A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib in Adult Patients With Moderate to Severe Atopic Dermatitis
Phase: PHASE3
Conditions: Atopic Dermatitis
Sponsor: Eli Lilly and Company

Protocol (c) I4V-MC-JAIW  
 
A Multicenter, Randomized, Double-Blind, Placebo Controlled, Phase 3 Study to Evaluate the 
Efficacy and Safety in Adult Patients with Moderate to Severe Atopic Dermatitis 
 
NCT03435081 
 
Approval Date: 10-Oct-2019 

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Protocol I4V-MC-JAIW(c)
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy 
and Safety of Baricitinib in Adult Patients with Moderate to 
Severe Atopic Dermatitis
BREEZE-AD5
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)
Study I4V-MC-JAIW is a Phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group, outpatient, 113-week study designed to evaluate the 
efficacy and safety of baricitinib 1-mg and 2-mg in patients with moderate to severe atopic 
dermatitis.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on 13 December 2017.
Amendment (a) Electronically Signed and Approved by Lilly on 6 July 2018.
Amendment (b) Electronically Signed and Approved by Lilly on 1 April 2019.
Amendment (c) Electronically Signed and Approved by Lilly on approval date provided 
below
Approval Date: 10-Oct-2019 GMT

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Table of Contents
Section
Page
Protocol I4V-MC-JAIW(c) A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and 
Safety of Baricitinib in Adult Patients with Moderate to Severe 
Atopic Dermatitis................................................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................13
3.
Introduction ......................................................................................................................17
3.1.
Background..................................................................................................................17
3.2.
Study Rationale............................................................................................................18
3.3.
Benefit/Risk Assessment..............................................................................................18
4.
Objectives and Endpoints..................................................................................................21
5.
Study Design.....................................................................................................................24
5.1.
Overall Design .............................................................................................................24
5.1.1.
Period 1:  Screening .............................................................................................24
5.1.2.
Period 2:  Double-Blind Placebo-Controlled Treatment, 
Weeks 0 to 104 ....................................................................................................25
5.1.3.
Period 3:  Post-Treatment Follow-Up...................................................................26
5.2.
Number of Participants.................................................................................................27
5.3.
End of Study Definition ...............................................................................................27
5.4.
Scientific Rationale for Study Design...........................................................................27
5.5.
Justification for Dose ...................................................................................................28
6.
Study Population...............................................................................................................30
6.1.
Inclusion Criteria..........................................................................................................30
6.2.
Exclusion Criteria ........................................................................................................33
6.3.
Lifestyle Restrictions....................................................................................................39
6.4.
Screen Failures.............................................................................................................39
7.
Treatments........................................................................................................................40
7.1.
Treatments Administered .............................................................................................40
7.1.1.
Packaging and Labeling .......................................................................................40
7.2.
Method of Treatment Assignment ................................................................................41
7.2.1.
Selection and Timing of Doses.............................................................................41
7.3.
Blinding .......................................................................................................................41
7.4.
Dosage Modification....................................................................................................42
7.5.
Preparation/Handling/Storage/Accountability...............................................................42

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7.6.
Treatment Compliance .................................................................................................42
7.7.
Concomitant Therapy...................................................................................................42
7.7.1.
Prohibited Medications and Procedures................................................................42
7.7.2.
Permitted Medications and Procedures.................................................................44
7.7.3.
Rescue Therapy....................................................................................................44
7.8.
Treatment after the End of the Study............................................................................46
7.8.1.
Continued Access.................................................................................................46
8.
Discontinuation Criteria ....................................................................................................47
8.1.
Discontinuation from Study Treatment.........................................................................47
8.1.1.
Temporary Interruption from Investigational Product...........................................47
8.1.2.
Permanent Discontinuation from Investigational Product .....................................48
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................50
8.2.
Discontinuation from the Study....................................................................................50
8.3.
Lost to Follow-Up........................................................................................................50
9.
Study Assessments and Procedures ...................................................................................51
9.1.
Efficacy Assessments...................................................................................................51
9.1.1.
Primary Efficacy Assessments .............................................................................51
9.1.2.
Secondary Efficacy Assessments..........................................................................51
9.1.2.1.
Eczema Area and Severity Index scores..........................................................51
9.1.2.2.
SCORing Atopic Dermatitis ...........................................................................51
9.1.2.3.
Hospital Anxiety Depression Scale.................................................................52
9.1.3.
Health Outcomes and Quality-of-Life Measures...................................................52
9.1.3.1.
Patient-Oriented Eczema Measure ..................................................................52
9.1.3.2.
Itch Numeric Rating Scale..............................................................................52
9.1.3.3.
Atopic Dermatitis Sleep Scale ........................................................................52
9.1.3.4.
Skin Pain Numeric Rating Scale .....................................................................52
9.1.3.5.
Patient Global Impression of Severity.............................................................53
9.1.3.6.
Dermatology Life Quality Index.....................................................................53
9.1.3.7.
European Quality of Life–5 Dimensions–5 Levels..........................................53
9.1.3.8.
Work Productivity and Activity Impairment 
Questionnaire–Atopic Dermatitis....................................................................53
9.1.4.
Appropriateness of Assessments ..........................................................................54
9.2.
Adverse Events ............................................................................................................54
9.2.1.
Serious Adverse Events........................................................................................54
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................55
9.2.2.
Adverse Events of Special Interest .......................................................................56
9.2.3.
Complaint Handling.............................................................................................56
9.3.
Treatment of Overdose.................................................................................................56

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9.4.
Safety...........................................................................................................................56
9.4.1.
Electrocardiograms ..............................................................................................56
9.4.2.
Vital Signs ...........................................................................................................56
9.4.3.
Physical Exam .....................................................................................................57
9.4.4.
Laboratory Tests ..................................................................................................57
9.4.5.
Columbia Suicide Severity Rating Scale...............................................................57
9.4.6.
Self-Harm and Follow-Up Supplement Forms......................................................57
9.4.7.
Chest X-Ray and Tuberculosis Testing.................................................................57
9.4.8.
Hepatitis B Virus DNA Monitoring......................................................................58
9.4.9.
Hepatic Safety Monitoring and Data Collection....................................................58
9.4.10.
VTE Assessment..................................................................................................59
9.4.11.
Safety Monitoring ................................................................................................59
9.5.
Pharmacokinetics .........................................................................................................60
9.6.
Pharmacodynamics ......................................................................................................60
9.7.
Pharmacogenetics.........................................................................................................60
9.7.1.
Blood Samples for Pharmacogenetic Research .....................................................60
9.8.
Biomarkers...................................................................................................................61
9.9.
Medical Resource Utilization and Health Economics ...................................................61
10.
Statistical Considerations ..................................................................................................62
10.1. Sample Size Determination ..........................................................................................62
10.2. Populations for Analyses..............................................................................................62
10.3. Statistical Analyses ......................................................................................................62
10.3.1.
General Statistical Considerations ........................................................................62
10.3.2.
Treatment Group Comparability...........................................................................66
10.3.2.1.
Patient Disposition..........................................................................................66
10.3.2.2.
Patient Characteristics ....................................................................................66
10.3.2.3.
Concomitant Therapy .....................................................................................67
10.3.2.4.
Treatment Compliance....................................................................................67
10.3.3.
Efficacy Analyses ................................................................................................67
10.3.3.1.
Primary Analyses ...........................................................................................67
10.3.3.2.
Secondary Analyses........................................................................................67
10.3.4.
Safety Analyses....................................................................................................68
10.3.5.
Other Analyses.....................................................................................................69
10.3.5.1.
Health Outcome Measures..............................................................................69
10.3.5.2.
Subgroup Analyses.........................................................................................69
10.3.6.
Interim Analyses..................................................................................................69
10.3.6.1.
Data Monitoring Committee ...........................................................................69
10.3.6.2.
Unblinded Study Team for Early Regulatory Submission ...............................70

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10.3.6.3.
Adjudication Committee.................................................................................70
11.
References ........................................................................................................................71
12.
Appendices .......................................................................................................................75

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List of Tables
Table
Page
Table JAIW.1.
Schedule of Activities....................................................................................13
Table JAIW.2.
Objectives and Endpoints...............................................................................21
Table JAIW.3.
Treatment Regimens......................................................................................40
Table JAIW.4.
Criteria for Temporary Interruption of Investigational Product.......................47

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List of Figures
Figure
Page
Figure JAIW.1.
Illustration of study design for Clinical Protocol I4V-MC-JAIW....................27
Figure JAIW.2.
Study I4V-MC-JAIW scheme structure..........................................................66

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................76
Appendix 2.
Clinical Laboratory Tests...............................................................................78
Appendix 3.
Study Governance Considerations..................................................................80
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................83
Appendix 5.
Liver Function Testing and Hepatic Safety Monitoring..................................84
Appendix 6.
Monitoring Tests for Confirmed VTE............................................................85
Appendix 7.
American Academy of Dermatology:  Criteria for the Diagnosis and 
Assessment of Atopic Dermatitis ...................................................................86
Appendix 8.
Classification of Potency for Topical Corticosteroids.....................................87
Appendix 9.
Multiple Imputation.......................................................................................88
Appendix 10.
Adjustment for Multiple Comparisons ...........................................................92
Appendix 11.
Investigator Global Assessment .....................................................................93
Appendix 12.
Protocol Amendment I4V-MC-JAIW(c) Summary - A Multicenter, 
Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to 
Evaluate the Efficacy and Safety of Baricitinib in Adult Patients with 
Moderate to Severe Atopic Dermatitis ...........................................................94

