proportions of patients achieving PedACR30/50/70/90/100 
response rates by PK exposure 
•
Time to disease flare in patients with JIA by PK exposure 
•
Change in JADAS-27 by PK exposure
•
To assess the patient acceptability and 
palatability of baricitinib tablets and oral 
suspension
•
Assessment of tablet or oral suspension product acceptability 
and palatability during the OLLI period
•
To assess the safety of baricitinib 
compared to placebo in patients with JIA
•
Adverse events including serious adverse events
•
Permanent discontinuation of investigational product
•
Temporary interruption of investigation product
Abbreviations:  CHAQ = Childhood Health Assessment Questionnaire; CHQ-PF50 = Child Health Questionnaire-
Parent Form 50; DBW = double-blind withdrawal; ERA = enthesitis-related juvenile idiopathic arthritis; 
ESR = erythrocyte sedimentation rate; HRQOL = health-related quality of life; hsCRP = high-sensitivity 
C-reactive protein; IgG = immunoglobulin G; JADAS-27 = Juvenile Arthritis Disease Activity Score-27; 
JIA = juvenile idiopathic arthritis; JPsA = juvenile psoriatic arthritis; JSpADA = Juvenile Spondyloarthritis 
Disease Activity Index; NK = natural killer; OLLI = open-label lead-in; PASI = Psoriasis Area and Severity 
Index; PedACR = Pediatric American College of Rheumatology; PK = pharmacokinetic(s); 
SPARCC = Spondyloarthritis Research Consortium of Canada; tDaP = tetanus, diphtheria, and pertussis; 
VAS = Visual Analogue Scale.
Summary of Study Design
Study I4V-MC-JAHV (JAHV) is a multicenter, randomized, double-blind, placebo-controlled,
medication-withdrawal study with a safety/pharmacokinetic (PK) assessment period, an 
open-label lead-in (OLLI) period, and a double-blind withdrawal (DBW) period in patients with 
JIA who have had an inadequate response or intolerance to treatment with at least 1 other 
conventional or biologic DMARD (bDMARD).
Treatment Arms and Duration
The study has a 2-week Safety/PK assessment period, a 12-week OLLI period, and a DBW 
period of up to 32 weeks.
The Safety/PK assessment period will evaluate if exposure to baricitinib in pediatric patients is 
consistent with baricitinib exposure in adults.  Patients will receive oral baricitinib at a fixed dose 
by age group QD for approximately 2 weeks.  Enrollment will be staggered by age group (12 to 
<18 years, 9 to <12, 6 to <9 years, and 2 to <6 years), with older groups enrolling before younger 
groups.
In the OLLI period, patients will receive baricitinib QD at a fixed dose by age group for 
approximately 12 weeks.  Patients who demonstrate disease response improvement of at least 
30% in at least 3 of 6 Pediatric American College of Rheumatology (PedACR) core response 
variables and >30% worsening in not more than 1 of the remaining variables (PedACR30; 
Giannini et al. 1997) will proceed to the DBW.  In the DBW period, patients will be randomized 
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to either receive placebo or to remain on the same baricitinib dose for up to 32 weeks or until the 
occurrence of a disease flare (whichever occurs first). Patients who do not achieve PedACR30 
will be considered nonresponders; these patients will be given the option of enrolling to the 
open-label extension (OLE) study.
Disease flare is defined as a worsening of ≥30% in at least 3 of the 6 PedACR core criteria for 
JIA and an improvement of ≥30% in no more than 1 of the criteria from the patient’s condition at 
Visit 9.  If either the number of joints with active arthritis or the number of joints with limitation 
of motion are used in the calculation of flare for a study visit, then a minimum worsening of at 
least 2 active joints or 2 joints with limitation of motion must be present.  An active joint is 
defined as a joint with swelling or, in the absence of swelling, limitation of motion accompanied by 
pain on motion and/or tenderness.  If either the Physician’s Global Assessment of Disease Activity 
or the Parent’s Global Assessment of Well-Being are used in the calculation of flare for a study 
visit, then a minimum worsening on a visual analogue scale (VAS) (as defined in the SAP) must 
be present. If ESR or CRP is used in the definition of “flare” and counts towards worsening, 
then the second value for ESR or CRP used in the calculation must be above the upper limit of 
normal for ESR (>20 mm/hour) or CRP. .
Patients who complete the DBW period may enroll into a separate OLE study (Study I4V-MC-
JAHX [JAHX]).  Additionally, patients whose baricitinib dose in safety/PK period is inconsistent 
with baricitinib 4-mg exposures in adults with rheumatoid arthritis and patients who experience a 
disease flare during the DBW period will discontinue the study and be offered immediate 
participation in the OLE.
Patients who do not enroll in the OLE will have a follow-up visit (Visit 801) approximately 
28 days after the last dose of the investigational product.
Number of Patients
Approximately 197 patients are planned to enter the OLLI period to allow 128 patients to be 
randomized into the DBW period (assuming that 65% of the patients meet the PedACR30 
criteria at the end of the OLLI period).  At least 10 of these patients will have ERA.  The 
nonresponder and dropout rates will be monitored during the OLLI period to adjust the overall 
sample size to ensure that a minimum of 128 patients are randomized in the DBW.  If the 
PedACR30 response rate during the OLLI period is higher than the assumed rate of 65%, fewer 
than 197 patients may be required.
Statistical Analysis
The primary endpoint will be the time-to-flare during the DBW period for randomized patients
following intent-to-treat principles. Patients who discontinue the DBW period without 
experiencing a flare will have their data censored.  Survival curves will be estimated using the 
Kaplan–Meier method for all “time-to” variables in the DBW period.
Efficacy and health outcome endpoints will be summarized using descriptive statistics for the 
OLLI population during the OLLI period. Treatment comparisons will be performed for the 
DBW population in the DBW period.  Continuous data will be summarized in terms of the mean, 
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standard deviation, minimum, maximum, and median.  Continuous efficacy and health outcome 
variables will be evaluated using an analysis of covariance (ANCOVA) model with treatment,
JIA patient category (polyarticular and extended oligoarticular versus ERA and JPsA), prior 
bDMARD use, baseline ESR category, and baseline score in the model.  The 
last-observation-carried-forward approach will be used to impute missing data.
Categorical data will be summarized as frequency counts and percentages.  Categorical efficacy 
variables will be evaluated using a logistic regression analysis with treatment, JIA patient 
category (polyarticular and extended oligoarticular versus ERA and JPsA), and prior bDMARD 
use in the model.  The proportions and 95% confidence interval will be reported.  Missing data 
will be imputed using the nonresponder imputation method.
A futility analysis will be conducted using the PedACR30 response rate observed in the first 
100 patients who have completed the OLLI phase.  The futility analysis will be based on 50% of 
patients achieving a PedACR30 response rate.  The study will stop for futility if <50% of the 
first 100 patients to complete the OLLI period have a PedACR30 response.
All safety data will be descriptively summarized in each treatment period using corresponding 
populations.  Comparison between baricitinib and placebo will be performed during the DBW 
period for the DBW population.  The Fisher exact test will be used for the adverse events, 
discontinuations, and other categorical safety data for between-treatment-group comparisons in 
the DBW period.  Continuous vital signs, body weight, and other continuous safety variables, 
including laboratory variables, will be analyzed using ANCOVA with treatment and baseline 
values as model covariates.
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2. Schedule of Activities
The Schedule of Activities described below should be followed for all participants enrolled in 
Study JAHV.  In the event participation in this study is affected by exceptional circumstances 
(such as pandemics or natural disasters), please refer to Appendix 8 and consult with the 
sponsor’s representative for additional guidance.
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Table JAHV.1.
Schedule of Activities for the Safety/PK Cohort
Safety/PK Cohort Onlya
Screening
Safety/PKb,c
Visit #
V1
V1a
V2b
baseline
V3
V4
Study Day (Approximately)
-42 to -1
1d
4
14
Visit Window (Days)
±3
Informed consent and assente
X
Complete medical history
X
Immunization record
X
X
X
Demographics
X
Physical examinationf
X
Tanner Staging in patients ≥8 years old (see Section 9.4.6.3)
X
Symptom-directed physical examinationf
X
X
X
X
Habits: tobacco and caffeine
X
Height
X
X
X
Weight
X
X
X
X-ray of wrist/hand/ finger, and knee
g
X
Occipital frontal circumference measurement 
in children 2 years of age
X
X
Vital signs (blood pressure, pulse, temperature)
X
X
X
Inclusion/exclusion criteria review
X
X
Preexisting conditions
X
JIA diagnosis (ILAR criteria)
X
Previous JIA therapy
X
Uveitis evaluationh
X
Concomitant medications
X
X
X
X
Adverse event
X
X
X
X
Log in IWRS
X
X
X
X
Randomization
Dispense study drug
X
X
Investigational product returned and compliance assessedi
X
Clinical Efficacy
Joint assessment
X
X
X
X
Physician’s Global Assessment of Disease Activity
X
X
X
X
Childhood Health Assessment Questionnairej
X
X
X
CHQ-PF50j
X
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Safety/PK Cohort Onlya
Screening
Safety/PKb,c
Visit #
V1
V1a
V2b
baseline
V3
V4
Study Day (Approximately)
-42 to -1
1d
4
14
Visit Window (Days)
±3
EQ-5D-Yj
X
SPARCC Enthesitis Indexk
X
X
Morning stiffness duration
X
X
Pain Numerical Rating Scale
X
X
Clinical sacroiliitisk
X
X
Back mobility (Schober’s test)k
X
X
PASIl
X
X
Product palatability and acceptability
X
Procedures and Laboratory Tests
Chest x-raym
X
Administer PPD/QuantiFERON®-TB Gold/T-SPOT® TBn
X
Read PPDn
X
ECGo
X
hsCRP
X
X
X
X
ESRp
X
X
X
HLA-B27
RF and ACPA
X
TSH
X
HIV/HCVq
X
HBV(HBsAg, HBcAb, HBsAb)
X
HBV DNAr
X
Serum pregnancy tests
X
Urine pregnancy tests
X
X
Clinical chemistryt
X
X
X
X
Hematology
X
X
X
X
Urinalysis
X
X
Iron studies (iron, TIBC and ferritin)
X
Fasting lipid panelu
X
IgA, IgG, IgM
X
Lymphocyte subsets (T, B, NK, and T- cell subsets)v
X
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Safety/PK Cohort Onlya
Screening
Safety/PKb,c
Visit #
V1
V1a
V2b
baseline
V3
V4
Study Day (Approximately)
-42 to -1
1d
4
14
Visit Window (Days)
±3
Antipneumococcal IgG multianalyte Ab assayw
At relevant visits for prevaccination, 
4 weeks post vaccination, and 12 weeks 
post vaccination 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 
post vaccination based on the vaccination 
schedule of each patient
IGF-1 and IGFBP-3
X
Gonadal hormonesx
X
Exploratory storage samples (RNA, serum, and plasma)
X
Pharmacogenetic (DNA) collection
PK sampley
X
X
X
Abbreviations:  Ab = antibody; ACPA = anti-citrullinated protein antibodies; CHQ-PF50 = Child Health Questionnaire-Parent Form 50; 
DNA = deoxyribonucleic acid; ECG = electrocardiogram; eCOA = electronic Clinical Outcome Assessment; eGFR = estimated glomerular filtration rate; 
EQ-5D-Y = European Quality of Life–5 Dimensions–Youth version; ERA = enthesitis related arthritis; 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;
ICF = informed consent form; 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; IWRS = interactive web-response 
system; JIA = juvenile idiopathic arthritis; JPsA = juvenile psoriatic arthritis; NK = natural killer; OLLI = open-label lead-in; PASI = Psoriasis Area and 
Severity Index; PK = pharmacokinetic(s); PPD = purified protein derivative; RF = rheumatoid factor; RNA = ribonucleic acid; SPARCC = Spondyloarthritis 
Research Consortium of Canada; TB = tuberculosis; tDaP = tetanus, diphtheria, and pertussis TIBC = total iron-binding capacity; TSH = thyroid-stimulating 
hormone; V = visit.
a
Following completion of the Safety/PK period, patients will advance to the OLLI period.
b
Pharmacokinetic samples will be collected as described in Section 9.5.2.  Other baseline laboratory samples should be taken before administration of 
investigational product. Day 1 will be used as the baseline for Safety/PK population. Safety/PK cohort will join the OLLI period at Visit 6.
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.  This applies only to patients who do not enter the Open-Label Extension Study.
d
This is the first day of taking the investigational product.
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e
The parent or legal guardian will sign the informed consent form (ICF) and the patient will sign the assent form (as applicable) per local requirements prior to 
any study assessments, examinations, or procedures being performed.
f
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 any time.  Must include an assessment of serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy attributable to JIA.
g
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 JAHV at the time of this amendment, 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.
h
All patients with active uveitis must be excluded at screening.  Signs and symptoms of active uveitis should be monitored.  
i
At Visit 4, patient will return all investigational products for drug accountability.  
j
Patient-reported questionnaires will be administered via an on-site eCOA device or paper and is recommended to be completed prior to any clinical 
examinations. 
k
Only for patients with enthesitis-related juvenile idiopathic arthritis (ERA) or juvenile psoriatic arthritis (JPsA).
l
Only for patients with JPsA.
m 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.
n
TB test(s) including 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 72hours 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.)
o
An ECG performed within 1 year prior to screening may be used.
p
Performed locally.  To be drawn prior to dosing early in the visit except for V3.
q
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.
r
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 (for patients in Japan, it is acceptable for sites to draw HBV DNA samples with the test of Visit 1).  
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.
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s
Pregnancy tests prior to first dose of investigational product for females ≥10 years old 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 Visit 2 must be known prior to first dose of investigational product.
t
Clinical chemistry will include eGFR (calculated by Bedside Schwartz 2009 formula or the Japanese Society for Pediatric Nephrology formula for patients in 
Japan).
u 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 ≤50kg: fast for 8 hours prior to laboratory test 
•
Children <8 years and weighing 10 to <25kg: fast for 6 hours prior to laboratory test 
•
Children <8 years and weighing <10kg: fast for 4 hours prior to laboratory test
v
Patients in the age cohort of age 2 to ≤7 years will not have flow cytometry testing due to blood volume limitations.
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 post vaccination, 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.
y
PK samples will be collected as described in Sections 9.5.2.
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 in Appendix 6.
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Table JAHV.2.
Schedule of Activities
Screening
Open-Label Lead-in Perioda
Double-Blind Randomized Withdrawal Period
Early 
Termination
Post-
Treatment 
Follow-Up
Visit #
V1
V1a
V5b
baseline
V6
V7
V8
V9
V10 V11 V12 V13 V14 V15 V16
V17
ETVc
V801d
Study Week
W0
W2
W4 W8 W12 W16 W20 W24 W28 W32 W36 W40
W44
Any Week
Study Day 
(Approximately)
-42 to -1
1e
14
28
56
84
112
140
168
196
224
252
280
308
Any Day
28 ± 5 Days 
after Last 
Dose
Visit Window 
(Days)
±3
±7
Informed consent
and assentf
X
Complete medical 
history
X
Immunization record
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Demographics
X
Physical 
examinationg
X
Tanner Staging in 
patients ≥8 years old 
(see Section 9.4.6.3)
X
Symptom-directed 
physical 
examinationg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Habits: tobacco and 
caffeine
X
Height
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-ray of wrist, 
hand, finger, and 
kneeh
X
Occipital frontal 
circumference 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Screening
Open-Label Lead-in Perioda
Double-Blind Randomized Withdrawal Period
Early 
Termination
Post-
Treatment 
Follow-Up
Visit #
V1
V1a
V5b
baseline
V6
V7
V8
V9
V10 V11 V12 V13 V14 V15 V16
V17
ETVc
V801d
Study Week
W0
W2
W4 W8 W12 W16 W20 W24 W28 W32 W36 W40
W44
Any Week
Study Day 
(Approximately)
-42 to -1
1e
14
28
56
84
112
140
168
196
224
252
280
308
Any Day
28 ± 5 Days 
after Last 
Dose
Visit Window 
(Days)
±3
±7
measurement in 
children 2 years of 
age
Vital signs (blood 
pressure, pulse, 
temperature)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion 
criteria review
X
X
Preexisting 
conditions
X
JIA diagnosis 
(ILAR criteria)
X
Previous JIA therapy
X
Uveitis evaluationi
X
Concomitant 
medications
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
Log in IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
Dispense study drugj
X
X
X
X
X
X
X
X
X
X
X
Investigational 
product returned 
and compliance 
assessedk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Joint assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Screening
Open-Label Lead-in Perioda
Double-Blind Randomized Withdrawal Period
Early 
Termination
Post-
Treatment 
Follow-Up
Visit #
V1
V1a
V5b
baseline
V6
V7
V8
V9
V10 V11 V12 V13 V14 V15 V16
V17
ETVc
V801d
Study Week
W0
W2
W4 W8 W12 W16 W20 W24 W28 W32 W36 W40
W44
Any Week
Study Day 
(Approximately)
-42 to -1
1e
14
28
56
84
112
140
168
196
224
252
280
308
Any Day
28 ± 5 Days 
after Last 
Dose
Visit Window 
(Days)
±3
±7
Physician’s Global 
Assessment of 
Disease Activity
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Childhood Health 
Assessment 
Questionnairel
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CHQ-PF50l
X
X
X
X
X
X
X
X
X
X
X
X
X
EQ-5D-Yl
X
X
X
X
X
X
X
X
X
X
X
X
X
SPARCC Enthesitis 
Indexm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Morning stiffness 
durationl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pain Numeric Rating 
Scalel
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical 
sacroiliitism
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Back mobilitym
(Schober’s test)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PASIn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Product palatability 
and acceptability
X
X
Chest x-rayo
X
Administer PPD/
QuantiFERON®-TB 
Gold/T-SPOT® TBp
X
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I4V-MC-JAHV(d) Clinical Protocol
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Screening
Open-Label Lead-in Perioda
Double-Blind Randomized Withdrawal Period
Early 
Termination
Post-
Treatment 
Follow-Up
Visit #
V1
V1a
V5b
baseline
V6
V7
V8
V9
V10 V11 V12 V13 V14 V15 V16
V17
ETVc
V801d
Study Week
W0
W2
W4 W8 W12 W16 W20 W24 W28 W32 W36 W40
W44
Any Week
Study Day 
(Approximately)
-42 to -1
1e
14
28
56
84
112
140
168
196
224
252
280
308
Any Day
28 ± 5 Days 
after Last 
Dose
Visit Window 
(Days)
±3
±7
Read PPDp
X
ECGq
X
hsCRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ESRr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HLA-B27
X
RF and ACPA
X
TSH
X
HIV/HCVs
X
HBV (hBsAg, 
hBcAb, hBsAb)
X
HBV DNAt
X
X
X
X
X
X
X
Serum pregnancy 
testu
X
Urine pregnancy 
testu
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical chemistryv
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
Urinalysis
X
X
X
X
X
X
X
X
X
Iron studies (iron, 
TIBC and ferritin)
X
X
X
X
X
X
Fasting lipid panelw
X
X
X
X
X
X
IgA, IgG, IgM
X
X
X
X
X
X
Lymphocyte subsets 
X
X
X
X
X
X
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I4V-MC-JAHV(d) Clinical Protocol
Page 25
Screening
Open-Label Lead-in Perioda
Double-Blind Randomized Withdrawal Period
Early 
Termination
Post-
Treatment 
Follow-Up
Visit #
V1
V1a
V5b
baseline
V6
V7
V8
V9
V10 V11 V12 V13 V14 V15 V16
V17
ETVc
V801d
Study Week
W0
W2
W4 W8 W12 W16 W20 W24 W28 W32 W36 W40
W44
Any Week
Study Day 
(Approximately)
-42 to -1
1e
14
28
56
84
112
140
168
196
224
252
280
308
Any Day
28 ± 5 Days 
after Last 
Dose
Visit Window 
(Days)
±3
±7
(T, B, NK, and T-
cell subsets)x
Antipneumococcal 
IgG multianalyte Ab 
assayy
At relevant visits for prevaccination, 4 weeks post vaccination, and 12 weeks post 
vaccination based on the vaccination schedule of each patient
Anti-tetanus toxoid 
IgG, anti-diphtheria 
toxoid, and anti-
pertussis toxoid Ab 
assayy
At relevant visits for prevaccination, 4 weeks post vaccination, and 12 weeks post 
vaccination based on the vaccination schedule of each patient
IGF-1 and IGFBP-3
X
X
X
X
X
Gonadal hormonez
X
X
X
X
X
Exploratory storage 
samples (RNA, 
serum, and plasma)
X
X
X
X
X
Pharmacogenetic 
(DNA) collection
X
PK sampleaa
X
X
X
X
X
X
Abbreviations:  Ab = antibody; ACPA = anti-citrullinated protein antibodies; CHQ-PF50 = Child Health Questionnaire-Parent Form 50; 
DNA = deoxyribonucleic acid; DBW = double-blind withdrawal; ECG = electrocardiogram; eCOA = electronic Clinical Outcome Assessment;
eGFR = estimated glomerular filtration rate; EQ-5D-Y = European Quality of Life–5 Dimensions–Youth version; ERA = enthesitis-related juvenile idiopathic 
arthritis; 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; = hepatitis C virus; HIV = human immunodeficiency virus; HLA-B27 = human leukocyte 
antigen-B27; hsCRP = high-sensitivity C-reactive protein; ICF = informed consent form; 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 
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Associations for Rheumatology; IWRS = interactive web-response system; JIA = juvenile idiopathic arthritis; JPsA = juvenile psoriatic arthritis; NK = natural 
killer; OLLI = open-label lead-in; PASI = Psoriasis Area and Severity Index; PedACR30 = Pediatric American College of Rheumatology 30 criteria;
PK = pharmacokinetic(s); PPD = purified protein derivative; RF = rheumatoid factor; RNA = ribonucleic acid; SPARCC = Spondyloarthritis Research 
Consortium of Canada; TB = tuberculosis; tDaP = tetanus, diphtheria, and pertussis ; TIBC = total iron-binding capacity; TSH = thyroid-stimulating hormone; 
V = visit; W = week.
a
The OLLI period ends on the same day the DBW period begins.
b
Pharmacokinetic samples will be collected as described in Sections 9.5.2 and 9.5.3.  Other baseline laboratory samples should be taken before administration 
of investigational product. Visit 5 (Day 1) will be used as the baseline for OLLI population.  Safety/PK cohort will join the OLLI period at Visit 6.  The 
actual study week and study day for the Safety/PK cohort are two weeks longer than that shown due to the additional 2-week safety/PK lead-in assessment 
period described in Table JAHV.1.
c
Early termination visit (ETV) occurs if the patient does not have a PedACR30 response rate at Week 12, experiences a flare during the double-blind 
withdrawal (DBW) (and are not moving to the open-label extension), or terminates participation early. If the ET 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.
d
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.  This applies only to patients who do not enter the Open-Label Extension Study.
e
This is the first day of taking the investigational product. .
f
The parent or legal guardian will sign the informed consent form (ICF) and the patient will sign the assent form (as applicable) per local requirements prior to 
any study assessments, examinations, or procedures being performed.
g
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.
h
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 JAHV at the time of this amendment, 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.
i
All patients with active uveitis must be excluded at screening.  Signs and symptoms of active uveitis should be monitored.  Patients with ERA and JPsA may 
have a higher risk of active uveitis so mandatory evaluation is required at W12 (V9), W44 (V17), ETV, and V801.
j
Study drug should not be dispensed before review of the Trial Manager report.
k Patients will return all investigational products for drug accountability.  
l
Patient-reported questionnaires will be administered via an on-site eCOA device or paper and is recommended to be completed prior to any clinical 
examinations.
m Only for patients with enthesitis-related juvenile idiopathic arthritis (ERA) or juvenile psoriatic arthritis (JPsA).
n Only for patients with JPsA.
o 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.
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p 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.  (Note:  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.)
q An ECG performed within 1 year prior to screening may be used.
r
Performed locally.  To be drawn prior to dosing early in the visit except for V6 and V7.
s
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.
t
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 (for patients in Japan, it is acceptable for sites to draw HBV DNA samples with the test of Visit 1).  
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 events.
u Pregnancy tests prior to first dose of investigational product for females ≥10 years old 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 Visit 5 must be known prior to first dose of investigational product.
v Clinical chemistry will include eGFR (calculated by Bedside Schwartz 2009 formula or the Japanese Society for Pediatric Nephrology formula for patients in 
Japan).
w 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 ≤50kg: fast for 8 hours prior to laboratory test 
•
Children <8 years and weighing 10 to <25kg: fast for 6 hours prior to laboratory test 
•
Children <8 years and weighing <10kg: fast for 4 hours prior to laboratory test
x Patients in the age cohort of age 2 to ≤7 years will not have flow cytometry testing due to blood volume limitations.
y 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 post vaccination, and 12 weeks post vaccination.
z
Estradiol (for females) or testosterone (for males) will be collected for the assessment of pubertal development in patients aged 8 to <18 years.
aa PK samples will be collected as described in Sections 9.5.2 and 9.5.3.
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 in Appendix 6.
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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) are still poorly understood, 
but JIA shares 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 similarly observed in RA.  Some studies have shown that levels of 
inflammatory cytokines elevated in adults with RA, such as IL-1β, IL-6, and tumor necrosis 
factor-alpha (TNFα), are also elevated in the synovial fluid and serum of patients with JIA.  
These cytokines also correlate with markers of disease activity such as C-reactive protein (CRP) 
and erythrocyte sedimentation rate (ESR) (Lepore et al. 1994; Mangge et al. 1995; Rooney et al. 
1995, 2000; De Benedetti et al. 1997).
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 (Ravelli and Martini 2007).
Pharmacologic interventions that target specific pathways may provide novel therapeutic 
approaches to disease management for JIA.
The primary treatments in JIA include nonsteroidal anti-inflammatory drugs (NSAIDs), 
intra-articular and systemic corticosteroids, methotrexate (MTX), and other conventional 
disease-modifying antirheumatic drug (cDMARDs) (Ringold et al. 2013. Biologic agents 
developed in the past 20 years have improved the treatments available to children with JIA.  


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Although these biological treatments led to significant improvements, many patients fail to 
respond and do not achieve long-lasting remission (Hinze et al. 2015).
Inhibition of JAK-STAT signaling by baricitinib can target multiple JIA-associated cytokine 
pathways and may provide novel therapeutic approaches to disease management.  Baricitinib has 
demonstrated clinical safety and efficacy in patients with RA in 4 completed Phase 3 studies 
(Taylor et al. 2017; Genovese et al. 2016; Dougados et al. 2017; Fleischmann et al. 2017) and is 
approved in the European Union, Japan, and other geographical regions for the treatment of adult 
patients with moderate-to-severe RA. The rationale for the current study is to evaluate the 
efficacy and safety of baricitinib when administered once daily (QD) to patients with JIA who 
have had an inadequate response to either conventional or biologic DMARDs (bDMARDs).  The 
safety and tolerability data from this study are intended to inform the benefit/risk relationship for 
baricitinib in patients with JIA.
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:  systemic arthritis, oligoarthritis (persistent or extended), rheumatoid factor (RF) 
negative polyarthritis, RF positive polyarthritis, juvenile psoriatic arthritis (JPsA), 
enthesitis-related juvenile idiopathic arthritis (ERA), and undifferentiated arthritis (Petty et al. 
2004).
The prognosis of JIA varies based on the individual patient as well as the distinct disease 
category.  Between 25% and 70% of children with JIA will still have active arthritis 10 years 
after disease onset; more than 40% will enter adulthood with active arthritis (Lovell 2006).  
Children with JIA are at risk for significant morbidity in terms of joint damage, impairments in 
physical function, and reduced health-related quality of life (HRQOL) (Prakken et al. 2011;
Gidman et al. 2015).
The goal of JIA treatment is rapid suppression of inflammation to prevent joint damage, 
maximize physical function, and promote normal growth and development.  First-line treatment 
for patients with nonsystemic JIA includes NSAIDs, corticosteroids, and cDMARDs, but a 
substantial proportion of patients do not achieve adequate response to these therapies (Ringold 
et al. 2013; Hinze et al; 2015). Biologic agents approved for RA have improved the treatments 
available to children with JIA over the past 20 years (Lovell et al. 2000; Ruperto et al. 2010; 
Brunner et al. 2015), which include etanercept, adalimumab, abatacept, and tocilizumab.  Of 
these, etanercept and adalimumab are TNF-blocking agents that have similar mechanisms of 
action.  Abatacept inhibits T cell production.  Tocilizumab is an anti–IL-6 receptor monoclonal 
antibody.  Although these biological treatments have led to clinical improvements, many patients 
do not respond and do not achieve long-lasting remission (Hinze et al. 2015).


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As noted in Section 3.1, the efficacy of baricitinib in adult patients with RA was demonstrated in 
4 completed global Phase 3 studies involving patients with moderately to severely active RA.
 Study I4V-MC-JADZ (RA-BEGIN) was a 52-week study that enrolled patients with 
limited or no prior DMARD exposure (Fleischmann et al. 2017).  Patients were 
randomized to 1 of 3 treatment arms:  MTX once weekly (QW [N = 210]), baricitinib 
4-mg QD ([N = 159]), or baricitinib 4-mg QD plus MTX QW (N = 215).  The primary 
objective of noninferiority of baricitinib monotherapy to MTX, based on 20% 
improvement in American College of Rheumatology criteria (ACR20) response at 
Week 24, was met with a response rate of 77% with baricitinib treatment versus 62% 
with MTX treatment (p≤0.01).
 Study I4V-MC-JADV (RA-BEAM) was a 52-week study that enrolled patients who had 
an inadequate response to prior established MTX therapy (continued as stable 
background therapy throughout the study) and no previous exposure to bDMARDs 
(Taylor et al. 2017).  Patients were randomized into 1 of 3 treatment arms: placebo QD 
for 24 weeks followed by a switch to baricitinib 4-mg QD from Week 24 to Week 52 
(N = 488), baricitinib 4-mg QD (N = 487), or adalimumab 40-mg every 2 weeks 
(N = 330).  More patients treated with baricitinib met the primary endpoint of an ACR20 
response at Week 12 compared to placebo (70% versus 40%, respectively; p≤0.001).  
Additionally, an increased ACR20 response rate at Week 12 was observed with 
baricitinib versus adalimumab (70% versus 61%, respectively; p = 0.014).
 Study I4V-MC-JADX (RA-BUILD) was a 24-week study that enrolled patients who had 
an inadequate response or were intolerant to cDMARD treatment and had no previous 
exposure to bDMARDs (Dougados et al. 2017).  Patients were randomized into 1 of 3 
treatment arms:  placebo QD (N = 228), baricitinib 2-mg (N = 229), or baricitinib 4-mg 
(N = 227).  More patients treated with baricitinib 4-mg met the primary endpoint of 
ACR20 response at Week 12 compared to placebo (62% versus 39%, p≤0.001).
 Study I4V-MC-JADW (RA-BEACON) was a 24-week study that enrolled patients who 
had an inadequate response or were intolerant to treatment with at least 1 biologic TNF 
inhibitor (Genovese et al. 2016).  Otherwise, no limit was placed on the number or nature 
of prior bDMARDs. Patients were randomized into 1 of 3 treatment arms:  placebo QD 
(N = 176), baricitinib 2-mg (N = 174), or baricitinib 4-mg (N = 177).  Significantly more 
patients receiving baricitinib at the 4-mg dose than those receiving placebo met the 
primary endpoint of ACR20 response at Week 12 (55% versus 27%, respectively, 
p≤0.001).
Table JAHV.3 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. 


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Table JAHV.3.
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 12 weeks
≤0.001
≤0.001
≤0.001
ng
≤0.001
≤0.001
≤0.001
≤0.001
ΔmTSS at 24 weeks
NS
≤0.05
≤0.001
ng
ng
ng
n/a
n/a
ΔDAS28-hsCRP at 
12 weeks
≤0.001
≤0.001
≤0.001
≤0.001
≤0.001
≤0.001
≤0.001
≤0.001
SDAI remission (≤3.3) 
at 12 weeks
≤0.01
≤0.001
≤0.001
ng
≤0.001
≤0.001
NS
NSc
MJS Duration at 
12 weeks
n/a
n/a
≤0.001
ng
≤0.001
ng
n/a
n/a
MJS Severity at 
12 weeks
n/a
n/a
≤0.001
ng
≤0.001
ng
n/a
n/a
Worst Tiredness at 
12 weeks
n/a
n/a
≤0.001
ng
≤0.05
ng
n/a
n/a
Worst Joint Pain at 
12 weeks
n/a
n/a
≤0.001
ng
≤0.001
ng
n/a
n/a
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; hsCRP = high-sensitivity C-reactive 
protein; 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.
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. 
Therefore, given promising results already observed in completed clinical studies of baricitinib 
in adults with RA, benefits in efficacy are expected for pediatric patients with JIA.  In addition, 
baricitinib is an orally ingested product, which may be preferable to injectable biologic agents 
for both patients and caregivers/legal guardians.
3.3.
Benefit/Risk Assessment
As summarized in Sections 3.1 and 3.2, 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 HRQOL. 


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Baricitinib is approved in multiple geographic regions for the treatment of adult patients with 
moderate-to-severe RA. Juvenile idiopathic arthritis and RA 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 provides evidence for potential efficacy for baricitinib in JIA. Given the 
results observed in completed baricitinib clinical studies in RA in adult populations and the 
nature of the pathophysiology of JIA, treating patients with JIA with baricitinib is expected to 
provide beneficial and therapeutic outcomes to this population.
Section 9.2.2 describes adverse events 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 seen 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 
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, 
following 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 
RA patients 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 (deep vein thrombosis or pulmonary embolism) 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 


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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.
Therefore, based on the efficacy of baricitinib demonstrated in a 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.
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of baricitinib is found in the Investigator’s 
Brochure (IB).


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4. Objectives and Endpoints
Table JAHV.4 shows the objectives and endpoints of the study.
Table JAHV.4.
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To evaluate the efficacy of baricitinib 
compared to placebo in children with 
JIA
•
Time to disease flare (flare defined as worsening of ≥30% in at 
least 3 of the 6 PedACR core criteria for JIA and an 
improvement of ≥30% in no more than 1 of the criteria) from the 
beginning of the double-blind withdrawal (DBW) period to the 
end of the DBW period
Secondary
•
To evaluate the efficacy of baricitinib 
in children with JIA
During the open-label lead-in (OLLI) period:
•
PedACR30/50/70/90/100 response rates
•
Changes from baseline in each of the 6 individual components of 
the PedACR Core Set variables  as follows:
o
Number of active joints
o
Number of joints with limited range of motion
o
Physician’s Global Assessment of Disease Activity
o
Parent’s Global Assessment of Well-Being
o
Physical function as measured by CHAQ
o
Acute-phase reactant (hsCRP) and ESR
•
Proportion of patients with inactive disease (as defined by 
Wallace et al. 2011)
•
Proportion of patients with minimal disease activity (as defined 
by Consolaro et al. 2012)
•
Change from baseline in the Physical Summary Score (PhS) and 
Psychosocial Summary Score (PsS) of the Child Health 
Questionnaire-Parent Form 50 (CHQ-PF50)
•
Change from baseline in caregiver burden as measured by the 
Parental Impact-Time and Parental Impact-Emotion scales of the 
CHQ-PF50
•
Change from baseline in Juvenile Arthritis Disease Activity 
Score-27 (JADAS-27)
•
Change from baseline in arthritis-related pain severity as 
measured by the CHAQ pain severity VAS item.