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1.
Synopsis
Title of Study:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety 
of Baricitinib in Adult Patients with Moderate to Severe Atopic Dermatitis
Rationale: 
Atopic dermatitis (AD) is a pruritic, chronic or chronically relapsing, highly symptomatic inflammatory skin disease 
characterized by excessive T cell activation leading to significant skin infiltration by T cells and dendritic cells 
(Bieber 2010).  Presentation is varied but includes skin manifestations and pruritus, with associated sleep 
disturbances and subsequent skin infections.  The course of disease includes relapses of varying duration and 
severity.
Baricitinib is an orally available, selective Janus kinase (JAK) inhibitor with potency and selectivity for JAK1 and 
JAK2 and less potency for JAK3 or tyrosine kinase 2 (TYK2) (Fridman et al. 2010).  The pathogenesis of AD is 
thought to be modulated through thymic stromal lymphopoietin (TSLP), interleukin (IL)-13, IL-4, IL-5, IL-22, and 
IL-31, many of which activate receptors with downstream signaling through intracellular JAK1/JAK2/TYK2
(Nomura and Kabashima 2015).  This activity profile suggests that baricitinib would inhibit many of the cytokines 
involved in AD pathogenesis.
Clinical studies have established that baricitinib is effective in autoimmune/autoinflammatory diseases involving the 
joints, kidneys, and skin.  Baricitinib was effective at reducing swollen and tender joints in patients with rheumatoid 
arthritis (RA) (Genovese et al. 2016; Dougados et al. 2017; Fleischmann et al. 2017; Taylor et al. 2017); was 
effective at reducing disease severity in patients with moderate to severe plaque psoriasis (Papp et al. 2016); was 
effective at reducing the urinary albumin-to-creatinine ratio in patients with diabetic kidney disease (Tuttle et al. 
2015); and in a recently completed Phase 2 study (Study I4V-MC-JAHG) was effective at reducing disease severity 
in patients with moderate to severe AD.  The mechanism of action, combined with demonstration of clinical benefit 
in inflammatory diseases involving joints, kidneys, and skin, provides the rationale for evaluating baricitinib in 
moderate to severe AD.

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Objectives/Endpoints:
Objectives
Endpoints
Primary
This is a prespecified objective that will be adjusted for multiplicity.
To test the hypothesis that baricitinib 2-mg QD is 
superior to placebo in the treatment of patients with 
moderate to severe AD

Proportion of patients achieving EASI75 at 
Week 16
Key Secondary
These are prespecified objectives that will be adjusted for multiplicity.
To compare the efficacy of baricitinib 1-mg QD or
2-mg QD to placebo in AD during the 16-week,
double-blind, placebo-controlled treatment period as 
measured by improvement in signs and symptoms 
of AD

Proportion of patients achieving IGA of 0 or 1 
with a ≥2-point improvement at Week 16

Proportion of patients achieving EASI75 at 
Week 16 (1-mg)

Proportion of patients achieving EASI90 at 
Week 16

Mean percent change from baseline in EASI score 
at Week 16

Proportion of patients achieving SCORAD75 at 
Week 16
To compare the efficacy of baricitinib 1-mg QD or
2-mg QD to placebo in AD during the 16-week,
double-blind, placebo-controlled treatment period as 
assessed by patient-reported outcome measures

Proportions of patients achieving a 4-point 
improvement in Itch NRS at 1 week, 2 weeks, 
4 weeks, and 16 weeks

Mean change from baseline in the score of Item 2 
of the ADSS at 1 week and 16 weeks

Mean change from baseline in Skin Pain NRS at 
Week 16
Other Secondary Objectives
These are prespecified objectives that will not be adjusted for multiplicity.
To compare the efficacy of baricitinib 1-mg QD or
2-mg QD to placebo in AD during the 16-week,
double-blind, placebo-controlled period as measured 
by improvement in signs and symptoms of AD

Proportion of patients achieving IGA of 0 or 1 
with a ≥2-point improvement at Week 4

Proportion of patients achieving EASI50 at 
Week 16

Proportion of patients achieving IGA of 0 at 
Week 16

Mean change from baseline in SCORAD at 
Week 16

Proportion of patients achieving SCORAD90 at 
Week 16

Mean change from baseline in body surface area 
affected at Week 16

Proportion of patients developing skin infections 
requiring antibiotic treatment by Week 16

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Objectives
Endpoints
To compare the efficacy of baricitinib 1-mg QD or 
2-mg QD to placebo in AD during the 16-week,
double-blind, placebo-controlled treatment period as 
assessed by patient-reported outcome/QoL measures

Mean percent change from baseline in Itch NRS at 
1 week and 16 weeks

Mean change from baseline in Itch NRS at 
4 weeks and 16 weeks

Mean change from baseline in the total score of 
the POEM at Week 16

Mean change in PGI-S-AD scores at Week 16

Mean change from baseline in the HADS at 
Week 16

Mean change in DLQI scores at Week 16

Mean change in WPAI-AD scores at Week 16

Mean change in EQ-5D-5L scores at Week 16
Other Secondary Objectives for responders beyond Week 16
To describe the long-term efficacy of baricitinib 
1-mg QD or 2-mg QD in AD as measured by 
improvement in signs and symptoms of AD

Proportion of patients with a response of IGA 0 
or 1 at Week 16 who maintain an IGA 0 or 1 at 
Weeks 28, 52, and 104

Proportion of patients with a response of IGA 0 
or 1 at Week 16 who achieve EASI75 assessed at 
Weeks 28, 52, and 104

Proportion of patients with a response of IGA 0 
or 1 at Week 16 who achieve SCORAD75 at 
Weeks 28, 52, and 104

Mean percent change from baseline in EASI 
score at Weeks 28, 52, and 104

Mean percent change from baseline in SCORAD
score at Weeks 28, 52, and 104

Mean percent change from baseline in SCORAD 
pruritus at Weeks 28, 52, and 104

Mean percent change from baseline in POEM at 
Weeks 28, 52, and 104
Abbreviations: AD = atopic dermatitis; ADSS = Atopic Dermatitis Sleep Scale; DLQI = Dermatology Life Quality 
Index; EASI = Eczema Area and Severity Index; EQ-5D-5L = the European Quality of Life–5 Dimensions–
5 Levels; HADS = Hospital Anxiety Depression Scale; IGA = Investigator’s Global Assessment; NRS = numeric 
rating scale; QD = once daily; PGI-S-AD = Patient Global Impression of Severity–Atopic Dermatitis; POEM = 
Patient-Oriented Eczema Measure; QoL = quality of life; SCORAD = SCORing Atopic Dermatitis; WPAI-AD = 
Work Productivity and Activity Impairment – Atopic Dermatitis.
Summary of Study Design:
Study I4V-MC-JAIW (JAIW) is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, outpatient study evaluating the efficacy and safety of baricitinib 2-mg once daily (QD) and 1-mg QD 
as compared to placebo in adult patients with moderate to severe AD. The study population will include patients 
aged ≥18 years who have moderate to severe AD and a history of inadequate response or intolerance to existing 
topical therapies.

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The study duration will be up to 113 weeks over 3 study periods:

Period 1:  Screening Period lasting from 8 to 35 days before Week 0 (baseline, Visit 2)

Period 2:  Double-Blinded Treatment Period, lasting from Week 0 (baseline, Visit 2) through Week 104
(Visit 15)

Period 3:  Post-Treatment Follow-Up Period (Visit 801), spanning the period from the last treatment visit at 
Week 104 (Visit 15) or Early Termination Visit (ETV) to approximately 4 weeks following the last dose of 
investigational product
Treatment Arms and Duration:
Patients will be randomized at Week 0 to 1 of 3 treatment groups:  placebo QD, baricitinib 1-mg QD, or baricitinib 
2-mg QD.  The study duration will be up to 113 weeks (Screening Period:  up to 5 weeks before randomization; 
Double-Blinded Treatment Period:  104 weeks; Post-Treatment Follow-up Period:  approximately 4 weeks after the 
last dose of investigational product).
Number of Patients:
This study will include approximately 450 patients with AD who will be randomized 1:1:1 to placebo QD, 
baricitinib 1-mg QD, or baricitinib 2-mg QD (150 patients per arm).
Statistical Analysis:
Unless otherwise specified, the efficacy and health outcome analyses will be conducted on the intent-to-treat 
population, and safety analyses will be conducted on those patients who receive at least 1 dose of investigational 
product.
Treatment comparisons of discrete efficacy variables will be made using a logistic regression analysis with 
treatment, baseline disease severity (IGA) and baseline score in the model.  Region may be added to the model if 
patient numbers allow. The proportions and 95% CI will be reported.  If a patient needs to use rescue medication, 
the data after rescue onward will be considered missing, and missing data will be imputed using the nonresponder 
imputation (NRI) method. All patients who discontinue the study or study treatment at any time for any reason will 
be defined as nonresponders for the NRI analysis for categorical variables after discontinuation onward. Additional 
analyses will be done using all observed data whether rescue medication was used or not.
Treatment comparisons of continuous efficacy and health outcome variables will be made using mixed-effects 
model of repeated measures (MMRM) with treatment, baseline disease severity (IGA),, visit, and treatment-by-visit
interaction as fixed categorical effects and baseline  and baseline -by-visit interaction as fixed continuous effects.
An unstructured covariance matrix will be used to model the within-patient variance–covariance errors.  Type III 
sums of squares for the least squares means (LSMs) will be used for the statistical comparison, and contrasts will be 
set up within the model to compare treatment groups at specific time points of interest.
Fisher’s exact test will be used for all adverse event (AE), baseline, discontinuation, and other categorical safety 
data.  Continuous vital signs and laboratory values will be analyzed by an analysis of covariance (ANCOVA) with 
treatment and baseline values in the model.

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2. Schedule of Activities
Table JAIW.1.
Schedule of Activities
Period 1:
Screening
Period 2: Double-Blinded Treatment Period
Period 3:
PTFU
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15/ET
a
801b
Weeks from Randomization
0
1
2
4
8
12
16
28
40
52
64
76
88
104
108
Visit tolerance interval (days)
-8 to -35
0
±2
±2
±2
±4
±4
±4
±7
±7
±7
±7
±7
±7
±4
28±4
after last 
dose
Procedure
Inclusion and exclusion review
X
X
Informed consent
X
Clinical Assessments
Demographics
X
Medical history
X
Substance Use (alcohol, tobacco)
X
Previous and current AD 
treatments
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Body mass index
X
X
Vital signs (BP and pulse)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exam
X
Symptom-directed physical examc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG (single)
X
Chest x-rayd (posterior–anterior 
view)
X
TB teste
X
Read PPD if applicable (48 to 
72 hours after PPD)
Xf
Pre-existing conditions
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ePRO (patient diary) dispensed
X
X
X
X
X
X
X
ePRO (patient diary) returned
X
X
X
X
X
X
X
Xg
Randomization
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IP dispensed
X
Xh
Xh
X
X
X
X
X
X
X
X
X
X

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Period 1:
Screening
Period 2: Double-Blinded Treatment Period
Period 3:
PTFU
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15/ET
a
801b
Weeks from Randomization
0
1
2
4
8
12
16
28
40
52
64
76
88
104
108
Visit tolerance interval (days)
-8 to -35
0
±2
±2
±2
±4
±4
±4
±7
±7
±7
±7
±7
±7
±4
28±4
after last 
dose
IP returned and compliance 
assessed
Xh
Xh
X
X
X
X
X
X
X
X
X
X
X
Dispense TCSi
X
X
X
X
X
X
X
X
X
X
X
X
X
Weigh (tube with cap) and record 
returned TCSi (as needed)
X
X
X
X
X
X
X
X
X
X
X
X
X
Scales
IGA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EASI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SCORAD
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Health Outcomes Measures and 
Other Questionnairesj
Itch NRS
X
X
X
X
X
X
X
Xg
Skin Pain NRS
X
X
X
X
X
X
X
Xg
ADSS
X
X
X
X
X
X
X
Xg
PGI-S-AD
X
X
X
X
X
X
X
Xg
POEM
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
DLQI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HADS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EQ-5D-5L
X
X
X
X
X
X
X
X
X
X
X
X
WPAI-AD
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS and Self-Harm 
Supplementk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Self-Harm Follow-Up Forml
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Lipids (fasting)m
X
X
X
X
X
Xn
X
Clinical chemistryo
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
Serum pregnancyp
X
FSHq
X
TSH
X
HIV
X
HCV antibodyr
X
HBV testing
X
HBV DNAs
X
X
X
X
X
X
X
X
X
X

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Period 1:
Screening
Period 2: Double-Blinded Treatment Period
Period 3:
PTFU
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15/ET
a
801b
Weeks from Randomization
0
1
2
4
8
12
16
28
40
52
64
76
88
104
108
Visit tolerance interval (days)
-8 to -35
0
±2
±2
±2
±4
±4
±4
±7
±7
±7
±7
±7
±7
±4
28±4
after last 
dose
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancyp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacogenetics: blood
X
Serum immunoglobulin (IgE)
X
X
X
X
X
Exploratory storage samples 
(serum and plasma)
X
X
X
X
X
RNA and biomarkers: blood
X
X
X
X
X
Abbreviations: AD = atopic dermatitis; ADSS = Atopic Dermatitis Sleep Scale; BP = blood pressure; C-SSRS = Columbia Suicide Severity Rating Scale 
11 categories suicidal ideation/suicidal behavior; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index;
ECG = electrocardiogram; EQ-5D-5L = the European Quality of Life–5 Dimensions 5 Levels; ET = early termination; ePRO = electronic patient-reported 
outcomes (device); FSH = follicle-stimulating hormone; HADS = Hospital Anxiety Depression Scale; HBcAb = Hepatitis B core antibody; 
HBsAb = Hepatitis B surface antibody; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IGA = Investigator’s 
Global Assessment; IgE = immunoglobulin E; IP = investigational product; IWRS = interactive web-response system; NRS = numeric rating scale; PGI-S-AD 
= Patient Global Impression of Severity–Atopic Dermatitis; POEM = Patient-Oriented Eczema Measure; PPD = purified protein derivative; 
PTFU = posttreatment follow-up; SCORAD = SCORing Atopic Dermatitis; TB = tuberculosis; TCS = topical corticosteroids; TSH = thyroid-stimulating 
hormone; WPAI-AD = Work Productivity and Activity Impairment-Atopic Dermatitis.
a
An ET visit should be conducted if a patient discontinues from the study before Week 104. ET visit activities do not need to be duplicated if occurring at the 
time of a scheduled visit.
b
Visit 801 is the PTFU visit, which occurs after the patient has been off baricitinib/IP for approximately 4 weeks.  Patients who have permanently discontinued 
IP but remain in the study for more than 28 days without IP will only complete Visit 15/ET, and Visit 801 (follow-up visit) is not required.  Patients choosing 
to enroll into the open-label study, Study I4V-MC-JAIX (JAIX), will not be required to complete Visit 801.
c
The symptom-directed physical examination may be repeated at the investigator’s discretion any time a patient presents with physical complaints.
d
A posterior–anterior chest x-ray will be performed at screening unless one has been performed within the past 6 months and the x-ray and reports are 
available.
e
TB test(s) include PPD, QuantiFERON®-TB Gold, and T SPOT®. See Exclusion Criterion [38] for description of TB testing. 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: 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 

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screening.)
f
If PPD testing was chosen to test for TB, then the patient must return and have her or his PPD test read 48 to 72 hours after Visit 1 (post-PPD).
g
Applies to ET Visit if conducted prior to Week 16 only.
h
New bottles of study drug tablets will NOT be dispensed at Weeks 1 and 2 (Visits 3 and 4, respectively) unless the patient requires additional tablets for the 
next visit window.  Patients will continue to take tablets from the bottles dispensed at Week 0 (Visit 2).  Compliance will be checked, and the bottle with 
remaining tablets will be returned to the patient for dosing the following visit window. If a new bottle is required, the patient will not have their previous 
bottle returned.  
i
Only required if patient met rescue criteria before Week 16 or at investigator discretion after Week 16 for low-potency TCS.
j
The following measures (Itch NRS, Skin Pain NRS, ADSS, PGI-S-AD, POEM, DLQI, HADS, EQ-5D-5L, WPAI-AD) should be completed before any 
clinical assessments being performed on days when study visits occur.
k
Suicidal ideation and behavior subscales excerpt. Adapted for the assessment of 11 preferred ideation and behavior categories.
l
The Self-Harm Follow-Up Form is required only if triggered by the Self-Harm Supplement Form.
m Fasting lipid profile.  Patients should not eat or drink anything except water for 12 hours before sample collection.  If a patient attends these visits in a 
nonfasting state, this will not be considered a protocol violation.  Unscheduled lipid testing can be performed at the discretion of the investigator.
n
For ET visits, collect fasting lipids when possible. 
o
Clinical chemistry will include the following value calculated from serum creatinine:  estimated glomerular filtration rate (calculated using the Chronic 
Kidney Disease Epidemiology Collaboration Creatinine 2009 equation).
p
For all women of childbearing potential, a serum pregnancy test (central laboratory) will be performed at Visit 1.  Urine pregnancy tests (local laboratory) will 
be performed at Visit 2 and at all subsequent study visits after Visit 3.  If required per local regulations and/or institutional guidelines, pregnancy testing can 
occur at other times during the study treatment period.
q
For female patients aged ≥40 and <60 years who have had a cessation of menses for ≥12 months, an FSH test will be performed to confirm nonchildbearing 
potential (FSH ≥40 mIU/mL).
r
For patients who are positive for HCV antibody, a follow-up test for HCV RNA will be performed automatically.  Patients who are positive for HCV antibody 
and negative for HCV RNA may be enrolled.
s
Patients who are positive for HBcAb and negative for HBV DNA may be enrolled.  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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3.
Introduction
3.1.
Background
AD, also known as eczema or atopic eczema, is a common, chronic, relapsing, highly 
symptomatic inflammatory skin disease (Bieber 2010).  Patients with AD may present with skin 
lesions that can be acute with oozing, crusted, eroded vesicles or papules on erythematous 
plaques.  Patients may also present with lesions that have a subacute appearance, with thick and 
excoriated plaques, or chronic appearance, with lichenified, slightly pigmented, excoriated 
plaques (Bieber 2010).  AD causes pruritus attacks throughout the day, which is the primary 
source of morbidity in this disorder (Simpson 2012). Pruritus often leads to an “itch–scratch” 
cycle, further compromising the epidermal barrier and resulting in dry skin, microbial 
colonization, and secondary infections (Krakowski et al. 2008), with 36% of patients reporting 
that they often or always scratch until their skin bleeds (Langenbruch et al. 2014). Pruritus from 
AD can worsen at night, resulting in sleep disturbances, with approximately 27% of adult 
patients with AD experiencing sleep disturbance as a result of itching (Langenbruch et al. 2014).
In adult patients with moderate to severe AD, poor sleep quality and latency were significantly 
associated with poor quality of life (Yano et al. 2013).
In clinical practice, AD is classified as mild, moderate, or severe based on a variety of clinical 
features, including severity of skin lesions and pruritus and extent of disease (body surface area 
[BSA] involved).
Until recently, there were no US Food and Drug Administration-approved systemic treatments 
for patients with moderate to severe AD, with the exception of systemic corticosteroids.  In 
March 2017, Dupixent® (dupilumab) injection, a IgG4 monoclonal antibody that inhibits IL-4 
and IL-13, was approved by the US Food and Drug Administration for this patient population.  
In the European Union, only cyclosporine has been approved for the treatment of patients with 
severe AD (Bieber and Straeter 2015).  A recently completed Phase 2 study 
(Study I4V-MC-JAHG [JAHG]) evaluated the safety and efficacy of baricitinib (a JAK inhibitor) 
in AD, and results showed significant improvement in disease severity compared to placebo, and 
no new safety concerns were identified.
In addition to AD, baricitinib has also been studied in Phase 3 in patients with RA and in Phase 2 
in patients with diabetic nephropathy, moderate to severe psoriasis, and systemic lupus 
erythematosus.
Through 13 February 2019, baricitinib has been studied in more than 548 healthy volunteers and 
6555 patients have received baricitinib in clinical studies. As of 13 February 2018, more than 
2700 patients have been treated with baricitinib for more than a year and more than 1800 patients 
have been treated with baricitinib for more than 2 years at doses of 2-mg once daily or 4-mg 
once daily across the RA clinical program. Baricitinib has been administered as single doses 
ranging from 1- to 40-mg and as repeat oral doses ranging from 2- to 20-mg to healthy 
subjects. Baricitinib has also been administered to patients with RA at doses up to 15-mg daily 
for 4 weeks, 10-mg daily for 24 weeks, 8-mg daily for 76 weeks, and lower doses up to 4-mg 
daily for up to approximately 7 years. 