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Objectives
Endpoints
•
To evaluate the efficacy of baricitinib 
compared to placebo in children with 
JIA
During the DBW period:
•
Proportion of patients with disease flare
•
PedACR30/50/70/90/100 response rates
•
Changes from baseline in each of the 6 individual components of 
the PedACR Core Set variables to the end of the DBW period 
(due to disease flare or completion) as follows:
o
Number of active joints
o
Number of joints with limited range of motion
o
Physician’s Global Assessment of Disease Activity
o
Parent’s Global Assessment of Well-Being
o
Physical function as measured by the CHAQ
o
Acute-phase reactant (hsCRP) and ESR
•
Proportion of patients with inactive disease (as defined by 
Wallace et al. 2011)
•
Proportion of patients with minimal disease activity (as defined 
by Consolaro et al. 2012)
•
Proportion of patients in remission (as defined by Wallace et al. 
2012)
•
Change from baseline in JADAS-27
•
Change from baseline in the PhS and PsS of the CHQ-PF50
•
Change from baseline in caregiver burden as measured by the 
Parental Impact-Time and Parental Impact-Emotion scales of the 
CHQ-PF50
•
Change from baseline in arthritis-related pain severity as 
measured by the CHAQ pain severity VAS item
•
To assess the efficacy of baricitinib in 
children with JPsA
•
Change in Psoriasis Area and Severity Index (PASI) score 
during the OLLI period.
•
To assess the efficacy of baricitinib 
compared to placebo in children with 
JPsA
•
Change from baseline in PASI score during the DBW period
•
To assess the efficacy of baricitinib in 
children with ERA or JPsA
•
Change in Spondyloarthritis Research Consortium of Canada 
(SPARCC) enthesitis index during the OLLI period.
•
Change in Juvenile Spondyloarthritis Disease Activity Index 
(JSpADA) during the OLLI period
•
To assess the efficacy of baricitinib 
compared to placebo in children with 
ERA or JPsA
•
Change from baseline in SPARCC enthesitis index at during the 
DBW period
•
Change from baseline in JSpADA during the DBW period
•
To evaluate the potential effects of 
baricitinib on the cellular and humoral 
immune system
•
Change in immunoglobulin levels and peripheral blood 
immunophenotyping (including T and B cells, T cell subsets, and 
NK cells) from baseline and at Week 4, Week 12, and Week 44
•
Change of IgG titers from pre-vaccination to 4 weeks and 
12 weeks post vaccination in patients eligible for vaccination 
with tDaP and/or pneumococcal conjugate vaccine according to 
local guidelines


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Objectives
Endpoints
•
To characterize baricitinib PK in the 
JIA population and explore 
relationships between baricitinib 
exposure and study endpoints
•
Population PK of baricitinib in patients with JIA
•
Proportions of patients achieving PedACR30/50/70/90/100 
response rates by PK exposure
•
Time to disease flare in patients with JIA by PK exposure 
•
Change in JADAS-27 by PK exposure
•
To assess the patient acceptability and 
palatability of baricitinib tablets and 
oral suspension
•
Assessment of tablet or oral suspension product acceptability and 
palatability during the OLLI period
•
To assess the safety of baricitinib 
compared to placebo in patients with 
JIA
•
Adverse events including serious adverse events
•
Permanent discontinuation of investigational product
•
Temporary interruption of investigation product
Exploratory

To evaluate the quality of life (QOL) in 
children with JIA treated with 
baricitinib

Change from baseline in European Quality of Life-5 
Dimensions–Youth version (EQ-5D-Y) scores during the OLLI 
period

To evaluate the QOL in children with 
JIA treated with baricitinib compared 
to placebo

Change from baseline in EQ-5D-Y scores during the DBW 
period

Change from baseline in the individual scales (Global Health; 
Physical Functioning; Role/Social Limitations-Physical; 
Role/Social Limitations-Emotional/Behavioral; Bodily 
Pain/Discomfort; Behavior; Global Behavior Item; Mental 
Health; Self-Esteem; General Health Perception; Change in 
Health; Parental-Impact-Time; Parental Impact-Emotion; 
Family-Activities; Family-Cohesion) as measured by the 
CHQ-PF50
Abbreviations:  CHAQ = Childhood Health Assessment Questionnaire; CHQ-PF50 = Child Health Questionnaire-
Parent Form 50; DBW = double-blind withdrawal; ERA = enthesitis-related juvenile idiopathic arthritis; 
ESR = erythrocyte sedimentation rate; HRQOL = health-related quality of life; hsCRP = high-sensitivity 
C-reactive protein; IgG = immunoglobulin G; JADAS-27 = Juvenile Arthritis Disease Activity Score-27; 
JIA = juvenile idiopathic arthritis; JPsA = juvenile psoriatic arthritis; JSpADA = Juvenile Spondyloarthritis 
Disease Activity Index; NK = natural killer; OLLI = open-label lead-in; PASI = Psoriasis Area and Severity 
Index; PedACR = Pediatric American College of Rheumatology; PK = pharmacokinetic(s); QOL = quality of 
life; SPARCC = Spondyloarthritis Research Consortium of Canada; tDaP = tetanus, diphtheria, and pertussis; 
VAS = Visual Analogue Scale.


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5. Study Design
5.1.
Overall Design
Study I4V-MC-JAHV (JAHV) is a multicenter, double-blind, randomized, placebo-controlled,
medication-withdrawal Phase 3 study in patients with JIA who have had an inadequate response 
or intolerance to treatment with at least 1 conventional or bDMARD.  Study JAHV has a 
safety/PK assessment period, an open-label lead-in (OLLI) period, and a double-blind 
withdrawal (DBW) period.
This study will include the following subsets:  polyarticular, extended oligoarticular, and 
enthesitis-related JIA (including juvenile-onset ankylosing spondylitis and JPsA).
Figure JAHV.1 illustrates the study design.
Study governance considerations are described in detail in Appendix 3.


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Abbreviations:  DBW = double-blind withdrawal; OLE = open-label extension; 
OLLI = open-label lead-in; PedACR30 = Pediatric American College of Rheumatology 
30 criteria; PK = pharmacokinetic(s); QD = once daily.
a
Staggered approach to enrollment by age group (12 to <18 years, 9 to <12 years, 6 
to <9 years, 2 to <6 years) will be implemented with older groups completing the 
safety/PK assessment period before younger groups are enrolled.  
b
Once the PK and safety profiles for an age group are confirmed, subsequent 
patients in that age group may enroll directly into the OLLI period.  If the 
comparability assessment in the safety/PK period for an age group is inconsistent
with baricitinib 4-mg exposures in adults with RA such that baricitinib dosage for 
the age group needs to be adjusted, the patients on the inconsistent dosage will 
discontinue the study and may enter the separate OLE study (JAHX).
c
Patients who experience a disease flare during the DBW period will discontinue 
the study and may proceed directly to the separate OLE study (JAHX).
Figure JAHV.1.
Study design for Clinical Protocol I4V-MC-JAHV.
Patients who complete the DBW period may enrol into a separate open-label extension (OLE)
study (Study JAHX).  Additionally, patients whose baricitinib dosage in safety/PK period is 
inconsistent with baricitinib 4-mg exposures in adults with RA based on comparability 
assessment for the age group as well as patients who experience a disease flare during the DBW 
period will discontinue this study and be offered participation in the OLE study (Study JAHX).
The study design allows for treatment with background cDMARDs, oral corticosteroids, and/or 
NSAIDs at a stable dose (refer to Section 7.7).


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5.1.1. Screening and Baseline Periods
The duration of 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 applicable) 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 will need to return 
within 48 to 72 hours later to read the skin test.  Treatments with concomitant JIA therapies 
during the study is permitted only as described in Section 7.7.  Patients will remain on 
background cDMARDs, oral corticosteroid, NSAIDs, and/or analgesics if patients are on stable 
doses of these treatments at screening (Sections 6.2 and 7.7). Patients who have previously been 
treated with bDMARDs are eligible for the study. However, treatment must have been 
discontinued 4 weeks prior to screening for TNF inhibitors, IL-1 inhibitors, IL-6 inhibitors, or 
abatacept and 6 months prior to baseline for rituximab.
Investigators should review the vaccination status of their patients and ensure that patients are up 
to date with all immunizations, and following 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 patients become eligible 
for vaccination with tetanus, diphtheria, and pertussis (tDaP) and/or pneumococcal 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. 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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5.1.2. Safety/PK Assessment
The Safety/PK assessment period will allow for collection of blood samples to determine if 
pediatric exposure to baricitinib in a cohort of 5 to 8 pediatric patients in each age group is 
consistent with baricitinib exposure in adults. Patients with estimated glomerular filtration rate 
(eGFR) <60 mL/min/1.73 m2 are excluded from the Safety/PK period, as described in 
Section 6.2.
Patients will receive baricitinib at a fixed dose by age group daily for approximately 2 weeks.  At 
least 5 (maximum of 8) patients will be enrolled in each age group for the JIA study to assess the
comparability of their PK and safety profile with that of baricitinib 4-mg in adults with RA.  The 
baricitinib dose will be adjusted as necessary if the comparability assessment demonstrates 
inconsistency with baricitinib 4-mg in adults with RA and an additional 5 to 8 patients from the 
respective age group will be enrolled to assess comparability.  The next age group may only be 
enrolled after the PK and safety profiles of the preceding age group are confirmed.  Enrollment 
will be staggered by age group (12 to <18 years, 9 to <12 years, 6 to <9 years, and 2 to <6 years;
see Appendix 7 for updated dosing based on the current data) with older age groups enrolling 
before younger groups.
This study uses “dual assessor” approach to avoid potential unblinding, which includes the Joint 
Assessor and the Physician Assessor (see Section 9).  Each assessment should be evaluated by 
the same assessor at all study visits including unscheduled and the scheduled final study visit 
whenever possible.
Patients who complete the Safety/PK assessment period will enter the OLLI period.  If the 
comparability assessment in Safety/PK period for an age group is inconsistent with baricitinib 
4-mg exposures in adults with RA and if the baricitinib dosage for the age group is adjusted for 
an additional comparability assessment, the patients on the inconsistent dosage will discontinue 
the study and be offered to enroll in the OLE Study JAHX. Patients who choose to enter Study 
JAHX will have their doses adjusted to the corrected dose.  Investigators will be notified of the 
Safety/PK assessment results and any potential adjustment to dosing.
5.1.3. Open-Label Lead-In Period
In the OLLI period, patients will receive oral baricitinib at a fixed dose by age group daily for 
approximately 12 weeks from baseline. This study uses “dual assessor” approach to avoid 
potential unblinding, which includes the Joint Assessor and the Physician Assessor (see 
Section 9). Each assessment should be evaluated by the same assessor at all study visits 
including unscheduled and the scheduled final study visit whenever possible.
5.1.4. Double-Blind Withdrawal Period
At Week 12, treatment response (based on PedACR30 criteria) will be reviewed for each patient.  
Patients who achieve at least a PedACR30 response will be randomized (1:1 ratio) to receive 
placebo or to remain on the same baricitinib dose for up to 32 weeks (DBW period) or until 
disease flare, whichever occurs first.  Patients who do not achieve PedACR30 will be considered 
nonresponders; these patients will be given the option of enrolling to the OLE study.


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Assessments of disease severity will be performed by the investigator at all study visits including 
unscheduled and the scheduled final study visit.  In this study, to prevent potential unblinding 
due to observed efficacy or laboratory changes, a “dual assessor” approach will be used to 
evaluate efficacy and safety at all study visits including unscheduled and the scheduled final 
study visit.  Refer to Section 9 for additional information regarding dual assessment procedures.
The primary efficacy endpoint is time to disease flare (flare defined as worsening of ≥30% in at 
least 3 of the 6 PedACR core criteria for JIA and an improvement of ≥30% in no more than 1 of 
the criteria) after being randomized to placebo or baricitinib at Week 12 through Week 44.  Refer 
to Section 9 for information regarding the PedACR core criteria.
To assess PedACR30 response at Week 12 for entry to the DBW phase and to diagnose disease 
flare on-site in a real-time manner, ESR is used as the acute-phase reactant for these measures.  
The sponsor will provide ESR kits to the site via the central laboratory.
5.1.5. 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. Patients who enroll in the OLE study (JAHX) do not need to return for a 
follow-up visit.
Patients who have received at least 1 dose of investigational product, do not have a PedACR30 
response rate at Week 12, experience a flare leading to discontinuation during the DBW (and are 
not moving to the OLE), or 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 chose 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
Approximately 197 patients will be enrolled with at least 128 patients (at least 10 patients with 
ERA [including JPsA]) randomized to be evaluated for the primary endpoint in the DBW.  The 
actual number of patients enrolled in the study may be adjusted upward or downward to allow 
for randomization of 128 patients.
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.


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5.4.
Scientific Rationale for Study Design
A withdrawal study design, as well as the primary endpoints of such a design (time to disease 
flare during the DBW period), are well accepted by pediatric rheumatologists and have been 
used in many other pediatric studies investigating treatments for JIA (Lovell et al. 2000, 2008; 
Ruperto et al. 2008; Brunner et al. 2015).
A withdrawal design offers all patients open-label treatment for a period of 12 weeks followed 
by a placebo-controlled randomized phase into which only responders from the OLLI phase are 
enrolled.  This design was selected because it is unethical to expose pediatric patients with JIA to 
placebo for an extended period of time.  This study design minimizes the amount of time patients 
will be exposed to placebo.  The study design also limits placebo exposure to those patients who 
have already experienced some benefit from the investigational product.
At the first disease flare in the DBW period, patients (receiving either placebo or baricitinib)
should be discontinued from Study JAHV and be offered the option to continue treatment with 
baricitinib in Study JAHX which allows the potential for additional concomitant medication. All 
patients in the DBW period who have achieved at least a PedACR30 at the end of OLLI period 
are considered to be responders to baricitinib.
5.5.
Justification for Dose
The dose selection for baricitinib in this JIA patient population is informed by the Phase 2 and 3 
data in adults with RA who demonstrated a positive benefit/risk profile for the 4-mg QD dose. 
Predicted concentration-versus-time data in RA patients 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; therefore, these patients will initially be dosed with 
4-mg QD dose (Figure JAHV.2; see Appendix 7 for updated dosing based on the current data). 
In contrast, concentrations in children <9 years would be expected to be toward the higher end of 
the range seen in adults; therefore this group of patients will initially receive a lower 2-mg QD 
dose.  If the interim analyses after the Safety/PK period demonstrate that the profiles are not 
comparable with the target PK in adults, adjusted baricitinib doses will be tested until both the 
PK are found to be comparable with the target profiles in adults.


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Abbreviations:  PK = pharmacokinetic; QD = once daily; RA = rheumatoid arthritis.
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 RA.
Figure JAHV.2.
Comparison of predicted steady-state concentrations of baricitinib in 
pediatric (solid lines) versus adults (gray dots) receiving 4-mg QD.


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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 with onset before the age of 16 years of any of the following 
forms of JIA as defined by ILAR criteria:
•
Polyarticular JIA (positive or negative for RF)
•
Extended oligoarticular JIA
•
ERA
•
JPsA
[3]
Have had an inadequate response or intolerance to treatment with ≥1 conventional 
or bDMARD.  Patients must have been treated for at least 12 weeks before 
inadequate response may be determined.
[4]
Patients with polyarticular JIA or extended oligoarticular JIA must have at least 
5 active joints at screening and baseline.  Those with JPsA must have at least 3 
active joints at screening and baseline.  Those with ERA must have (a) at least 3 
active joints at screening and baseline or (b) involvement of at least 1 sacroiliac 
joint AND a physician global assessment of at least 3 (on the 21-circle numeric 
rating scale [NRS]). Active joint is defined as the presence of joint swelling or, in 
the absence of swelling, joints with limitation of motion plus pain on motion and/or 
tenderness on palpation.
Informed Consent
[5]
Both the child or adolescent and a parent or legal guardian are able to understand 
and fully participate in the activities of the clinical study and sign their assent and 
consent, respectively, accordance to local guidelines.
Contraception
[6]
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).


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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, 
post-ovulation methods and withdrawal are not acceptable methods of 
contraception.
Otherwise, patients and their partners of childbearing potential must agree to 
use 2 effective methods of contraception, where at least 1 form is highly 
effective for the entirety of the study and for at least 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 childbearing potential.
Women of nonchildbearing potential are not required to use birth control 
and they are defined as:


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•
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 have any of the following criteria at 
screening and/or at baseline as specified below:
Medical Conditions
[7]
Have systemic JIA, as defined by ILAR criteria, with or without active systemic 
features.
[8]
Have persistent oligoarticular arthritis as defined by ILAR criteria.
[9]
Have a history or presence of any autoimmune inflammatory condition other than 
JIA, such as Crohn’s disease or ulcerative colitis.
[10] Have active anterior uveitis or are receiving concurrent treatment for anterior 
uveitis (patients with a history of uveitis should not be excluded).
[11] Have active fibromyalgia or other chronic pain conditions that, in the investigator’s 
opinion, would make it difficult to appropriately assess disease activity for the 
purposes of this study.
[12] 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.
[13] Bone, joint infections within 6 months prior to screening.
[14] Have symptomatic herpes simplex at baseline.
[15] Have had symptomatic herpes zoster infection within 12 weeks prior to baseline.
[16] Have a history of multidermatomal herpes zoster, complicated herpes zoster (e.g., 
ocular or motor nerve involvement or disseminated herpes zoster such as systemic 
infection).
[17] 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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[18] 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.
[19] Have evidence of human immunodeficiency virus (HIV) infection and/or positive 
HIV antibodies.
[20] Have had household contact with a person with active tuberculosis (TB) and did 
not receive appropriate and documented prophylaxis for TB.
[21] Have evidence of active TB or latent TB
a.
Have evidence of active TB, defined in this study as the following:

Positive PPD test (≥5 mm induration between approximately 2 and 
3 days 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
•
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).


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Exception:  Patients who have evidence of latent TB may be enrolled if 
they complete at least 4 weeks of appropriate treatment prior to 
randomization and agree to complete the remainder of treatment 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.
[22] Major surgery within 8 weeks prior to screening or requiring major surgery during 
the study that in the opinion of the investigator in consultation with Lilly or its 
designee would pose an unacceptable risk to the patient.
[23] 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.
[24] History of a VTE or are considered at high risk of VTE as deemed by the 
investigator.
[25] Largely or wholly incapacitated, such as being bedridden.
[26] History of lymphoproliferative disease; or have signs or symptoms suggestive of 
possible lymphoproliferative disease, including lymphadenopathy or splenomegaly; 
or have primary or recurrent malignant disease.
[27] History of chronic alcohol abuse, IV drug abuse, or other illicit drug abuse within 
the 2 years prior to screening.
[28] Presence of significant uncontrolled neuropsychiatric disorder, history of a suicide 
attempt or suicidal ideation, or clinically judged by the investigator to be at risk for 
suicide.
[29] History of hypogammaglobulinemia.
[30] Body temperature ≥38°C (100.5°F) at baseline.
[51] Have experienced hypersensitivity to the active substance or to any of the 
excipients.


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Prior/Concomitant Therapy
[31] Have initiated or changed dosage of concomitant cDMARDs (other than MTX) 
within 4 weeks prior to screening (such as, but not limited to, hydroxychloroquine, 
sulfasalazine, gold salts, cyclosporine, or azathioprine).  The dose of cDMARDs is 
expected to remain stable throughout the study and may be adjusted only for safety 
reasons.
[32] MTX use at doses of >20 mg/m2/week.
If continuing on MTX, must be on a stable dose of 20 mg/m2/week for the 
8 weeks preceding the screening. The dose of MTX is expected to remain 
stable throughout the study and may be adjusted only for safety reasons.
[33] Are currently receiving concomitant treatment with combination of >2 cDMARDs 
(including MTX).
[34] Have received prior biologic agents for any indication less than 4 weeks prior to 
screening for TNF inhibitors (e.g., etanercept, infliximab, certolizumab, 
adalimumab, golimumab), IL-1 inhibitors (e.g., anakinra), IL-6 inhibitors 
(e.g., tocilizumab), or abatacept and less than 6 months before baseline for
rituximab.
[35] Prior treatment with analgesics, including NSAIDs, on an unstable dose within 
1 week of baseline.
[36] Prior treatment with any parenteral corticosteroid administered by intra-articular, 
intramuscular, or intravenous injection within 4 weeks of baseline.
[37] Oral corticosteroid use at average daily doses of greater than 10 mg/day or 
0.2 mg/kg/day prednisone equivalent, whichever is less, or have done so within 
2 weeks prior to screening.  If continuing oral corticosteroids, must be on stable 
dose for 6 weeks prior to baseline.
[38] 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.
[39] Received any JAK inhibitors (including, but not limited to, tofacitinib or 
baricitinib) previously.
[40] Received 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.
[41] Patients who are receiving thyroxine as replacement therapy may participate in the 
study, provided stable therapy has been administered for ≥12 weeks and 
thyroid-stimulating hormone (TSH) is within the laboratory’s reference range.


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Exception: Patients who are receiving stable thyroxine replacement therapy 
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
[42] 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 are excluded from enrolling in the 
study (Bedside Schwartz formula 2009 or The Japanese Society for 
Pediatric Nephrology formula for patients in Japan)
•
eGFR <60 mL/min/1.73 m2 are excluded from the Safety/PK 
period of the study (Bedside Schwartz formula 2009 or The 
Japanese Society for Pediatric Nephrology formula for patients in 
Japan).
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.
[43] 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
[44] 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.
[45] 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.


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[46] Previously completed or withdrawn from this study or any other study investigating 
baricitinib.
Other Exclusions
[47] Donated blood within 4 weeks prior to screening or intend to donate blood during 
the course of the study.
[48] 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.
[49] Are Lilly or Incyte employees or immediate family.
[50] 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 [7] to [11] exclude individuals with conditions that may confound 
safety or efficacy analyses.
•
Exclusion Criteria [12] to [21] exclude individuals who are at an increased risk for 
infections or infectious complications.
•
Exclusion Criteria [22] to [30], and [51] exclude individuals with previous or 
concomitant medical conditions that increase the risk for their participation in the study.
•
Exclusion Criteria [31] to [41] exclude individuals who are taking or who may take JIA
medications or treatments that interfere with the ability to assess the safety and efficacy 
of baricitinib.
•
Exclusion Criteria [42] to [43] exclude individuals with laboratory parameters that may 
increase the risk for their participation in the study.
•
Exclusion Criteria [44] to [50] 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 from the 
previous screening date.  Each time rescreening is performed the legal representative must sign a 
new ICF and the child would sign an assent, as applicable. The individual will be assigned a 
new identification number.


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7. Treatments
7.1.
Treatments Administered
This study involves a comparison of baricitinib dose, by age (4-mg for children ≥9 years of age
and adolescents 12 to <18 years of age and 2-mg for children <9 years of age as the starting 
dose; see Appendix 7 for updated dosing based on the current data), with placebo in the DBW 
period. The dosages will be adjusted if the interim analyses after the Safety/PK period 
demonstrate that the profiles are not comparable with the target PK or safety profiles in adults. 
Therefore, a 1-mg dose is described in Table JAHV.5 should this be needed.
Baricitinib will be dosed as tablets or oral suspension QD based on the age of the patient at 
Visit 2 (for patients enrolled in the Safety/PK portion) and at Visit 5 (for all other patients); 
formulation will not change during the study.  Baricitinib should be taken with sufficient water 
or fluid to allow easy swallowing of the medication.  All patients <6 years of age will receive 
oral suspension. Patients ≥6 to <12 years old have the option of receiving the oral suspension. 
Patients >12 years old will be supplied tablets. Based on PBPK modeling, initial doses will be 
4-mg for adolescents 12 to <18 years old and in children ≥9 to <12 years old, and 2-mg in 
children <9 years old to produce exposures similar to those in adults after 4-mg QD 
administration. Refer to Section 5.5 for additional information. Table JAHV.5 shows the 
treatment regimens.
Table JAHV.5.
Treatment Regimens
Treatment Group
Treatments Administered
Safety/PK and OLLI Period
DBW Period
Baricitinib 4-mg
Baricitinib 4-mg oral QD tablet
Baricitinib 2-mg/mL oral suspension
Baricitinib 4-mg oral QD tablet
Baricitinib 2-mg/mL oral suspension
Baricitinib 2-mg
Baricitinib 2-mg oral QD tablet
Baricitinib 2-mg/mL oral suspension
Baricitinib 2-mg oral QD tablet
Baricitinib 2-mg/mL oral suspension
Baricitinib 1-mg
Baricitinib 1-mg oral QD tablet
Baricitinib 2-mg/mL oral suspension
Baricitinib 1-mg oral QD tablet
Baricitinib 2-mg/mL oral suspension
Placebo comparator
N/A
Baricitinib 4-mg placebo oral QD tablet
Baricitinib 2-mg placebo oral QD tablet
Baricitinib 1-mg placebo oral QD tablet
Baricitinib 2-mg/mL placebo oral 
suspension
Abbreviations: DBW = double-blind withdrawal; eGFR = estimated glomerular filtration rate; N/A = not 
applicable; OLLI = open-label lead-in; PK = pharmacokinetics; QD = once daily.
Note: Initial doses of baricitinib 4-mg for adolescent patients (12 to <18 years of age) and children ≥9 years of age
and baricitinib 2-mg for children <9 years of age will be given.  The oral suspension dose may be administered as 
4-mg, 2-mg, 1-mg, and 0.5-mg as needed.
Note: Patients with renal impairment or renal immaturity (defined as eGFR <60 mL/min/1.73 m2) at baseline will 
have their dose reduced by 50%.  Patients receiving the 1-mg dose who have renal impairment or renal 
immaturity will receive a dose-of 0.5-mg using the oral suspension.


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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
•
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 that all unused medication is to be 
destroyed by the site, as allowed by local law.
Placebo tablets are composed of lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, and magnesium stearate.  Tablet coating is comprised of polyvinyl alcohol–partially 
hydrolyzed, titanium dioxide, polyethylene glycol 3350, talc, lecithin (soya), and iron oxide red.
7.1.1. Packaging and Labeling
The sponsor (or its designee) will provide the following investigational products:
•
Tablets containing 4-mg of baricitinib
•
Tablets containing 2-mg of baricitinib
•
Tablets containing 1-mg of baricitinib
•
Placebo tablets to match baricitinib 4-mg tablets, 2-mg tablets, and 1-mg tablets
•
Suspension containing 2-mg/mL of baricitinib
•
Placebo to match suspension containing 2-mg/mL of baricitinib
Each tablet has a distinctive shape and color:  4-mg versus 2-mg versus 1-mg.  Each strength 
tablet has a matching placebo. Baricitinib oral suspension (containing 2-mg/mL baricitinib) and 
matching placebo 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.
Clinical study materials will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Patients who enter the PK lead-in period will be assigned a dose based on age.  Pharmacokinetic
samples will be collected as described in Section 9.5.  Doses of subsequent patients who enter 
the PK lead-in period may be adjusted until a dose is found that produces exposures within the 
range produced by baricitinib 4-mg in adults with RA.  All patients who enter the OLLI period 
will receive a fixed age-based dose of baricitinib as determined in the PK lead-in period.
Patients who meet the PedACR30 response criteria at the end of the OLLI period will be 
randomized in a 1:1 ratio (baricitinib age-based dose or matching placebo) to double-blind 
treatment at Week 12.  The randomization will be stratified by history of prior bDMARD use
(Yes versus No), the JIA category (polyarticular and extended oligoarticular versus ERA and 


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JPsA), and predose exposure ESR category (elevated [>20 mm/hour] and not elevated in the 
polyarticular JIA patients).  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 bottles containing double-blind investigational product to each patient.  All 
patients <6 years of age will receive oral suspension. Patients ≥6 to <12 years old have the 
option of receiving the oral suspension.  Patients >12 years will be supplied tablets only.  
Site personnel will confirm that they have located the correct packages by entering a 
confirmation number found on the packages into the IVRS or IWRS before dispensing to the 
patient.
Refer to Section 5.1.2 for additional information regarding dosing in the Safety/PK assessment 
and OLLI period.
7.2.1. Selection and Timing of Doses
The doses should be administered at approximately the same time each day.  The actual time of 
doses administered at a visit where a PK sample is collected will be recorded in the patient’s
electronic case report form (eCRF) according to Section 9.5.
7.3.
Blinding
The PK lead-in and OLLI periods of this study are open-label.  
The DBW period of this study is double-blind.  To preserve the blinding of the study during the 
DBW period, a minimum number of Lilly personnel will see the randomization table and 
treatment assignments before the study is complete.  All study assessments will be performed by 
study personnel who are blinded to the patient’s treatment group.  Except in clinical 
circumstances where unblinding is required, the patients, investigators, Lilly study team, and any 
personnel interacting directly with patients or investigative sites will remain blinded to 
baricitinib and placebo assignment until after database lock for the DBW period.  It is expected 
that the need for unblinding a patient’s treatment prior to database lock for DBW period will be 
extremely rare.  Every effort should be made to preserve the blind unless there is a compelling 
reason that knowledge of the specific treatment would alter the patient’s medical care.
Where feasible and when timing of the emergent situation permits, the investigator should 
attempt to contact the Lilly medical monitor before unblinding a subject’s treatment assignment.
Emergency unblinding for AEs may be performed through the IWRS.  This option may be used 
only if the patient’s well-being requires knowledge of the patient’s treatment assignment.  All 
unblinding events are recorded and reported by the IWRS.  If an investigator, site personnel 
performing assessments, or patient is unblinded, the patient must be discontinued from the study.  
In cases where there are ethical reasons to have the patient remain on the investigational product, 
the investigator must obtain specific approval from a Lilly clinical research physician for the 
patient to continue in the study or to discontinue the JAHV study, or to continue treatment with 
baricitinib in the OLE.


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Processes to maintain blinding during the interim analysis conducted by the data monitoring 
committee (DMC) are described in Section 10.3.11.
7.4.
Dosage Modification
The baricitinib dose for an individual patient will not change during the course of this study.  
However, the baricitinib dose for an age-based cohort may change based on the PK and safety 
profile of doses evaluated during the PK lead-in period.  All patients who complete the PK 
lead-in period will enter the OLLI period on the dose they received at the start of the PK lead-in 
period.  If the dose is modified for an age group after patients have already entered the OLLI
period, they will be discontinued from the study and will be given the option to move to a 
separate OLE and receive the modified dose.  Data from these patients will be censored from 
statistical analyses of efficacy endpoints in the present study.
The baricitinib dose for patients will be reduced by 50% in those who have renal impairment 
(defined as eGFR <60 mL/min/1.73 m2) at baseline.  Patients receiving the 1-mg tablet who have 
renal impairment at baseline will be dose-reduced to 0.5-mg using the oral suspension.
Patients with eGFR <60 mL/min/1.73 m2 are excluded from the safety/PK assessment period as 
described in Section 6.2.
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.
Only participants enrolled in the study 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 at each visit (except Visit 3) during 
the treatment period (baseline through Week 44).
Patients treated with baricitinib or placebo 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).


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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 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 JIA therapies during the study is permitted only as described below 
and in Table JAHV.6. The dosages of concomitant treatment may be adjusted only for safety 
reasons.
•
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 6 weeks prior to 
baseline and remain on the same dose throughout the study.  Patients should not 
receive other systemic corticosteroids during the study including intra-muscular or 
intra-articular corticosteroids.  Topical, intranasal, intra-ocular, and inhaled 
corticosteroids are permitted.
•
Chronic stable use of MTX is permitted and defined as average dose of 
≤20 mg/m2/week for at least 8 weeks prior to screening and continuation of that 
dose throughout the study.  Local standard of care should be followed for 
concomitant administration of folic acid.
•
Chronic stable usage of cDMARDs (other than MTX) is permitted on stable dose 
for at least 4 weeks prior to screening and continuation of that dose throughout the 
study.
•
Concomitant usage of >2 cDMARDs (including MTX) are not allowed.
•
Chronic stable use of NSAIDs and analgesics is permitted.  Patients must be on a 
stable dose for at least 1 week prior to baseline and increase in dose and/or 
introduction of new NSAIDs and analgesics are not permitted throughout the study.  
Dose reductions and/or termination of NSAIDs and analgesics are permitted.


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•
Patients receiving Organic Anion Transporter 3 (OAT3) inhibitors with a strong 
inhibition potential, such as probenecid, will have their dose of baricitinib reduced 
by 50%.
The following therapies will not be permitted during the course of the study as specified in the 
exclusion criteria (Section 6.2):
•
bDMARDs
•
Parenteral corticosteroids administered by intramuscular, intra-articular, or intravenous 
injection
•
Live vaccine (within 28 days prior to baseline or are expected to need/receive live 
vaccine during the course of the study) except booster immunization with attenuated 
vaccine for MMR or VZV.  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.


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Table JAHV.6.
Concomitant JIA Therapies
Drug Class
As Needed
Chronic Use
Conditions for Use
MTXa
No
Yes
If on MTX, must be on a stable average dose of 
≤20 mg/m2/week for the 8 weeks preceding screening and 
must continue at that dose throughout the study
cDMARDs other than 
MTXa
No
Yes
If receiving cDMARDs (other than MTX), must be on a 
stable dose for at least 4 weeks prior to the screening and 
must continue at that dose throughout the study.
Oral corticosteroids
No
Yes
If receiving oral corticosteroids, daily doses of 
≤10 mg/day or 0.2 mg/kg/day prednisone equivalent, 
whichever is less.  Must be on stable dose for at least 
2 weeks prior to screening and 6 weeks prior to baseline;
the dose must be continued throughout the study.
NSAIDsb
•
including 
cyclooxygenase-
2 inhibitors, e.g.,
celecoxib
No
Yes
•
Must be on stable dose at least 1 week prior to
baseline.
•
Changes in dose, discontinuation and/or 
introduction of new NSAIDs are only allowed
for treatment of an AE.
Analgesics
•
including local 
anaesthetics, e.g.,
lidocaine, and
•
topical 
anaesthetics, e.g.,
EMLA cream.
No
Yes
•
Must be on stable dose at least 1 week prior to
baseline.
•
Changes in dose, discontinuation and/or 
introduction of new analgesics are only allowed
for treatment of an AE.
Abbreviations:  cDMARD = conventional disease-modifying antirheumatic drug; MTX = methotrexate;
NSAID = nonsteroidal anti-inflammatory drug.
a
Concomitant use of >2 of any cDMARDs (including MTX) is not allowed.
b
For use as an anti-inflammatory agent.
7.8.
Treatment after the End of the Study
7.8.1. Study Extensions
Patients who complete this study and have a flare during the DBW period may be eligible to 
participate in the OLE (Study JAHX) if enrollment criteria for the OLE are met.
7.8.2. Special Treatment Considerations
Patients who experience a flare during the DBW period may proceed to Study JAHX if 
enrollment criteria for Study JAHX are met.  Additionally, if the comparability assessment in 
Safety/PK assessment period for an age group is inconsistent with baricitinib 4-mg exposures in 
adults with RA and baricitinib dose for the age group is adjusted for an additional comparability 
assessment, the patient on the inconsistent dosage will discontinue the study and may enter a 


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separate OLE study (JAHX) and be censored from statistical analyses of efficacy endpoints from 
the present study.
7.9.
Continued Access
After the conclusion of the study, continued access to baricitinib will not be provided unless the 
patient proceeds to Study JAHX.