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3.2. Study Rationale
The underlying cause of AD is not completely understood.  Loss of function mutationsin the 
gene forfilaggrin(filament aggregatingprotein), a key protein in terminal differentiation of the
epidermis contributing to barrier function, has been identified as the strongest genetic risk factor
for AD in European populations(Palmer et al. 2006). At a cellular level, AD is characterized by 
excessive Tcell activationcaused by genetic andenvironmental factors, leading to significant 
skin infiltration by Tcells and dendritic cells. Thecytokine TSLP is thought to act as a master 
switch that triggersthe initiation and maintenance of AD (Moniaga et al. 2013; Ziegler et al. 
2013). Overexpressionof TSLP in keratinocytes, the most prevalent cell type in the skin, 
triggers robust itch-evokedscratching and the development of an AD-like skin phenotype in 
mice (Li et al. 2005). In addition to directly inducing itch by activating sensory neurons inthe 
skin, TSLP also enhances maturation and differentiation of dendriticcells and naive CD4+ 
Tcells and induces production of Th2-related cytokines involved in ADpathogenesis (Wilson 
etal. 2013; Divekar and Kita 2015). TSLPand otherkey cytokines involved in AD 
pathogenesis, such as IL-13, IL-5,IL-22, and IL-31, signalthrough receptors associated with 
intracellular JAK1/JAK2/TYK2 signaling(Ziegler et al. 2013; Nomura and Kabashima 2015).
JAKs are afamily of tyrosine kinases that mediatecytokine receptor signalling through 
phosphorylation and activation of signal transducers and activators of transcriptionproteins.  
There are 4 known JAK family members:  JAK1,JAK2, JAK3, and TYK2(Clark et al.2014).
The relative affinity of JAK inhibitors fordifferentmembers of the JAK kinase family allows for 
differentiation of JAK inhibitors in relation to theirenzymatic inhibitory profile. In vitro assays 
indicatethat baricitinib is a selective inhibitor of JAKswith potency and selectivity for JAK1/2 
andless potency for JAK3 or TYK2 (Fridman et al. 2010).  The balanced JAK1/JAK2 inhibitory 
profile of baricitinib suggests that baricitinib will have the greatest modulatory effect in 
cytokines signalling through a JAK1/JAK2 heterodimer intracellularly (or a JAK1/JAK2/TYK2), 
such as IL-6, TSLP, 
CCI
IL-13, or IL-31(Vaddi and Luchi 2012).
The recently completed Phase2 study of baricitinib in AD, StudyJAHG, met its primary 
objectiveof proportion of patients achieving a 50% improvement from baseline in Eczema Area 
and Severity Index (EASI)scores compared to placebo. Baricitinib also showed statistically 
significant improvements for other disease severity analyses as well as multiple different 
patient-reported outcomescales compared to placebo, further validating the hypothesis that 
JAK1/JAK2 signaling plays a key rolein ADpathogenesis.
 
 
 

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CCI
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 

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CCI
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  

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4.
Objectives and Endpoints
Table JAIW.2 shows the objectives and endpoints of the study.
Table JAIW.2.
Objectives and Endpoints
Objectives
Endpoints
Primary
This is a prespecified objective that will be adjusted for multiplicity.
To test the hypothesis that baricitinib 2-mg QD is 
superior to placebo in the treatment of patients with 
moderate to severe AD

Proportion of patients achieving EASI75 at 
Week 16
Key Secondary
These are prespecified objectives that will be adjusted for multiplicity.
To compare the efficacy of baricitinib 1-mg QD or
2-mg QD to placebo in AD during the 16-week,
double-blind, placebo-controlled treatment period 
as measured by improvement in signs and 
symptoms of AD

Proportion of patients achieving IGA of 0 or 1 with 
a ≥2-point improvement at Week 16

Proportion of patients achieving EASI75 at 
Week 16 (1-mg)

Proportion of patients achieving EASI90 at 
Week 16

Mean percent change from baseline in EASI score 
at Week 16

Proportion of patients achieving SCORAD75 at 
Week 16
To compare the efficacy of baricitinib 1-mg QD or
2-mg QD to placebo in AD during the 16-week,
double-blind, placebo-controlled treatment period 
as assessed by patient-reported outcome measures

Proportions of patients achieving a 4-point 
improvement in Itch NRS at 1 week, 2 weeks, 
4 weeks, and 16 weeks

Mean change from baseline in the score of Item 2 of 
the ADSS at 1 week and 16 weeks

Mean change from baseline in Skin Pain NRS at 
Week 16
Other Secondary Objectives
These are prespecified objectives that will not be adjusted for multiplicity.
To compare the efficacy of baricitinib 1-mg QD or
2-mg QD to placebo in AD during the 16-week,
double-blind, placebo-controlled period as 
measured by improvement in signs and symptoms 
of AD

Proportion of patients achieving IGA of 0 or 1 with 
a ≥2-point improvement at Week 4

Proportion of patients achieving EASI50 at 
Week 16

Proportion of patients achieving IGA of 0 at 
Week 16

Mean change from baseline in SCORAD at 
Week 16

Proportion of patients achieving SCORAD90 at 
Week 16

Mean change from baseline in body surface area 
affected at Week 16

Proportion of patients developing skin infections 
requiring antibiotic treatment by Week 16

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Objectives
Endpoints
To compare the efficacy of baricitinib 1-mg QD or 
2-mg QD to placebo in AD during the 16-week,
double-blind, placebo-controlled treatment period 
as assessed by patient-reported outcome/QoL 
measures

Mean percent change from baseline in Itch NRS at 
1 week and 16 weeks

Mean change from baseline in Itch NRS at 4 weeks
and 16 weeks

Mean change from baseline in the total score of the 
POEM at Week 16

Mean change in PGI-S-AD scores at Week 16

Mean change from baseline in the HADS at 
Week 16

Mean change in DLQI scores at Week 16

Mean change in WPAI-AD scores at Week 16

Mean change in EQ-5D-5L scores at Week 16
Other Secondary Objectives for responders beyond Week 16
To describe the long-term efficacy of baricitinib 
1-mg QD or 2-mg QD in AD as measured by 
improvement in signs and symptoms of AD

Proportion of patients with a response of IGA 0 or 
1 at Week 16 who maintain an IGA 0 or 1 at 
Weeks 28, 52, and 104

Proportion of patients with a response of IGA 0 or 
1 at Week 16 who achieve EASI75 assessed at 
Weeks 28, 52, and 104

Proportion of patients with a response of IGA 0 or 
1 at Week 16 who achieve SCORAD75 at 
Weeks 28, 52, and 104

Mean percent change from baseline in EASI score 
at Weeks 28, 52, and 104

Mean percent change from baseline in SCORAD
score at Weeks 28, 52, and 104

Mean percent change from baseline in SCORAD 
pruritus at Weeks 28, 52, and 104

Mean percent change from baseline in POEM at 
Weeks 28, 52, and 104
Exploratory Objectives/Endpoints

Frequency of patient-reported “no itch” (Itch NRS score = 0) days from daily diaries from Week 12 to 
Week 16

Frequency of patient-reported “no pain” (Skin Pain NRS score = 0) days from daily diaries from Week 12 
to Week 16

Mean change from baseline in the score of Item 1 of the ADSS at 1 week and 16 weeks 

Mean change from baseline in the score of Item 3 of the ADSS at 1 week and 16 weeks

Exploratory objectives evaluating the response to baricitinib treatment regimens on other patient reported 
outcomes will be specified in the SAP. These endpoints may include dichotomous endpoints or change 
from baseline for the following measures: POEM, DLQI, Itch NRS, ADSS, Skin Pain NRS, PGI-S-AD, 
HADS.

To evaluate changes from baseline in IgE levels during the study

To evaluate changes from baseline in eosinophil levels during the study

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Abbreviations: AD = atopic dermatitis; ADSS = Atopic Dermatitis Sleep Scale; DLQI = Dermatology Life Quality 
Index; EASI = Eczema Area and Severity Index; EQ-5D-5L = the European Quality of Life–5 Dimensions–5 
Levels; HADS = Hospital Anxiety Depression Scale; IgE = immunoglobulin E; IGA = Investigator’s Global 
Assessment; NRS = numeric rating scale; QD = once daily; QoL = quality of life; PGI-S-AD = Patient Global 
Impression of Severity–Atopic Dermatitis; POEM = Patient-Oriented Eczema Measure; SCORAD = SCORing 
Atopic Dermatitis; WPAI-AD = Work Productivity and Activity Impairment – Atopic Dermatitis.

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5.
Study Design
5.1.
Overall Design
Study JAIW is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, outpatient study evaluating the efficacy and safety of baricitinib 1-mg QD and 
2-mg QD as compared to placebo in adult patients with moderate to severe AD.  The study is 
divided into 3 periods:  a 5-week Screening Period, a 104-week Double-Blinded Treatment 
Period, and a 4-week Post-Treatment Follow-Up Period.  
Approximately 450 patients aged ≥18 years who have responded inadequately to or who are 
intolerant of topical therapy will be randomized at a 1:1:1 ratio to receive placebo QD, baricitinib 
1-mg QD, or baricitinib 2-mg QD (approximately 150 patients per group).  Patients will be 
stratified at randomization according to disease severity (Investigator’s Global Assessment 
[IGA] 3 versus 4) and geographic region if the planned country allocation justifies.
All procedures to be conducted during the study, including timing of all procedures, are indicated 
in the Schedule of Activities (Section 2).  Section 9.4.4 describes collection of laboratory 
samples; Appendix 2, Appendix 4, Appendix 5, and Appendix 6 list the specific laboratory tests 
that will be performed for this study.  Study governance considerations are described in detail in 
Appendix 3.  Section 10.3.6.1 outlines information regarding the data monitoring committee 
(DMC) and interim analyses.
5.1.1.
Period 1:  Screening
The duration of the Screening Period is between 8 and 35 days before Visit 2 (Week 0).  At 
Visit 1, the patient will sign the informed consent form (ICF) before any study assessments, 
examinations, or procedures are performed (see 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 Visit 1 will need to return within 48 to 72 hours later to have 
the skin test read. Before randomization, treatments for AD will be washed out:  4 weeks for 
systemic treatments and 2 weeks for topical treatments (not including emollients).  Patients will 
be required to use emollients daily during the 14 days preceding randomization and throughout 
the study.  If patients have been using emollients daily at the time of screening, then those 
cumulative days can be utilized to meet inclusion criterion [8].  Additionally, collection of data 
through daily diaries will be required throughout the Screening Period.  The baseline for the 
daily patient-reported outcome assessments will be the average score of the 7 days before 
randomization; thus, the minimum screening window was set at 8 days.  
All patients who are eligible to receive the herpes zoster vaccine (per local guidelines) and who 
have not received it by screening will be encouraged to do so before randomization. 
Investigators should review the vaccination status of their patients and follow the local 
guidelines for vaccination of those aged ≥18 years with nonlive vaccines intended to prevent 
infectious disease before entering patients into the study. Refer to Exclusion Criterion [27] in 
Section 6.2 for additional information regarding herpes zoster vaccinations. 

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Patients who meet all of the inclusion and none of the exclusion criteria (Section 6.2) will 
continue to Visit 2.
5.1.2.
Period 2:  Double-Blind Placebo-Controlled Treatment, 
Weeks 0 to 104
At Visit 2 (Week 0, baseline), study eligibility for each patient will be reviewed, on the basis of 
all inclusion (Section 6.1) and exclusion criteria (Section 6.2) and laboratory test results.  
Patients who meet all criteria will proceed to randomization and begin the double-blind, 
placebo-controlled treatment period.
At Visit 2, after laboratory samples are collected and all assessments are completed, patients will 
take the first dose of investigational product.  
Patients will be randomized at a 1:1:1 ratio into 1 of the 3 treatment groups (placebo QD, 
baricitinib 1–mg QD, or baricitinib 2–mg QD).  Investigational product will be administered QD
for 104 weeks (treatment period, Visits 2 through 15; see Section 7).  All patients will be 
required to use emollients daily.  Daily diaries will continue to be utilized through Week 16.  
Download of this data will be required at study visits.  The use of topical corticosteroids (TCS), 
topical calcineurin inhibitors (TCNIs), topical phosphodiesterase-4 (PDE-4) inhibitor 
(crisaborole), and systemic therapies for the treatment of AD are not allowed during the first 
16 weeks of the study, except as part of rescue therapy for patients not responding to treatment. 
After Week 16 (primary endpoint), patients are allowed to use low-potency TCS (for example, 
hydrocortisone 2.5% ointment) in combination with investigational product if they experience 
worsening in AD signs or symptoms.  Details of rescue therapy and criteria are included in 
Section 7.7.3.  Assessments of disease severity will be performed by the investigator at all study 
visits including unscheduled and ETVs.
The primary efficacy endpoint will be at Week 16 (Visit 8). All patients who permanently 
discontinue investigational product before the primary endpoint, including patients rescued with
other systemic medications, should remain in the study to complete the schedule of study visits 
per protocol up to Week 16 (primary endpoint), when they will complete an ETV.  If the patient 
refuses to continue up to Week 16 and wishes to withdraw consent, an ETV should be completed 
as soon as logistically possible.
At Week 16, all patients who meet IGA 0 or 1 and who have not required rescue therapy before 
Week 16 will be allowed to continue on this study. All other patients will be discontinued from 
this study and may be eligible to enroll in a separate open-label study (Study I4V-MC-JAIX 
[JAIX; BREEZE-AD6]).  Patients need to complete at least 16 weeks in Study JAIW to be 
eligible to enroll in the open-label extension (Study JAIX).  Patients who choose to enroll into 
the open-label study (Study JAIX) will not be required to complete the Study JAIW post-
treatment follow up visit.  
Patients experiencing worsening in disease severity resulting in an IGA score of ≥3 after 
Week 16 of Study JAIW will also have to be discontinued from this study and may be eligible to 
enroll in the open-label Study JAIX. 

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Patients who complete week 104 (Visit 15) will have the option to transition to open-label Study 
JAIX if eligibility criteria are met, regardless of responder status, or continue to the post-
treatment follow-up. 
5.1.3.
Period 3:  Post-Treatment Follow-Up
Patients who complete the study through Visit 15 (Week 104) will have a post-treatment 
follow-up visit (Visit 801) approximately 28 days after the last dose of investigational product, 
unless the patient is transitioning to open-label Study JAIX.
Patients who have received at least 1 dose of investigational product and discontinue early from 
the study must have an ETV and return for the post-treatment safety follow-up visit (Visit 801) 
approximately 28 days after the last dose of investigational product.
Patients who have discontinued investigational product but remain in the study for more than 
28 days without investigational product will have an ETV if they choose to discontinue early; 
however, a separate follow-up visit (Visit 801) is not required.
Patients should not initiate new systemic AD treatment during this period.  However, if patients 
or investigators must initiate treatment, investigators should make every attempt to conduct 
efficacy and safety assessments immediately before administering any new treatment. An 
unscheduled visit can be used for this purpose if necessary.
For patients who are discontinued from this study because of lack of efficacy (either at Week 16 
or after) and who opt to enroll into the open-label extension (Study JAIX), a separate follow-up 
visit (Visit 801) is not required.
Figure JAIW.1 illustrates the study design.  The 3 dosing regimens are described in Section 7.1.  
The blinding procedure is described in Section 7.3.

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Abbreviations:  AD = atopic dermatitis; QD = once daily; V = visit; W = week.
a At Week 16, all patients who achieve an IGA 0 or 1 and who have not required rescue therapy 
before Week 16 will be allowed to continue in this study.  All other patients will be 
discontinued from this study and may be eligible to enroll in the separate open-label Study 
JAIX.
b    Patients who complete this study will be eligible for assessment to enroll in open-label Study 
JAIX.
c Occurs approximately 28 days after the last dose of investigational product.
Figure JAIW.1.
Illustration of study design for Clinical Protocol I4V-MC-JAIW.
5.2.
Number of Participants
Approximately 450 participants will be enrolled; approximately 750 patients will be screened to
achieve this enrollment.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
This study will enroll moderate to severe AD patients with a history of inadequate response or 
intolerance to existing topical therapies for which a systemic treatment such as baricitinib may 
therefore be appropriate.

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During the Screening Period (Period 1), a washout of systemic and topical treatments for AD is
incorporated before randomization to minimize confounding effects because of background 
treatment.  The double-blind, placebo-controlled treatment period (Period 2) is designed to 
minimize bias in the evaluation of the efficacy and safety of 2 baricitinib doses relative to 
placebo through the primary endpoint at Week 16.
In consideration of the disease severity, all patients in Study JAIW are eligible for rescue to TCS.  
Investigators are allowed to rescue patients who are experiencing unacceptable or worsening 
symptoms of AD.  Once rescue medication is used, the patient will be determined to be a 
nonresponder (see Section 7.7.3).
Both EASI score and IGAs are commonly used in clinical trials, both for qualifying patients for 
enrollment and for evaluating treatment efficacy (Langley et al. 2015; Futamura et al. 2016; 
Bożek and Reich, 2017). There is no single “gold standard” disease severity scale for AD; 
however, IGA scales provide clinically meaningful measures to patients and investigators that 
are easily described and that correspond to disease severity categories (for example, moderate to 
severe), and a 75% improvement from Baseline (EASI75) is a commonly used measure of 
treatment effect in AD clinical trials. 
The IGA scale that will be used in this trial, the validated Investigator’s Global Assessment of 
Atopic Dermatis (vIGA-AD, referred to throughout the protocol as IGA; Appendix 11), has been 
developed internally and assesses AD severity using a 5-point scale.
The 16-week efficacy endpoint was chosen because it is probable that a robust clinical effect will
be observed with baricitinib within this time frame on the basis of the Phase 2 study results in 
AD and previous studies in another inflammatory skin condition.  Patients who do not achieve 
IGA 0 or 1 at Week 16 will be discontinued from the study. Similarly, patients who achieve an 
IGA of 0 or 1 at Week 16, and experience worsening in their disease resulting in an IGA score of 
≥3 at any time after Week 16 will also be discontinued from the study. Patients who are 
discontinued from Study JAIW may be eligible to enroll in open-label Study JAIX.
The Post-Treatment Follow-Up Period (Period 3) is for safety monitoring after the patient has 
been off investigational product for approximately 28 days.
5.5.
Justification for Dose
The doses proposed for Study JAIW are baricitinib 1-mg QD and 2-mg QD.  These doses were 
chosen primarily on the basis of the recently completed Phase 2 AD study, Study JAHG, and are 
additionally supported by pharmacokinetic, safety, and efficacy data for baricitinib in Phase 2 
and Phase 3 RA studies and a Phase 2 psoriasis study.
In the Phase 2 Study JAHG, both the 2-mg and 4-mg doses showed benefit on the primary and 
major secondary endpoints (EASI, IGA, SCORing Atopic Dermatitis [SCORAD], 
Patient-Oriented Eczema Measure [POEM], and Dermatology Life Quality Index [DLQI]) as 
compared to placebo, and both doses had an acceptable safety profile at Week 16.  As baricitinib 
2-mg QD and 4-mg QD doses showed similar efficacy for multiple endpoints, a lower dose, 

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baricitinib 1-mg QD, was included in this study to assess if a lower dose can also provide 
reasonable efficacy in AD.  