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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 JAHV.7.
For the abnormal laboratory findings and clinical events (regardless of relatedness) listed in 
Table JAHV.7, 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 JAHV.7 may be restarted at the discretion of the investigator.
Table JAHV.7.
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/μL
(<2.00 x 103/μL or <2.00 billion/L)
WBC count ≥3000 cells/μL
(≥3.00 x 103/μL or ≥3.00 billion/L)
ANC <1000 cells/μL
(<1.00 x 103/μL or <1.00 billion/L)
ANC ≥1500 cells/μL
(≥1.50 x 103/μL or ≥1.50 billion/L)
Lymphocyte count <500 cells/μL
(<0.50 x 103/μL or <0.50 billion/L)
Lymphocyte count ≥1000 cells/μL
(≥1.00x103/μL or ≥1.00 billion/L)
Platelet count <75,000/μL
(<75 x 103/μL or <75 billion/L)
Platelet count ≥100,000/μL
(≥100 x 103/μL 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.
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.


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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 total bilirubin level (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/μL (1.00 x 103/μL or 1.00 billion/L)
•
ANC <500 cells/μL (0.50 x 103/μL or 0.50 billion/L)
•
Lymphocyte count <200 cells/μL (0.20 x 103/μL 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 JAHV.7) 
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.
In addition, patients will be discontinued from investigational product in the following 
circumstances:
•
Pregnancy
•
Malignancy
•
HBV DNA detected with a value above limit of quantitation (see Section 9.4.4)
•
Development of a VTE (DVT/PE) during the study 


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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
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).
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 by the DMC 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.
•
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).


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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 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.
In this study, to prevent potential unblinding due to observed efficacy or laboratory changes, a 
“dual assessor” approach will be used to evaluate efficacy and safety.
The Joint Assessor (or designee) should be a rheumatologist or skilled joint assessor and will be 
responsible for completing the joint counts for swelling, tenderness, and limited range of motion.
Additionally, the Joint Assessor will perform assessment of enthesitis and sacroiliitis (psoriatic 
arthritis and ERA populations). To ensure consistent joint evaluation throughout the study, 
individual patients should be evaluated by the same Joint Assessor for all study visits whenever 
possible. The Joint Assessor will not be involved in patient care and are asked to refrain from 
discussing disease activity or treatment with the patient, caregiver/legal guardian, principal 
investigators, or other site personnel. Likewise, the Joint Assessor should not access 
patient/parent/family-reported forms, Physician’s Global Assessment of Disease Activity, or
safety assessments.
The Physician Assessor (or designee) should be a pediatric rheumatologist (or medically 
qualified physician) and will have access to both safety and efficacy data. The Physician
Assessor may be the principal investigator. The Physician Assessor will be responsible for 
completing the Physician’s Global Assessment of Disease Activity. The Physician Assessor may 
delegate other assessments to another appropriately qualified assessor. To ensure consistent 
assessment throughout the study, this instrument should be completed by the same assessor at all 
study visits, whenever possible. The Physician Assessor will have access to source documents,
laboratory results, and case report forms (CRFs), and will be responsible for making treatment
decisions based on a patient’s clinical response and laboratory parameters.
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 paediatric phlebotomy should perform blood draws at the clinic.  
Blood draws should be consolidated and the number of attempts should be kept to the minimum 
number required.  The number of sampling attempts should be minimized, in keeping with local 
guidelines and procedures.  For example, it is recommended that after one unsuccessful attempt, 
another experienced person should take over the procedure.


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9.1.
Efficacy Assessments
9.1.1. Primary Efficacy Assessments
The primary efficacy assessment is to determine the time to disease flare from Week 12 to the 
end of the DBW period.  Disease flare is defined as a worsening of ≥30% in at least 3 of the 
6 PedACR core criteria for JIA and an improvement of ≥30% in no more than 1 of the criteria 
from the patient’s condition at the conclusion of the OLLI period.  If either the number of joints 
with active arthritis or the number of joints with limitation of motion are used in the calculation 
of flare for a study visit, then a minimum worsening of at least 2 active joints or 2 joints with 
limitation of motion must be evident.  If either the Physician’s Global Assessment of Disease 
Activity or the Parent’s Global Assessment of Well-Being are used in the calculation of flare for 
a study visit, then a minimum worsening on a visual analogue scale (as defined in the SAP) must 
be evident (Brunner et al. 2002, Ruperto et al. 2008).  In order to diagnose PedACR30 response 
at Week 12 and “flare” during the DBW period on-site in a timely manner, ESR is used as the 
acute phase reactant in PedACR core criteria.
9.1.2. Secondary Efficacy Assessments
Secondary endpoints (assessed at each visit, except Visit 3) are as follows:
•
Proportion of patients with disease flare during the DBW period.
•
Changes from baseline in each of the 6 individual components of the PedACR core set 
variables during the OLLI period and during the DBW period
•
PedACR30/50/70/90/100 response rates during the OLLI period and during the DBW 
period.
•
Changes from baseline in the Physical Summary Score (PhS) and Psychosocial Summary 
Score (PsS) of the Child Health Questionnaire-Parent Form 50 (CHQ-PF50) during the 
OLLI period and during the DBW period.
•
Changes from baseline in caregiver burden as measured by the Parental Impact-Time and 
Parental Impact-Emotion scales of the CHQ-PF50 during the OLLI period and during the
DBW period.
•
Proportion of patients with inactive disease (as defined by Wallace et al. 2011) during the 
OLLI period and during the DBW period.
•
Proportion of patients in remission (as defined by Wallace et al. 2012) during the DBW 
period.
•
Proportion of patients with minimal disease activity (as defined by Consolaro et al. 2012)
during the OLLI period and during the DBW period.
•
Change from baseline in JADAS-27 during the OLLI period and during the DBW period.
•
Changes from baseline in arthritis-related pain severity as measured by the CHAQ pain
severity VAS item during the OLLI period and during the DBW period.
•
In patients with JPsA:
o
Change from baseline in PASI score during the OLLI period and during the DBW 
period.
•
In patients with JPsA or ERA:


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o
Change from baseline in SPARCC enthesitis index during the OLLI period and 
during the DBW period.
o
Change from baseline in the JSpADA during the OLLI period and during the 
DBW period.
•
Change in immunoglobulin levels and peripheral blood immunophenotyping (including 
T and B cells, T cell subsets, and NK cells) from baseline during the OLLI period and 
during the DBW period.
•
Change of IgG titers from pre-vaccination to 4 weeks and 12 weeks post-vaccination in 
patients eligible for vaccination with tDaP and/or pneumococcal conjugate vaccine 
according to local guidelines.
•
Assessment of tablet or oral suspension product acceptability and palatability at baseline
and Week 12.
•
Safety variables
o
AEs including SAEs
o
Permanent discontinuation of investigational product
o
Temporary interruption of investigational product
9.1.2.1. PedACR30/50/70/90/100 Assessments
The PedACR30 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%. Pediatric ACR50 and ACR70 improvement 
criteria are defined as above with improvements of 50% and 70%, respectively.
•
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
•
Physician’s Global Assessment of Disease Activity (21-circle visual analogue scale 
[VAS]) (Section 9.1.2.7)
•
Parent’s Global Assessment of Well-Being (Section 9.1.5)
•
Physical function as assessed by the Childhood Health Assessment Questionnaire 
(CHAQ) (Section 9.1.5)
•
Acute-phase reactant (hsCRP and ESR)
ACR50, ACR70, ACR90, and ACR100 responses are efficacy measures that are calculated as 
improvements of at least 50%, 70%, 90% and 100%, respectively, in the PedACR Core Set 
values listed above.  
9.1.2.2. Juvenile Arthritis Disease Activity Score-27
The JADAS-27 score is a validated composite disease activity measure for JIA (Consolaro et al. 
2012).  Recently, the scoring system was adapted to use the 27-joint count (Bazso et al. 2009), 
and hsCRP or ESR for the inflammatory marker component (Nordal et al. 2012).  The 
JADAS-27 includes the following joints: cervical spine, elbows, wrists, metacarpophalangeal 
joints (from first to third), proximal interphalangeal joints, hips, knees, and ankles.


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JADAS-27 score will be determined based on 4 components:
•
Physician’s Global Assessment of Disease Activity (Section 9.1.2.7)
•
Parent’s Global Assessment of Well-Being (from CHAQ; Section 9.1.5)
•
Number of joints with active disease (27-joint assessment)
•
hsCRP or ESR as applicable
9.1.2.3. Disease Activity
Minimal Disease Activity
Minimal disease activity is calculated based on the scores from the Physician’s Global Assessment 
of Disease Activity (Section 9.1.2.7), Parent’s Global Assessment of Well-Being (Section 9.1.5), 
and the number of swollen joints as described in the SAP and Consolaro et al. 2012.
Inactive Disease
Inactive disease is indicated by the presence of all of the following (Wallace et al. 2011):
•
No joints with active arthritis based on JADAS-27 (Section 9.1.2.1)
•
No fever, rash, serositis, splenomegaly, hepatomegaly, or generalized lymphadenopathy
attributable to JIA as assessed by the investigator
•
No active uveitis as assessed by the investigator
•
Normal erythrocyte (ESR) or hsCRP (i.e., within normal limits in the local laboratory or, 
if elevated, not attributable to JIA)
•
Physician’s Global Assessment of Disease Activity indicating no active disease (best 
possible score on scale [0]) (Section 9.1.5)
•
Duration of morning stiffness ≤15 minutes
Remission
Remission is defined as inactive disease for at least 24 consecutive weeks (Wallace et al. 2012).
9.1.2.4. Psoriasis Area and Severity Index
The PASI combines assessments of the extent of body-surface involvement in 4 anatomical 
regions (head, trunk, arms, and legs).  It also assesses the severity of erythema (redness), plaque 
induration/infiltration (thickness), and desquamation (scaling) in each region, yielding an overall 
score of 0 (no psoriasis) to 72 (most severe disease [Fredriksson and Pettersson 1978; 
Mease 2011]).
The head, upper extremities, lower extremities, and trunk are assessed separately and then 
combined using weighting based on the surface area represented by each area (head = 0.1, upper 
extremities = 0.2, trunk = 0.3, and lower extremities = 0.4).  The degree of erythema, induration, 
and scale in each area is judged on a 0 to 4 scale, the sum of which represents disease severity.  
The area of involvement of each area is graded from 0 to 6, depending on the estimated 
percentage of lesional area (0 = 0%, 1 = 1% to 9%, 2 = 10% to 29%, 3 = 30% to 49%, 4 = 50% 
to 69%, 5 = 70% to 89%, and 6 = 90% to 100%).  These body scores are multiplied by the 
disease severity score and the weighting for each body area, yielding a score between 0 and 72.  
The PASI score will be program-generated.


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Further practical details help the assessment:  (1) the neck is assessed as part of the head; (2) the 
axillae and groin are assessed as part of the trunk; (3) the buttocks are assessed as part of the 
lower limbs; (4) when scoring the severity of erythema, scales should not be removed.
9.1.2.5.
Spondyloarthritis Research Consortium of Canada Enthesitis Index 
The SPARCC enthesitis index is used to measure the severity of enthesitis, which assesses 16 
sites for enthesitis using a score of “0” for no activity or “1” for activity (Maksymowych et al. 
2009).  The SPARCC enthesitis index is the sum of all site scores (range 0 to 16), with higher 
scores indicating more severe enthesitis.  The sites assessed include medial epicondyle (left/right 
[L/R]), lateral epicondyle (L/R), supraspinatus insertion into greater tuberosity of humerus (L/R), 
greater trochanter (L/R), quadriceps insertion into superior border of patella (L/R), patellar 
ligament insertion into inferior pole of patella or tibial tubercle (L/R), Achilles tendon insertion 
into calcaneum (L/R), and plantar fascia insertion into calcaneum (L/R).
9.1.2.6. Juvenile Spondyloarthritis Disease Activity Index
The JSpADA is used to evaluate the disease activity of juvenile spondyloarthritis (Weiss et al. 
2014).  The range of possible scores is 0 to 8, where higher scores indicate more disease activity.
The Juvenile Spondyloarthritis Disease Activity Index scores will be determined by 8 
components:
•
Active joint count: 0 joints = 0, 1 to 2 joints = 0.5, >2 joints = 1
•
Active enthesitis count: 0 entheses = 0, 1 to 2 entheses = 0.5, >2 entheses = 1
•
Pain over the past week as assessed using a 0-10 NRS (0 = no pain; 10 = pain as bad as 
your child can imagine: 0 = 0, 1 to 4 = 0.5, 5 to 10 = 1
•
CRP level related to juvenile spondyloarthritis activity: normal = 0, 1 to 2 times 
normal = 0.5, >2 times normal = 1
•
Morning stiffness >15 minutes: Absent = 0, Present = 1
•
Clinical sacroiliitis (defined as the presence of ≥2 of the following: tenderness on 
examination, positive Patrick’s test or flexion, abduction and external rotation (FABER) 
test, and inflammatory back pain): Absent = 0, Present = 1
•
Uveitis (any uveitis including acute/symptomatic and chronic/asymptomatic disease): 
Absent = 0, Present =1
•
Back mobility (abnormal back mobility defined as modified Schober’s test <20 cm): 
Normal = 0, Abnormal = 1
9.1.2.7. Physician’s Global Assessment of Disease Activity
The Physician’s Global Assessment of Disease Activity is used 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. Exploratory Efficacy Assessment
The EQ-5D-Y is a widely used, generic questionnaire that assesses health status “today”
(Ravens-Sieberer et al. 2010).  The first part assesses 5 dimensions (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression).  This part of the EQ-5D-Y can be used to 


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generate a health state index score, which is often used to compute a quality-adjusted life years 
(QALY) for utilization in health economic analyses.
9.1.4. 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 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) to Week 4, 12, and 44 (end of DBW 
period) will be assessed.
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 are 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.
9.1.5. Health Outcomes
Childhood Health Assessment Questionnaire
The Childhood Health Assessment Questionnaire (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; 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 (Ruperto et al. 2001):
•
Parent’s Global Assessment of Well-Being
o
This is a component of the PedACR core response set as well as the JADAS-27
o
The instrument is a 0 to 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 to 100 mm VAS that assesses the current level of pain 
severity over the past week, where 0 = “No pain”  and 100 = “Very severe pain”.


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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
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.
European Quality of Life-Five Dimensions-Youth (EQ-5D-Y)
The EQ-5D-Y is a widely used, generic questionnaire that assesses health status “today” (The 
EuroQol Group 2014).  It is completed by parents (proxy) for children aged 4 to 7 years; for 
children aged 8 years and older, the EQ-5D-Y will be self-completed (children aged <4 years
will not complete this assessment per developer recommendation); respondents will continue 
with the version of the instrument they begin the study with even if they change age during the 
course of the study.  The questionnaire consists of 2 parts:  the first part assesses 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) that have 3 
possible levels of response (no problems, some problems, or a lot of problems).  This part of the 
EQ-5D-Y can be used to generate a health state index score, which is often used to compute 
QALY for utilization in health economic analyses.  The health state index score is calculated 
based on the responses to the 3 dimensions, providing a single value on a scale from less than 0 
(where zero is a health state equivalent to death; negative values are valued as worse than dead) 
to 1 (perfect health), with higher scores indicating better health utility.
The second part of the questionnaire consists of a visual analog scale on which the patient rates 
their perceived health state from 0 (“the worst health you can imagine”) to 100 (“the best health 
you can imagine”).  Published studies by EuroQol Group members showed preliminary evidence 
of the instrument’s feasibility, reliability, and validity (Ravens-Sieberer et al. 2010).  The scale 
will be given to the parent/patient by the site investigator and self-completed by the 
parent/patient while they are at the site.  The investigator will be responsible for checking for 
missing responses.


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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 duration.  Responses are yes/no.
Patient’s Assessment of Pain Numeric Rating Scale (NRS)
The physician will ask the parent/legal guardian to rate their child’s worst level of pain over the 
past week using a 0-10 NRS (0 = no pain; 10 = pain as bad as your child can imagine). 
Product Acceptability and Palatability Assessments
The caregiver/legal guardian/patient will be asked to provide responses to questions designed to 
assess the acceptability and palatability of the formulations, either tablet or oral suspension.  The 
questionnaire for tablet acceptability will assess the subject’s ability to swallow the tablet.  The 
questionnaire for suspension acceptability and palatability will assess the subject’s experience 
relating to the taste and smell of the suspension and ease of administering and taking the 
suspension (Davies and Tuleu 2008; Kozarewicz 2014).
The appropriate questionnaire will be administered at baseline (after initial dose) and Visit 9
(after approximately 12 to 14 weeks of use). The questionnaire will be responded to by parents 
(proxy) for children aged 2 to 7 years. For children aged 8 years and older, the questionnaire
will be self-completed.
9.1.6. Appropriateness of Assessments
All assessments utilized in this study are standard, widely used, and generally recognized as 
reliable, accurate, and relevant.
9.2.
Adverse Events
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.


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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 their assessment of the potential relatedness of each AE to 
protocol procedure and/or investigational product, via electronic data entry.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to 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:
•
Death
•
Initial or prolonged in-patient 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 patient has signed the ICF and Assent Form (as applicable) and has 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 as per 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 a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 


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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 
electronic data entry system.
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/she considers the event reasonably possibly related to 
the study treatment or study participation, the investigator must promptly notify Lilly.
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 the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the 
identification, recording, and expedited reporting of SUSARs that are consistent with global 
regulations and the associated detailed guidances.
9.2.2. 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 9.4.6)
•
Venous thromboembolism (deep vein thrombosis and pulmonary embolism)
•
Arterial thrombotic events (see Section 9.4.6)
Sites 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 to 
facilitate process and product improvements.
Patients (or caregivers/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.


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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 
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). 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.  Patients in the age cohort of age 2 to 
≤7 years will not have flow cytometry testing due to blood volume limitations.
Use of local anesthetics (e.g., EMLA cream) consistent with local prescribing information is
permitted during the study visit to ease discomfort associated with venipunctures.  With the 
exception of laboratory test results that may unblind the study, Lilly or its designee will provide 
the investigator with the results of laboratory tests analyzed by 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 AE via electronic data entry.


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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 in Section 2).
Patients who are hBcAb positive and HBV DNA negative (undetectable) at screening will 
require measurement of HBV DNA at Visit 9, Visit 12, Visit 15, Visit 17, ETV, 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 kinase to confirm the 
abnormality and to determine if it is increasing or decreasing. If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator and in 
consultation with the study medical monitor. Monitoring of ALT, AST, TBL, and ALP should
continue until levels normalize or return to approximate baseline levels. 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)


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•
permanent discontinuation of investigational product due to hepatic event or 
hepatic lab abnormality
•
hepatic SAE
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.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the DMC (refer to Interim Analyses section, Section 10.3.11) 
can request additional analyses of the safety data.
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 in a blinded manner by Lilly during the clinical
study.  These reports will be reviewed to ensure completeness and accuracy but will not be
unblinded to Lilly during the clinical study.  If a death or a clinical AE is deemed serious,
unexpected, and possibly related to investigational product, only Lilly Global Patient Safety will
be unblinded for regulatory reporting and safety monitoring purposes.  These measures will
preserve the integrity of the data collected during this study and minimize any potential for bias
while providing for appropriate safety monitoring.
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, stroke), other 
cardiovascular events (such as hospitalization for unstable angina, hospitalization 
for heart failure, serious arrhythmia, resuscitated sudden death, cardiogenic shock, 
coronary interventions), arterial thromboembolic events, 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 deep vein thrombosis or pulmonary embolism, 
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 


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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 baseline and postbaseline for the assessment of physical 
growth according to the Schedule of Activities (Section 2). Height and weight changes in 
pediatric patients (both at 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 (IGF-BP)-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 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. MRI instead of 
x-ray), the local addendum should be followed. Otherwise, the current protocol amendment 
should be followed with regard to knee x-rays. 
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).
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 Davies 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.
9.5.
Pharmacokinetics
9.5.1. Pharmacokinetic Strategy
The doses for this study were selected based on PK modeling such that the highest dose in an age 
cohort is expected to produce baricitinib exposure similar to that produced by 4-mg in adult 
patients with RA.  For adolescent patients (aged 12 to <18 years) and children ≥9 years, that dose 
is expected to be 4-mg QD, whereas in children aged ≥6 to <9 and ≥2 to <6 years the dose is
expected to be 2-mg QD.


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Before enrolling a majority of patients, the PK in adolescent patients receiving 4-mg QD will be 
evaluated in a small number of lead-in patients to confirm the suitability of this dose in 
adolescent patients with JIA.  Patients will be dosed QD and serial blood samples will be 
collected at steady state for analysis of baricitinib concentrations.  Refer to Section 9.5.2 for 
details.  The PK in individual patients will be evaluated using noncompartmental methods and 
will inform dose selection for subsequent adolescent patients.  No adolescent patients will be 
enrolled directly into the OLLI period until the PK in the lead-in patients has been evaluated.
For younger cohorts of PK lead-in patients (aged ≥9 to <12 years, aged 6 to <9 years and aged 2 
to <6 years), the same lead-in process will be performed as that for adolescents.  The PK lead-in 
period for patients aged ≥9 to 12 years will complete before the PK lead-in period for patients 
aged 6 to <9 years can begin, and this one will also complete before the PK lead-in period for 
patients 2 to <6 years can begin (Section 5.1.2).
For patients enrolled directly into the OLLI period, sparse blood samples for PK analysis will be 
collected as described in Section 9.5.3.  These will be analyzed at the end of the study using 
population PK methods.  Microsampling may be used by patients participating in the Safety/PK
period if kits and assays are available for some of the PK sample collections.
9.5.2. Safety/PK Assessment Lead-in Period
A blood sample will be collected at the times indicated in the Schedule of Activities (Section 2).  
These blood samples will be used to determine the concentrations of baricitinib using a validated 
bioanalytical method.  The timing will be as follows:
•
At Day 1, patients will take their investigational product and PK samples will be 
collected 15 minutes and 1 hour postdose.
•
At Day 4, patients will take their investigational product at home.  The first blood 
sampling collected during this visit is collected 2 hours after the dose is taken and 
includes a microsample and venous blood sample. The second blood sample, which can 
be collected as a microsample, is collected 4 hours after the dose is taken.
•
At Day 14, a PK sample will be collected BEFORE the investigational product is taken.  
Immediately after the PK sample is collected, the patient will take the investigational 
product.  A PK sample will also be collected at each of the following times after the dose 
is given: 30 minutes and 6 hours.
For visits where PK samples will be collected, the actual date and 24-hour clock time of sample 
collection, and the date and time of the last 2 doses should be recorded.  At Day 4 and Day 14, 
these 2 doses should be the dose given on the morning of the day of sample collection and the 
dose given the previous day. This sampling schedule should be followed as closely as possible; 
however, failure to take PK samples at these specified times will not be considered a protocol 
violation. If the patient fails to follow the directions for a particular visit, the sample should still 
be collected at that visit, and the date and 24-hour clock time of sample collection and the date 
and 24-hour clock time of the 2 doses prior to the sample being drawn should be recorded.


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Safety variables (AEs including SAEs, permanent discontinuation of investigative product, 
temporary interruptions of investigative product) will be assessed throughout this period. Refer 
to Section 10.3.4 for additional information regarding safety assessments.
9.5.3. OLLI Assessment Period
A venous blood sample will be collected at the times indicated in the Schedule of Activities 
(Section 2).  These blood samples will be used to determine plasma concentrations of baricitinib
using a validated bioanalytical method. The timing will be as follows:
•
At Visit 5, patients will take their investigational product in the clinic, and PK 
samples will be collected 15 minutes and 1 hour postdose.
•
At Visit 6, patients will be asked to take their investigational product at home 
prior to visiting the clinic.  The clinic visit should be scheduled so that the blood 
sample collected during this visit is collected 2 to 4 hours after the dose is taken at 
home.
•
At Visit 7, patients will be asked to take their investigational product at home 
prior to visiting the clinic.  The clinic visit should be scheduled so that the blood 
sample collected during this visit is collected 4 to 6 hours after the oral dose is
taken at home.
•
For Visit 8 and Visit 9, patients will be asked to not take their investigational 
product before visiting the clinic and a blood sample will be collected at any time 
predose on the day of the clinic visits.  If the patient has taken the oral dose prior 
to the visit, the sample may be collected anytime postdose.
•
For an early termination visit prior to Visit 9, a sample may be drawn anytime if 
the last dose of investigational product was taken within the last 48 hours.
Visit 5 samples will not be collected for patients who were in the PK lead-in portion of the study.
For visits at which PK samples will be collected, the actual date and 24-hour clock time of 
sample collection, and the date and time of the last 2 doses prior to the sample being collected, 
will be recorded.  At Week 2 and Week 4, the 2 previous doses should be the dose taken on the 
morning of the day of sample collection and the dose taken the day before that.  At Week 8 and 
Week 12, these 2 doses should be the dose given on the morning prior to the day of sample 
collection and the dose given the day before that.
If the patient fails to follow the directions for a particular visit, the sample should still be 
collected at that visit.  The date and 24-hour clock time of sample collection and the date and 
time of the 2 doses prior to the sample being collected will be recorded.
Pharmacokinetic samples will be stored at a laboratory facility designated by the sponsor.  
Pharmacokinetic samples may also be assayed for additional exploratory analyses.  
Pharmacokinetic results will not be provided to investigative sites.  Bioanalytical samples 
collected to measure investigational product concentration will be retained for a maximum of 
1 year following the last patient visit for the study.


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9.6.
Pharmacodynamics
Refer to Section 10.3.6.
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 samples 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, mechanism of action of baricitinib, and/or research 
method, or to validate diagnostic tools or assay(s) related to JIA.
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, or for a shorter period if local regulations require.  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.
9.8.
Medical Resource Utilization and Health Economics
The EQ-5D-Y is being collected in this study to collect data for input into economic models.  See 
Section 9.1.5 for instrument description.


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10.
Statistical Considerations
10.1. Sample Size Determination
A total of 128 patients will be randomized in a 1:1 ratio to baricitinib or placebo (64 per 
treatment arm) in the DBW period.  This sample size will provide approximately 80% power to 
detect the difference in time to disease flare between the 2 treatment groups using a 2-sided test 
with a significance level of 0.05, assuming that the expected percentages of patients experiencing 
disease flare in the DBW period are 35% for baricitinib and 60% for placebo and that the 
dropout rate is no greater than 10% in this period.
It is estimated that 197 patients are required to enter the OLLI period to allow 128 patients to be 
randomized into the DBW period (assuming that 65% of the patients meet the PedACR30 
criteria at the end of the OLLI period).  The nonresponder and dropout rate will be monitored 
during the OLLI period to adjust the overall sample size to ensure that a minimum of 
128 patients will be randomized in the DBW.  If the PedACR30 response rate during the OLLI 
period is higher than the assumed rate of 65%, fewer than 197 patients may be required.
The above sample size and power estimates are based on nQuery®+nTerim 4.0.
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined based on the different treatment 
period:
Population
Description
Entered population
All participants who sign informed consent.
Safety/PK population
All patients who received at least 1 dose of investigational product in Safety/PK
assessment period.
OLLI population
All participants who take at least 1 age-based final dose as confirmed by PK 
assessments of investigational product in the OLLI period, other than the 
Safety/PK population.
DBW population
All randomized patients in DBW period following intent-to-treat (ITT)
principles.
DBW safety population
All randomized patients in DBW period who receive at least 1 dose of 
investigational product.
General safety population
All patients who received at least 1 dose of investigational product.
Abbreviations:  OLLI = open-label lead-in; DBW = double-blind withdrawal; ITT = intent to treat; 
PK = pharmacokinetic.


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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 
statistical analysis plan (SAP) describing the statistical methodologies will be developed by Lilly 
or its designee.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.
The primary endpoint will be the time-to-flare during the DBW period for randomized patients.  
Patients who discontinue the DBW period without experiencing a flare will have their data 
censored.  Survival curves will be estimated using the Kaplan–Meier method for all “time-to” 
variables in the DBW period.
Efficacy and health outcome endpoints will be summarized using descriptive statistics for the 
OLLI population during OLLI period. Treatment comparisons will be performed for the DBW 
population in the DBW period.
Continuous data will be summarized in terms of the mean, standard deviation, minimum, 
maximum, and median.  Continuous efficacy and health outcome variables will be evaluated 
using an analysis of covariance (ANCOVA) model with treatment, JIA patient category 
(polyarticular and extended oligoarticular versus ERA and JPsA), prior bDMARD use, and 
baseline score in the model.  The last observation carried forward (LOCF) approach will be used 
to impute missing data.
Categorical data will be summarized as frequency counts and percentages.  Categorical efficacy 
variables will be evaluated using a logistic regression analysis with treatment, JIA patient 
category (polyarticular and extended oligoarticular versus ERA and JPsA), and prior bDMARD 
use in the model.  The proportions and 95% confidence interval will be reported.  Missing data 
will be imputed using the nonresponder imputation (NRI) method.
A futility analysis will be conducted using the PedACR30 response rate observed in the first 
100 patients complete OLLI phase.  The futility analysis will be based on 50% of patients 
achieving a PedACR30 response rate at the end of OLLI phase.  The study will stop for futility if 
<50% of the first 100 patients to complete the OLLI period have a PedACR30 response.
All safety data will be descriptively summarized in each treatment period using corresponding 
populations.  Comparison between baricitinib and placebo will be performed during the DBW 
period for the DBW population.  The Fisher exact test will be used for the AEs, discontinuations, 
and other categorical safety data for between-treatment-group comparisons in the DBW period.  
Continuous vital signs, body weight, and other continuous safety variables, including laboratory 
variables, will be analyzed using ANCOVA with treatment and baseline value in the model in 
the DBW population.
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 


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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 was approved before the first patient visit in Study JAHV.  
Missing Data Imputation
The following methods for imputation of missing data will be used:
1. Nonresponder imputation (NRI):  All patients who discontinue the study will be defined 
as nonresponders for the NRI analysis for categorical variables, such as
PedACR30/50/70/90/100, from the time of discontinuation and onward.
2. 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.
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
The number of patients along with enrolled, OLLI, DBW, and safety populations will be 
summarized.  Frequency counts and percentages will be presented.  All patients who discontinue 
from the study will be identified, and the extent of their participation in the study will be reported 
along with their reason for discontinuation.  Reasons for discontinuation from the study will be 
summarized.
10.3.2.2. Patient Characteristics
Demographic and baseline characteristics will be summarized descriptively.  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 ACR pediatric JIA core set variables, JADAS, SPARCC (for patients 
with enthesitis at baseline), and JSpADA.
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.


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10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary efficacy endpoint is time to disease flare (flare defined as worsening of ≥30% in at 
least 3 of the 6 PedACR core criteria for JIA and an improvement of ≥30% in no more than 1 of 
the criteria) during the DBW period for the DBW population.  If either the number of joints with 
active arthritis or the number of joints with limitation of motion are used in the calculation of 
flare for a study visit, then a minimum worsening of at least 2 active joints or 2 joints with 
limitation of motion must be present.  An active joint is defined as a joint with swelling or, in the 
absence of swelling, limitation of motion accompanied by pain on motion and/or tenderness.  If 
either the Physician’s Global Assessment of Disease Activity or the Parent’s Global Assessment 
of Well-Being are used in the calculation of flare for a study visit, then a minimum worsening (as 
defined in the SAP) on the visual analogue scale (VAS) must be present. If ESR or CRP is used 
in the definition of “flare” and counts towards worsening, then the second value for ESR or CRP 
used in the calculation must be above the upper limit of normal for ESR (>20 mm/hour) or CRP.
In JAHV, for primary analysis, disease flare definition will only use ESR.
The 6 PedACR core criteria (Gianni et al. 1997) includes: 
•
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
•
Physician’s Global Assessment of Disease Activity
•
Parent’s Global Assessment of Well-Being 
•
Physical function as assessed by the CHAQ
•
Acute-phase reactant (hsCRP and ESR)
Patients who discontinue the DBW period without experiencing a flare will have their data
censored.  A stratified logrank test across all JIA subtypes will be used as the primary analysis 
method. Survival curves will be estimated using the Kaplan–Meier method for all “time-to” 
variables in the DBW period.
10.3.3.2. Secondary Analyses
Secondary efficacy and health outcomes analyses (Table JAHV.8) will be based on the following 
study periods and study populations:
•
OLLI period population: All participants who take at least 1 age-based final dose as 
confirmed by PK assessments of investigational product in the OLLI period, other than 
the Safety/PK population.  Baseline is defined as Week 0.
•
DBW period population: All randomized patients in DBW period following intent-to-
treat (ITT) principles.


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Table JAHV.8.
Secondary Efficacy Endpoint Analyses
Endpoint
Population
Analysis Period
Treatment 
Comparisons
Analysis Method
Proportion of disease flare
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
Logistic regression 
with NRI
PedACR core set variables: 
change from baseline 
OLLI
Week 2 to Week 12
No comparison
Summary statistics
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
ANCOVA with LOCF
PedACR30/50/70/90/100 
response rates (compare to 
patient’s condition prior to first 
dose of investigational product)
OLLI
Week 2 to Week 12
No comparison
Summary statistics
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
Logistic regression 
with NRI
PhS and PsS scores (CHQ-
PF50): change from baseline
OLLI
Week 2 to Week 12
No comparison
Summary statistics
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
ANCOVA with LOCF
Parental Impact –Time/Emotion 
scores (CHQ-PF50): change 
from baseline
OLLI
Week 2 to Week 12
No comparison
Summary statistics
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
ANCOVA with LOCF
Inactive disease: proportion
OLLI
Week 2 to Week 12
No comparison
Summary statistics
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
Logistic regression 
with NRI
Minimal disease activity: 
proportion
OLLI
Week 2 to Week 12
No comparison
Summary statistics
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
Logistic regression 
with NRI
Remission: proportion
DBW
Week 28 to Week 44
Baricitinib versus 
placebo
Logistic regression 
with NRI
JADAS-27: change from 
baseline
OLLI
Week 2 to Week 12
No comparison
Summary statistics
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
ANCOVA with LOCF
Pain severity VAS (CHAQ):
change from baseline
OLLI
Week 2 to Week 12
No comparison
Summary statistics
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
ANCOVA with LOCF
Abbreviations:  ANCOVA = analysis of covariance; CHQ-PF50 = Child Health Questionnaire-Parent Form 50; 
DBW = double-blind withdrawal; HRQOL = health-related quality of life; JADAS-27 = Juvenile Arthritis 
Disease Activity Score 27; LOCF = last observation carried forward; NRI = nonresponder imputation; OLLI = 
open-label lead-in; PedACR = Pediatric American College of Rheumatology; VAS = visual analog scale.
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 investigation product


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•
AEs leading to discontinuation
•
AEs of special interest
•
Laboratory analytes (hematology and chemistry [including ALT and AST], neutrophil 
counts, and immunological measurements)
•
Vital signs
Primary safety analyses will summarize baricitinib and placebo treatment groups for DBW
population in DBW period. The Fisher exact test will be used for the AEs, discontinuation, and 
other categorical safety data for between-treatment-group comparisons in the DBW period.  
Continuous vital signs, body weight, and other continuous safety variables, including laboratory 
variables, will be analyzed using ANCOVA with treatment and baseline value in the model.
Summaries of safety data will be presented for baricitinib in OLLI period using OLLI population 
and throughout the study using general safety population unless otherwise stated.
Sensitivity analysis may be performed when there are patients who did not take investigational 
product after randomization in DBW.  Pharmacokinetic analysis will be conducted using all 
evaluable PK data in safety/PK population.  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 safety analysis plan.  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)
•
malignancies
•
hepatic events (Section 9.4.5)
•
MACE as adjudicated by the external Clinical Event Committee (Section 10.3.11.1)
•
thrombotic events (such as deep vein thrombosis and pulmonary embolism)
Sites will provide details on these AEs as instructed on the eCRF and may be asked for 
additional description by Lilly.