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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.
Study investigator(s) will review patient history and screening test results at Visit 1 and Visit 2 to 
determine if the patient meets all inclusion criteria and none of the exclusion criteria to qualify 
for randomization in the study.  All screening activities must be completed and reviewed before 
the patient is randomized.
6.1.
Inclusion Criteria
Informed Consent
[1]
are aged ≥18 years at the time of informed consent.
Note:  Use local requirements to provide consent if the age of adulthood is 
defined as >18 years 
[2]
are able to read, understand, and give documented (electronic or paper 
signature) informed consent.
Type of Patient and Disease Characteristics
[3]
have a diagnosis of AD at least 12 months before screening, as defined by the 
American Academy of Dermatology:  Criteria for the Diagnosis and 
Assessment of Atopic Dermatitis (see Appendix 7).
[4]
have moderate to severe AD, including all of the following:
a.
EASI score ≥16 at screening (Visit 1) and at randomization (Visit 2)
b. IGA score of ≥3 at screening (Visit 1) and at randomization (Visit 2)
c.
≥10% of BSA involvement at screening (Visit 1) and at randomization 
(Visit 2).
[5]
have a documented history by a physician and/or investigator of inadequate 
response to existing topical medications within 6 months of screening, or 
history of intolerance to topical therapy as defined by at least 1 of the 
following:
a.
inability to achieve good disease control defined as mild disease or better 
(for example, IGA ≤2) after use of at least a medium-potency TCS for at 
least 4 weeks, or for the maximum duration recommended by the product 
prescribing information (for example, 14 days for super-potent TCS), 
whichever is shorter.  TCS may be used with or without TCNIs.
b. documented history of clinically significant adverse reactions with the use 
of TCS such as skin atrophy, allergic reactions, or systemic effects that in 
the opinion of the investigator outweigh the benefits of retreatment.

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c.
patients who failed systemic therapies intended to treat AD (such as 
cyclosporine, methotrexate, azathioprine, or mycophenolate mofetil) 
within 6 months of screening will also be considered as surrogates for 
having inadequate response to topical therapy.
[6]
agree to discontinue use of the following excluded medications/treatments for
at least 4 weeks before randomization (Visit 2):
a.
oral systemic corticosteroids and leukotriene inhibitors
b. systemic immunomodulators, including but not limited to cyclosporine, 
methotrexate, mycophenolate mofetil, and azathioprine
c.
sedating antihistamines, including but not limited to alimemazine, 
chlorphenamine, clemastine, cyproheptadine, diphenhydramine, 
hydroxyzine, ketotifen, and promethazine
Note: Patients may use newer, less sedating antihistamines (for example,
fexofenadine, loratadine, cetirizine).
d. any other systemic therapy used to treat AD or symptoms of AD 
(approved or off-label use)
e.
phototherapy, includes therapeutic phototherapy (psoralen plus 
ultraviolet-A, ultraviolet-B), excimer laser, as well as self-treatment with 
tanning beds.
[7]
agree to discontinue use of the following excluded medications for at least 
2 weeks before randomization (Visit 2):
a.
TCS or topical immune modulators (for example, tacrolimus or 
pimecrolimus)
b. Topical PDE-4 inhibitor (crisaborole).
[8]
have applied emollients daily for at least 14 days before randomization and 
agree to use emollient daily throughout the treatment period.
[9]
Patients who are receiving chronic treatments to improve sleep should be on a 
stable dose for at least 2 weeks before screening as determined by the 
investigator.  Sedating antihistamines (see above) are not permitted.
Patient Characteristics
[10] are male or nonpregnant, nonbreastfeeding female patients, and
a.
Male patients will either remain abstinent (if this is their preferred and 
usual lifestyle) or agree to use 2 forms of birth control (1 must be highly 
effective, see below) while engaging in sexual intercourse with female 
partners of childbearing potential while enrolled in the study and for at 
least 4 weeks following the last dose of investigational product.
Men who are in exclusively same sex relationships (when it is their 
preferred and usual lifestyle) are not required to use contraception.

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b. Female patients of childbearing potential who are abstinent (if this is 
complete abstinence, as their preferred and usual lifestyle) or in a 
same-sex relationship (as part of their preferred and usual lifestyle) must 
agree to either remain abstinent or stay in a same-sex relationship without 
sexual relationships with males. Periodic abstinence (for example,
calendar, ovulation, symptothermal, post-ovulation methods), declaration 
of abstinence just for the duration of a trial, and withdrawal are not 
acceptable methods of contraception. 
Otherwise, female patients of childbearing potential must agree to use 
2 forms of birth control when engaging in sexual intercourse with a male 
partner while enrolled in the study and for at least 4 weeks following the 
last dose of investigational product.
The following birth control methods are considered acceptable (the patient 
should choose 2 to be used with their male partner, and 1 must be highly 
effective):
o
Highly effective birth control methods: oral, injectable, or implanted 
hormonal contraceptives (combined estrogen/progesterone or 
progesterone only, associated with inhibition of ovulation); 
intrauterine device or intrauterine system (for example,
progestin-releasing coil); or, vasectomized male (with appropriate 
post-vasectomy documentation of the absence of sperm in the 
ejaculate).
o
Effective birth control methods: condom with a spermicidal foam, gel, 
film, cream, or suppository; occlusive cap (diaphragm or cervical/vault 
caps) with a spermicidal foam, gel, film, cream, or suppository; or, 
oral hormonal contraceptives.
Note:  When local guidelines concerning highly effective or effective 
methods of birth control differ from the above, the local guidelines 
must be followed.
c.
Females of nonchildbearing potential are not required to use birth control.
They are defined as:
o
women aged ≥60 years or women who are congenitally sterile, or
o
women aged ≥40 and <60 years who have had a cessation of menses 
for ≥12 months and a follicle-stimulating hormone test confirming 
nonchildbearing potential (≥40 mIU/mL or ≥40 IU/L), or women who 
are surgically sterile (that is, have had a hysterectomy or bilateral 
oophorectomy or tubal ligation).

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6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria:
Medical Conditions Related to Atopic Dermatitis
[11] are currently experiencing or have a history of other concomitant skin 
conditions (for example, psoriasis or lupus erythematosus) that would 
interfere with evaluations of the effect of study medication on AD.
[12] patients who are currently experiencing or have a history of erythrodermic, 
refractory, or unstable skin disease that requires frequent hospitalizations 
and/or intravenous treatment for skin infections that, in the opinion of the 
investigator, may interfere with participation in the study.
[13] a history of eczema herpeticum within 12 months of screening.
[14] a history of 2 or more episodes of eczema herpeticum.
[15] patients who are currently experiencing a skin infection that requires treatment 
or is currently being treated with topical or systemic antibiotics.
Note:  Patients may not be rescreened until at least 4 weeks after the date of 
their screen failure and at least 2 weeks after resolution of the infection.
[16] have any serious concomitant illness that is anticipated to require the use of
systemic corticosteroids or otherwise interfere with study participation or
require frequent monitoring (for example, unstable chronic asthma).
[17] have been treated with the following therapies:
a.
monoclonal antibody (for example, ustekinumab, omalizumab, 
dupilumab) for less than 5 half-lives before randomization.
b. received prior treatment with any oral JAK inhibitor (for example,
tofacitinib, ruxolitinib) less than 4 weeks before randomization.
c.
received any parenteral corticosteroid administered by intramuscular or 
intravenous injection within 6 weeks of planned randomization (Visit 2)
or are anticipated to require parenteral injection of corticosteroids during 
the study.
d. have had an intra-articular corticosteroid injection within 6 weeks of
planned randomization (Visit 2).
Note:  Intranasal or inhaled steroid use is allowed during the trial.
e.
probenecid at the time of randomization (Visit 2) that cannot be 
discontinued for the duration of the study.
Medical Conditions in General
[18] are largely or wholly incapacitated permitting little or no self-care, such as 
being bedridden.

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[19] have uncontrolled arterial hypertension characterized by a repeated systolic 
blood pressure >160 mm Hg or diastolic blood pressure >100 mm Hg in a 
seated position.
[20] have had any major surgery within 8 weeks of screening or will require major 
surgery during the study that, in the opinion of the investigator in consultation 
with Lilly or its designee, would pose an unacceptable risk to the patient.
[21] are immunocompromised and, in the opinion of the investigator, at an 
unacceptable risk for participating in the study.
[22] have experienced any of the following within 12 weeks of screening: 
myocardial infarction (MI), unstable ischemic heart disease, stroke, or 
New York Heart Association Stage III/IV heart failure.
[23] have a history of VTE, or are considered at high risk for VTE as deemed by 
the investigator, or have 2 or more of the following risk factors for VTE:
a.
Aged >65 years.
b. BMI >35 kg/m2.
c.
Oral contraceptive use and current smoker.
[24] have a history or presence of cardiovascular, respiratory, hepatic, 
gastrointestinal, endocrine, hematological, neurological, or neuropsychiatric 
disorders or any other serious and/or unstable illness that, in the opinion of the 
investigator, could constitute an unacceptable risk when taking investigational 
product or interfere with the interpretation of data.
[25] have a history of lymphoproliferative disease; or have signs or symptoms 
suggestive of possible lymphoproliferative disease, including 
lymphadenopathy or splenomegaly; or have active primary or recurrent 
malignant disease; or have been in remission from clinically significant 
malignancy for <5 years.
a.
Patients with cervical carcinoma in situ that has been appropriately 
treated with no evidence of recurrence or metastatic disease for at least 
3 years may participate in the study.
b. Patients with basal cell or squamous epithelial skin cancers that have been 
appropriately treated with no evidence of recurrence for at least 3 years 
may participate in the study.
[26] have a current or recent clinically serious viral, bacterial, fungal, or parasitic 
infection, including but not limited to the following:
Note:  A recent viral upper respiratory tract infection or uncomplicated 
urinary tract infection should not be considered clinically serious.
a.
symptomatic herpes zoster infection within 12 weeks of screening.

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b. a history of disseminated/complicated herpes zoster (for example,
multidermatomal involvement, ophthalmic zoster, central nervous system
involvement, or post-herpetic neuralgia).
c.
symptomatic herpes simplex at the time of randomization.
d. active or chronic viral infection from hepatitis B virus (HBV), hepatitis C 
virus (HCV), or human immunodeficiency virus (HIV).
e.
household contact with a person with active tuberculosis (TB) and have
not received appropriate and documented prophylaxis for TB.
f.
evidence of active TB or have previously had evidence of active TB and 
have not received appropriate and documented treatment.
g. clinically serious infection or received intravenous antibiotics for an 
infection, within 4 weeks of randomization.
h. any other active or recent infection within 4 weeks of randomization that, 
in the opinion of the investigator, would pose an unacceptable risk to the 
patient if participating in the study.
[27] have been exposed to a live vaccine within 12 weeks of planned 
randomization or are expected to need/receive a live vaccine during the course 
of the study (with the exception of herpes zoster vaccination).
Note:  All patients who are eligible to receive the herpes zoster vaccine (per 
local guidelines) and who have not received it by screening will be 
encouraged to do so before randomization; vaccination must occur >4 weeks 
before randomization and first dose of investigational product.  Patients will 
be excluded if they were exposed to herpes zoster vaccination within 4 weeks 
of planned randomization.  
[28] have a history of chronic alcohol abuse, IV drug abuse, or other illicit drug 
abuse within 2 years of screening.
[29] presence of significant uncontrolled neuropsychiatric disorder, are clinically 
judged by the investigator to be at risk for suicide, or have a “yes” answer to 
any of the following within the 2 months before Visit 1:
a.
Question 4 (Active Suicidal Ideation with Some Intent to Act, Without 
Specific Plan) on the “Suicidal Ideation” portion of the Columbia Suicide 
Severity Rating Scale (C-SSRS) or
b. Question 5 (Active Suicidal Ideation with Specific Plan and Intent) on the 
“Suicidal Ideation” portion of the C-SSRS or
c.
Any of the suicide-related behaviors (actual attempt, interrupted attempt, 
aborted attempt, preparatory act or behavior) on the “Suicidal Behavior” 
portion of the C-SSRS.

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Note:  A patient does not necessarily have to be excluded if they have 
self-injurious behavior that would be classified as nonsuicidal self-injurious 
behavior.  If this situation arises, the subject should be referred to a 
psychiatrist or appropriately trained professional as indicated.
[30] have donated more than a single unit of blood within 4 weeks of screening or 
intend to donate blood during the course of the study.
Other Exclusions
[31] are unable or unwilling to make themselves available for the duration of the 
study and/or are unwilling to follow study restrictions/procedures, including 
use of data collection devices.
[32] are currently enrolled in any other clinical trial involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study.
[33] have participated in a clinical study involving an investigational product
within the last 30 days.  If the previous investigational product has a long 
half-life (2 weeks or longer), at least 3 months or 5 half-lives (whichever is 
longer) must have passed.
[34] have previously been randomized in this study or any other study 
investigating baricitinib.
[35] are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.
[36] are Lilly or Incyte employees or their designee.
Diagnostic Assessments
[37] have screening electrocardiogram (ECG) abnormalities that, in the opinion of 
the investigator, are clinically significant and indicate an unacceptable risk for 
the patient’s participation in the study.
[38] have evidence of active TB or latent TB
a.
have evidence of active TB, defined in this study as the following:
o
documented by a positive PPD test (≥5 mm induration between 
approximately 48 and 72 hours after application, regardless of 
vaccination history), medical history, clinical features, and abnormal 
chest x-ray at screening.
o
The 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.

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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, 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 for PPD, QuantiFERON-TB Gold test, or T-SPOT TB test but 
must have a chest x-ray at screening.
b. have evidence of untreated/inadequately or inappropriately treated latent 
TB, defined in this study as the following:
o
documented to have a positive PPD test (≥5 mm induration between 
approximately 48 and 72 hours after application, regardless of 
vaccination history), no clinical features consistent with active TB, and 
a chest x-ray with no evidence of active TB at screening; or 
o
PPD test is positive, and if 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
o
QuantiFERON-TB Gold test or T-SPOT TB test (as available and if 
compliant with local TB guidelines) may be used instead of the PPD 
test.  If the test results are positive, the patient will be considered to 
have latent TB.  If the test is not negative, the test may be repeated 
once within approximately 2 weeks of the initial value.  If the repeat 
test results are again not negative, the patient will be considered to 
have latent TB (for purposes of this study).
Exception:  Patients who have evidence of latent TB may be enrolled if he 
or she completes at least 4 weeks of appropriate treatment before 
randomization and agrees to complete the remainder of treatment while in 
the trial.
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, 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 for PPD, QuantiFERON-TB Gold test, or T-SPOT TB test but 
must have a chest x-ray at screening.
[39] have a positive test for HBV infection, defined as:
a.
positive for hepatitis B surface antigen, or
b. positive for hepatitis B core antibody (HBcAb) and positive HBV DNA.

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Note:  Patients who are HBcAb positive and HBV DNA negative may be 
enrolled in the study. Patients who meet these criteria at screening will be 
identified by the central laboratory and monitored during the study.
[40] have HCV infection (positive for anti-hepatitis C antibody with confirmed 
presence of HCV 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.
[41] have evidence of HIV infection and/or positive HIV antibodies.
[42] have screening laboratory test values, including thyroid-stimulating hormone 
(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.
Note:  Patients who are receiving thyroxine as replacement therapy may 
participate in the study provided stable therapy has been administered for 
≥12 weeks and TSH is within the laboratory’s reference range.  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.
[43] have any of the following specific abnormalities on screening laboratory tests:
a.
AST or ALT ≥2 × upper limit of normal (ULN)
b. alkaline phosphatase (ALP) ≥2 × ULN
c.
total bilirubin ≥1.5 × ULN
d. hemoglobin <10.0 g/dL (100.0 g/L)
e.
total white blood cell count <2500 cells/µL (<2.50 × 103/µL or 
<2.50 GI/L)
f.
neutropenia (absolute neutrophil count <1200 cells/µL) (<1.20 × 103/µL 
or <1.20 GI/L)
g. lymphopenia (lymphocyte count <750 cells/µL) (<0.75 × 103/µL or 
<0.75 GI/L)
h. thrombocytopenia (platelets <100,000/µL) (<100 × 103/µL or <100 GI/L)
i.
estimated glomerular filtration rate <60 mL/min/1.73 m2 (Chronic Kidney 
Disease Epidemiology Collaboration equation Creatinine 2009 equation).
Note: For cases with any of the aforementioned laboratory abnormalities
(Exclusion Criteria [42] and [43]), the tests may be repeated during screening, 
and values resulting from repeat testing may be accepted for enrollment 
eligibility if they meet the eligibility criterion.

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6.3.
Lifestyle Restrictions
Not applicable.
6.4.
Screen Failures
Patients who are entered into the study but do not meet the eligibility criteria for participation in 
this study (screen failure) may be rescreened a maximum of 2 times.  If patients are rescreened, 
rescreening cannot occur until at least 4 weeks after the date of their previous screen failure.  
When rescreening is performed, the individual must sign a new ICF and will be assigned a new 
identification number. Additionally, all necessary screening procedures must be conducted at 
rescreen to ensure all eligibility criteria are met.

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7. Treatments
7.1.
Treatments Administered
This study involves a comparison of placebo, baricitinib 1-mg, and baricitinib 2-mg administered 
orally QD.  Table JAIW.3 shows the treatment regimens.
Table JAIW.3.
Treatment Regimens
Regimen
Investigational Product Supplied
Dose
Baricitinib 2–mg QD
Baricitinib 2-mg tablets
2 tablets per day
Placebo to match 1-mg tablets
Baricitinib 1–mg QD
Baricitinib 1-mg tablets
2 tablets per day
Placebo to match 2-mg tablets
Placebo QD
Placebo to match 2-mg tablets
2 tablets per day
Placebo to match 1-mg tablets
Abbreviation:  QD = once daily.
The investigator or his or her designee is responsible for the following:

explaining the correct use of the investigational agent(s) to the patient

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

returning all unused medication to Lilly or its designee at the end of the study,
unless the sponsor and sites have agreed all unused medication is to be destroyed 
by the site, as allowed by local law
7.1.1.
Packaging and Labeling
The sponsor (or its designee) will provide the following investigational products:

tablets containing 2-mg of baricitinib (Bottle A)

tablets containing 1-mg of baricitinib (Bottle B)

placebo tablets to match baricitinib 2-mg tablets (Bottle A)

placebo tablets to match baricitinib 1-mg tablets (Bottle B)
Baricitinib 1-mg and 2-mg tablets and packaging will be identical in appearance to the respective 
placebo tablets to maintain the blind.  
Investigational product tablets will be provided in bottles. Clinical trial materials will be labeled 
according to the country’s regulatory requirements, and the double-blind label will include the 
designation A or B on the front panel.  Patients will be instructed to take 1 tablet from bottle 
A and 1 tablet from bottle B each day for blinded dosing.