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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 Center 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. Pharmacokinetic/Pharmacodynamic Analyses
In the safety/PK assessment period, plasma concentrations from each group will be analyzed by 
noncompartmental analysis and/or graphical overlay of PK observations with the anticipated 
therapeutic concentration range from adult patients with RA.  After all PK data have been 
collected, plasma baricitinib concentration–time data will be pooled and evaluated using 
population PK methods.  A covariate screen of patient and study-specific factors will be included 
in the analyses based on factors investigated in previous and (if any) ongoing PK analyses and on 
their relevance to the target population.  Exploratory and/or model-based analyses examining the 
relationships between baricitinib exposure and efficacy and response endpoints will be 
conducted.  Other analyses of efficacy and safety outcome measures may also be assessed as 
scientifically appropriate and warranted by available data.  Details about the analyses to be 
conducted will be contained in the PK/PD analysis plan.
10.3.6. 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) at Weeks 4, 12, and at the end of DBW 
period 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.


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10.3.7. Health Outcomes
The health outcome measures will be analyzed using methods described for continuous or 
categorical data as described for efficacy measures in Section 10.3.1.  More detailed analytical 
methods will be described in the SAP.
10.3.8. Product Acceptability and Palatability
Responses from the tablet and suspension acceptability and palatability questionnaires will be 
summarized categorically (frequency and percentage) by age group, for each visit separately and 
in aggregate.  In addition, general trends from baseline and Week 12 in acceptability and 
palatability will be analyzed.
10.3.9. Subgroup Analyses
The summary statistical analysis will be conducted for the following subset of patients at each 
visit.
In the subset of patients with JPsA:
•
Change from baseline in PASI score during the OLLI period and during the DBW period.
In the patients with JPsA or ERA:
•
Change from baseline in SPARCC index of entheseal assessment during the OLLI period 
and during the DBW period.
•
Change from baseline in JSpADA during the OLLI period and during the DBW period.
10.3.10.
Exploratory Analysis
The change from baseline in EQ-5D-Y scores during the OLLI period and during the DBW 
period will be analyzed using methods described for continuous or categorical data as described 
for efficacy measures in Section 10.3.3.  More detailed analytical methods will be described in 
the SAP.
10.3.11.
Interim Analyses
A DMC will oversee the conduct of all the Phase 3 clinical studies evaluating baricitinib in 
patients with JIA.  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 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 for studies of patients with JIA 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.
Access to the unblinded interim data will be limited to the statisticians who conduct the interim 
analyses and the DMC.  The statisticians conducting the interim analyses will be independent 
from the study team.  The study team will not have access to the unblinded data.  Study sites will 


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receive information about interim results ONLY if they need to know for the safety of their 
patients.
Data that the DMC will review includes, but is not limited to, study discontinuation data, AEs 
including SAEs, clinical laboratory data, vital signs data, and growth.  The DMC may 
recommend continuation of the study as designed, temporary suspension of enrollment, or 
discontinuation of a particular dose regimen or discontinuation of the entire study. The DMC 
may request to review efficacy data to investigate the benefit/risk relationship in the context of 
safety observations for ongoing patients in the study.  Details of the DMC and interim safety 
analyses will be documented in a DMC charter and DMC analysis plan.
In addition to the DMC members, a limited number of prespecified individuals may gain access 
to the unblinded PK, safety, and efficacy data (as specified in the unblinding plan) prior to the 
final database lock to initiate the exploration and/or final population of the PK/PD model 
development processes.  Information that may unblind the study during the analyses will not be 
reported to study sites or the blinded study team until the database is locked.
Lilly will conduct a futility analysis after 100 patients complete the OLLI period.  The study will 
stop for futility if the observed PedACR30 response rate is <50% in the OLLI period.  Due to the 
open-label feature, there will be no alpha adjustment for futility analysis.
10.3.11.1.
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), 
venous thrombotic events, arterial thromboembolic events 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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12.
Appendices


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Appendix 1. Abbreviations and Definitions
Term
Definition
ACR20
20% 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
ANC
absolute neutrophil count
ANCOVA
analysis of covariance
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
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
CAP
College of American Pathologists
cDMARD
conventional disease-modifying antirheumatic drug
CHAQ
Childhood Health Assessment Questionnaire


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Term
Definition
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
DBW
double-blind withdrawal
disease flare
Worsening of 30% or more in at least 3 of the 6 PedACR core criteria for JIA and an 
improvement of 30% or more in no more than 1 of the criteria from the patient’s 
condition at the conclusion of the OLLI period
disease response
Improvement of 30% or more in at least 3 of 6 PedACR core-response variables 
without a worsening of greater than 30% in more than 1 variable
DMARD
disease-modifying antirheumatic drug
DMC
data monitoring committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
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.
EQ-5D-Y
European Quality of Life-5 Dimensions–Youth version
ERA
enthesitis-related juvenile idiopathic arthritis
ETV
early termination visit
EULAR
European League Against Rheumatism
GCP
good clinical practice


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Term
Definition
hBsAb
hepatitis B surface antibody
hBsAg
hepatitis B virus surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
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
Ig
immunoglobulin
IGF-1
insulin-like growth factor-1
IGFBP-3
insulin-like growth factor-binding protein-3
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.
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.
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.


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Term
Definition
IWRS
interactive web-response system
JADAS
Juvenile Arthritis Disease Activity Score
JAK
Janus kinase
JIA
juvenile idiopathic arthritis
JPsA
juvenile psoriatic arthritis
JSpADA
Juvenile Spondyloarthritis Disease Activity Index
LOCF
last observation carried forward
MACE
major adverse cerebro-cardiovascular events
MedDRA
Medical Dictionary for Regulatory Activities
MMR
measles, mumps, and rubella
MTX
methotrexate
NRI
nonresponder imputation
NRS
numeric rating scale
NSAID
nonsteroidal anti-inflammatory drug
OLE
open label extension
OLLI
open-label lead-in
PBPK
physiologically based pharmacokinetic
PD
pharmacodynamic(s)
PedACR30
Pediatric American College of Rheumatology 30 responder index
PK
pharmacokinetic(s)
PPD
purified protein derivative
Q2W
once every 2 weeks
QALY
quality-adjusted life years
QD
once daily
QW
once every week
RA
rheumatoid arthritis


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Term
Definition
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.  
SPARCC
Spondyloarthritis Research Consortium of Canada
STAT
signal transducer and activator of transcription
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.
TNF
tumor necrosis factor-alpha
TSH
thyroid-stimulating hormone
TYK2
tyrosine kinase 2
ULN
upper limit of normal
VAS
visual analogue scale
VTE
venous thromboembolism
VZV
varicella zoster virus


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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 DNAg
Ketones
Human immunodeficiency virus (HIV)e
Bilirubin
Thyroid-stimulating hormone (TSH)
Urobilinogen
Exploratory storage samples (serum, plasma)
Blood
Pharmacogenetic Sample (DNA)
Leukocyte esterase
Pregnancy Test (serum)h
Nitrite
Pregnancy Test (urine)h
High sensitivity C-reactive protein (hsCRP)i
Lipidsa,b
Rheumatoid factor
Total cholesterol
QuantiFERON®-TB Gold or T-SPOT®.TBj
Low-density lipoprotein
Purified protein derivative (PPD)j
High-density lipoprotein
ACPA (Anti-CCP)
Triglycerides
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)i
Baricitinib plasma concentration (PK sample)
IGF-1
IGFBP-3
Gonadal hormone (estradiol for females aged 8 to <18 years, 
testosterone for males aged 8 to <18 years)


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Abbreviations: ACPA = anti-citrullinated protein antibodies; ALP = alkaline phosphatase; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CPK = creatine 
phosphokinase; DNA = deoxyribonucleic acid; eGFR = estimated glomerular filtration rate; ESR = erythrocyte 
sedimentation rate; hBcAb = hepatitis B core antibody; hBsAb = hepatitis B surface antibody; hBsAg = hepatitis 
B surface antigen; HBV = hepatitis B virus; HIV = human immunodeficiency 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; NK = natural 
killer; OLLI = open-label lead-in; PK = pharamacokinetic; PPD = purified protein derivative; RBC = red blood 
cell; RNA = ribonucleic acid; TB = tuberculosis; TIBC = total iron-binding capacity ; TSH = thyroid-stimulating 
hormone; 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 glucose and lipids will be required at baseline and Week 12 of OLLI.  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 ≤50kg: fast for 8 hours prior to laboratory test 
•
Children <8 years and weighing 10 to <25kg: fast for 6 hours prior to laboratory test 
•
Children <8 years and weighing <10kg: fast for 4 hours prior to laboratory test
  These tests may be performed in a nonfasting state at all other visits.
c
eGFR calculated by Bedside Schwartz 2009 formula or the Japanese Society for Pediatric Nephrology formula 
for patients in Japan.
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 childbearing potential at screening only and 
will be performed centrally; after screening, urine pregnancy test will be performed locally for females of 
childbearing potential.
i
Test results of hsCRP and lymphocyte subsets will be blinded after Visit 9, and the test results will not be sent to 
the study sites.
j
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.
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:
•
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 (as applicable) 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 
patient/patient’s legal representative willingness to continue his or her participation in the 
study.
•
ensuring that a copy of the ICF and Assent Form (as applicable) 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.
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.
Documentation of ERB approval of the protocol and the ICF and Assent Form (as applicable) 
must be provided to Lilly before the study may begin at the investigative site(s).  Lilly or its 


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representatives must approve the ICF and Assent Form (as applicable), including any changes 
made by the ERBs, before it is used at the investigative site(s).  All ICFs and Assent Forms (as 
applicable) 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 (as applicable)
•
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
•
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 (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 their 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 their 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.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.


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Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:
•
provide instructional material to the study sites, as appropriate
•
provide sponsor start-up training to instruct the investigators and study 
coordinators.  This training will give instruction on the protocol, the completion 
of the CRFs, and study procedures.
•
make periodic visits to the study site
•
be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax
•
review and verify data reported to detect potential errors 
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.
An electronic data capture 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 


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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
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
The publication policy for Study I4V-MC-JAHV is described in the Clinical Study Agreement.


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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; 
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. Weight-Based Prioritization Chart for 
Blood Sampling
Patients with a body weight lower than 30 kg if ≥8 years, or lower than 18 kg if <8 years, 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 JAHV. This 
prioritization chart uses a conservative estimate for weight, i.e., the third percentile of weight 
from the CDC Weight-for-age Chart (CDC [WWW]) for the youngest age in an age group.
The laboratory kits used in Study JAHV have been developed to accommodate blood volume 
limitations.  Lilly will use visit- and age-specific laboratory kits for patients ≥8 years old and 
<8 years old.  The kits for patients <8 years old exclude testosterone, estradiol, flow cytometry, 
and serum and plasma long-term storage samples.  Lilly also recommends that purified protein 
derivative is used for tuberculosis testing instead of Quantiferon Gold or T-Spot in patients aged 
<8 years who weigh <18 kg.  Lilly will provide training to sites along with the prioritization 
chart of laboratory samples to collect based on patient age and weight.
Weight-Based Prioritization Chart for Blood Sampling
Age
Weight
Excluded Testing – will not be collected
≥8 years
≥30 kg
N/A
≥27 to <30 kg
• Long-term storage samples:  RNA, serum, and plasma
≥18 to <27 kg
• Long-term storage samples: RNA, serum, and plasma
• Flow cytometry
<18 kg
• Long-term storage samples: RNA, serum, and plasma
• Testosterone or estradiol
• Flow cytometry
<8 years
≥18 kg
• Long-term storage samples: serum and plasma
• Testosterone or estradiol
• Flow cytometry
≥10 to <18 kg
• Long-term storage samples: RNA, serum and plasma
• Testosterone or estradiol
• Flow cytometry
<10 kg
• Long-term storage samples: RNA, serum and plasma
• Testosterone or estradiol
• Flow cytometry
• Consult Lilly medical if additional exclusions are required
Abbreviations:  N/A = not applicable; RNA = ribonucleic acid.


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Appendix 7. 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).
Current 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 or JIA-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 physiological-based pharmacokinetics (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 JAHV
An updated summary of dosing for Study JAHV is provided in the table below. Lilly has 
initiated the following for Study JAHV: 
•
Lilly enrolled the required patients aged 6 to <9 years in the PK cohort 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, 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 JAHV Dosing Summary
Age Group
Current Status of Enrollment
Baricitinib Dose
12 to <18 years old
Safety/PK completed; 
OLLI currently enrolling
4 mg
9 to <12 years old
Safety/PK completed; 
OLLI currently enrolling
4 mg 
6 to <9 years old
Safety/PK enrollment completed 
as of October 2020
2 mg (based on predicted data – to be 
confirmed with observed data) 
2 to <6 years old
Safety/PK to be initiated
2 mga
Abbreviations: OLLI = open-label lead-in; PK = pharmacokinetic; 
a
To be confirmed after evaluating data from patients aged 6 to <9 years.


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Appendix 8. Provisions for Changes in Study Conduct 
During Exceptional Circumstances
Exceptional circumstances, such as pandemics or natural disasters, may cause disruptions to the 
conduct of the study. Examples of such disruptions include limitations in the ability to conduct 
study procedures or ability to have on-site participant visits.
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 and if permitted by local regulations. These provisions for 
changes in study conduct are temporary and will be repealed once the restrictions are 
lifted.  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. 
2. Remote Assessment and Data Collection
Patient visit and data collection can be done remotely for OLLI visits following the protocol visit 
windows. The PI/Sub-I is to document all teleconferences/remote visits in the patient’s 
records. Site facing assessments will be completed on paper (preferably eCOA if the site is able) 
and patient facing assessments will be conducted in interview format with the PI/SubI or other 
qualified personnel documenting the patient’s responses on paper. Sponsor will provide 
guidance for performing these assessments (CHQ-PF50, EQ-5D-Y). Patients cannot proceed in 
JAHV past Visit 9 due to the requirement of PedACR30 responder/nonresponder criteria being 
defined at this visit to determine eligibility for randomization into DBW phase. Because most 
PedACR components cannot be collected by remote assessment, patients will be terminated from 
JAHV at Visit 9 and offered enrollment into JAHX (long term extension).


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3. Investigational product and ancillary supplies (including participant diaries)
In cases when a patient is unable to come to the 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  
•
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 participant’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 AE in the AE eCRF. 
For patients unable to access investigator sites, laboratory testing will be conducted at least every 
8 weeks in the OLLI and DBW periods. The first collection should be 8 weeks from the 
patient’s last collected central laboratory samples. 
Failure to have labs collected within the described ranges above may result in patient termination 
from the study.
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.
Note: Any results that are obtained from local laboratories will need to be retained by the 
investigator for their respective patients.


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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 the
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 for these select parameters:
•
WBC
•
ANC
•
Lymphocyte count
•
Hemoglobin
•
Platelet count
•
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 verbal consent for having remote visits
and remote dispensing of IP and/or ancillaries prior to implementation of these 
activities. 
•
Source document(s) that are generated at an off-site location (e.g., 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 eCRFs. While protocol deviations may be 
unavoidable in an 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.


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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 9. Protocol Amendment I4V-MC-JAHV(d) 
Summary - A Randomized, Double-Blind, Placebo-
Controlled, Withdrawal, Safety and Efficacy Study of 
Oral Baricitinib in Patients from 2 Years to Less Than 
18 Years Old with Juvenile Idiopathic Arthritis (JIA)
Overview
Protocol I4V-MC-JAHV—A Randomized, Double-Blind, Placebo-Controlled, Withdrawal, 
Safety and Efficacy Study of Oral Baricitinib in Patients from 2 Years to Less Than 18 Years 
Old with Juvenile Idiopathic Arthritis (JIA)—has been amended.  The new protocol is indicated 
by amendment (d) and will be used to conduct the study in place of any preceding version of the 
protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table.  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-JAHV Amendment (d)
*Changes marked only apply if Amendment (c) is in effect. These changes are not applicable in 
Amendment (d).
Section # and Name
Description of Change
Brief Rationale
Synopsis
•
Disease flare improvement 
defined at Visit 9 instead of 
baseline
•
Cohorts adjusted
Clarification
Section 2. Schedule of 
Activities
Appendix 8. Provision 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 additional 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
Baseline assessment of sexual maturity 
(Tanner Staging) was included based 
on feedback from regulatory agencies.
Section 2. Schedule of 
Activities
Height measurements adjusted.
The additional measurements for height 
were added for additional growth 
monitoring.


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Section # and Name
Description of Change
Brief Rationale
*Only applicable if Amendment C is in 
effect
Addition of weight measurement to 
Visit 1
To calculate eGFR
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.
Addition of language to uveitis footnote 
Clarification of study visits and 
monitoring of active uveitis. 
Addition of footnote related to
dispensing of study drug (Table 2)
Requirement for review of Trial 
Manager report prior to study drug 
dispensing.
Deletion of eGFR rows
eGFR is already mentioned in footnote 
“Clinical chemistry will include eGFR”
Removed AP positioning from knee X-
rays
Not specified
Added information about imaging 
required for skeletal maturity.  
Removed AP positioning. 
For clarity 
Added sentence on patients in Japan to 
specify HBV DNA samples draws in 
footnote r (Table 1) and footnote t
(Table 2). 
For clarity 
Section 5.1 Overall Design 
Cohorts adjusted 
For clarity 
Section 5.1.2. Safety/PK 
Assessment
Section 5.5. Justification for 
Dose
Section 7.1. Treatments 
Administered
•
Addition of language to reference 
Appendix 7 for dosing guidance
•
Cohorts adjusted 
•
Dosing was updated per protocol 
requirement after PK analysis of 
study JAHV.
•
For clarity 
Section 6.2. Exclusion Criteria
•
Exclusion Criteria for 
hypogammaglobinemia adjusted 
•
IgG, IgM, IgA are not included in 
screening test.
Section 6.3. Screen Failures
Clarified that rescreening should be at 
least 4 weeks from the previous 
screening date.
For clarity 
Section 7.7. Concomitant 
Therapy, Table JAHV.6.
Changes to NSAIDs and analgesics 
section
Clarification
Section 8.1.3. Discontinuation 
of Inadvertently Enrolled 
Addition of Lilly template language 
Clarification of discontinuation of 
inadvertently enrolled participants and 


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Section # and Name
Description of Change
Brief Rationale
Patients
safety follow-up.
*Only applicable if Amendment C is in 
effect.
Section 9.4.4. Hepatitis B 
Virus DNA Monitoring
Weeks were changed to visits
Changed for consistency.
Section 9.4.6.2. Growth 
Monitoring
Addition of language related to height 
measurement
Specification of stadiometer as device 
to be used for height measurement.
Addition of language on x-rays and 
country specific addenda
Guidance on previous country specific 
addenda containing additional imaging.
Section 9.5.1. 
Pharmacokinetic Strategy
Cohorts adjusted
For clarity 
Section 9.5.2. Safety/PK 
Assessment Lead-in Period
Added sentence in regards to specifying 
sampling scheduled 
For clarity 
Appendix 2. Clinical 
Laboratory Tests
Update of footnote in table for hsCRP
Clarification to sites of test results for 
hsCRP.  
Appendix 6. Weight-Based 
Prioritization Chart for Blood 
Sampling
Addition of RNA exclusion for testing 
for ≥8 years at weight <18 kg 
Correction to include RNA in 
exclusionary testing for ≥8 years at 
weight <18 kg for long-term storage 
sample.
Appendix 7. Data-Based
Dosing Cohorts
•
Addition of Appendix 7 related to 
data-based dosing cohorts
•
Changed “will enroll” to “enrolled
the required” patients
•
Dosing was updated per protocol 
requirement after PK analysis of 
Study JAHV.
•
For clarity. 
Appendix 8. Provisions for 
Changes in Study Conduct 
During Exceptional 
Circumstances
•
Removed utilizing the lab operating 
guidance document (included at the 
end of this proposal form) wording
•
Laboratory collections adjusted
Clarification


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
1. Synopsis
Treatment Arms and Duration
…
Disease flare is defined as a worsening of ≥30% in at least 3 of the 6 PedACR core criteria for 
JIA and an improvement of ≥30% in no more than 1 of the criteria from the patient’s condition at 
baselineVisit 9.  If either the number of joints with active arthritis or the number of joints with 
limitation of motion are used in the calculation of flare…
2. Schedule of Activities
The Schedule of Activities described below should be followed for all participants enrolled in 
Study JAHV.  In the event participation in this study is affected by exceptional circumstances 
(such as pandemics or natural disasters), please refer to Appendix 8 and consult with the 
sponsor’s representative for additional guidance.


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Table JAHV.1 Schedule of Activities for the Safety/PK Cohort
Safety/PK Cohort Onlya
Screening
Safety/PKb,c
Visit #
V1
V1a
V2b
baseline
V3
V4
Study Day (Approximately)
-42 to -1
1d
4
14
Visit Window (Days)
±3
Tanner Staging in patients ≥8 years old (see Section 9.4.6.3)
X
Height
X
X
X
Weight
X
X-ray of wrist, hand, finger, and AP kneeg
X
Uveitis evaluationgh
X
Investigational product returned and compliance assessedhi
X
Clinical Efficacy
Childhood Health Assessment Questionnaireij
X
X
X
CHQ-PF50ij
X
EQ-5D-Yij
X
SPARCC Enthesitis Indexjk
X
X
Clinical sacroiliitisjk
X
X
Back mobility (Schober’s test)jk
X
X
PASIkl
X
X
Procedures and Laboratory Tests
Chest x-raylm
X
Administer PPD/QuantiFERON®-TB Gold/T-SPOT® TBmn
X
Read PPDmn
X
ECGno
X
ESRop
X
X
X
HIV/HCVpq
X
HBV DNAqr
X
Serum pregnancy testrs
X
Urine pregnancy testrs
X
X
Clinical chemistryst
X
X
X
X
eGFR
X
Fasting lipid paneltu
X
Lymphocyte subsets (T, B, NK, and T- cell subsets)uv
X


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Safety/PK Cohort Onlya
Screening
Safety/PKb,c
Visit #
V1
V1a
V2b
baseline
V3
V4
Study Day (Approximately)
-42 to -1
1d
4
14
Visit Window (Days)
±3
Antipneumococcal IgG multianalyte Ab assayvw
At relevant visits for prevaccination, 
4 weeks post vaccination, and 12 weeks 
post vaccination based on the vaccination 
schedule of each patient
Anti-tetanus toxoid IgG, anti-diphtheria toxoid, and anti-pertussis 
toxoid Ab assayvw
At relevant visits for prevaccination, 
4 weeks post vaccination, and 12 weeks 
post vaccination based on the vaccination 
schedule of each patient
Gonadal hormoneswx
X
PK samplexy
X
X
X


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Abbreviations: AP = anteroposterior;
g Semiannual wrist, hand, finger, and AP 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 Study JAHV at the time of this amendment, 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.
hg All patients with active uveitis must be excluded at screening.  If investigators consider it necessary, evaluation can be added at any visit.Signs and symptoms 
of active uveitis should be monitored.  
ih At Visit 4, patient will return all investigational products for drug accountability.  
ji Patient-reported questionnaires will be administered via an on-site eCOA device or paper and is recommended to be completed prior to any clinical 
examinations. 
kj Only for patients with enthesitis-related juvenile idiopathic arthritis (ERA) or juvenile psoriatic arthritis (JPsA).
lk Only for patients with JPsA.
ml 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.
nmTB test(s) including 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 72hours 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.)
on An ECG performed within 1 year prior to screening may be used.
po Performed locally.  To be drawn prior to dosing early in the visit except for Visit 3.
qp 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.
rq 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 (for patients in Japan, it is acceptable for sites to draw HBV DNA samples with the test of Visit 1).  
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.
sr Pregnancy tests prior to first dose of investigational product for females ≥10 years old 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 Visit 2 must be known prior to first dose of investigational product.
ts Clinical chemistry will include eGFR (calculated by Bedside Schwartz 2009 formula or the Japanese Society for Pediatric Nephrology formula for patients in 
Japan).


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ut 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 ≤50kg: fast for 8 hours prior to laboratory test 
•
Children <8 years and weighing 10 to <25kg: fast for 6 hours prior to laboratory test 
•
Children <8 years and weighing <10kg: fast for 4 hours prior to laboratory test
vu Patients in the age cohort of age 2 to ≤7 years will not have flow cytometry testing due to blood volume limitations.
wvIf 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 post vaccination, and 12 weeks post vaccination.
xwEstradiol (for females) or testosterone (for males) will be collected for the assessment of pubertal development in patients aged 8 to <18 years.
yx PK samples will be collected as described in Sections 9.5.2.
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 in Appendix 6.


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Table JAHV.2 Schedule of Activities
Screening
Open-Label Lead-in Perioda
Double-Blind Randomized Withdrawal Period
Early 
Termination
Post-
Treatment 
Follow-Up
Visit #
V1
V1a
V5b
baseline
V6
V7
V8
V9
V10 V11 V12 V13 V14 V15 V16
V17
ETVc
V801d
Study Week
W0
W2
W4 W8 W12 W16 W20 W24 W28 W32 W36 W40
W44
Any Week
Study Day 
(Approximately)
-42 to -1
1e
14
28
56
84
112
140
168
196
224
252
280
308
Any Day
28 ± 5 Days 
after Last 
Dose
Visit Window 
(Days)
±3
±7
Tanner Staging in 
patients ≥8 years old 
(see Section 9.4.6.3)
X
Height
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-ray of wrist, 
hand, finger, and 
AP kneeh
X
Uveitis evaluationhi
X
Dispense study drugj
X
X
X
X
X
X
X
X
X
X
X
Investigational 
product returned 
and compliance 
assessedik
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Childhood Health 
Assessment 
Questionnairejl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CHQ-PF50jl
X
X
X
X
X
X
X
X
X
X
X
X
X
EQ-5D-Yjl
X
X
X
X
X
X
X
X
X
X
X
X
X
SPARCC Enthesitis 
Indexkm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Morning stiffness 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Screening
Open-Label Lead-in Perioda
Double-Blind Randomized Withdrawal Period
Early 
Termination
Post-
Treatment 
Follow-Up
Visit #
V1
V1a
V5b
baseline
V6
V7
V8
V9
V10 V11 V12 V13 V14 V15 V16
V17
ETVc
V801d
Study Week
W0
W2
W4 W8 W12 W16 W20 W24 W28 W32 W36 W40
W44
Any Week
Study Day 
(Approximately)
-42 to -1
1e
14
28
56
84
112
140
168
196
224
252
280
308
Any Day
28 ± 5 Days 
after Last 
Dose
Visit Window 
(Days)
±3
±7
durationjl
Pain Numeric Rating 
Scalejl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical 
sacroiliitisim
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Back mobilitykm
(Schober’s test)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PASIln
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chest x-raymo
X
Administer PPD/
QuantiFERON®-TB 
Gold/T-SPOT®
TBnp
X
Read PPDnp
X
ECGoq
X
hsCRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ESRpr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HLA-B27
X
RF and ACPA
X
TSH
X
HIV/HCVqs
X
HBV (hBsAg, 
hBcAb, hBsAb)
X
HBV DNArt
X
X
X
X
X
X
X


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Screening
Open-Label Lead-in Perioda
Double-Blind Randomized Withdrawal Period
Early 
Termination
Post-
Treatment 
Follow-Up
Visit #
V1
V1a
V5b
baseline
V6
V7
V8
V9
V10 V11 V12 V13 V14 V15 V16
V17
ETVc
V801d
Study Week
W0
W2
W4 W8 W12 W16 W20 W24 W28 W32 W36 W40
W44
Any Week
Study Day 
(Approximately)
-42 to -1
1e
14
28
56
84
112
140
168
196
224
252
280
308
Any Day
28 ± 5 Days 
after Last 
Dose
Visit Window 
(Days)
±3
±7
Serum pregnancy 
testsu
X
Urine pregnancy 
testsu
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical chemistrytv
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
eGFR
X
Fasting lipid 
paneluw
X
X
X
X
X
X
Lymphocyte subsets 
(T, B, NK, and T-
cell subsets)vx
X
X
X
X
X
X
Antipneumococcal 
IgG multianalyte Ab 
assaywy
At relevant visits for prevaccination, 4 weeks post vaccination, and 12 weeks post 
vaccination based on the vaccination schedule of each patient
Anti-tetanus toxoid 
IgG, anti-diphtheria 
toxoid, and anti-
pertussis toxoid Ab 
assaywy
At relevant visits for prevaccination, 4 weeks post vaccination, and 12 weeks post 
vaccination based on the vaccination schedule of each patient
Gonadal hormonexz
X
X
X
X
X
PK sampleyaa
X
X
X
X
X
X


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Abbreviations: AP = anteroposterior;
h Semiannual wrist, hand, finger, and AP 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 Study JAHV at the time of this amendment, 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.
hi All patients with active uveitis must be excluded at screening. If investigators consider it necessary, evaluation can be added at any visitSigns and symptoms 
of active uveitis should be monitored. Patients with ERA and JPsA should have a uveitis evaluation at W12 (V9), W44 (V17), ETV and V801. may have a 
higher risk of active uveitis so mandatory evaluation is required at W12 (V9), W44 (V17), ETV, and V801.
j
Study drug should not be dispensed before review of the Trial Manager report.
ik Patients will return all investigational products for drug accountability.  
jl Patient-reported questionnaires will be administered via an on-site eCOA device or paper and is recommended to be completed prior to any clinical 
examinations.
kmOnly for patients with enthesitis-related juvenile idiopathic arthritis (ERA) or juvenile psoriatic arthritis (JPsA).
ln Only for patients with JPsA.
moOnly 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.
np 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.  (Note: 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.)
oq An ECG performed within 1 year prior to screening may be used.
pr Performed locally.  To be drawn prior to dosing early in the visit except for V6 and V7.
qs 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.
rt 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 (for patients in Japan, it is acceptable for sites to draw HBV DNA samples with the test of Visit 1).  
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 events.
su Pregnancy tests prior to first dose of investigational product for females ≥10 years old 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 Visit 5 must be known prior to first dose of investigational product.
tv Clinical chemistry will include eGFR (calculated by Bedside Schwartz 2009 formula or the Japanese Society for Pediatric Nephrology formula for patients in 
Japan).


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uwFasting 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 ≤50kg: fast for 8 hours prior to laboratory test 
•
Children <8 years and weighing 10 to <25kg: fast for 6 hours prior to laboratory test 
•
Children <8 years and weighing <10kg: fast for 4 hours prior to laboratory test
vx Patients in the age cohort of age 2 to ≤7 years will not have flow cytometry testing due to blood volume limitations.
wyIf 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 post vaccination, and 12 weeks post vaccination.
xz Estradiol (for females) or testosterone (for males) will be collected for the assessment of pubertal development in patients aged 8 to <18 years.
yaa
PK samples will be collected as described in Sections 9.5.2 and 9.5.3.
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 in Appendix 6.


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5.1 Overall Design
…
a
Staggered approach to enrollment by age group (12 to <18 years,6 9 to <12 years,
6 to <9 years, 2 to <6 years) will be implemented with older groups completing 
the safety/PK assessment period before younger groups are enrolled.  
b
Once the PK and safety profiles for an age group are confirmed, subsequent 
patients in that age group may enroll directly into the OLLI period.  If the 
comparability assessment in the safety/PK period for an age group is inconsistent
with baricitinib 4-mg exposures in adults with RA such that baricitinib dosage for 
the age group needs to be adjusted, the patients on the inconsistent dosage will 
discontinue the study and may enter the separate OLE study (JAHX).
c
Patients who experience a disease flare during the DBW period will discontinue 
the study and may proceed directly to the separate OLE study (JAHX).
5.1.2 Safety/PK Assessment
…
…Enrollment will be staggered by age group (12 to <18 years, 96 to <12 years, 6 to <9 years,
and 2 to <6 years; see Appendix 7 for updated dosing based on the current data) with older age
groups enrolling before younger groups.
5.5. Justification for Dose
…The modeling predicted that baricitinib concentrations in adolescents 12 to <18 years old and 
in children 69 to <12 years old would be expected to be similar to those in adults; therefore, 
these patients will initially be dosed with 4-mg QD dose (Figure JAHV.2; see Appendix 7 for 
updated dosing based on the current data).  In contrast, concentrations in children <69 years 
would be expected to be toward the higher end of the range seen in adults;
6.2 Exclusion Criteria
[29] History of hypogammaglobulinemia. or a serum immunoglobulin (Ig)G, IgM, or IgA 
concentration less than the lower limit of normal of the reference range.
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 from the 
previous screening date.  Each time rescreening is performed the legal representative must sign a 
new ICF and the child would sign an assent, as applicable.  The individual will be assigned a 
new identification number.
7.1. Treatments Administered
This study involves a comparison of baricitinib dose, by age (4-mg for children ≥69 years of age
and adolescents 12 to <18 years of age and 2-mg for children <69 years of age as the starting 
dose; see Appendix 7 for updated dosing based on the current data), with placebo in the DBW 
period.  The dosages will be adjusted if the interim analyses after the Safety/PK period 


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demonstrate that the profiles are not comparable with the target PK or safety profiles in adults.  
Therefore, a 1-mg dose is described in Table JAHV.5 should this be needed.
Baricitinib will be dosed as tablets or oral suspension QD based on the age of the patient at 
Visit 2 (for patients enrolled in the Safety/PK portion) and at Visit 5 (for all other patients); 
formulation will not change during the study.  Baricitinib should be taken with sufficient water 
or fluid to allow easy swallowing of the medication.  All patients <6 years of age will receive 
oral suspension. Patients ≥6 to <12 years old have the option of receiving the oral suspension. 
Patients >12 years old will be supplied tablets. Based on PBPK modeling, initial doses will be 
4-mg for adolescents 12 to <18 years old and in children ≥69 to <12 years old, and 2-mg in 
children <69 years old to produce exposures similar to those in adults after 4-mg QD 
administration.  Refer to Section 5.5 for additional information. Table JAHV.5 shows the 
treatment regimens.
Table JAHV.5.
Treatment Regimens
Treatment Group
Treatments Administered
Safety/PK and OLLI Period
DBW Period
Baricitinib 4-mg
Baricitinib 4-mg oral QD tablet
Baricitinib 2-mg/mL oral suspension
Baricitinib 4-mg oral QD tablet
Baricitinib 2-mg/mL oral suspension
Baricitinib 2-mg
Baricitinib 2-mg oral QD tablet
Baricitinib 2-mg/mL oral suspension
Baricitinib 2-mg oral QD tablet
Baricitinib 2-mg/mL oral suspension
Baricitinib 1-mg
Baricitinib 1-mg oral QD tablet
Baricitinib 2-mg/mL oral suspension
Baricitinib 1-mg oral QD tablet
Baricitinib 2-mg/mL oral suspension
Placebo comparator
N/A
Baricitinib 4-mg placebo oral QD tablet
Baricitinib 2-mg placebo oral QD tablet
Baricitinib 1-mg placebo oral QD tablet
Baricitinib 2-mg/mL placebo oral 
suspension
Abbreviations: DBW = double-blind withdrawal; eGFR = estimated glomerular filtration rate; N/A = not 
applicable; OLLI = open-label lead-in; PK = pharmacokinetics; QD = once daily.
Note:  Initial doses of baricitinib 4-mg for adolescent patients (12 to <18 years of age) and children ≥69 years of age
and baricitinib 2-mg for children <69 years of age will be given.  The oral suspension dose may be administered 
as 4-mg, 2-mg, 1-mg, and 0.5-mg as needed.
Note: Patients with renal impairment or renal immaturity (defined as eGFR <60 mL/min/1.73 m2) at baseline will 
have their dose reduced by 50%.  Patients receiving the 1-mg dose who have renal impairment or renal 
immaturity will receive a dose-of 0.5-mg using the oral suspension.
7.7. Concomitant Therapy


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Table JAHV.6. Concomitant JIA Therapies
Drug Class
As 
Needed
Chronic 
Use
Conditions for Use
NSAIDsb
including 
cyclooxygenase-2 
inhibitors, e.g.,
celecoxib
No
Yes
Must be on stable dose for at least 1 week prior to baseline.
Changes in dose, discontinuation and/or introduction of new 
analgesics are only allowed for treatment of an AE.
Analgesics
including local 
anaesthetics, e.g.,
lidocaine, and
topical anaesthetics, 
e.g., EMLA cream.
No
Yes
Must be on stable dose at least 1 week prior to baseline.
Changes in dose, discontinuation and/or introduction of new 
analgesics are only allowed for treatment of an AE.
Permitted analgesics include:
 acetaminophen
 NSAIDs, e.g. ibuprofen
 cyclooxygenase-2 inhibitors, e.g. celecoxib
 opioids, e.g. tramadol, codeine, or morphine
 local anaesthetics, e.g. lidocaine, and
 topical anaesthetics, e.g. EMLA cream
b For use as an anti-inflammatory agent.
8.1.3. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient participant who did not meet enrollment criteria 
and was inadvertently enrolled, then the patient participant should be discontinued from the 
investigational productstudy 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).
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.
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 in Section 2).
Patients who are hBcAb positive and HBV DNA negative (undetectable) at screening will 
require measurement of HBV DNA at Week Visit 9, Visit 12, Week 24Visit 15, Week 36Visit 
17, Week 44, ETV, and the follow-up visit, regardless of their hepatitis B surface antibody 
(hBsAb) status.
9.4.6.2. Growth Monitoring


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Height and weight will be measured at baseline and postbaseline for the assessment of physical 
growth according to the Schedule of Activities (Section 2). Height and weight changes in 
pediatric patients (both at an individual and group level) will be reviewed by the DMC. Height 
measurements will be made using a stadiometer.
…
A semiannual wrist, hand, finger, and 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., MRI instead of 
x-ray), the local addendum should be followed. Otherwise, the current protocol amendment 
should be followed with regard to knee x-rays. 
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).
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 Davies 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.
9.5.1 Pharmacokinetic Strategy
The doses for this study were selected based on PK modeling such that the highest dose in an age 
cohort is expected to produce baricitinib exposure similar to that produced by 4-mg in adult 
patients with RA.  For adolescent patients (aged 12 to <18 years) and children ≥69 years, that 
dose is expected to be 4-mg QD, whereas in children aged ≥6 to <9 and >≥2 to <6 years the dose 
is expected to be 2-mg QD.
Before enrolling a majority of patients, the PK in adolescent patients receiving 4-mg QD will be 
evaluated in a small number of lead-in patients to confirm the suitability of this dose in 
adolescent patients with JIA.  Patients will be dosed QD and serial blood samples will be 
collected at steady state for analysis of baricitinib concentrations.  Refer to Section 9.5.2 for 
details.  The PK in individual patients will be evaluated using noncompartmental methods and 
will inform dose selection for subsequent adolescent patients.  No adolescent patients will be 
enrolled directly into the OLLI period until the PK in the lead-in patients has been evaluated.
For younger cohorts of PK lead-in patients (aged ≥69 to <12 years, aged 6 to <9 years and aged 2 
to <6 years), the same lead-in process will be performed as that for adolescents.  The PK lead-in 


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period for patients aged ≥69 to 12 years will complete before the PK lead-in period for patients 
aged 26 to <69 years can begin, and this one will also complete before the PK lead-in period for 
patients 2 to <6 years can begin (Section 5.1.2).
9.5.2 Safety/PK Assessment Lead-in Period
…
For visits where PK samples will be collected, the actual date and 24-hour clock time of sample 
collection, and the date and time of the last 2 doses should be recorded.  At Day 4 and Day 14, 
these 2 doses should be the dose given on the morning of the day of sample collection and the 
dose given the previous day. This sampling schedule should be followed as closely as possible; 
however, failure to take PK samples at these specified times will not be considered a protocol 
violation. If the patient fails to follow the directions for a particular visit, the sample should still 
be collected at that visit, and the date and 24-hour clock time of sample collection and the date 
and 24-hour clock time of the 2 doses prior to the sample being drawn should be recorded.
11.
References
Chavarro JE, Watkins DJ, Afeiche MC, Zhang Z, Sánchez BN, Cantonwine D, Mercado-García 
A, Blank-Goldenberg C, Meeker JD, Téllez-Rojo MM, Peterson KE. Validity of self-assessed 
sexual maturation against physician assessments and hormone levels. J Pediatr. 
2017;186:172-178.e3.
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 
1969;44(235):291–303.
Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child. 
1970;45(239):13–23.
Tanner JM, Davies PS. Clinical longitudinal standards for height and height velocity for North 
American children. J Pediatr. 1985;107(3):317-329.
Appendix 1.
Abbreviations and Definitions
Term
Definition
AP
anteroposterior
CAP
College of American Pathologists
CLIA
Clinical Laboratory Improvement Amendments
Appendix 2.
Clinical Laboratory Tests
i
Test results of hsCRP and lymphocyte subsets will be blinded after Week 12Visit 9, and the 
test results will not be sent to the study sites.


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Appendix 6.
Weight-Based Prioritization Chart for Blood Sampling
Weight-Based Prioritization Chart for Blood Sampling
Age
Weight
Excluded Testing – will not be collected
≥8 years
≥30 kg
N/A
≥27 to <30 kg
• Long-term storage samples:  RNA, serum, and plasma
≥18 to <27 kg
• Long-term storage samples: RNA, serum, and plasma
• Flow cytometry
<18 kg
• Long-term storage samples: RNA, serum, and plasma
• Testosterone or estradiol
• Flow cytometry
Appendix 7.
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).
Current 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 or JIA-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 physiological-based pharmacokinetics (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 JAHV
An updated summary of dosing for Study JAHV is provided in the table below. Lilly has 
initiated the following for Study JAHV: 


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•
Lilly will enroll 5 to 8 enrolled the required patients aged 6 to <9 years in the PK cohort 
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, 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.
Updated Study JAHV Dosing Summary
Age Group
Current Status of Enrollment
Baricitinib Dose
12 to <18 years old
Safety/PK completed; 
OLLI currently enrolling
4 mg 
9 to <12 years old
Safety/PK completed; 
OLLI currently enrolling
4 mg 
6 to <9 years old
Safety/PK currently enrolling 5 to 
8 patients enrollment completed 
as of October 2020
2 mg (based on predicted data – to be 
confirmed with observed data) 
2 to <6 years old
Safety/PK to be initiated
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.
Appendix 8.
Provisions for Changes in Study Conduct During Exceptional Circumstances
Exceptional circumstances, such as pandemics or natural disasters, may cause disruptions to the 
conduct of the study.  Examples of such disruptions include limitations in the ability to conduct 
study procedures or ability to have on-site participant visits.
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 and if permitted by local regulations.  These provisions for 
changes in study conduct are temporary and will be repealed once the restrictions are 
lifted.  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)


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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. 
2. Remote Assessment and Data Collection
Patient visit and data collection can be done remotely for OLLI visits following the protocol visit 
windows. The PI/Sub-I is to document all teleconferences/remote visits in the patient’s 
records. Site facing assessments will be completed on paper (preferably eCOA if the site is able) 
and patient facing assessments will be conducted in interview format with the PI/SubI or other 
qualified personnel documenting the patient’s responses on paper. Sponsor will provide 
guidance for performing these assessments (CHQ-PF50, EQ-5D-Y). Patients cannot proceed in 
Study JAHV past Visit 9 due to the requirement of PedACR30 responder/nonresponder criteria 
being defined at this visit to determine eligibility for randomization into DBW phase. Because 
most PedACR components cannot be collected by remote assessment, patients will be terminated 
from Study JAHV at Visit 9 and offered enrollment into Study JAHX (long-term extension).
3. Investigational product and ancillary supplies (including participant diaries)
In cases when a participant is unable to come to the 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  
•
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 participant’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.


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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 AE in the AE eCRF. 
For patients unable to access investigator sites, laboratory testing will be conducted at least every 
8 weeks in the OLLI and DBW periods. The first collection should be 8 weeks from the 
patient’s last collected central laboratory samples. 
Failure to have labs collected within the described ranges above may result in patient termination 
from the study.
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.
Note: Any results that are obtained from local laboratories will need to be retained by the 
investigator for their respective patients.
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 the
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 for these select parameters:
•
WBC
•
ANC
•
Lymphocyte count
•
Hemoglobin
•
Platelet count
•
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


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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 verbal consent for having remote visits 
and remote dispensing of IP and/or ancillaries prior to implementation of these 
activities. 
•
Source document(s) that are generated at an off-site location (e.g., 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 eCRFs. While protocol deviations may be 
unavoidable in an 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.


Leo Document ID = 91425c0c-ee4b-46a2-a442-bfd8c866bca5
Approver:
Approval Date & Time: 06-Nov-2020 21:02:33 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 07-Nov-2020 20:11:24 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
 
 
 
JAHV stat analysis plan 
 
A Randomized, Double-Blind, Placebo-Controlled, Withdrawal, Safety and Efficacy Study of 
Oral Baricitinib in Patients From 2 Years to Less Than 18 Years Old With Juvenile Idiopathic 
Arthritis (JIA) 
  
NCT03773978 
Approval Date: 14-Mar-2022 
 
 


I4V-MC-JAHV Statistical Analysis Plan Version 2
Page 1
LY3009104
1.
Statistical Analysis Plan: 
I4V-MC-JAHV: A Randomized, Double-Blind, Placebo-
Controlled, Withdrawal, Safety and Efficacy Study of Oral 
Baricitinib in Patients from 2 Years to Less Than 18 Years 
Old with Juvenile Idiopathic Arthritis (JIA)
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of 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) Juvenile Idiopathic Arthritis
Study I4V-MC-JAHV (JAHV) is a multicenter, randomized, double-blind, placebo-controlled, 
medication-withdrawal study with a safety/pharmacokinetic (PK) assessment period, an 
open-label lead-in (OLLI) period, and a double-blind withdrawal (DBW) period in patients 
with JIA who have had an inadequate response or intolerance to treatment with at least 1 
other conventional or biologic DMARD (bDMARD).
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I4V-MC-JAHV
Phase 3
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 14-Mar-2022 GMT


I4V-MC-JAHV Statistical Analysis Plan Version 2
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:  I4V-MC-JAHV: A Randomized, Double-
Blind, Placebo-Controlled, Withdrawal, Safety and Efficacy Study of 
Oral Baricitinib in Patients from 2 Years to Less Than 18 Years Old 
with Juvenile Idiopathic Arthritis (JIA) ...............................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................7
4.
Study Objectives.................................................................................................................8
4.1.
Primary Objective ..........................................................................................................8
4.2.
Secondary Objectives.....................................................................................................9
4.3.
Exploratory Objectives.................................................................................................12
5.
Study Design.....................................................................................................................13
5.1.
Summary of Study Design............................................................................................13
5.2.
Determination of Sample Size ......................................................................................14
5.3.
Method of Assignment to Treatment ............................................................................15
6.
A Priori Statistical Methods ..............................................................................................16
6.1.
General Considerations ................................................................................................16
6.1.1.
Analysis Populations............................................................................................16
6.1.2.
Definition of Baseline and Postbaseline Measures................................................17
6.1.3.
Definition of OLLI and DBW Analysis Periods ...................................................18
6.1.4.
Analysis Methods.................................................................................................18
6.2.
Adjustments for Covariates ..........................................................................................20
6.3.
Handling of Dropouts or Missing Data.........................................................................20
6.3.1.
Last Observation Carried Forward (LOCF) ..........................................................20
6.3.2.
Non-Responder Imputation (NRI)........................................................................21
6.3.3.
Mixed Model for Repeated Measures (MMRM)...................................................21
6.4.
Multicenter Studies ......................................................................................................21
6.5.
Multiple Comparisons/Multiplicity...............................................................................21
6.6.
Patient Disposition .......................................................................................................21
6.7.
Patient Characteristics ..................................................................................................22
6.7.1.
Historical Illness and Pre-existing Conditions ......................................................24
6.8.
Treatment Compliance .................................................................................................25
6.9.
Concomitant Therapy...................................................................................................25
6.10. Efficacy Analyses ........................................................................................................27
6.10.1.
Primary Outcome and Methodology.....................................................................27
6.10.2.
Secondary Efficacy Analyses ...............................................................................28


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6.10.3.
More Supplementary Analysis .............................................................................43
6.11. Planned Exploratory Analyses......................................................................................46
6.11.1.
X-ray and Structure Data......................................................................................46
6.12. Acceptability and Palatability Analysis ........................................................................46
6.13. Health Outcomes/Quality-of-Life Analyses..................................................................46
6.14. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................47
6.15. Evaluation of Immunological Measures........................................................................47
6.16. Subgroup Analysis .......................................................................................................47
6.17. Analysis on Subsets of Patients ....................................................................................48
6.18. Safety Analyses............................................................................................................53
6.18.1.
Extent of Exposure...............................................................................................55
6.18.2.
Adverse Events ....................................................................................................56
6.18.3.
Clinical Laboratory Evaluation.............................................................................57
6.18.4.
Vital Signs and Other Physical Findings...............................................................57
6.18.4.1.
Standardized Growth......................................................................................59
6.18.5.
Special Safety Topics, including Adverse Events of Special 
Interest.................................................................................................................60
6.18.5.1.
Abnormal Hepatic Tests .................................................................................60
6.18.5.2.
Hematologic Changes.....................................................................................61
6.18.5.3.
Lipid Effects...................................................................................................62
6.18.5.4.
Renal Function Effects ...................................................................................63
6.18.5.5.
Elevations in Creatine Phosphokinase (CPK)..................................................63
6.18.5.6.
Infections........................................................................................................63
6.18.5.7.
Allergic Reactions and Hypersensitivities.......................................................64
6.18.5.8.
Major Adverse Cardiovascular Events and Other 
Cardiovascular Events ....................................................................................66
6.18.5.9.
Thromboembolic Events.................................................................................66
6.18.5.10. Malignancies ..................................................................................................67
6.18.5.11. Gastrointestinal Perforations...........................................................................67
6.19. COVID-19 Trial Impact ...............................................................................................68
6.20. Protocol Deviations......................................................................................................68
6.21. Interim Analyses and Data Monitoring.........................................................................68
6.21.1.
Interim Analysis Plan...........................................................................................69
6.22. Annual Report Analyses...............................................................................................70
6.23. Clinical Trial Registry Analyses...................................................................................70
7.
Unblinding Plan................................................................................................................72
8.
References ........................................................................................................................73


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Table of Contents
Table
Page
Table JAHV.4.1. Primary Objective and Endpoint ......................................................................8
Table JAHV.4.2. Secondary Objectives and Endpoints ...............................................................9
Table JAHV.4.3. Exploratory Objectives and Endpoints...........................................................12
Table JAHV.6.1. Analysis Populations .....................................................................................16
Table JAHV.6.2. Patient Characteristics....................................................................................23
Table JAHV.6.3. Concomitant JIA Therapies ...........................................................................27
Table JAHV.6.4. Description and Derivation of Primary, Secondary Efficacy 
Endpoints and Health Outcomes ....................................................................29
Table JAHV.6.5. Description of Analysis Period and Analysis Method of Secondary 
Endpoint and Health Outcome .......................................................................39
Table JAHV.6.6. Description of the Use of ESR and hsCRP in Endpoints Derivation...............44
Table JAHV.6.7. Description hsCRP Related Supplementary Analysis.....................................45
Table JAHV.6.8. Description and Derivation of Endpoints for Subsets of Patient .....................49
Table JAHV.6.9. Description of Analysis Period and Analysis Method of Subsets of 
Patients Analysis ...........................................................................................52
Table JAHV.6.10.
Summary of Safety Analysis Population, Period, Duration of 
Exposure and Baseline...................................................................................54
Table JAHV.6.11.
Summary Tables Related to Adverse Events.............................................56
Table JAHV.6.12.
Summary Tables Related to Clinical Laboratory Evaluations....................57
Table JAHV.6.13.
Summary Tables Related to Vital Signs ....................................................58
Table JAHV.6.14.
Categorical Criteria for Abnormal Treatment-Emergent Blood 
Pressure and Pulse Measurements for Children and Adolescents....................59
Table JAHV.6.15.
Summary Tables Related to Hepatic Safety...............................................60
Table JAHV.6.16.
Summary Tables Related to Hematologic Changes ...................................61
Table JAHV.6.17.
Summary Tables Related to Lipid Effects .................................................62
Table JAHV.6.18.
Acceptable, Borderline-High, and High Plasma Lipid, 
Lipoprotein, and Apolipopretein Concentrations for Children and 
Adolescents ...................................................................................................62
Table JAHV.6.19.
Summary Tables Related to Effects on Renal Function.............................63
Table JAHV.6.20.
Summary Tables Related to Effects on CPK .............................................63


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Table JAHV.6.21.
Summary Tables Related to Infections......................................................64
Table JAHV.6.22.
Summary Tables Related to Allergic Reactions/Hypersensitivities............66
Table JAHV.6.23.
Summary Tables Related to MACE and Other Cardiovascular 
Events............................................................................................................66
Table JAHV.6.24.
Summary of Tables Related to VTE Events ..............................................67
Table JAHV.6.25.
Summary of Tables Related to ATE Events ..............................................67
Table JAHV.6.26.
Summary Tables Related to Malignancies.................................................67
Table JAHV.6.27.
Summary Tables Related to Gastrointestinal Perforations .........................68


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List of Figures
Figure
Page
Figure JAHV.1. Study design for Clinical Protocol I4V-MC-JAHV. .......................................14


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3.
Revision History
Statistical Analysis Plan (SAP) Version 1 was approved prior to the first patient visit.
Statistical Analysis Plan (SAP) Version 2 was approved prior to the primary outcome database 
lock and includes the following changes:
•
Updated the secondary and exporatory endpoints based on protocol I4V-MC-JAHV(d).
•
Updated the study design figure footnote on enrollment by age group for clarity based on 
the current protocol I4V-MC-JAHV(d).
•
Updated the analysis population for clarity regarding analyses in the open-label periods. 
Added OLLI population 2 that includes patients from the Safety/PK assessment period
for efficacy/health outcomes analyses in the open-label periods. Added clarification on all 
participents in the open-label period including Safety/PK and OLLI population.
•
Added clarification of baseline and postbaseline measures in Section 6.1.2.
•
Clarified variables adjusted for Cox proportional hazards regression.
•
Clarified time to disease flare calculation in Section 6.10.1.
•
Updated subgroup analysis section by demographic and clinical characteristics 
subgroups.
•
Safety analysis update:
o
Updated analysis strategy and corresponding period and population is defined in 
Section 6.1.1 and Table JAHV.6.10.
o
Updated details on SMQ in corresponding safety topic 
o
Adding COVID-19 Trial Impact in Section 6.19
•
Other minor typographical corrections and clarifications not affecting content.


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4.
Study Objectives
4.1.
Primary Objective
Study objectives are listed in Table JAHV.4.1.  
Estimands (International Conference on Harmonisation [ICH] E9 R1) of the study are defined 
based on the following 4 attributes: 
•
The population of interest is patients with juvenile idiopathic arthritis (JIA) who have had 
an inadequate response or intolerance to treatment with at least 1 other conventional or 
biologic disease-modifying antirheumatic drug (bDMARD). Analysis populations are 
defined in Section 6.1.1. The analysis population corresponding to each of the efficacy 
and health outcome endpoints is specified in Table JAHV.6.4, and Table JAHV.6.8.
•
Primary, major secondary, and exploratory endpoints/variables are listed in 
Table JAHV.4.1, Table JAHV.4.2, and Table JAHV.4.3. A full list of efficacy and health 
outcome endpoints/variables are given in Table JAHV.6.4, Table JAHV.6.7, and 
Table JAHV.6.8.
•
Population Level Summary: categorical variables will be summarized by proportion and
continuous variables will be summarized by average. Details are given in Section 6.7.
•
Intercurrent Event(s) Strategy: intercurrent events will be handled by the while-on-
treatment strategy and the composite strategy approaches as primary strategies. The 
hypothetical strategy will also be used in supplementary analysis. Specific statistical 
methods to be used for handling intercurrent events under different strategies are 
described in Section 6.3. Statistical methods corresponding to each of the efficacy and 
health outcome variables are summarized in Table JAHV.6.4 and Table JAHV.6.8.
Table JAHV.4.1.
Primary Objective and Endpoint
Objectives
Endpoint
Primary
To evaluate the efficacy of baricitinib compared to 
placebo in children with JIA
Time to disease flare (flare defined as worsening of 
≥30% in at least 3 of the 6 PedACR core criteria for JIA 
and an improvement of ≥30% in no more than 1 of the 
criteria) from the beginning of the double-blind 
withdrawal (DBW) period to the end of the DBW period
Abbreviations: JIA = juvenile idiopathic arthritis; PedACR = Pediatric American College of Rheumatology.


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4.2.
Secondary Objectives
Table JAHV.4.2.
Secondary Objectives and Endpoints
Objectives
Endpoints
Secondary
•
To evaluate the efficacy of baricitinib in children 
with JIA
During the open-label lead-in (OLLI) period:
•
PedACR30/50/70/90/100 response rates 
•
Changes in each of the 6 individual core set
components variables of the PedACR Core Set as 
follows:
o
Number of active joints
o
Number of joints with limited range of motion
o
Physician’s Global Assessment of Disease 
Activity
o
Parent’s Global Assessment of Patient’s 
Overall Well-Being
o
Physical function as measured by the 
Childhood Health Assessment Questionnaire 
(CHAQ)
o
Acute-phase reactant (high-sensitivity c-
reactive protein [hsCRP]) and erythrocyte 
sedimentation rate (ESR)
•
Proportion of patients with inactive disease (as 
defined by Wallace et al. 2011)
•
Proportion of patients with minimal disease activity 
(as defined by Consolaro et al. 2012)
•
Change from baseline in the Physical Summary 
Score (PhS) and Psychosocial Summary Score 
(PsS) of the Child Health Questionnaire-Parent 
Form 50 (CHQ-PF50)
•
Changes from baseline in caregiver burden as 
measured by the Parental Impact-Time and Parental 
Impact-Emotion scales of the CHQ-PF50
•
Change from baseline in Juvenile Arthritis Disease 
Activity Score-27(JADAS27)
•
Changes from baseline in arthritis-related pain as 
measured by the CHAQ pain severity Visual 
Analogue Scale (VAS) item


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Secondary Objectives and Endpoints
Objectives
Endpoints
•
To evaluate the efficacy of baricitinib compared to 
placebo in children with JIA
During the DBW period:
•
Proportion of patients with disease flare
•
PedACR30/50/70/90/100 response rates
•
Changes from baseline in each of the 6 individual 
components of the PedACR Core Set variables (due 
to disease flare or completion) as follows:
o
Number of active joints
o
Number of joints with limited range of motion
o
Physician’s Global Assessment of Disease 
Activity
o
Parent’s Global Assessment of Patient’s 
Overall Well-Being
o
Physical function as measured by the CHAQ
o
Acute-phase reactant (hsCRP) and ESR
•
Proportion of patients with inactive disease (as 
defined by Wallace et al. 2011)
•
Proportion of patients with minimal disease activity 
(as defined by Consolaro et al. 2012)
•
Proportion of patients in remission (as defined by 
Wallace et al. 2011)
•
Change from baseline in JADAS-27
•
Change from baseline in the PhS and PsS of the 
CHQ-PF50
•
Change from baseline in caregiver burden as 
measured by the Parental Impact-Time and Parental 
Impact-Emotion scales of the CHQ-PF50Changes
from baseline in arthritis-related pain as measured 
by the CHAQ pain severity VAS item
•
To assess the efficacy of baricitinib in children with 
JPsA
•
Change in Psoriatic Area and Severity Index
(PASI) score during the OLLI period
•
To assess the efficacy of baricitinib compared to 
placebo in children with JPsA
•
Change from baseline in PASI score during the 
DBW period
•
To assess the efficacy of baricitinib in children with 
ERA or JPsA
•
Change in Spondyloarthritis Research Consortium 
of Canada (SPARCC) enthesitis index during the 
OLLI period
•
Change in Juvenile Spondyloarthritis Disease 
Activity Index (JSpADA) during the OLLI period
•
To assess the efficacy of baricitinib compared to 
placebo in children with ERA or JPsA
•
Change from baseline in SPARCC enthesitis index 
during the DBW period
•
Change from baseline in JSpADA during the DBW 
period


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Secondary Objectives and Endpoints
Objectives
Endpoints
•
To evaluate the potential effects of baricitinib on 
the cellular and humoral immune system
•
Change in immunoglobulin levels and peripheral 
blood immunophenotyping (including T and B 
cells, T cell subsets, and NK cells) from baseline 
and at Week 4, Week 12, and Week 44
•
Change of IgG titers from pre-vaccination to 4 weeks 
and 12 weeks post vaccination in patients eligible for 
vaccination with tetanus, diphtheria, and pertussis
(TDaP) and/or pneumococcal conjugate vaccine 
according to local guidelines
•
To characterize baricitinib PK in the JIA population 
and explore relationships between baricitinib 
exposure and study endpoints
•
Population PK of baricitinib in patients with JIA
•
Proportions of patients achieving 
PedACR30/50/70/90/100 response rates by PK 
exposure 
•
Time to disease flare in patients with JIA by PK 
exposure
•
Change in JADAS-27 by PK exposure 
•
To assess the patient acceptability and palatability
of baricitinib tablets and oral suspension
•
Assessment of tablet or oral suspension product 
acceptability and palatability during the OLLI 
period  
•
To assess the safety of baricitinib compared to 
placebo in patients with JIA
•
Adverse events including serious adverse events
•
Permanent discontinuation of investigational 
product
•
Temporary interruption of investigation product
Abbreviations: CHQ-PF50 = Child Health Questionnaire-Parent Form 50; DBW = double-blind withdrawal; 
ERA = enthesitis-related juvenile idiopathic arthritis; hsCRP = high-sensitivity C-reactive protein; HRQoL = 
Health-related Quality of Life; IgA = immunoglobulin A; IgG = immunoglobulin G; JIA = juvenile idiopathic 
arthritis; JADAS = Juvenile Arthritis Disease Activity Score; JPsA = juvenile psoriatic arthritis; NK = natural 
killer; OLLI = open-label lead-in; PedACR = Pediatric American College of Rheumatology; 
PK = pharmacokinetic(s); VAS = Visual Analog Scale.


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4.3.
Exploratory Objectives
Table JAHV.4.3.
Exploratory Objectives and Endpoints
Objectives
Endpoints
Exploratory
•
To evaluate the quality of life (QOL) in children 
with JIA treated with baricitinib
•
Change in European Quality of Life-5 Dimensions–
Youth version (EQ-5D-Y) scores during the OLLI 
period
•
To evaluate the QOL in children with JIA treated 
with baricitinib compared to placebo
•
To evaluate the efficacy of baricitinib compared to 
placebo in structural joint damage 
•
Describe the skeletal age in pediatric patients
•
Change from baseline in EQ-5D-Y scores during the 
DBW period  
•
Change from baseline in the individual scales (Global 
Health; Physical Functioning; Role/Social 
Limitations-Physical; Role/Social Limitations-
Emotional/Behavioral; Bodily Pain/Discomfort; 
Behavior; Global Behavior Item; Mental Health; 
Self-Esteem; General Health Perception; Change in
Health; Parental-Impact-Time; Parental Impact-
Emotion; Family-Activities; Family-Cohesion) as 
measured by the CHQ-PF50
•
Change from the baseline (Week 0) to the end of the 
double-blind withdrawal (DBW) period of 
radiographic images of the hands/wrists using 
modified Total Sharp Score (mTSS [van der Heijde 
method]; van der Heijde 2000; Ravelli et al. 2007)
•
Change from baseline (Week 0) to the end of the 
DBW in skeletal age based on hand/wrist radiograph
and chronological age.
Abbreviations: DBW = double-blind withdrawal; JIA = juvenile idiopathic arthritis; OLLI = open-label lead-in.


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5.
Study Design
5.1.
Summary of Study Design
Study I4V-MC-JAHV (JAHV) is a multicenter, randomized, double-blind, placebo-controlled,
medication-withdrawal study with a safety/pharmacokinetic (PK) assessment period, an 
open-label lead-in (OLLI) period, and a double-blind withdrawal (DBW) period in patients with 
JIA who have had an inadequate response or intolerance to treatment with at least 1 other 
conventional or bDMARD. This includes patients with polyarticular JIA (rheumatoid factor 
positive or rheumatoid factor negative), extended oligoarticular course JIA, enthesitis-related JIA 
(ERA), and juvenile psoriatic arthritis (JPsA) as defined by the International League of 
Associations for Rheumatology (ILAR) criteria. The safety and tolerability data from this study 
are intended to establish an understanding of the benefit/risk relationship for baricitinib in 
patients with nonsystemic JIA.


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Abbreviations: OLE = open-label extension; PedACR30 = Pediatric American College of Rheumatology 30 criteria; 
PK = pharmacokinetic(s); QD = once daily.
a
Staggered approach to enrollment by age group (12 to <18 years, 9 to <12 years, 6 to <9 years, 2 to <6 years) 
will be implemented with older groups completing the safety/PK assessment period before younger groups are 
enrolled.  
b
Once the PK and safety profiles for an age group are confirmed, subsequent patients in that age group may enroll 
directly into the OLLI period. If the comparability assessment in the safety/PK period for an age group is
inconsistent with baricitinib 4-mg exposures in adults with RA such that baricitinib dosage for the age group 
needs to be adjusted, the patients on the inconsistent dosage will discontinue the study and may enter the separate 
OLE study (JAHX).
c
Patients who experience a disease flare during the DBW period will discontinue the study and may proceed 
directly to the separate OLE study (JAHX).
Figure JAHV.1.
Study design for Clinical Protocol I4V-MC-JAHV.
5.2.
Determination of Sample Size
A total of 128 patients will be randomized in a 1:1 ratio to baricitinib or placebo (64 per 
treatment arm) in the DBW period. This sample size will provide approximately 80% power to 
detect the difference in time to disease flare between the 2 treatment groups using a 2-sided test 
with a significance level of 0.05, assuming that the expected percentages of patients experiencing 
disease flare in the DBW period are 35% for baricitinib and 60% for placebo and that the 
dropout rate is no greater than 10% in this period.
It is estimated that 197 patients are required to enter the OLLI period to allow 128 patients to be 
randomized into the DBW period (assuming that 65% of the patients meet the Pediatric 
American College of Rheumatology (PedACR) 30 criteria at the end of the OLLI period). The 
nonresponder and dropout rate will be monitored during the OLLI period to adjust the overall 
sample size to ensure that a minimum of 128 patients will be randomized in the DBW. If the 


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PedACR30 response rate during the OLLI period is higher than the assumed rate of 65%, fewer 
than 197 patients may be required.
The above sample size and power estimates are based on nQuery®+nTerim 4.0.
5.3.
Method of Assignment to Treatment
Patients who enter the PK lead-in period will be assigned a dose based on age. Doses of 
subsequent patients who enter the PK lead-in period may be adjusted until a dose is found that 
produces exposures within the range produced by baricitinib 4-mg in adults with RA. All 
patients who enter the OLLI period will receive a fixed age-based dose of baricitinib as 
determined in the PK lead-in period.
Patients who meet the PedACR30 response criteria at the end of the OLLI period will be 
randomized in a 1:1 ratio (baricitinib age-based dose or matching placebo) to double-blind 
treatment at Week 12. The randomization will be stratified by:
•
history of prior bDMARD use (Yes versus No)
•
the JIA categories (polyarticular and extended oligoarticular [combined] versus ERA and 
JPsA [combined])
•
Predose exposure erythrocyte sedimentation rate (ESR) categories (elevated 
[>20 mm/hour] and not elevated) in the polyarticular JIA patients
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 bottles containing double-blind investigational product to each patient. All patients 
<6 years of age will receive oral suspension. Patients ≥ 6 to <12 years old have the option of 
receiving the oral suspension. Patients >12 years will be supplied tablets only. Site personnel 
will enter the confirmation number found on the bottles into the IWRS, which confirms that 
they have located the correct bottles.


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6.
A Priori Statistical Methods
6.1.
General Considerations
This plan describes a priori statistical analyses for efficacy, health outcomes, and safety that will 
be performed.  
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (Lilly). The 
statistical analyses will be performed using SAS® Version 9.4 or higher. 
Not all displays described in this SAP will necessarily be included in the clinical study report 
(CSR). Not all displays will necessarily be created as a “static” display. Some may be 
incorporated into interactive display tools instead of or in addition to a static display. Any 
display described in this SAP and not included in the CSR would be available upon request.
Statistical tests of treatment effects and confidence intervals (CIs) will be performed at a 2-sided 
significance level of 0.05, unless otherwise stated. 
Data collected at early termination visits will be mapped to the next scheduled visit number for 
that patient. For by-visit summaries, only visits in which a measure was scheduled to be 
collected will be summarized. Any unscheduled visit data will be included in the patient-level 
listings. However, the data might still be used in other analyses, including change from baseline 
to endpoint using last observation carried forward (LOCF) analyses and other categorical 
analyses.  
6.1.1. Analysis Populations
For purposes of analysis, the following populations are defined based on the different treatment 
period as shown in Table JAHV.6.1.
Table JAHV.6.1.
Analysis Populations
Population
Description
Entered population
All participants who sign informed consent.
Efficacy Analysis 
population
Safety/PK population
All patients who received at least 1 dose of investigational 
product in the Safety/PK assessment period.
OLLI population
All participants who take at least 1 age-based final dose, as 
confirmed by PK assessments of investigational product, in 
the OLLI period, other than the Safety/PK population.
OLLI population 2
All patients who received at least 1 dose of investigational 
product in the OLLI period.
Safety/PK and OLLI 
population
All enrolled patients who were initially assigned to the open-
label investigational product in Safety/PK assessment period 
and OLLI period, following intent-to-treat (ITT) principles.
DBW population
All randomized patients in the DBW period following intent-
to-treat (ITT) principles.


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Population
Description
Safety Analysis 
population
DBW safety population
All randomized patients in the DBW period who receive at 
least 1 dose of investigational product.
General safety 
population
All patients who received at least 1 dose of investigational 
product, which is baricitinib.
Abbreviations: DBW = doubleblind withdrawal; OLLI = open-label lead-in; PK = pharmacokinetic.
Efficacy analyses will be conducted by treatment periods with the corresponding analysis 
population, where the primary efficacy analysis will focus on the DBW period with the DBW 
population. Safety analyses will be performed by treatment periods with the corresponding safety 
population.
The patients who participate in the Safety/PK period and participate in the OLLI period with the
age-based final dose will be eligible to participate in the DBW period if the patient is a 
PedACR30 responder at the end of the OLLI period. Thus, such patients from the Safety/PK
assessment period will be included in the OLLI population 2 and DBW population. Also, 
Safety/PK assessment period and OLLI period may be combined for efficacy/safety analysis
with the corresponding population that includes such patients.
In the rare situation where a patient is lost-to-follow-up at the first postbaseline visit but some 
safety data exist (e.g., unscheduled laboratory assessments) after first dose of study drug, a 
listing of the data or a patient profile will be provided. 
6.1.2. Definition of Baseline and Postbaseline Measures
The baseline value for the efficacy (except flare), health outcomes is defined as the last non-
missing measurement on or prior to the date of first study baricitinib administration. For patients
who participate in the Safety/PK period, this value will be recorded on or before Visit 2 (Day 1); 
for the other patients who started with the OLLI period, this value will be recorded on or before
Visit 5 (Week 0).   
The baseline value for disease flare analyses is defined as the last non-missing measurement on 
or prior to the date of randomization (beginning of the DBW period). This value will be recorded 
on or before Visit 9 (Week 12).
Baseline for the safety analyses is defined in Section 6.18. Postbaseline measurements are 
collected after study drug administration through Visit 17 (Week 44) or early discontinuation 
visit. For data collected in the electronic Clinical Outcomes Assessment (eCOA) tablet 
(including Patient-Reported Outcomes [PRO] and Clinician-Reported Outcomes [ClinRO]) and 
related to efficacy assessments, unscheduled postbaseline visits that fall within the visit windows 
defined by Lilly will be summarized in the by-visit analyses if there is no scheduled visit 
available. Refer to clinical protocol I4V-MC-JAHV(d) for detail of the visit windows. If there is 
more than 1 unscheduled visit within the defined visit window and no scheduled visit is available, 
the unscheduled visit closest to the scheduled visit date will be used. If 2 unscheduled visits of 
equal distance are available, then the latter of the 2 will be used.


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Postbaseline measures for the safety analyses are defined as the nonmissing scheduled (planned)
measurements after the date of first study drug administration for continuous measures by-visit
analyses and all nonmissing measurements after the date of first study drug administration for all
other analyses.
6.1.3. Definition of OLLI and DBW Analysis Periods
The OLLI period starts at:
•
The completion of Safety/PK assessment period for Safety/PK population patients
•
The time of first age-based dose of baricitinib for OLLI population patients
The OLLI period ends for the following study events:
•
Week 12 (Visit 9) for patients who do not meet the randomization criteria, or
•
Visit of early discontinuation of study treatment in the OLLI period.
The DBW period starts at the time of randomization and ends at the following study events:
•
Patient experience disease flare (defined in Table JAHV.6.4)
•
Week 44 (Visit 17) for patients who do not flare, or
•
Visit of early discontinuation of study treatment in the randomized double-blind 
withdrawal period.
6.1.4. Analysis Methods
The primary endpoint will be the time-to-flare during the DBW period for randomized patients.  
Patients who discontinue or complete the DBW period without experiencing a flare will have 
their data censored at the time of their discontinuation date or completion date. The censored 
patients will contribute to the at-risk set in the stratified logrank test. Survival curves will be 
estimated using the Kaplan–Meier method in the DBW period. Treatment comparisons will be 
performed using a stratified log-rank test across JIA categories (polyarticular and extended 
oligoarticular [combined] versus ERA and JPsA [combined]) for the DBW population in the 
DBW period. Treatment comparisons may also be analyzed using a Cox proportional hazards 
model adjusted for stratification variables. The hazard ratio with 95% CIs will be reported. And 
the similarity of treatment effect across JIA categories (polyarticular and extended oligoarticular 
[combined] versus ERA and JPsA [combined]) will be evaluated using Cox proportional hazards 
regression adjusted for stratification variables. If any of these variables are redundant for a 
particular model, they will be dropped.
Secondary efficacy and health outcomes analyses (Table JAHV.6.4 and Table JAHV.6.5) will be 
based on treatment period and respective study populations.
Efficacy, health outcomes, and safety data collected in OLLI period will be summarized without 
inferential statistics.


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In the DBW period, the main analysis of categorical efficacy variables and health outcomes 
variables will use a logistic regression analysis with treatment, JIA categories (polyarticular and 
extended oligoarticular [combined] versus ERA and JPsA [combined]), predose exposure ESR 
categories (elevated [>20 mm/hour] and not elevated), history of prior bDMARD use (Yes or 
No) as covariates in the model. The p-value and 95% CI for the odds ratio from the logistic 
regression model are used for statistical inference.  
In the DBW period, the main analysis for all continuous efficacy and health outcomes variables 
will use analysis of covariance (ANCOVA) model with treatment, JIA patient categories 
(polyarticular and extended oligoarticular [combined] versus ERA and JPsA [combined]), 
predose exposure ESR categories(elevated [>20 mm/hour] and not elevated), history of prior 
bDMARD use (Yes or No), and baseline score as covariates in the model. For ESR and high-
sensitivity C-reactive protein (hsCRP) analysis, predose ESR level categories will not be 
included as a covariate. Type III sums of squares for the least-squares mean (LSM) will be used 
for the statistical comparison of treatment groups, and the LSM difference, standard error, p-
value and 95% CI will also be reported. The LOCF approach will be used to impute missing 
data. 
The mixed model repeated measures (MMRM) analysis will also be considered as a 
supplemental analysis method. The MMRM will use a restricted maximum likelihood (REML) 
estimation. The model will include treatment, JIA patient categories (polyarticular and extended 
oligoarticular [combined] versus ERA and JPsA [combined]), predose exposure ESR categories
(elevated [>20 mm/hour] and not elevated), history of prior bDMARD use (Yes or No), visit, 
treatment-by-visit-interaction, baseline score and baseline-by-visit-interaction as fixed effects. If 
any of these are redundant for a particular model, they will be dropped. An unstructured 
(co)variance structure will be used to model the between- and within-patient errors. If this 
analysis fails to converge, the heterogeneous autoregressive [ARH(1)], followed by the 
heterogeneous compound symmetry (CSH), followed by the heterogeneous Toeplitz (TOEPH)
will be used. The Kenward-Roger method will be used to estimate the degrees of freedom. Type 
III tests for the LSM will be used for the statistical comparison. The LSM difference, standard 
error, p-value, and 95% CI will also be reported.  
The primary safety analysis will be conducted during the DBW period for the DBW safety 
population. Fisher’s exact test will be used for the adverse events (AEs), discontinuation, and 
other categorical safety data for between-treatment group comparisons. Continuous vital signs, 
body weight, and other continuous safety variables, including laboratory variables will be 
analyzed by an ANCOVA with treatment group and baseline value in the model. The 
significance of within-treatment group changes from baseline will be evaluated by testing 
whether or not the treatment group LSM changes from baseline are different from zero; the 
standard error and within-group p-value for the LSM change will also be displayed. In addition, 
the LSM difference between baricitinib and placebo groups, the corresponding p-value, and 95% 
CI will be provided. Treatment-emergent high/low for categorical laboratory safety analyses will 
also be produced.


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6.2.
Adjustments for Covariates
The randomization to treatment groups at Week 12 (Visit 9) is stratified by: 
•
history of prior bDMARD use (Yes versus No)  
•
the JIA categories 
o
polyarticular and extended oligoarticular [combined] or
o
enthesitis-related JIA and JPsA [combined]
•
predose exposure ESR categories (elevated [>20 mm/hour] and not elevated) in the 
polyarticular JIA patients
Unless otherwise specified, the statistical analysis models will adjust for JIA patient category 
(polyarticular and extended oligoarticular versus ERA and JPsA), history of prior bDMARD use
(Yes or No), and predose exposure ESR categories (above 20 mm/L or below 20 mm/L). If any 
of these are redundant for a particular model, they will be dropped. The covariates used in the 
ANCOVA model for continuous data generally will include the parameter value at baseline.
When an MMRM analysis is performed, baseline value and baseline-by-visit interactions will be 
included as covariates.  
6.3.
Handling of Dropouts or Missing Data
Intercurrent events (ICH E9R1) are events which occur after the treatment initiation and make it 
impossible to measure a variable or influence how it should be interpreted. Examples of such 
events include treatment discontinuation due to death or AEs, and loss to follow-up. In this study, 
intercurrent events will be handled by the while-on-treatment strategy and the composite strategy 
approaches as primary strategies. The hypothetical strategy will also be used in supplementary 
analysis. 
The censoring rule: The efficacy and health outcome data collected after permanent study drug 
discontinuation will be excluded from the analyses. This censoring rule will be applied to all 
continuous and categorical efficacy and health outcome endpoints.
For binary response variables that are derived from component scores, the following steps will 
be implemented unless otherwise specified: If all component scores are missing at a visit, the 
response status will be set to nonresponse; if at least 1 component score is nonmissing at a visit, 
the LOCF approach will be applied to impute the missing components within a treatment period. 
If the binary response status still cannot be determined after LOCF, the binary response status 
will be set to nonresponse. The detail of the missing data definition and imputation rule is 
documented in Table JAHV.6.4 and Table JAHV.6.5. 
6.3.1. Last Observation Carried Forward (LOCF)
According to ICH E9 R1, the while-on-treatment strategy could be applied based on the last 
postbaseline value at or before the visit of interest while the patient was still on study drug. The
primary endpoint for efficacy evaluation, time to disease flare, is an endpoint that reflects loss of 


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treatment effect. Therefore, for patients who completed DBW via flare, the LOCF values
appropriately estimate their disease status at this time and beyond.
All continuous endpoints will be imputed using the LOCF methodology after applying the 
censoring rule to those who discontinued study drug. For patients who permanently discontinue
study treatment or discontinue from the study for any reason at any time, the last nonmissing 
postbaseline observation on or prior to discontinuation will be carried forward to subsequent 
time points for evaluation. LOCF will not be applied across OLLI and DBW analysis periods.
6.3.2. Non-Responder Imputation (NRI)
A non-responder imputation (NRI) imputation method can be justified based on the composite 
strategy (ICH E9R1) for handling intercurrent events. In this strategy 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 makes them 
a non-responder.  
Binary efficacy and health outcome variables will be imputed using NRI after applying the 
censoring rule to those who discontinued study drug. Patients will be considered a non-responder 
for the NRI analysis if they do not meet the clinical response criteria or are entirely missing the 
visit at the analysis time point. Randomized patients without at least 1 postbaseline observation
will also be defined as non-responders for the NRI analysis.
6.3.3. Mixed Model for Repeated Measures (MMRM)
An MMRM method can be justified based on the hypothetical strategy (ICH E9 R1) for handling 
intercurrent events. In this strategy the effect of study treatment is assessed in a hypothetical trial 
where all patients have complete data and continue to take study treatment without dropping out 
of the study. The MMRM method assumes that missing data can bias results, but the bias can be 
attenuated by modeling random effects using the within-subject error correlation structure. 
These correlations between the repeated measurements provide the platform used to account for 
the bias from subject dropout by assuming the dropout follows missing at random (MAR) 
assumption. 
Selected efficacy and health outcomes variables will be assessed using MMRM as a 
supplementary analysis. The details are described in Table JAHV.6.5. 
6.4.
Multicenter Studies
This study will be conducted by multiple investigators at multiple sites internationally. The 
countries will be categorized into geographic regions, as described in Table JAHV.6.2.
6.5.
Multiple Comparisons/Multiplicity
No multiplicity control measures will be used.
6.6.
Patient Disposition
An overview of patient disposition will be summarized by treatment periods with the 
corresponding safety population. Frequency counts and percentages of patients excluded by 


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primary reason for exclusion will be provided for patients who failed to meet study entry 
requirements during screening.
Frequency counts and percentages of patients who complete the study treatment or discontinue 
early from the study, along with their discontinuation reasons and whether they completed 
follow-up or enrolled into the extension, will be summarized. A by-treatment summary will 
provide for the DBW period with the DBW safety population.
A listing of patient disposition will be provided for all enrolled patients, with the extent of their 
participation in the study and the reason for discontinuation. A listing of all randomized patients 
with their treatment assignment will also be provided.
6.7.
Patient Characteristics
Patient characteristics including demographics, baseline characteristics, historical illnesses, and 
preexisting conditions will be summarized descriptively at the study baseline by treatment 
periods with the corresponding analysis population. They will also be summarized descriptively
by treatment group for the DBW period with the DBW population. No formal statistical 
comparisons will be made among treatment groups unless otherwise stated.
Table JAHV.6.2 describes the specific variables and how they may be summarized.  


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Table JAHV.6.2.
Patient Characteristics
Variable
Continuous 
measure 
Summary
Categorical Summary
Age a
Yes
12 to <18 years, 9 to <12 years, 6 to <9 years, and 2 to <6 years
Sex
No
Male, Female
Race
No
American Indian/Alaska Native, Asian, Black/African American, 
Native Hawaiian or other Pacific Islander, White, or Multiple
Geographic region
No
By Country
No
Asia, South America, Europe and rest of world
Height (cm)
Yes
None
Weight (kg)
Yes
None
BMIb
Yes
Underweight (<18.5 kg/m2), Normal (≥18.5 and <25 kg/m2),
Overweight (≥25 and <30 kg/m2), Obese (≥30 and <40 kg/m2), 
Extreme obese (≥40 kg/m2)
Tobacco use
No
Never, Current, Former
Prior biologic JIA therapyc
No
Never used, Ever used
Number of prior biologics 
JIAc
No
0, 1, 2, >2
Prior non-biologic JIA 
therapyd
No
Never used, Ever used
Number of non-biologic JIA 
therapiesd
No
0, 1, 2, >2
MTX usage at baseline
No
Yes, No
Duration of JIA diagnosis 
(years)e
Yes
0 to <2 years, 2 to <5 years, 5 to <10 years, ≥10 years
Age at JIA onset (years)e
Yes
12 to <18 years, 6 to <12 years, and 2 to <6 years
Baseline number of active 
joints 
Yes
None
Baseline number of joints with 
limited range of motion 
Yes 
None 
Baseline Physician’s Global 
Assessment of Disease 
Activity
Yes 
None 
Baseline Parent’s Global 
Assessment of Patient’s 
Overall Well-Being 
Yes
None 
Baseline Physical function 
measured by CHAQ
Yes 
None
Baseline ESR
Yes 
Elevated (above 20 mm/L) or Not Elevated (not above 20 mm/L)
Baseline hsCRP
Yes
above 3 mg/L or not above 3 mg/L
Baseline Juvenile Arthritis 
Disease Activity Score 
(JADAS)-27
Yes
None
Baseline Physical Summary 
Score (PhS) and Psychosocial 
Summary Score (PsS) of the 
Child Health Questionnaire-
Parent Form 50 (CHQ-PF50)
Yes
None
Baseline caregiver burden as 
measured by Parental Impact-
Time and Parental Impact-
Yes
None


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Variable
Continuous 
measure 
Summary
Categorical Summary
Emotion scales of the CHQ-
PF50
Baseline Arthritis-related pain 
measured by CHAQ pain 
severity 
Yes 
None
Variable
Continuous 
measure 
Summary
Categorical Summary
Baseline SPARCC f, g  
Yes
None
Baseline JSpADA f, g
Yes
None
Baseline PASI score f
Yes
None
Latest screening period renal 
function status
No
impaired (eGFR <60 mL/min/1.73 m2) or not impaired (eGFR 
≥60 mL/min/1.73 m2)
Immunoglobulin level
(Including T and B cells, T 
cell subsets and NK cells)
Yes
None
Peripheral blood 
immunophenotyping 
(Including T and B cells, T 
cell subsets and NK cells)
Yes
None
pre-vaccination IgG titerh
Yes 
None
Abbreviations: BMI = body mass index; CHAQ = Childhood Health Assessment Questionnaire; 
CHQ-PF50 = Child Health Questionnaire-Parent Form 50; ESR = erythrocyte sedimentation rate; 
IgG = immunoglobulin G; JIA = juvenile idiopathic arthritis; JSpADA = Juvenile Spondyloarthritis Disease 
Activity Index; NK = natural killer; PASI = Psoriasis Area and Severity Index; SPARCC = Spondyloarthritis 
Research Consortium of Canada.
a
Age in years will be calculated as length of the time interval from the imputed date of birth (July 1st in the year 
of birth collected in the electronic case report form( eCRF)) to the informed consent date.
b
Body Mass Index (BMI) will be calculated as: ܤܯܫሺ݇݃/ ݉ଶሻൌܹ݄݁݅݃ݐሺ݇݃ሻ/ሺܪ݄݁݅݃ݐሺ݉ሻሻଶ.
c
Biologic JIA therapies for example: anakinra, canankinumab, tocilizumab, sarilumab, rituximab, etanercept, 
adalimumab, abatacept, tocilizumab, and golimumab
d
Non-biologics JIA therapies for example: methotrexate,celecoxib, diclofenac, ibuprofen and corticosteroids.
e
Age at diagnosis in years will be calculated as the time interval from the imputed date of birth (July 1st in the 
year of birth collected in the eCRF) to the date of JIA diagnosis.
f
For JPsA patients who have this score available.
g
For ERA patients who have this score available.
h
In patients eligible for vaccination with tetanus, diphtheria, and pertussis (TDaP) and/or pneumococcal conjugate 
vaccine according to local guidelines.
6.7.1. Historical Illness and Pre-existing Conditions
Historical illnesses are defined as those conditions recorded in the Preexisting Conditions and 
Medical History electronic case report form (eCRF) with an end date prior to the informed 
consent date. The number and percentage of patients with selected historical diagnoses will be 
summarized for the OLLI population, also they will be summarized by treatment group using the 
DBW population. Historical diagnoses will be categorized using the Medical Dictionary for 


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Regulatory Activities (MedDRA®, most current available version) algorithmic Standardized 
MedDRA Queries (SMQs) or similar predefined lists of Preferred Terms (PTs) of interest.
Preexisting conditions are defined as those conditions recorded in the Preexisting Conditions and 
Medical History eCRF or the Adverse Events eCRF with a start date prior to the date of 
informed consent and an end date after informed consent or missing. For events occurring on the 
day of the first dose of study treatment, the date and time of the onset of the event will both be 
used to determine if the event was preexisting. Conditions with a partial or missing start date (or 
time if needed) will be assumed to be ‘not preexisting’ unless there is evidence, through 
comparison of partial dates, to suggest otherwise. Preexisting conditions will be categorized
using the MedDRA SMQs or similar predefined lists of PTs of interest. Frequency counts and 
percentages of patients with selected preexisting conditions will be summarized for the OLLI 
population, and also will be summarized by treatment group using the DBW population.
6.8.
Treatment Compliance
Treatment compliance with investigational product will be summarized by treatment periods
with corresponding population. Patients will be considered compliant for each treatment period if 
they miss <20% of the expected doses. Proportions of patients compliant will be summarized. 
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.  
Compliance in the period of interest up to Visit x will be calculated as follows:
Compliance ൌtotal number of tablets ሺor weight of suspensionሻdispensed – total number of tablets ሺor weight of suspension ሻreturned
expected number of total tablets ሺor weight of suspensionሻ
where 
•
Total number of tablets (or weight of suspension) dispensed: sum of tablets (or 
weight of suspension) dispensed in the period of interest prior to Visit x; 
•
Total number of tablets (or weight of suspension) returned: sum of the tablets (or 
weight of suspension) returned in the period of interest prior to and including Visit x;
•
Expected number of tablets (or weight of suspension): number of days in the period 
of interest*number of tablets (or weight of suspension) taken per day = [(date of visit 
– date of first dose + 1) – number of days of temporary drug interruption]*number of 
tablets (or weight of suspension) taken per day 
Descriptive statistics for percent compliance and noncompliance rates will be summarized for the 
OLLI population for Week 0 through Week 12 and will also be summarized for the DBW 
population by treatment group for Week 12 through Week 44. Subintervals of interest, such as 
compliance between visits, may also be presented. The number of expected tablets or suspension
dispensed, tablets or suspension returned, and percent compliance may be listed by patient for 
Week 0 through Week 44.
6.9.
Concomitant Therapy
Summaries of previous and concomitant medications will be provided by analysis population. .


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At screening, previous and current JIA treatments are recorded for each patient. A summary of 
previous medications used for JIA, including vaccination with tetanus, diphtheria, and pertussis 
(TDaP) and/or pneumococcal conjugate and medications that are discontinued after screening 
and before the first dose of study drug, will be prepared using frequency counts and percentages
by preferred medication name, with preferred medication names sorted by frequency. 
Concomitant therapy will be recorded at each visit and will be classified similarly. An additional 
summary for previous medications used for JIA will be created containing the reason of 
discontinuation.
Concomitant therapy for the treatment period is defined as therapy that starts before or during the 
treatment period and ends during the treatment period or is ongoing (has no end date or ends 
after the treatment period). Should there be insufficient data to make this comparison (for 
example, the concomitant therapy stop year is the same as the treatment start year, but the 
concomitant therapy stop month and day are missing), the medication will be considered as 
concomitant for the treatment period.  
Summaries of previous medications will be provided for the following categories:
•
previous JIA therapies
•
previous JIA therapies including reason for discontinuation
Summaries of concomitant medications will be provided for the following categories:
•
concomitant medications for JIA
•
concomitant medications for non-JIA


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Table JAHV.6.3.
Concomitant JIA Therapies
Drug Class
As Needed
Chronic Use
Conditions for Use
MTXa
No
Yes
If on MTX, must be on a stable average dose of 
≤20 mg/m2/week for the 8 weeks preceding screening and 
must continue at that dose throughout the study
cDMARDs other than 
MTXa
No
Yes
If receiving cDMARDs (other than MTX), must be on a 
stable dose for at least 4 weeks prior to the screening and 
must continue at that dose throughout the study.
Oral corticosteroids
No
Yes
If receiving oral corticosteroids, daily doses of 
≤10 mg/day or 0.2 mg/kg/day prednisone equivalent, 
whichever is less. Must be on stable dose for at least 
2 weeks prior to screening and 6 weeks prior to baseline;
the dose must be continued throughout the study.
NSAIDsb
•
including 
cyclooxygenase-
2 inhibitors, e.g.,
celecoxib
No
Yes
•
Must be on stable dose at least 1 week prior to
baseline.
•
Changes in dose, discontinuation and/or 
introduction of new NSAIDs are only allowed
for treatment of an AE.
Analgesics
•
including local 
anaesthetics, e.g.,
lidocaine, and
•
topical
anaesthetics, e.g.,
EMLA cream.
No
Yes
•
Must be on stable dose at least 1 week prior to
baseline.
•
Changes in dose, discontinuation and/or 
introduction of new analgesics are only allowed
for treatment of an AE.
Abbreviations: cDMARD = conventional disease-modifying antirheumatic drug; NSAID = nonsteroidal 
anti-inflammatory drug; MTX = methotrexate.
a
Concomitant use of >2 of any cDMARDs (including MTX) is not allowed.
b
For use as an anti-inflammatory agent.
6.10. Efficacy Analyses
6.10.1. Primary Outcome and Methodology
Time to disease flare (time is measured by week) is used as the primary outcome, which will be 
calculated as follows:
ሺܦܽݐ݁݋݂ܨ݈ܽݎ݁െܦܽݐ݁݋݂ܴܽ݊݀݋݉݅ݖܽݐ݅݋݊݅݊ݐ݄݁ܦܤܹ൅1ሻ/7
The flare-ESR is calculated based on the flare definition and PedACR core criteria defined in 
Section 4.1, Table JAHV.4.1, Table JAHV.4.2, and Table JAHV.6.6, and uses ESR as acute-
phase reactant. The detail of disease flare calculation is documented in separate disease flare and 
PedACR response calculation algorithm document. Patients completing the DBW period without 
flare will be censored at the date of completion (ie, the date of the last visit in the period).  


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Patients who discontinued treatment early in the DBW period without flare will be censored at 
the treatment discontinuation date.  
The primary analysis of the study is to test for the hypotheses that baricitinib is superior to 
placebo in prolonging the time to disease flare in PedACR 30 responders from Week 12 to 
Week 44 using the DBW population.  
A stratified logrank test will be used as the primary analysis method, in which the log-rank test 
will be stratified on the JIA categories:
•
polyarticular and extended oligoarticular[combined]
•
enthesitis-related JIA and JPsA[combined]
The p-value and median time to flare (if applicable) by treatment group will be reported.
Treatment comparisons may also be analyzed using a Cox proportional hazards model adjusted 
for stratification variables. The hazard ratio with 95% CIs will be reported. The Kaplan-Meier 
product limit method will be used to estimate the survival curves for time-to flare. Time-to flare
will also be summarized graphically by treatment group using Kaplan-Meier techniques.
6.10.2. Secondary Efficacy Analyses
Secondary efficacy and health outcomes analyses (Table JAHV.6.4) will be based on treatment
periods with the respective population at each visit. The analysis method is described in Table 
JAHV.6.5. There will be no adjustment for multiple comparisons.


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Table JAHV.6.4.
Description and Derivation of Primary, Secondary Efficacy Endpoints and Health Outcomes
Measure 
Description
Variable 
Derivation/Comment
Imputation
Approach if with 
Missing 
Components 
Disease flare
Disease flare is defined as a worsening of ≥30% in at 
least 3 of the 6 PedACR core criteria for JIA and an 
improvement of ≥30% in no more than 1 of the criteria 
from the patient’s condition at randomization baseline. 
In disease flare-ESR, ESR measure is used as acute-
phase reactant in the core criteria.
•
If either the number of joints with active arthritis 
or the number of joints with limitation of motion 
are used in the calculation of flare for a study 
visit, then a minimum worsening of at least 2 
active joints or 2 joints with limitation of motion 
must be present.  
•
An active joint is defined as a joint with swelling 
or, in the absence of swelling, limitation of 
motion accompanied by pain on motion and/or 
tenderness. 
•
If either the Physician’s Global Assessment of 
Disease Activity or the Parent’s Global 
Assessment of Well-Being are used in the 
calculation of flare for a study visit, then a 
minimum worsening of at least 20 mm in 0-100 
mm visual analogue scale (VAS) must be present.
•
If ESR is used in the definition of “flare” and 
counts towards worsening, then the second value 
for ESR used in the calculation must be above the 
upper limit of normal for ESR (>20 mm/hour).
Time to disease flare
The details of disease flare calculation 
are documented in separate disease 
flare and PedACR response 
calculation algorithm document.  
Calculation:
Date of disease flare-ESR minus date 
of randomization+1
Component is 
missing if baseline 
or postbaseline 
value is missing.
LOCF will be 
applied for post 
baseline missing 
values. If more 
than 3 components 
are missing, there 
will not be 
sufficient 
information; thus, 
the patient will be 
considered as a 
non-flare patient.
The details of 
handling of missing 
data are
documented in 
separate disease 
flare and PedACR 
response 
calculation 
algorithm 
document.
Proportion of patients
with disease flare
The detail of disease flare calculation 
is documented in separate disease 
flare and PedACR response 
calculation algorithm document.  


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Secondary Efficacy Endpoint Analyses
Measure 
Description
Variable 
Derivation/Comment
Imputation
Approach if with 
Missing 
Components 
PedACR
response 
Pediatric American College of Rheumatology 
(PedACR x%) responder is defined as patients who 
demonstrate disease response improvement of ≥x% in 
at least 3 of 6 Pediatric American College of 
Rheumatology (PedACR) core response variables and 
>30% worsening in not more than 1 of the remaining 
variables. (PedACR30; Giannini et al. 1997). When 
PedACR response is analyzed as secondary endpoint, 
ESR measure is used as acute-phase reactant in the 
core criteria.
PedACR
30/50/70/90/100 
response rates 
(compare to patient’s 
condition prior to 
first dose of 
investigational 
product)
The detail of disease flare calculation 
is documented in separate disease 
flare and PedACR response 
calculation algorithm document.  
Component is 
missing if baseline 
or postbaseline 
value is missing.
LOCF will be 
applied for post 
baseline missing 
values. If more 
than 3 components 
are missing, there 
will not be 
sufficient 
information; thus, 
the patient will be 
considered as a 
non-responder.
The detail of 
handling of missing 
data is documented 
in separate disease 
flare and PedACR 
response 
calculation 
algorithm 
document.


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Secondary Efficacy Endpoint Analyses
Measure 
Description
Variable 
Derivation/Comment
Imputation
Approach if with 
Missing 
Components 
Active joint 
count 
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.
Change from baseline 
of active joint count
Calculation:
Change from baseline: observed active 
joint count at visit minus baseline 
active joint count
Missing if baseline 
or postbaseline 
value is missing.
LOCF will be 
applied for post 
baseline missing 
values.
Limited range 
of motion 
joint count 
Number of joints with limited range of motion in 69 
joints
Change from baseline 
of limited of motion 
joint count 
Calculation:
Change from baseline: observed 
limited range of motion joint count at 
visit minus baseline limited range of 
motion joint count
Missing if baseline 
or postbaseline 
value is missing.
LOCF will be 
applied for post 
baseline missing 
values.
Physician's 
global 
assessment of 
disease 
activity
(VAS)
The Physician’s Global Assessment of Disease 
Activity is used 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).
Change from baseline 
of physician's global 
assessment of disease 
activity 
Calculation:
Change from baseline: observed score 
at visit minus baseline score
Missing if baseline 
or postbaseline 
value is missing.
LOCF will be 
applied for post 
baseline missing 
values.
Parent’s
global 
assessment of 
overall well-
being
measured by 
CHAQ (10cm 
VAS)
The parent is generally asked to make a global 
assessment of the child's overall well-being on a 10 cm 
VAS, with anchors of ‘0 = very good’ and ‘10 = very 
poor’, which is located at the bottom of the Childhood 
Health Assessment Questionnaire (CHAQ) 
questionnaire 
Change from baseline 
of parent’s global 
assessment of overall 
well-being
Calculation:
Change from baseline: observed score 
at visit minus baseline score
Missing if baseline 
or postbaseline 
value is missing.
LOCF will be 
applied for post 
baseline missing 
values.


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Secondary Efficacy Endpoint Analyses
Measure 
Description
Variable 
Derivation/Comment
Imputation
Approach if with 
Missing 
Components 
Physical 
function as 
measured by
CHAQ (0-3)
The Childhood Health Assessment Questionnaire 
(CHAQ) assesses health status and physical function 
over the past week in children with juvenile arthritis 
over the past week, which the parent or legal guardian 
completes, regardless of the age of the patient.
Physical function is measured by CHAQ from 
disability index. The Disability Index contains 30 items 
grouped into the following 8 domains (not including 
assistive devices/aids questions): physical function, 
dressing, and grooming (4 items), arising (2 items), 
eating (3 items), walking (2 items), hygiene (5 items), 
reach (4 items), grip (5 items), and activities (5 items).  
Each item is scored from 0 to 3 (0 = no difficulty; 1 = 
some difficulty; 2 = much difficulty; 3 = unable to do 
or not applicable) (Singh et al. 1994). The total score is 
the average of domain score, which is range from 0 to 
3.
At least 6 domains are required in calculation.
Change from baseline 
of physical function
The details of physical function 
calculations are documented in 
separate CHAQ instruction document.   
Calculation:
Change from baseline: observed score 
at visit minus baseline score
Missing if baseline 
or postbaseline 
value is missing.
LOCF will be 
applied for post 
baseline missing 
values.
hsCRP
(mg/L) 
The hsCRP test is a highly sensitive quantification of 
C-Reactive protein (CRP), an acute-phase protein that 
increases during inflammation.
Change from baseline 
of hsCRP
Calculation:
Change from baseline: observed lab 
value at visit minus baseline lab value
Missing if baseline 
or postbaseline 
value is missing.
LOCF will be 
applied for post 
baseline missing 
values.


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Secondary Efficacy Endpoint Analyses
Measure 
Description
Variable 
Derivation/Comment
Imputation
Approach if with 
Missing 
Components 
ESR (mm/hr) 
An erythrocyte sedimentation rate (ESR) is a type of 
blood test that measures how quickly erythrocytes (red 
blood cells) settle at the bottom of a test tube that 
contains a blood sample. Normally, red blood cells 
settle relatively slowly. A faster-than-normal rate may 
indicate inflammation in the body. 
Change from baseline 
of ESR
Calculation:
Change from baseline: observed lab 
value at visit minus baseline lab value
Missing if baseline 
or postbaseline 
value is missing.
LOCF will be 
applied for post 
baseline missing 
values.
Physical 
Summary 
Score (PhS) 
and 
Psychosocial 
Summary 
Score (PsS)
Physical Summary Score (PhS) and Psychosocial 
Summary Score (PsS) from Child Health
Questionnaire-Parent Form 50 (CHQ-PF50) will be 
used to address physical and psychosocial health status.
The CHQ-PF50 is a generic QOL instrument designed 
to capture the physical, emotional, and social 
components of health status of children as well as 
caregiver burden over the past 4 weeks 
(HealthActCHQ 2013). The CHQ-PF50 is completed 
by the parent and has been validated for use in JIA 
patients (Ruperto et al. 2001).
Change from baseline 
in the Physical 
Summary Score 
(PhS) and 
Psychosocial 
Summary Score 
(PsS) of the Child 
Health 
Questionnaire-Parent 
Form 50 (CHQ-
PF50)
The Physical Summary Score (PhS) 
and Psychosocial Summary Score 
(PsS) will be scored according to the 
manual, “CHQ Scoring and 
Interpretation manual”. 
(HealthActCHQ 2013).
Calculation:
Change from baseline: observed score 
at visit minus baseline score
Missing if baseline 
or postbaseline 
value is missing.
LOCF will be 
applied for post 
baseline missing 
values.
Caregiver 
burden  
Caregiver burden is measured by Parental Impact-Time 
and Parental Impact-Emotion scales from CHQ-PF50 
will be used to address burden to the parent/legal 
guardian.
Change from baseline 
of caregiver burden 
score measured by 
the Parental Impact-
Time and Parental 
Impact-Emotion 
scales of the CHQ-
PF50
The caregiver burden will be scored 
according to the manual, “CHQ 
Scoring and Interpretation manual”. 
(HealthActCHQ 2013).
Calculation:
Change from baseline: observed score 
at visit minus baseline score
Missing if baseline 
or postbaseline 
value is missing.
LOCF will be 
applied for post 
baseline missing 
values.


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Secondary Efficacy Endpoint Analyses
Measure 
Description
Variable 
Derivation/Comment
Imputation
Approach if with 
Missing 
Components 
Inactive 
disease
Inactive disease is indicated by the presence of all of 
the following (Wallace et al. 2011):
• No joints with active arthritis based on JADAS-27
• No fever, rash, serositis, splenomegaly, 
hepatomegaly, or generalized lymphadenopathy 
attributable to JIA as assessed by the investigator
• No active uveitis as assessed by the investigator
• Normal erythrocyte (ESR) or hsCRP (ie, within 
normal limits in the local laboratory or, if elevated, 
not attributable to JIA)
• Physician’s Global Assessment of Disease Activity 
indicating no active disease (best possible score on 
scale [0]) 
• Duration of morning stiffness less than 15 minutes
• In inactive disease analysis as secondary endpoint, 
ESR measure is used as acute-phase reactant 
measure.
Proportion of patients 
who achieved 
inactive disease 
• Step 1: If joint with active arthritis 
isn’t 0, stop; else 
• Step 2: If there is fever, rash, 
serositis, splenomegaly, 
hepatomegaly, or generalized 
lymphadenopathy attributable, 
stop; else 
• Step 3: If uveitis, stop; else
• Step 4: If ESR>20, stop; else
• Step 5: If physician’s global 
assessment of disease activity isn’t 
0, stop; else
• Step 6: If stiffness >15min, stop; 
else
• Step 7: Conclude the patient 
achieved inactive disease status.
Missing if any 
component is 
missing.
NRI will be applied 
to missing data.


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Secondary Efficacy Endpoint Analyses
Measure 
Description
Variable 
Derivation/Comment
Imputation
Approach if with 
Missing 
Components 
Minimal 
disease 
activity    
Minimal disease activity is calculated based on the 
scores from the Physician’s Global Assessment of 
Disease Activity, Parent’s Global Assessment of 
Patient’s overall Well-Being, and the number of 
swollen joints as described in Consolaro et al. 2012.
Proportion of patients 
who achieved 
minimal disease 
activity
•
if physician’s global assessment of 
disease activity ≤3.5, and 
• if parent’s global rating of patient’s 
overall well-being ≤2.5, and 
• if swollen joint count ≤1, then 
conclude the patient reaches 
minimal disease activity;
all else conclude the minimal disease 
activity is not reached.
Component is 
missing if baseline 
or postbaseline 
value is missing.
LOCF will be 
applied for post 
baseline missing 
values.
If all components 
are missing after 
LOCF, NRI will be 
applied to missing 
data.


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Secondary Efficacy Endpoint Analyses
Measure 
Description
Variable 
Derivation/Comment
Imputation
Approach if with 
Missing 
Components 
Disease 
remission 
Remission is defined as inactive disease for at least 24 
consecutive weeks (Wallace et al. 2011). In inactive 
disease as secondary endpoint, ESR measure is used as 
acute-phase reactant in the core criteria. Thus, the 
disease remission as secondary endpoint is based on 
ESR.
Proportion of patients
who achieved 
minimal disease 
activity
• At Visit 13, check if there are 
inactive disease status in all Visit 7, 
Visit 8, Visit 9, Visit 10, Visit 11, 
Visit 12, if yes, conclude the 
patient has achieved disease 
remission status.
• At Visit 14, check if there are 
inactive disease status at Visit 8, 
Visit 9, Visit 10, Visit 11, Visit 12, 
Visit 13, if yes, conclude the 
patient has achieved disease 
remission status.
• At Visit 15, check if there are 
inactive disease status at Visit 9, 
Visit 10, Visit 11, Visit 12, Visit
13, Visit14, if yes, conclude the 
patient has achieved disease 
remission status.
• At Visit 16, check if there are 
inactive disease status at Visit 10, 
Visit 11, Visit 12, Visit 13, Visit
14, Visit 15, if yes, conclude the 
patient has achieved disease 
remission status.
• At Visit 17, check if there are 
inactive disease status at Visit 11, 
Visit 12, Visit 13, Visit 14, Visit
15, Visit 16, if yes, conclude the 
patient has achieved disease 
remission status.
Missing if item is 
missing.
NRI will be applied 
to missing data.


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Secondary Efficacy Endpoint Analyses
Measure 
Description
Variable 
Derivation/Comment
Imputation
Approach if with 
Missing 
Components 
JADAS-27   
The JADAS-27 score is a validated composite disease 
activity measure for JIA (Consolaro et al. 2012).  
Recently, the scoring system was adapted to use the 
27-joint count (Bazso et al. 2009) and hsCRP or ESR 
for the inflammatory marker component (Nordal et al. 
2012). The JADAS 27 includes the following joints:  
cervical spine, elbows, wrists, metacarpophalangeal 
joints (from first to third), proximal interphalangeal 
joints, hips, knees, and ankles. In JADAS-27 analysis 
as secondary endpoint, ESR measure is used as acute-
phase reactant measure,
Change from baseline 
of JADAS-27 score 
JADAS-27 score (0-57) will be 
determined based on 4 components:
• PHY: Physician’s Global 
Assessment of Disease Activity 
(0-10 VAS) 
• PGA: Parent’s Global Assessment 
of Patient’s overall Well-Being 
(0-100 mm VAS)
• Joint27: Number of joints with 
active disease (27-joint assessment)
• ESR (mm/hr)
Calculation:
NormESR: Normalized ESR (0-10)
NormESR=(ESR-20)/10
Scaled PGA= scaled Parent’s Global 
Assessment of Patient’s overall Well-
Being (0-10)
Scaled PGA=PGA/10
JADAS(ESR)27=PHY+ScaledPGA+j
oint27+NormESR
Change from baseline: observed 
JADAS(ESR)-27 at visit minus 
baseline JADAS-27
Missing if baseline 
is missing.
For observed value, 
missing if all the 
components are 
missing. LOCF will 
be applied for post 
baseline missing 
value. 
If at least one 
component is non-
missing, LOCF will 
be applied on the 
missing
components prior 
to LOCF being 
applied to the 
composite score 


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Secondary Efficacy Endpoint Analyses
Measure 
Description
Variable 
Derivation/Comment
Imputation
Approach if with 
Missing 
Components 
Pain (VAS)  
The pain assessment item will be collected from the 
CHAQ.
Change from baseline 
of pain vas score 
Calculation:
Change from baseline: observed score 
at visit– baseline score
Missing if baseline 
or postbaseline 
value is missing.
LOCF will be 
applied for post 
baseline missing 
value.
Abbreviations: CHQ-PF50 = Child Health Questionnaire-Parent Form 50; ESR = erythrocyte sedimentation rate; hsCRP = high-sensitivity C-reactive protein; 
JADAS = Juvenile Arthritis Disease Activity Score; JIA = juvenile idiopathic arthritis; LOCF = last observation carried forward; NRI = nonresponder 
imputation; PedACR = Pediatric American College of Rheumatology; VAS = Visual Analog Scale.


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Table JAHV.6.5.
Description of Analysis Period and Analysis Method of Secondary Endpoint and Health Outcome
Measure 
Variable
Population
Analysis Timepoint 
Treatment 
Comparisons
Analysis Method
Analysis Type
Disease flare 
Proportion of patients
with disease flare
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
Logistic regression 
Secondary analysis 
PedACR response 
PedACR30/50/70/90/
100 response rates 
(compare to patient’s 
condition prior to first 
dose of investigational 
product)
Safety/PK, 
OLLI, 
OLLI2
Week 2 to Week 12
No comparison
Summary statistics
Secondary analysis 
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
Logistic regression 
Secondary analysis 
Active joint count 
Change from baseline 
of active joint count
OLLI2
Week 2 to Week 12
No comparison
Summary statistics
Secondary analysis 
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
ANCOVA
Secondary analysis 
MMRM
Supplementary analysis
Limited of range 
motion joint count 
Change from baseline 
of limited range of 
motion joint count 
OLLI2
Week 2 to Week 12
No comparison
Summary statistics
Secondary analysis 
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
ANCOVA
Secondary analysis 
MMRM
Supplementary analysis
Physician's global 
assessment of 
disease activity
Change from baseline 
of physician's global 
assessment of disease 
activity 
OLLI2
Week 2 to Week 12
No comparison
Summary statistics
Secondary analysis 
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
ANCOVA
Secondary analysis 
MMRM
Supplementary analysis
Physical function as 
measured by 
CHAQ
Change from baseline 
of physical function
OLLI2
Week 2 to Week 12
No comparison
Summary statistics
Secondary analysis 
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
ANCOVA
Secondary analysis 
MMRM
Supplementary analysis


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Description of Analysis Period and Analysis Method of Secondary Endpoint and Health Outcome
Measure 
Variable
Population
Analysis Timepoint 
Treatment 
Comparisons
Analysis Method
Analysis Type
Parent’s global 
assessment of 
overall well-being 
as measured by 
CHAQ
Change from baseline 
of parent’s global 
assessment of overall 
well-being
OLLI2
Week 2 to Week 12
No comparison
Summary statistics
Secondary analysis 
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
ANCOVA
Secondary analysis 
MMRM
Supplementary analysis


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Description of Analysis Period and Analysis Method of Secondary Endpoint and Health Outcome  
Measure 
Variable
Population
Analysis Timepoint
Treatment 
Comparisons
Analysis Method
Analysis Type
hsCRP (mg/L) 
Change from baseline 
of hsCRP
OLLI2
Week 2 to Week 12
No comparison
Summary statistics
Secondary analysis 
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
ANCOVA
Secondary analysis 
MMRM
Supplementary analysis
ESR (mm/hr) 
Change from baseline 
of ESR
OLLI2
Week 2 to Week 12
No comparison
Summary statistics
Secondary analysis 
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
ANCOVA
Secondary analysis 
MMRM
Supplementary analysis
Physical Summary 
Score (PhS) and 
Psychosocial 
Summary Score 
(PsS)
Change from baseline 
in the Physical 
Summary Score (PhS) 
and Psychosocial 
Summary Score (PsS) 
of the Child Health 
Questionnaire-Parent 
Form 50 (CHQ-PF50)
OLLI2
Week 2 to Week 12
No comparison
Summary statistics
Secondary analysis 
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
ANCOVA
Secondary analysis 
Caregiver burden  
Change from baseline 
of caregiver burden 
score, as measured by 
the Parental Impact-
Time and Parental 
Impact-Emotion scales 
of the CHQ-PF50
OLLI2
Week 2 to Week 12
No comparison
Summary statistics
Secondary analysis 
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
ANCOVA
Secondary analysis 
Inactive disease   
Proportion of patients
who achieved inactive 
disease 
OLLI2
Week 2 to Week 12
No comparison
Summary statistics
Secondary analysis 
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
Logistic regression 
Secondary analysis
Minimal disease 
activity    
Proportion of patients
who achieved minimal 
disease activity
OLLI2
Week 2 to Week 12
No comparison
Summary statistics
Secondary analysis 
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
Logistic regression 
Secondary analysis 
Disease remission
Proportion of patients
who achieved minimal 
disease activity
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
Logistic regression 
Secondary analysis 


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JADAS-27   
Change from baseline 
of JADAS-27 score 
OLLI2
Week 2 to Week 12
No comparison
Summary statistics
Secondary analysis 
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
ANCOVA
Secondary analysis 
MMRM
Supplementary analysis
Description of Analysis Period and Analysis Method of Secondary Endpoint and Health Outcome
Measure 
Variable
Population
Analysis Timepoint
Treatment 
Comparisons
Analysis Method
Analysis Type
Pain (VAS)  
Change from baseline 
of pain VAS item score 
OLLI2
Week 2 to Week 12
No comparison
Summary statistics
Secondary analysis 
DBW
Week 16 to Week 44
Baricitinib versus 
placebo
ANCOVA
Secondary analysis 
Abbreviations: ANCOVA = analysis of covariance; CHAQ = Childhood Health Assessment Questionnaire; CHQ-PF50 = Child Health Questionnaire-Parent 
Form 50; DBW = DBW = double-blind withdrawal; hsCRP = high-sensitivity C-reactive protein; JADAS = Juvenile Arthritis Disease Activity Score; 
MMRM = mixed model repeated measures; OLLI = open-label lead-in; PedACR = Pediatric American College of Rheumatology; VAS = Visual Analog 
Scale. 


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6.10.3. More Supplementary Analysis
For the composite measures/endpoints which have acute-phase reactant ESR or CRP as 
component, in general, the ESR version of derivation will be used as the main version of 
derivation for the first and secondary analysis. The hsCRP version of derivation will be used as a 
supplementary version for the supplementary analysis and will be provided for selected visits
only, as defined in Table JAHV.6.6 and Table JAHV.6.7.


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Table JAHV.6.6.
Description of the Use of ESR and hsCRP in Endpoints Derivation
Endpoint 
Version 
Calculation difference between ESR 
version and hsCRP version
Measure
Type of the 
endpoint
Analysis 
flare
ESR version 
Derivation refer to Table JAHV.6.4
time to flare
primary endpoint 
primary analysis 
ESR version 
Derivation refer to Table JAHV.6.4
proportion of patients who have 
disease flare
secondary 
endpoint 
secondary 
analysis
PedACR 
response
ESR version 
Derivation refer to Table JAHV.6.4
proportion of patients who 
achieve PedACR response 
secondary 
endpoint 
secondary 
analysis
PedACR (hsCRP) 
response
Derivation logic is same as ESR 
version 
proportion of patients who 
achieve PedACR-hsCRP 
response 
supplementary 
supplementary 
analysis 
JADAS-27
ESR version
Derivation refer to Table JAHV.6.4
change from baseline of 
JADAS-27
secondary 
endpoint 
secondary 
analysis
hsCRP version 
Derivation logic is same as ESR 
version, use Norm hsCRP=(hsCRP-
10)/10 instead of NormESR
change from baseline of 
JADAS-hsCRP-27
supplementary 
supplementary 
analysis 
inactive 
disease
ESR version
Derivation refer to Table JAHV.6.4
proportion of patients who 
achieve inactive disease status 
secondary 
endpoint 
secondary 
analysis
hsCRP version 
Derivation logic is same as ESR 
version, use hsCRP>3 instead of 
ESR>20
proportion of patients who 
achieve inactive disease status 
(hsCRP)
supplementary 
supplementary 
analysis 
disease 
remission
ESR version
Derivation refer to Table JAHV.6.4
proportion of patients who 
achieve disease remission status 
secondary 
endpoint 
secondary 
analysis
hsCRP version 
Derivation logic is same as ESR 
version, use hsCRP>3 instead of 
ESR>20
proportion of patients who 
achieve disease remission status 
(hsCRP)
supplementary 
supplementary 
analysis 
Abbreviations: ESR = erythrocyte sedimentation rate; hsCRP = high-sensitivity C-reactive protein; 
JADAS = Juvenile Arthritis Disease Activity Score; PedACR = Pediatric American College of Rheumatology.


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Table JAHV.6.7.
Description hsCRP Related Supplementary Analysis
Measure 
Variable
Population
Analysis Time 
Point
Treatment Comparisons
Analysis Method
Analysis Type
PedACR-
hsCRP 
response 
PedACR-hsCRP 
30/50/70/90/100 response 
rates (compare to patient’s 
condition prior to first dose of 
investigational product)
OLLI2
Week 12
No comparison
Summary 
statistics
Supplementary 
analysis 
DBW
Week 16, week 
32, Week 44
Baricitinib versus placebo
Logistic 
regression 
Supplementary 
analysis 
Inactive 
disease status 
(hsCRP)   
Proportion of patients who 
achieved inactive disease 
status (hsCRP)
OLLI2
Week 12
No comparison
Summary 
statistics
Supplementary 
analysis 
DBW
Week 16, Week 
32, Week 44
Baricitinib versus placebo
Logistic 
regression 
Supplementary 
analysis 
Disease 
remission 
status 
(hsCRP)
Proportion of patients who 
achieved disease remission 
status (hsCRP)
DBW
Week 16, Week 
32, Week 44
Baricitinib versus placebo
Logistic 
regression 
Supplementary 
analysis 
JADAS-
hsCRP-27   
Change from baseline of 
JADAS-hsCRP-27 score 
OLLI2
Week 12
No comparison
Summary 
statistics
Supplementary 
analysis 
DBW
Week 16, Week 
32, Week 44
Baricitinib versus placebo
ANCOVA
Supplementary 
analysis 
MMRM
Supplementary 
analysis 
Abbreviations: DBW = double-blind withdrawal ; hsCRP = high-sensitivity C-reactive protein; JADAS = Juvenile Arthritis Disease Activity Score; OLLI = 
open-label lead-in; PedACR = Pediatric American College of Rheumatology.


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6.11. Planned Exploratory Analyses
In consideration of the limited sample size in JIA categories (polyarticular and extended 
oligoarticular [combined] versus ERA and JPsA [combined]), a non-stratified logrank test may 
be applied to analysis of time to flare as an exploratory analysis. The p-value and median time to 
flare (if applicable) by treatment group will be reported. Treatment comparisons may also be 
analyzed using a Cox proportional hazards model. The hazard ratio with 95% CIs will be 
reported. The Kaplan-Meier product limit method will be used to estimate the survival curves for 
time-to flare. Time-to flare will also be summarized graphically by treatment group using 
Kaplan-Meier techniques.
6.11.1. X-ray and Structure Data
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 at the time of protocol amendment
(d), the x-ray procedures will be optional. For 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.
Descriptive statistics will be used to summarize the modified total Sharp score (mTSS) (when 
data are available), skeletal age, and chronological age at baseline for all the patients who have a 
baseline value available.
For patients in the DBW period, an analysis of covariance model with baseline mTSS, presence 
of erosion at baseline (yes or no), and treatment group in the model will test the treatment 
difference between baricitinib and placebo in change from baseline to Week 44 in mTSS when 
data are available. Linear extrapolation will be applied for patients who are missing the 
radiograph at Week 44 but who have baseline and postbaseline radiographs available. 
The skeletal age can deviate from the chronological age calculated from the date of birth.  
Results will include a description of the skeletal age, the chronological age, and the difference 
between skeletal age and chronological age at baseline and post baseline when data are available.  
6.12. Acceptability and Palatability Analysis
Acceptability and palatability data will be collected and analyzed to address secondary and 
exploratory objectives of this study. The detail will be described by Lilly in separate 
acceptability and palatability analysis plans.
6.13. Health Outcomes/Quality-of-Life Analyses
Besides the health outcomes/ QOL measures discussed in Section 6.10.2 and Table JAHV.6.3.  
The change from baseline in European Quality of Life-5 Dimensions–Youth version (EQ-5D-Y)
scores by treatment periods with the corresponding analysis population will be analyzed as 
exploratory analyses using methods described for continuous or categorical data as described for 
efficacy measures. The EQ-5D-Y will be scored according to the EQ-5D-Y user guide (Van 
Reenen et al. 2014).


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Change from baseline in the individual scales (Global Health; Physical Functioning; Role/Social 
Limitations-Physical; Role/Social Limitations-Emotional/Behavioral; Bodily Pain/Discomfort; 
Behavior; Global Behavior Item; Mental Health; Self-Esteem; General Health Perception; 
Change in Health; Parental-Impact-Time; Parental Impact-Emotion; Family-Activities; Family-
Cohesion) as measured by the CHQ-PF50 by treatment group during the DBW period will also 
be included as exploratory analyses. The individual scales of the CHQ-PF50 will be scored 
according to the manual, “CHQ Scoring and Interpretation manual”. (HealthActCHQ 2013).
6.14. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods
Pharmacokinetic, pharmacodynamic and biomarker analyses to address secondary and 
exploratory objectives of this study will be described by Lilly in separate PK/PD and Biomarker 
analysis plans.
6.15. Evaluation of Immunological Measures
Change from baseline in immunoglobulin levels and peripheral blood immunophenotyping 
(including T and B cells, T cell subsets, and natural killer [NK] cells) at Weeks 4, 12, and at the 
end of the DBW period will be evaluated and summarized using descriptive statistics. Patients who 
are immunized with TDaP or pneumococcal conjugate vaccines will have their immunoglobulin G 
(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.
6.16. Subgroup Analysis
Cox proportional hazards regression will be used to evaluate the similarity of treatment effect 
across the JIA categories (polyarticular and extended oligoarticular [combined] versus ERA and 
JPsA [combined]). The model will have treatment and stratification variables as factors in the 
model. If any of these variables are redundant for a particular model, they will be dropped.
For the primary endpoint, selected secondary endpoints, and selected growth measurements, 
following subgroup analysis may be conducted:
•
Gender: (Male; Female)
•
Age group (12 to <18 years, 9 to <12 years, 6 to <9 years, 2 to <6 years)
•
Geographic region (Asia, South America, Europe and rest of world)
•
JIA categories (polyarticular and extended oligoarticular [combined] versus ERA and
JPsA [combined])
•
JIA categories (polyarticular, extended oligoarticular, ERA, JPsA)
•
Predose exposure ESR categories (elevated [>20 mm/hour] and not elevated)
•
history of prior bDMARD use (Yes or No)
•
MTX usage at baseline (Yes or No)


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6.17. Analysis on Subsets of Patients
Additional analysis on subpopulation of patients may be conducted based on country or 
geographic region.
The summary statistical analysis will be conducted for the following subsets of patients at each 
visit. 
In the subset of patients with JPsA:
•
change from baseline in Psoriasis Area and Severity Index (PASI) score 
during the OLLI period and during the DBW period.
In the subset of patients with JPsA or ERA:
•
change from baseline in Spondyloarthritis Research Consortium of Canada 
(SPARCC) index of entheseal assessment during the OLLI period and during 
the DBW period
•
change from baseline in Juvenile Spondyloarthritis Disease Activity Index
(JSpADA) during the OLLI period and during the DBW period
The detail of the calculation is documented in Table JAHV.6.8.


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Table JAHV.6.8.
Description and Derivation of Endpoints for Subsets of Patient
Measure 
Description
Variable 
Derivation/Comment
Imputation 
approach if with 
missing 
components
Psoriasis Area 
and Severity 
Index (PASI)
Psoriasis Area and Severity Index (PASI): 
combines assessments of the extent of body-
surface involvement in 4 anatomical regions 
(head and neck, trunk, arms, and legs) and the 
severity of scaling (S), redness (R), and plaque 
induration/infiltration (thickness, T) in each 
region, yielding an overall score of 0 for no 
psoriasis to 72 for the most severe disease 
(Fredriksson and Pettersson 1978). 
Severity is rated for each index (R, S, T) on a 
0-4 scale (0 for no involvement up to 4 for 
severe involvement):
0 = none
1 = slight
2 = moderate
3 = severe
4 = very severe
The body is divided into four anatomical 
regions comprising the head (h), upper limb 
(u), trunk (t), and lower limb (l). In each of 
these areas, the fraction of total body surface 
area affected is graded on a 0-6 scale (0 for no 
involvement; up to 6 for 90% - 100% 
involvement):  
0 = 0% (clear)
1 = >0% to <10%
2 = 10% to <30%
3 = 30% to <50%
4 = 50% to <70%
PASI change from 
baseline
The composite PASI score is calculated by 
multiplying the sum of the individual-
severity scores for each area by the 
weighted area-of-involvement score for that 
respective area, and then summing the four 
resulting quantities as follows: 
PASI = 0.1(Rh + Th + Sh)Ah + 0.2(Ru + 
Tu + Su)Au + 0.3(Rt + Tt + St)At + 0.4(Rl 
+ Tl + Sl)Al
Where, Rh, Ru, Rt, Rl = redness score of 
plaques on the head, upper limb, trunk, and 
lower limb, scored 0-4 respectively;
Th, Tu, Tt, Tl = thickness score of plaques 
on the head, upper limb, trunk, and lower 
limb, scored 0-4 respectively;
Sh, Su, St, Sl = scaliness score of plaques 
on the head, upper limb, trunk, and lower 
limb, scored 0-4 respectively; 
Ah, Au, At, Al = numerical value 
translation of % area of psoriatic 
involvement score for the head, upper limb, 
trunk, and lower limb, respectively.
PASI scores are treated as a continuous 
score, with 0.1 increments within these 
values. 
Calculated as: observed PASI minus
If any individual 
score is missing, the 
PASI score will not 
be calculated, hence, 
missing. LOCF will 
be applied


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Measure 
Description
Variable 
Derivation/Comment
Imputation 
approach if with 
missing 
components
5 = 70% to <90%
6 = 90% to 100%
The various body regions are weighted to 
reflect their respective proportion of body 
surface area.
baseline PASI
Spondyloarthritis 
Research 
Consortium of 
Canada 
(SPARCC) 
enthesitis
SPARCC enthesitis is an index used to measure 
the severity of enthesitis (Maksymowych et al. 
2009). The SPARCC assesses 16 sites for 
enthesitis using a score of “0” for no activity 
and “1” for activity. Sites assessed include 
Medial epicondyle (left/right [L/R]), Lateral 
epicondyle (L/R), Supraspinatus insertion into 
greater tuberosity of humerus (L/R), Greater 
trochanter (L/R), Quadriceps insertion into 
superior border of patella (L/R), Patellar 
ligament insertion into inferior pole of patella 
or tibial tubercle (L/R), Achilles tendon 
insertion into calcaneum (L/R), and Plantar 
fascia insertion into calcaneum (L/R).   
SPARCC enthesitis 
change from 
baseline 
The SPARCC is the sum of all site scores
Range: 0–16, higher scores indicate more 
severe enthesitis.
Calculated as: observed SPARCC enthesitis
score – baseline SPARCC enthesitis score
If any individual 
component is 
missing, the 
SPARCC score will 
not be calculated, 
hence, missing. 
LOCF will be 
applied
Juvenile 
Spondyloarthritis 
Disease Activity 
(JSpADA) Index
The JSpADA is used to evaluate the disease 
activity of juvenile spondyloarthritis (Weiss et 
al. 2014). The range of possible scores is 0 to 8, 
where higher scores indicate more disease 
activity.  
JSpADA change 
from baseline 
The Juvenile Spondyloarthritis Disease 
Activity Index scores will be determined by 
8 components:
• Active joint count: 0 joints = 0, 1 to 2 
joints = 0.5, >2 joints = 1
• Active enthesitis count: 0 entheses = 0, 1 
to 2 entheses = 0.5, >2 entheses = 1
• Pain over the past week as assessed 
using a 0-10 NRS (0 = no pain; 10 = 
pain as bad as your child can imagine):  
0 = 0, 1 to 4 = 0.5, 5 to 10 = 1
If any individual 
score is missing, the 
JSpADA score will 
not be calculated, 
hence, missing. 
LOCF will be 
applied


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Measure 
Description
Variable 
Derivation/Comment
Imputation 
approach if with 
missing 
components
• CRP level related to juvenile 
spondyloarthritis activity: normal = 0, 1 
to 2 times normal = 0.5, >2 times normal 
= 1
• Morning stiffness >15 minutes: Absent = 
0, Present = 1
• Clinical sacroiliitis (defined as the 
presence of ≥2 of the following:  
tenderness on examination, positive 
Patrick’s test or flexion, abduction and 
external rotation (FABER) test, and 
inflammatory back pain): Absent = 0, 
Present = 1
• Uveitis (any uveitis including 
acute/symptomatic and 
chronic/asymptomatic disease): Absent = 
0, Present =1
• Back mobility (abnormal back mobility 
defined as modified Schober’s test <20 
cm): Normal = 0, Abnormal = 1
Total score= sum of 8 domain score
Calculated as: observed JSpADA score –
baseline JSpADA score 
Abbreviations: LOCF – last-observation-carried-forward.


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Table JAHV.6.9.
Description of Analysis Period and Analysis Method of Subsets of Patients Analysis
Variable 
Population
Analysis Period
Treatment 
Comparisons
Analysis Method 
Analysis Type 
PASI change 
from baseline
For JPsA patient in OLLI2
Week 2 to Week 12
No comparison
Summary statistics
Secondary analysis 
For JPsA patient in DBW
Week 16 to Week 44
No comparison
Summary statistics 
by treatment group 
Secondary analysis 
SPARCC 
enthesitis change 
from baseline 
For JPsA and ERA patient in 
OLLI2
Week 2 to Week 12
No comparison
Summary statistics
Secondary analysis 
For JPsA and ERA patient in 
DBW
Week 16 to Week 44
No comparison
Summary statistics 
by treatment group 
Secondary analysis 
JSpADA change 
from baseline 
For JPsA and ERA patient in 
OLLI2
Week 2 to Week 12
No comparison
Summary statistics
Secondary analysis 
For JPsA and ERA patient in 
DBW
Week 16 to Week 44
No comparison
Summary statistics 
by treatment group 
Secondary analysis 
Abbreviations: DBW = double-blind withdrawal; ERA = enthesitis-related juvenile idiopathic arthritis; Psoriasis Area and Severity Index; JSpADA = Juvenile 
Spondyloarthritis Disease Activity Index; OLLI = open-label lead-in; SPARCC = Spondyloarthritis Research Consortium of Canada.


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6.18. Safety Analyses
The planned safety analyses are consistent with compound-level standards, which are based on 
various sources, including company standards, internal and external subject matter experts, and 
cross-industry initiatives (e.g., white papers produced by a PhUSE Computational Science 
Working Group [a collaboration with FDA and PhUSE], published in the PhUSE Deliverables 
Catalog). Descriptions of the safety analyses are provided in this SAP; however, some details are 
in compound-level safety standards.
The detail of analysis and corresponding period and population is defined in Section 6.1.1 and 
Table JAHV.6.10.


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Table JAHV.6.10.
Summary of Safety Analysis Population, Period, Duration of 
Exposure and Baseline
Population for 
safety analysis 
(Section 6.1.1)
General Safety Population 
DBW Safety Population
Baricitinib
Placebo
Treatment period 
OLLI period and Safety/PK assessment period
DBW period
Duration of study 
drug exposure
date of last dose of baricitinib in safety/PK
assessment or OLLI period – date of first dose of 
baricitinib in Safety/PK assessment or OLLI period
+ 1
date of last dose of treatment in DBW period –
date of randomization in DBW period + 1
Baseline for LLT 
used in defining 
treatment-
emergence and 
change from 
baseline analysis 
Baseline period: The start of screening and ends prior to the time of first dose of bari administration.
(For labs, vital signs and growth: baseline will be all scheduled and unscheduled measurements
recorded during baseline period.)
Postbaseline for 
LLT used in 
defining treatment-
emergence and 
change from 
baseline analysis 
The event start time (onset time) is on or after first 
dose of baricitinib in Safety/PK assessment period or 
OLLI period, before time of randomization in DBW 
period (include up to 30 days off-drug follow-up 
time if patient did not enter DBW period). 
For treatment-emergent abnormal labs, vital signs 
and shift summaries in labs, all scheduled and 
unscheduled measurements will be included.
For change from baseline labs, vital signs and 
growth, only scheduled visits will be included. The 
early termination visits (ETV) are considered 
scheduled visits.
The event start time (onset time) is on or after 
time of randomization in DBW period, up to 30 
days off-drug follow-up time.
For treatment-emergent abnormal labs, vital 
signs and shift summaries in labs, all scheduled 
and unscheduled measurements will be 
included.
For change from baseline labs, vital signs and 
growth, only scheduled visits will be included. 
The early termination visits (ETV) are 
considered scheduled visits.
Abbreviations: Bari = baricitinib; DBW = double-blind withdrawal; OLLI = open-label lead-in; JIA = juvenile 
idiopathic arthritis; LLT = Lowest Level Term; PK = pharmacokinetics.
Safety topics that will be addressed include the following: AEs, clinical laboratory evaluations, 
vital signs and physical characteristics, safety in special groups and circumstances, including 
adverse events of special interest (AESI) (see Section 6.18.5).
Unless otherwise specified, by-visit summaries will include planned on-treatment visits. For 
tables that summarize events (such as AEs, categorical lab abnormalities, shift to maximum 
value), post-last dose follow-up data will be included. For deaths and malignancies, all available 
follow-up data up to the end of the study will be included. Listings will include all safety data.


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The following statistical methods will be used for safety analysis during the DBW period with
the DBW safety population unless otherwise noted:
•
The Fisher exact test will be used for treatment comparisons of proportions, and odds 
ratios with corresponding 95% confidence intervals will be provided.       
•
Treatment differences in mean change for continuous measurements will be assessed 
using an ANCOVA model fitting “baseline” as a covariate. Type 3 sums of squares will 
be used.   
Though p-values will be provided for many of the safety analyses, they should not be 
overinterpreted. They correspond to data-driven hypotheses and are only useful as a flagging 
mechanism.  
Statistical significance is designated at 2-sided p-values (rounding up to 3 decimal places) ≤0.05 
for tests of treatment differences. However, p-values should not be overinterpreted.
Exposure-adjusted incidence rate (EAIR) will be provided for selected topics. The EAIR is 
evaluating the incidence of a first event per 100 patient-years at risk (PYR). Exposure will be 
calculated based on the analysis period defined as the treatment period plus up to 30 days off-
drug follow-up time. Exposure time for a patient with an event will be counted up to the time of 
the start of event. Exposure time for a patient without an event will be censored at the end of the 
analysis period. For each EAIR provided, a Poisson distribution 95% CI may be calculated. 
Treatment group comparisons, when provided, will be provided based on the incidence rate 
difference (IRD) together with its 95% CI.  
Not all displays described in this SAP will necessarily be included in the CSR. Any display 
described in this SAP and not provided in the CSR would be available upon request. Not all 
displays will necessarily be created as a “static” display. Some may be incorporated into 
interactive display tools instead of or in addition to a static display. Any display created 
interactively will be included in the CSR if deemed relevant to the discussion.
6.18.1. Extent of Exposure
Duration of exposure (in days) to study drug will be summarized by treatment period with 
corresponding safety population, which is defined in Table JAHV.6.10.
Total PY of exposure will be reported for overall duration of exposure. Descriptive statistics (n, 
mean, standard deviation [SD], minimum, 1st quartile, median, 3rd quartile and maximum) will 
be provided for patient-days of exposure, and the frequency of patients falling into different 
exposure ranges will be summarized. Exposure ranges will generally be reported in weeks using 
the following as a general guide:  
•
≥4 weeks, ≥16 weeks, ≥ 26 weeks, ≥ 52 weeks


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•
>0 to <4 weeks, ≥4 weeks to <16 weeks, ≥16 weeks to <26 weeks, ≥26 to <52 weeks, 
and ≥52 weeks
Overall exposure will be summarized in total PY which is calculated according to the following 
formula:
PYE = sum of duration of exposure in days (for all patients in treatment group) / 365.25
6.18.2. Adverse Events
Adverse events are recorded in the eCRFs. The planned summaries are provided in 
Table JAHV.6.11 and are described more fully in compound-level safety standards and in the 
adverse event-related PhUSE white paper [Analysis and Displays Associated with Adverse 
Events: Focus on Adverse Events in Phase 2-4 Clinical Trials and Integrated Summary 
Document (PhUSE 2017)]. The analysis population and period are defined in Table JAHV.6.11,
and by-treatment analysis will provided for the DBW safety population in the DBW period.
If study drug is temporarily interrupted and subsequently restarted during the treatment period, 
the measurements taken during the temporary interruption will be included in the analysis.  
Where applicable, the time elapsed during the temporary interruption will also be included in 
analyses.
For events that are gender-specific (as defined by the MedDRA), the denominator and
computation of the percentage will include only patients from the given sex.
Table JAHV.6.11.
Summary Tables Related to Adverse Events
Analysis
An overview table, with the number and percentage of patients in the safety set with death, an SAE, any TEAE, 
discontinuation from the study due to an AE, permanent discontinuation from study drug due to an AE, or a severe 
TEAE
The number and percentages of patients with TEAEs will be summarized using MedDRA Preferred Term nested 
within System Organ Class.
The number and percentages of patients with TEAEs will be summarized using MedDRA Preferred Term.
The number and percentages of patients with TEAEs will be summarized using MedDRA Preferred Term for the 
common TEAEs (occurring in >=1%, before rounding, of treated patients).
The number and percentages of patients with TEAEs by maximum severity will be summarized using MedDRA 
Preferred Term for the common TEAEs. Only counts and percentages will be included for the TEAEs by 
maximum severity.
A listing of all deaths will be provided. 
The number and percentage of patients who experienced a serious adverse event (including deaths and SAEs 
temporally associated or preceding deaths) will be summarized using MedDRA Preferred Term nested within 
System Organ Class.
A listing of SAEs will be provided.
The number and percentage of patients who permanently discontinued from study drug due to an adverse event 
(including adverse events that led to death) will be summarized using MedDRA Preferred Term nested within 
System Organ Class.
The number and percentage of patients who temporarily interrupted study drug due to an adverse event will be 
summarized using MedDRA Preferred Term nested within System Organ Class.


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Abbreviations: AE=adverse event; MedDRA = Medical Dictionary for Regulatory Activities; SAE = serious adverse 
event; TEAE = treatment emergent adverse event.
6.18.3. Clinical Laboratory Evaluation
The planned summaries for clinical laboratory evaluations are provided in Table JAHV.6.12 and 
are described more fully in compound-level safety standards and in the laboratory-related 
PhUSE white papers [Analyses and Displays Associated with Measures of Central Tendency –
Focus on Vital Sign, Electrocardiogram, and Laboratory Analyte Measurements in Phase 2-4 
Clinical Trials and Integrated Submission Documents (PhUSE 2013) and Analyses and Displays 
Associated with Outliers or Shifts from Normal to Abnormal: Focus on Vital Signs, 
Electrocardiogram, and Laboratory Analyte Measurements in Phase 2-4 Clinical Trials and 
Integrated Summary Documents (PhUSE 2015)]. The analysis population and period are defined 
in Table JAHV.6.12, and by-treatment analysis will provided for the DBW safety population in 
the DBW period.
There is one special circumstance for laboratory values to be derived. The low-density
lipoprotein (LDL)/high-density lipoprotein (HDL) ratio will be derived as the ratio of LDL
cholesterol to HDL cholesterol. Similarly, the ratio of HDL to LDL will be derived. There are no 
central laboratory reference ranges for the LDL/HDL or HDL/LDL ratio.
For the categorical laboratory analyses (shift and treatment-emergent), the analysis period is
defined as the treatment period plus up to 30 days off-drug follow-up time. The analysis period
for the continuous by-visit laboratory analyses including change from baseline by visit and to 
last observation is defined as the treatment period excluding off-drug follow-up time.
Table JAHV.6.12.
Summary Tables Related to Clinical Laboratory Evaluations
Analysis
Box plots for observed values by visit and change from baseline by visit.
Tables with number and percentages of patients who shift from normal/high to low (ie, treatment-emergent low) 
and number and percentages of patients who shift from normal/low to high (ie, treatment-emergent high)
Listing of abnormal findings for laboratory analyte measurements, including qualitative measures
6.18.4. Vital Signs and Other Physical Findings
The planned summaries for vital signs and physical measurement (systolic blood pressure [BP], 
diastolic BP, pulse, weight, , height, body mass index [BMI], temperature) are provided in Table 
JAHV.6.13 and are described more fully in compound-level safety standards and in the vitals-
related PhUSE white papers [Analyses and Displays Associated with Measures of Central 
Tendency – Focus on Vital Sign, Electrocardiogram, and Laboratory Analyte Measurements in 
Phase 2-4 Clinical Trials and Integrated Submission Documents (PhUSE 2013) and Analyses 
and Displays Associated with Outliers or Shifts from Normal to Abnormal: Focus on Vital 
Signs, Electrocardiogram, and Laboratory Analyte Measurements in Phase 2-4 Clinical Trials 
and Integrated Summary Documents (PhUSE 2015)]. 


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Table JAHV.6.13.
Summary Tables Related to Vital Signs
Analysis
Box plots for observed values by visit and change from baseline by visit.
Tables with number and percentages of patients who shift from normal/high to low (ie, treatment-emergent low) 
and percentages of patients who shift from normal/low to high (ie, treatment-emergent high). The limits are 
defined in the compound-level safety standards and are based on literature.
For vital signs and physical characteristics, original-scale data will be analyzed. Mean changes 
from baseline and as incidence of abnormal values will be summarized. The observed values at 
each visit (starting at OLLI baseline) and change from baseline to each scheduled visit, 
respectively, will be displayed in box plots for patients by treatment period with the 
corresponding safety population. These box plots will be used to evaluate trends over time and to 
assess a potential impact of outliers on central tendency summaries. The scheduled 
visits/measurements will be included. The unscheduled visits and the repeat measurements will 
be excluded.  


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Table JAHV.6.14.
Categorical Criteria for Abnormal Treatment-Emergent Blood 
Pressure and Pulse Measurements for Children and Adolescents
Age
(years)
Systolic BP, mm Hg
(supine or sitting forearm at 
heart level)
Diastolic BP, mm Hg 
(supine or sitting forearm 
at heart level)
Pulse/HR bpm
(supine or sitting)
Child 2-4
Low
≤75 (low limit) and decrease 
from lowest value during 
baseline ≥15 if >75 at each 
baseline visit
≤40 (low limit) and 
decrease from lowest value 
during baseline ≥10 if >40 
at each baseline visit
<60 (low limit) and 
decrease from lowest value 
during baseline ≥25 if ≥60 
at each baseline visit
Higha
≥110 (high limit) and increase 
from highest value during 
baseline ≥15 if <110 at each 
baseline visit
≥76 (high limit) and 
increase from highest value 
during baseline ≥10 if <76 
at each baseline visit
>160 (high limit) and 
increase from highest value 
during baseline ≥25 if ≤160 
at each baseline visit
Child 5-9
Low
≤80 (low limit) and decrease 
from lowest value during 
baseline ≥15 if >80 at each 
baseline visit
≤45 (low limit) and 
decrease from lowest value 
during baseline ≥10 if >45 
at each baseline visit
<60 (low limit) and 
decrease from lowest value 
during baseline ≥25 if ≥60 
at each baseline visit
Higha
≥119 (high limit) and increase 
from highest value during 
baseline ≥15 if <119 at each 
baseline visit
≥78 (high limit) and 
increase from highest value 
during basline ≥10 if <78 at 
each baseline visit
>150 (high limit) and 
increase from highest value 
during baseline ≥25 if ≤150 
at each baseline visit
Child 10-12
Low
≤85 (low limit) and decrease 
from lowest value during 
baseline ≥20 if >85 at each 
baseline visit
≤50 (low limit) and 
decrease from lowest value 
during baseline ≥10 if <50 
at each baseline visit
<60 (low limit) and 
decrease from lowest value 
during baseline ≥25 if ≥60 
at each baseline visit
Higha
≥126 (high limit) and increase 
from highest value during 
baseline ≥20 if <126 at each 
baseline visit
≥82 (high limit) and 
increase from highest value 
during baseline ≥10 if <82 
at each baseline visit
>140 (high limit) and 
increase from highest value 
during baseline ≥25 if ≤140 
at each baseline visit
Adolescent 
13 - 17
Low
≤90 (low limit) and decrease 
from lowest value during 
baseline ≥20 if >90 at each 
baseline visit
≤50 (low limit) and 
decrease from lowest value 
during baseline ≥10 if >50 
at each baseline visit
<50 (low limit) and 
decrease from lowest value 
during baseline ≥15 if ≥50 
at each baseline visit
Higha
≥129 (high limit) and increase 
from highest value during 
baseline ≥20 if <129 at each 
baseline visit 
≥86 (high limit) and 
increase from highest value 
during baseline ≥10 if <86 
at each baseline visit
>120 (high limit) and 
increase from highest value 
during baseline ≥15 if ≤120 
at each baseline visit
Abbreviations: BP = blood pressure; HR = heart rate.
a
The high limit values shown in this table correspond to 95th percentile for the age group under the 2017 
American College of Cardiology/American Heart Association task Force on Clinical Practice Guidelines revised 
criteria for hypertension. Values higher than 95th percentile are consistent with Stage 1 or Stage 2 hypertension.  
Under some circumstances it may be appropriate to conduct analyses considering only the change from baseline 
reference limit.  
6.18.4.1. Standardized Growth
Weight, height, and BMI data will be merged to the Centers for Disease Control and Prevention 
(CDC) standard growth data (released in 2000) by age and gender in order to compare patients’ 
growth with the standard. Z-score and standardized percentile of weight, height, and BMI at each 
visit will be calculated based on the 2000 CDC growth charts.


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The z-score and percentile calculations are based on algorithms and data provided by the 
National Center for Health Statistics. The details are provided in the CDC website
(https://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm).
•
The following summaries will be provided by treatment period with the 
corresponding safety population: baseline, mean change of actual measure, z-score 
and standardized percentile of weight, height, and BMI will be summarized.
•
Patients’ mean weight, height, and BMI standardized percentile will be plotted versus 
investigational product exposure time.
By-patient listings of actual measures, z-scores, standardized percentiles in weight, height, and
BMI for each visit will be provided.
6.18.5. Special Safety Topics, including Adverse Events of Special 
Interest
In addition to general safety parameters, safety information on specific topics of special interest 
will also be presented. Additional special safety topics may be added as warranted. The topics 
outlined in this section include the protocol-specified AESI.
In general, for topics regarding safety in special groups and circumstances, patient profiles 
and/or patient listings, where applicable, will be provided when needed to allow for medical 
review of the time course of cases/events, related parameters, patient demographics, study drug 
treatment, and meaningful concomitant medication use. In addition to the safety topics for which 
provision or review of patient data are specified, these will be provided when summary data are 
insufficient to permit adequate understanding of the safety topic.
The analysis and summary will be provided by treatment period with the corresponding safety 
population, where the detailed definition of the population and baseline can be found in 
Section 6.1.1 and Table JAHV.6.10.
6.18.5.1. Abnormal Hepatic Tests
Hepatic labs include alanine aminotransferase (ALT), aspartate transaminase (AST), total 
bilirubin (TBL), and serum alkaline phosphatase (ALP). When criteria are met for hepatic 
evaluations, investigators will complete a follow-up hepatic safety eCRF. The planned 
summaries are provided in Table JAHV.6.15.
Table JAHV.6.15.
Summary Tables Related to Hepatic Safety
Analysis
ALT and AST: The number and percentages of patients with a measurement greater than or equal to 3 times 
(3X), 5 times (5X), and 10 times (10X) the central lab upper limit of normal (ULN) for all patients with a 
postbaseline value and for subsets based on various levels of baseline value.
TBL: The number and percentages of patients with a measurement greater than or equal to 2 times (2X) the 
central lab ULN will be summarized for all patients with a postbaseline value and for subsets based on various 
levels of baseline value.


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ALP: The number and percentages of patients with a measurement greater than or equal to 1.5 times (1.5X) the 
central lab ULN will be summarized for all patients with a postbaseline value and for subsets based on various 
levels of baseline value.
Plot of maximum postbaseline ALT vs. maximum postbaseline total bilirubin.
Patient profiles including demographics, disposition, information collected on the hepatic-safety CRF (where 
applicable) and a display of study drug exposure, adverse events, medications, blood pressure, heart rate, and the 
liver-related measurements over time will be provided for patients with information collected on the hepatic-
safety CRF and any additional patients meeting ALT or AST measurement greater than or equal to 5X ULN (on 
a single measurement) or ALP measurement greater than or equal to 2X ULN (on a single measurement).
Treatment-Emergent Potential Hepatic Disorders Based on MedDRA SMQs: treatment-emergent potentially 
drug-related hepatic disorders are defined by using the MedDRA preferred terms contained in any of the 
following SMQs:
•
Broad and narrow terms in the Liver related investigations, signs and symptoms SMQ (20000008)
•
Broad and narrow terms in the Cholestasis and jaundice of hepatic origin SMQ (20000009)
•
Broad and narrow terms in the Hepatitis noninfections SMQ (20000010)
•
Broad and narrow terms in the Hepatic failure, fibrosis and cirrhosis, and other liver damage SMQ 
(20000013) 
Narrow terms in the liver-related coagulation and bleeding disturbances SMQ (20000015)
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate transaminase; CRF = 
case report form; MedDRA = Medical Dictionary for Regulatory Activities; SMQ = Standardized MedDRA 
Query; ULN = upper limit of normal; TBL = total bilirubin.
6.18.5.2. Hematologic Changes
Hematologic changes will be assessed through analysis of hemoglobin, white blood cell 
(leukocyte) count, absolute neutrophil count, lymphocyte count, and platelet count. Common 
Terminology Criteria for Adverse Events (CTCAEs) will be applied for laboratory tests 
potentially related to myelosuppressive events. The planned summaries are provided in 
Table JAHV.6.16 and are described more fully in compound-level safety standards.  
Table JAHV.6.16.
Summary Tables Related to Hematologic Changes
Analysis
Shift tables showing the number and percentage of patients based on baseline to maximum will be created, with 
baseline depicted by the most extreme CTCAE grade during the baseline period. With each shift table, a 
summary displaying the number and percentage of patients who decreased, increased, or stayed the same in 
CTCAE grade category will be presented.
The number and percentages of patients with treatment-emergent shifts at any time will be summarized, based on 
any increase to CTCAE Grade 1 or above, Grade 2 or above, Grade 3 or above, and Grade 4 or above.
The number and percentages of patients with treatment-emergent thrombocytosis will be summarized, defined as 
an increase in platelet count from a maximum baseline value ≤600 billion/L to any postbaseline value >600 
billion/L. Similar analysis will use a cut-off of 400 billion/L. Planned and unplanned measurements will be 
included.
Listing of patients with treatment-emergent thrombocytosis
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events.


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6.18.5.3. Lipid Effects
Lipid effects will be assessed through analysis of elevated total cholesterol, elevated low-density 
lipoprotein (LDL) cholesterol, decreased and increased high-density lipoprotein (HDL)
cholesterol, and elevated triglycerides. The planned summaries are provided in Table JAHV.6.17
and are described more fully in compound-level safety standards.  
Table JAHV.6.17.
Summary Tables Related to Lipid Effects
Analysis
Shift tables showing the number and percentage of patients based on baseline to maximum will be created, with 
baseline depicted by the most extreme NCEP-based level during the baseline period. With each shift table, a 
summary displaying the number and percentage of patients who decreased, increased, or stayed the same in 
NCEP-based level will be presented.
The number and percentages of patients with treatment-emergent shifts at any time will be summarized, based on 
increases to various levels of NCEP-based categories.
The number and percentages of patients with treatment-emergent potential hyperlipidemia will be summarized 
using a predefined MedDRA list of PTs that is a subset of the narrow scope PTs in the MedDRA SMQ 
“Dyslipidemia” (code 200000026) (see compound-level safety standards)..
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities; NCEP = National Cholesterol Education 
Program; PT = Preferred Term; SMQ = Standardised MedDRA Query.
Categorical analyses will be performed using Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents (2011) as shown in the 
Table JAHV.6.18.
Table JAHV.6.18.
Acceptable, Borderline-High, and High Plasma Lipid, Lipoprotein, 
and Apolipopretein Concentrations for Children and Adolescents
Category 
Low 
(mg per dL)a
Acceptable 
(mg per dL)
Borderline-high
(mg per dL)a
High
(mg per dL)a
total cholesterol 
--
<170
170 to 199
≥200
LDL cholesterol 
<110
110 to 129
≥130
Non-HDL cholesterol 
<120
120 to 144
≥145
Apoliprotein B
<90
90 to 109
≥110
Triglycerides
0 to 9 years of age 
<75
75 to 99
≥100
10 to 19 years of age
<90
90 to 129
≥130
HDL Cholesterol 
<40
>45
40 to 45
Apolipoprotein A-1
<115
>120
120
Abbreviations: HDL= high-density lipoprotein; LDL= Low-density lipoprotein
a
Low cut point for HDL cholesterol and apolipoprotein A-1 represent approximately the 10th percentile. The cut 
points for high and borderline-high represent approximately the 95th and 75th percentiles, respectively. 


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6.18.5.4. Renal Function Effects
Effects on renal function will be assessed through analysis of elevated creatinine. The planned 
summaries are provided in Table JAHV.6.19 and are described more fully in compound-level 
safety standards.  
Table JAHV.6.19.
Summary Tables Related to Effects on Renal Function
Analysis
Shift tables showing the number and percentage of patients based on baseline to maximum will be created, with 
baseline depicted by the most extreme CTCAE grade during the baseline period. With each shift table, a 
summary displaying the number and percentage of patients who decreased, increased, or stayed the same in 
CTCAE grade category will be presented.
The number and percentages of patients with treatment-emergent shifts at any will be summarized, based on any 
increase to CTCAE Grade 1 or above, Grade 2 or above, Grade 3 or above, and Grade 4 or above.
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events.
6.18.5.5. Elevations in Creatine Phosphokinase (CPK)
The planned summaries are provided in Table JAHV.6.20 and are described more fully in 
compound-level safety standards.  
Table JAHV.6.20.
Summary Tables Related to Effects on CPK
Analysis
Shift tables showing the number and percentage of patients based on baseline to maximum will be created, with 
baseline depicted by the most extreme CTCAE grade during the baseline period. With each shift table, a 
summary displaying the number and percentage of patients who decreased, increased, or stayed the same in 
CTCAE grade category will be presented.
The number and percentages of patients with treatment-emergent shifts at any time will be summarized, based on 
any increase to CTCAE Grade 1 or above, Grade 2 or above, Grade 3 or above, and Grade 4 or above.
Treatment-emergent adverse events potentially related to muscle symptoms may also be analyzed based on 
reported AEs. The Muscle Symptoms special search category is a predefined MedDRA search criteria list that 
contains the narrow scope terms from the Rhabdomyolysis/myopathy SMQ (code 20000002) plus selected terms 
from the Musculoskeletal SOC
Abbreviations: AE = adverse event; CPK = creatine phosphokinase; CTCAE = Common Terminology Criteria for 
Adverse Events; MedDRA = Medical Dictionary for Regulatory Activities; PT = Preferred Term; SOC = System 
Organ Class.
6.18.5.6. Infections
Infections will be defined using all the PTs from the MedDRA Infections and Infestations 
System Organ Class (SOC). The MedDRA terms used to identify infections considered to be 
opportunistic infections (OIs) are based on Winthrop and colleagues (2015) and are listed in the 
compound-level safety standards. The list contains narrow (more specific) and broad (less 
specific) PTs.   
The planned summaries are provided in Table JAHV.6.21 and are described more fully in 
compound-level safety standards.  


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Table JAHV.6.21.
Summary Tables Related to Infections
Analysis
The number and percentage of patients with treatment-emergent infections, serious infections, and infections 
resulting in permanent study drug discontinuation will be summarized using MedDRA PTs.
The number and percentage of patients with TEAEs of infections by maximum severity will be summarized 
using MedDRA PTs.
Listing of patients experiencing TEAE infections will be provided. The listing will include patient 
demographics, treatment group, treatment start and stop dates, infectious PT event, event start and stop dates, 
total leukocytes, total lymphocytes, absolute neutrophils, event seriousness, and event outcome.
Summary of Opportunistic Infections based on MedDRA PTs after the potential opportunistic infections are 
reviewed by medical and confirmed as opportunistic infections.
Listing of Opportunistic Infections based on MedDRA PTs during the study.
A summary table of herpes zoster will be provided, including event maximum severity, seriousness, whether 
resulting in temporary study drug interruption, whether resulting in study drug discontinuation, whether treated 
with antiviral medication, and event outcome. 
The summary table of herpes simplex will include event maximum severity, seriousness, whether resulting in 
temporary study drug interruption, whether resulting in study drug discontinuation, and whether treated with 
antiviral medication.  
A listing of patients with detectable HBV DNA will be provided.
Hepatitis B virus DNA status (not detectable, detectable but not quantifiable [ie, < lower limit of detection 
(LLOD)], quantifiable [ie, ≥LLOD]) will be summarized, stratified by applicable baseline HBV serology status.
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities; OI = opportunistic infection; PT = 
Preferred Term; TEAE = treatment-emergent adverse event; HBV = hepatitis B virus.
6.18.5.7. Allergic Reactions and Hypersensitivities
A search for relevant events related to allergic reaction and hypersensitivity will be performed 
using the following SMQs:
•
Anaphylactic reaction SMQ (20000021)
•
Hypersensitivity SMQ (20000214)
•
Angioedema SMQ (20000024)
Events that satisfy the queries will be listed, by temporal order within patient ID, and will 
include SOC, PT, SMQ event categorization including detail on the scope (narrow or broad), 
reported AE term, AE onset and end dates, severity, seriousness, outcome, etc.
The summaries described in Table JAHV.6.22 will be created if there are sufficient numbers of
events to warrant further examination beyond the listing specified above.  
The anaphylactic reaction SMQ consists of a narrow search containing PTs that represent core 
anaphylactic reaction terms, a broad search that contains additional terms (signs and symptoms 


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possibly indicative of anaphylactic reaction) that are added to those included in the narrow 
search, and an algorithm.
The algorithmic approach (Algorithm 1) (which is similar to the algorithm approach defined in 
Sampson, et al 2006) comprises 1 or more events associated with an individual administration of 
study drug, where the events include:
•
A narrow term from the anaphylactic reaction SMQ (Category A of the SMQ) or
•
Paired terms from the anaphylactic reaction SMQ, comprising terms from at least 2 of the 
following 3 categories from the SMQ: 
o
Category B - (Upper Airway/Respiratory signs and symptoms)
o
Category C - (Angioedema/Urticaria/Pruritus/Flush signs and symptoms)
o
Category D - (Cardiovascular/Hypotension signs and symptoms).
Within the paired terms approach, it is important to recognize that occurrence of these events 
should be nearly coincident and develop rapidly after exposure to an antigen; a window wherein 
onset or severity change of the events occur within the same calendar day will be used.  
In addition, a second algorithmic approach (Algorithm 2) will be calculated similarly to the 
algorithm approach defined above (Algorithm 2) but includes an additional category, Category E.  
The paired terms according to Algorithm 2 will comprise terms from at least 2 of 4 categories 
(Categories B, C, D, and E). Categories B, C and D are already defined, and Category E includes 
any of the Gastrointestinal preferred term events (Nausea, Vomiting, Diarrhoea, and Abdominal 
pain). A patient’s listing will be generated based on Algorithm 2 and individual cases will be 
examined to determine if the cases suggest anaphylaxis. Those cases suggestive of anaphylaxis 
will be described in CSR.


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Table JAHV.6.22.
Summary Tables Related to Allergic Reactions/Hypersensitivities
Analysis
Two listings for Allergic Reaction and Hypersensitivities for events that satisfy the queries defined in this section 
will be listed, by temporal order within patient ID, and will include SOC, PT, SMQ event categorization 
including detail on the scope (narrow, algorithmic, or broad), reported AE term, AE onset and end dates, 
severity, seriousness, outcome, etc.
The number and percentages of patients with TEAEs will be summarized using MedDRA Preferred Term for 
any narrow or algorithmic term in the compound-level safety standard from any one of the 3 SMQs (each SMQ 
and SMQs combined)
The number and percentages of patients with TEAEs will be summarized using MedDRA Preferred Term for 
any broad term (each SMQ separately)
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities; SMQ = Standardised MedDRA Query; 
TEAE = treatment-emergent adverse event.
6.18.5.8. Major Adverse Cardiovascular Events and Other Cardiovascular Events
Major Adverse Cardiovascular Events (MACE) and other cardiovascular events will be 
adjudicated by an independent, external adjudication committee. All confirmed events after 
adjudication will be used for the analysis.  
The planned summaries are provided in Table JAHV.6.23 and are described more fully in 
compound-level safety standards.
Table JAHV.6.23.
Summary Tables Related to MACE and Other Cardiovascular 
Events
Analysis
The number and percentage of patients with MACE, other cardiovascular events, non-cardiovascular death, and 
all-cause death, as positively adjudicated, will be summarized based on the categories and subcategories as 
defined in compound-level safety standards.
A listing of the MACE and other CV events sent for cardiovascular adjudication will be provided to include data 
concerning the MedDRA PT related to the event, the seriousness of the event, and the event outcome, along with 
the adjudicated result.
Abbreviations: MACE = Major Adverse Cardiovascular Event; MedDRA = Medical Dictionary for Regulatory 
Activities; PT = Preferred Term.
6.18.5.9. Thromboembolic Events
Venous thromboembolic (VTE) events will be adjudicated by an independent, external 
adjudication committee. Venous and pulmonary artery thromboembolic events will be classified 
as deep vein thrombosis (DVT), pulmonary embolism (PE), or other peripheral venous 
thrombosis. Additionally, arterial thromboembolic (ATE) events will be adjudicated by an 
independent, external adjudication committee. All confirmed events after adjudication will be 
used for the analysis.   
The planned summaries for VTE are provided in Table JAHV.6.24 and are described more fully 
in compound-level safety standards.


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Table JAHV.6.24.
Summary of Tables Related to VTE Events
Analysis
The number and percentage of patients with a VTE, DVT/PE, DVT, PE, and other peripheral venous thrombosis, 
as positively adjudicated, will be summarized 
A listing of the VTEs sent for adjudication will be provided to include data concerning the MedDRA PT related 
to the event, the seriousness of the event, and the event outcome, along with the adjudicated result.
Summary of Tables Related to VTE Events
Abbreviations: DVT = deep vein thrombosis; MedDRA = Medical Dictionary for Regulatory Activities; PE = 
pulmonary embolism; PT = Preferred Term; VTE = venous thromboembolic.
Arterial Thrombosis(ATE) Events 
The planned summaries for ATE are provided in Table JAHV.6.25 and are described more fully 
in compound-level safety standards.
Table JAHV.6.25.
Summary of Tables Related to ATE Events
Analysis
The number and percentage of patients with a positively adjudicated ATE
A listing of the ATEs sent for adjudication to include data concerning the MedDRA PT related to the event, the 
seriousness of the event, and the event outcome, along with the adjudicated result
Abbreviations:  ATE = arterial thromboembolic; MedDRA = Medical Dictionary for Regulatory Activities; PT = 
preferred term; VTE = venous thromboembolism.
6.18.5.10.
Malignancies
Malignancies will be identified using terms from the Malignant tumors SMQ. Malignancies 
excluding nonmelanoma skin cancers (NMSC) and NMSC will be reported separately. All the 
cases identified by the Malignant tumors SMQ (SMQ code = 20000194) will be assessed 
through medical review to determine confirmed NMSC cases.
The planned summaries are provided in Table JAHV.6.26 and are described more fully in 
compound-level safety standards.
Table JAHV.6.26.
Summary Tables Related to Malignancies
Analysis
The number and percentage of patients with treatment-emergent malignancies excluding NMSC and NMSC will 
be summarized.
Listing of all malignancy cases, with an NMSC flag.
Abbreviations: NMSC = nonmelanoma skin cancers.
6.18.5.11.
Gastrointestinal Perforations
Potential gastrointestinal (GI) perforations will be identified using terms from the GI perforations 
SMQ. Potential GI perforations identified by the SMQ (SMQ code = 20000107) search will be 
provided as a listing for internal review by the medical safety team. Each case will be assessed to 
determine whether it is a GI perforation. All confirmed events after medical review will be used 


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for the analysis. The planned summaries are provided in Table JAHV.6.27 and are described 
more fully in compound-level safety standards.  
Table JAHV.6.27.
Summary Tables Related to Gastrointestinal Perforations
Analysis
The number and percentage of patients with treatment-emergent gastrointestinal perforations will be summarized 
using MedDRA PTs.
Listing of all treatment-emergent gastrointestinal perforations during the study.
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities; PT = Preferred Term.
6.19. COVID-19 Trial Impact
Patients who experience an impact to their trial participation due to quarantine and/or travel 
restrictions related to COVID-19 will have their type of impact summarized. COVID-19 specific 
impacts will be summarized by the following by-patient listings:
•
Listing of study and treatment discontinuation related to COVID-19
•
Listing of COVID-19 adverse events based on SMQ=20000237 using the narrow 
term classification.
•
Summary of COVID-19 TEAE using MedDRA PT based on SMQ=20000237 with 
the narrow term classification
6.20. Protocol Deviations
Protocol deviations will be tracked by the clinical team, and their importance will be assessed by 
key team members during protocol deviation review meetings. Out of all protocol deviations 
identified, a subset occurring during the OLLI prior to the Week 12 with the potential to affect 
futility analyses, will result in exclusion from futility analysis. 
Potential examples of protocol deviations include patients who receive excluded concomitant 
therapy, significant noncompliance with study medication, patients incorrectly enrolled in the 
study, and patients whose data are questionable due to significant site quality or compliance 
issues. 
Refer to a separate document for the important protocol deviations.
The number and percentage of patients having IPD(s) will be summarized in the OLLI and the
DBW periods (by treatment) within category and subcategory of deviation using the OLLI and 
DBW populations. Individual patient listings of IPDs will be provided. A summary of reasons 
patients were excluded from the futility analysis will be provided.
6.21. Interim Analyses and Data Monitoring
A Data Monitoring Committee (DMC) will oversee the conduct of this trial. 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 


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compounds. Data Monitoring Committee membership will include, at a minimum, specialists 
with expertise in rheumatology, statistics, and other appropriate specialties.
The DMC will be authorized to review unblinded results of analyses by treatment group prior to 
final database lock, including study discontinuation data, AEs including SAEs, clinical 
laboratory data, vital sign data, etc. The DMC may recommend continuation of the study, as 
designed; temporary suspension of enrollment; or the discontinuation of a particular dose 
regimen or 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. 
However, the study will not be stopped for positive efficacy results. Hence, no alpha is spent.  
Details of the DMC, including its operating characteristics, are documented in the Baricitinib 
Pediatric Joint DMC charter, and further details are given in the Interim Analysis Plan in 
Section 6.21.1.
Besides DMC members, a limited number of preidentified individuals may gain access to the 
limited unblinded data, as specified in the unblinding plan, prior to the interim or final database 
lock, to initiate the final population PK/pharmacodynamic (PD) model development processes or 
for preparation of regulatory documents. Information that may unblind the study during the 
analyses will not be reported to study sites or the blinded study team until the study has been 
unblinded.
A futility analysis will be conducted using the PedACR(ESR) 30 response rate observed in the 
first 100 patients who complete the OLLI period, this will include:
•
patients who participate Safety/PK assessment period and complete OLLI period with 
age based final dose,
•
patients who start from OLLI period and take at least 1 age-based final dose
The OLLI patients (Section 6.1.1) who discontinue early will be included. The patients who have 
important protocol deviations will be excluded; the detail is described in Section 6.20. The 
missing data imputation rule will align with Section 6.3 and Table JAHV.6.4 for PedACR(ESR) 
30 response imputation. The study will stop for futility if the proportion of patient who achieve
PedACR(ESR) 30 response is less than 50%. The futility analysis will based on the observed 
response rate, no statistical inference will be conducted. 
Unblinding details are given in Section 7.
6.21.1. Interim Analysis Plan
Analyses for the DMC will include listings and/or summaries of the following information:
•
patient disposition, demographics, and baseline characteristics
•
exposure
•
adverse events, to include the following:
o
treatment-emergent adverse events


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o
serious adverse events, including deaths
o
selected special safety topics 
•
clinical laboratory results
•
vital signs
•
growth parameters (for example, height, weight, assessment of bone age)
All listings will include patient ID. Summaries will include TEAEs, SAEs, special topics AEs, 
and treatment-emergent high and low laboratory and vital signs in terms of counts, percentages 
and incidence rates, where applicable. For continuous analyses, box plots of laboratory analytes 
will be provided by time point.
The DMC may request efficacy data if they feel there is value and to confirm a reasonable 
benefit/risk profile for ongoing patients in the studies. If efficacy data are requested, they will be
time to disease flare and proportion of patients who are PedACR30 responders during OLLI 
period or proportion of patients who maintain PedACR 30 response during DBW period.
Further details are given in the DMC charter.
6.22. Annual Report Analyses
Annual report analyses, such as for the Development Update Safety Report (DSUR), will be 
documented in a separate document. 
6.23. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include a summary of AEs, provided as a dataset 
which will be converted to an XML file. Both SAEs and ‘Other’ AEs are summarized by 
treatment group in the DBW period, by MedDRA PT.
•
An AE is considered ‘Serious’ whether or not it is a TEAE.
•
An AE is considered in the ‘Other’ category if it is both a TEAE and is not 
serious. For each SAE and ‘Other’ AE, for each term and treatment group in the 
DBW period, the following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.
•
Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in 
fewer than 5% of patients/subjects in every treatment group may not be included 
if a 5% threshold is chosen (5% is the minimum threshold).
•
Adverse event reporting is consistent with other document disclosures, for 
example, the CSR, manuscripts, and so forth. 


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Similar methods will be used to satisfy the European Clinical Trials Database (EudraCT) 
requirements. 


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7.
Unblinding Plan
Refer to a separate blinding and unblinding plan document for details. 


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8.
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Leo Document ID = 27b5c7a9-d3aa-48b1-898d-be46c8296d3c
Approver:
Approval Date & Time: 14-Mar-2022 19:04:47 GMT
Signature meaning: Approved
PPD