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7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized in a 1:1:1 ratio (placebo, 
baricitinib 1-mg, or baricitinib 2-mg) to double-blind treatment at Visit 2 (Week 0).  
Randomization will be stratified by geographic region (North America, rest-of-world) if the 
planned country allocation justifies and disease severity at baseline (IGA 3 versus 4). 
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, 
each containing double-blind investigational product tablets to each patient, starting at Visit 2 
(Week 0), and at visits per the Schedule of Activities (Section 2), up to and including Visit 14
(Week 88).  Site personnel will confirm that they have located the correct bottles by entering a 
confirmation number found on the bottle into the IWRS.
7.2.1.
Selection and Timing of Doses
The investigational product (1 tablet from Bottle A and 1 tablet from Bottle B) should be taken 
QD without regard to food and, if possible, at approximately the same time every day, usually at 
the start of the patient’s day, to aid patient compliance.  
7.3.
Blinding
This is a double-blind study. To preserve the blinding of the study, 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.  Every effort should 
be made to preserve the blind unless there is a compelling reason that knowledge of the specific 
treatment would alter the medical care of the patient.  
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event.  The 
patient’s safety must always be the first consideration in making such a determination.  If a 
patient’s treatment assignment is unblinded, Lilly must be notified immediately.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
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 in the study, the investigator 
must obtain specific approval from a Lilly clinical research physician for the patient to continue 
in the study.
Processes to maintain blinding during the interim analysis conducted by the DMC are described 
in Section 10.3.6.1.

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7.4.
Dosage Modification
Not applicable.
7.5.
Preparation/Handling/Storage/Accountability
All investigational product (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 trial materials.
Follow storage and handling instructions on the investigational product packaging.
7.6.
Treatment Compliance
Patient compliance with study medication will be assessed at each visit during the treatment 
period (Visit 3 through Visit 15) by counting returned tablets.  
A patient will be considered significantly noncompliant if he or she misses more than 20% of the 
prescribed doses of investigational product during the study, unless the patient’s investigational 
product is withheld by the investigator for safety reasons.  Similarly, a patient will be considered 
significantly noncompliant if he or she is judged by the investigator to have intentionally or 
repeatedly taken 20% more than the prescribed amount of medication during the study.
Patients will be counseled by study staff on the importance of taking the investigational product 
as prescribed, as appropriate.
Patients’ compliance will be further defined in the statistical analysis plan (SAP).
7.7.
Concomitant Therapy
All concomitant medication, whether prescription or over the counter, used at baseline and/or
during the course of the study must be recorded on the Concomitant Medication electronic case 
report form (eCRF).  Patients will be instructed to consult the investigator or other appropriate 
study personnel at the site before taking any new medications or supplements during the study.  
For AD therapies permitted as part of rescue therapy, see Section 7.7.3.
7.7.1.
Prohibited Medications and Procedures
Prohibited Medications and Procedures Not Requiring Interruption of Investigational 
Product
The following therapies will not be allowed during the study, unless otherwise specified.  Some 
therapies may be used after completion of Visit 8 (Week 16), as outlined below.

TCS, TCNIs (for example, tacrolimus and pimecrolimus), or topical PDE-4 inhibitor 
(that is, crisaborole) are not allowed, except when given as rescue therapy as described in 
Section 7.7.3. Low-potency TCS is allowed after Week 16 (see Section 7.7.2).

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
Topical antihistamines or sedating, systemic antihistamines including but not limited to 
alimemazine, chlorphenamine, clemastine, cyproheptadine, diphenhydramine, 
hydroxyzine, ketotifen, and promethazine are not allowed before Week 16 (Visit 8).

Leukotriene inhibitors (for example, montelukast [Singulair®], zafirlukast [Accolate], 
and zileuton [Zyflo®]) are not allowed before Week 16 (Visit 8).

Allergen immunotherapy is not allowed in the study.

Phototherapy, including PUVA (psoralen and ultraviolet A), ultraviolet B, tanning booth,
and excimer laser, is not allowed in the study.

Bleach baths are not allowed in the study.
Prohibited Medications Requiring Temporary Interruption of Investigational Product
The following therapies will not be allowed during the course of the study and, if taken by or 
administered to the patient, temporary interruption of investigational product is required.

Live vaccines (including Bacillus Calmette-Guérin or herpes zoster), (see Exclusion 
Criterion [27])
o
For Bacillus Calmette-Guérin vaccination, investigational product should be 
temporarily interrupted for 12 weeks.
o
For herpes zoster vaccination, investigational product should be temporarily 
interrupted for 4 weeks. 

Probenecid:  If a patient is inadvertently started on probenecid, the investigational 
product should be temporarily interrupted and can be resumed after patient has 
discontinued probenecid. If a patient is not able to discontinue probenecid, then the 
investigational product should be permanently discontinued.

Systemic corticosteroids may be used for the treatment of an AE (for example, worsening 
of existing condition, such as asthma flare) after Visit 8 (Week 16). Investigational 
product may be restarted if systemic corticosteroids were used for a short duration 
(<30 days). If used for >30 days, sponsor approval to restart investigational product is 
required.  
Prohibited Medications Requiring Permanent Discontinuation of Investigational Product

Systemic corticosteroids are not allowed before Visit 8 (Week 16), and if used it will be 
considered rescue therapy, and investigational product should be discontinued (see 
Section 7.7.3). Systemic corticosteroids may not be used to treat AD, before or after 
Week 16.

Any systemic therapy, investigational or commercial (approved or off-label use), used for 
the treatment of AD or symptoms of AD (except for antihistamines, as specified above) is 
not allowed.

Other JAK inhibitors (for example, tofacitinib and ruxolitinib) are not allowed.

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
Systemic immunosuppressive/immunomodulatory substances, including but not limited 
to cyclosporine, methotrexate, mycophenolate mofetil, interferon γ, azathioprine, or 
biologic agents are not allowed.
7.7.2.
Permitted Medications and Procedures
Treatment with concomitant AD therapies during the study is permitted only as described below.

Daily use of emollients is required as background treatment.  Moisturizers with 
additives such as antipruritics or antiseptics are not permitted.  If daily 
applications are missed, it will not be considered a protocol violation.
o
Patients should not apply emollients on the day of their study visit before study 
procedures to allow adequate assessment of skin dryness.

For those patients on stable dosing of prescription sleep medications at entry, 
downward dose adjustments or discontinuation of treatment may occur during the 
study.

Nonsedating antihistamines including but not limited to acrivastine, bilastine, 
cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, mizolastine, and 
rupatadine are allowed.

Intra-articular or soft tissue (bursa, tendons, and ligaments) corticosteroid 
injection:  No more than 1 intra-articular or soft tissue (bursa, tendons, and 
ligaments) corticosteroid injection is allowed up until Week 16 (Visit 8).  After 
Week 16, such injections are permitted.  

Intranasal or inhaled steroid use is allowed.

Topical anesthetics and topical and systemic anti-infective medications are 
allowed.

Nonlive seasonal vaccinations and/or emergency vaccination, such as rabies or 
tetanus vaccinations, are allowed.

Low-potency TCS (for example, hydrocortisone 2.5% ointment) is permitted after 
Week 16 (Visit 8).
Any changes of these concomitant medications must be recorded in the Concomitant Therapy of 
Special Interest eCRF.
Treatment with concomitant therapies for other medical conditions such as diabetes and 
hypertension is permitted during the study.
7.7.3.
Rescue Therapy
Rescue therapy is only available during the first 16 weeks of treatment.
Criteria for Rescue Therapy Initiation 
Investigators should attempt to manage patients with emollients; however, investigators are
allowed to rescue patients who are experiencing unacceptable or worsening symptoms of AD at 

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any time before primary endpoint assessment at Visit 8 (Week 16).  Before rescue, it is 
recommended that increased frequency of emollient use is attempted to at least twice a day or 
more in an effort to control symptoms.  The rationale for rescue will be documented.  All rescued 
patients will be considered nonresponders at Week 16 and will be discontinued from the study.  
Patients may be eligible to enroll in the open-label extension.
After Week 16 patients are allowed to use low-potency TCS if needed as described below.  
Choice of Rescue Therapy Treatment before Week 16

Triamcinolone 0.1% cream and/or hydrocortisone 2.5% ointment.  Where possible, both 
of these treatments will be supplied by the sponsor.  In the event where providing 1 or 
both of these topical formulations is not possible, an alternate, equivalent-potency TCS 
cream and/or ointment may be provided by the sponsor.  TCS use, supplied by the 
sponsor, should be recorded via weight of returned tubes as indicated in the Schedule of 
Activities (Section 2).  
o
In the event that the sponsor is unable to supply TCS, commercially available 
triamcinolone 0.1% cream and/or hydrocortisone 2.5% ointment may be supplied 
by the sites. Where providing triamcinolone 0.1% cream and/or hydrocortisone 
2.5% ointment is not possible, an equivalent-potency TCS cream and/or ointment 
that is in line with local practices can be supplied. Refer to Appendix 8 for 
guidance on potency equivalence.  
o
If the TCS supplied by the sponsor is not considered suitable for an individual 
patient, an equivalent-potency TCS cream and/or ointment that is in line with 
local practices can be supplied by the sites. Refer to Appendix 8 for guidance on 
potency equivalence.

Investigators may also elect to use TCNIs and/or crisaborole where approved, 
with or without TCS.  If TCNIs are prescribed, use should be limited to problem 
areas only (for example, face, neck, skin folds, genital areas).

On the days of study visits, topical therapy should not be applied before the patient has 
undergone all study procedures and clinical evaluations to allow adequate assessment of 
skin dryness.

Patients rescued to topical therapy will continue to take investigational product, 
and use of rescue therapy will be documented in the eCRF.
During the first 16 weeks of the treatment period, in patients who do not improve sufficiently 
with the provided rescue topical therapy after 7 days, a higher-potency TCS may be used (see 
Appendix 8), and investigational product may continue.  It is recommended that if a patient 
reaches “clear” to “almost clear” skin after topical rescue, then medium- and/or high-potency 
TCS and TCNI should be stopped, and low-potency TCS (for example, hydrocortisone 2.5% 
ointment) should be used QD for an additional 7 days, then stopped.  If lesions return, patients 
can be retreated with TCS with or without TCNIs and/or crisaborole as before, at the discretion 
of the investigator.

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If topical rescue therapy as described above fails to sufficiently control AD symptoms, then oral 
systemic medications may be used as rescue (for example, corticosteroids, cyclosporine, 
methotrexate); however, investigational product will be required to be permanently discontinued, 
and the patient will be discontinued from the study after assessment of the primary endpoint at 
Week 16.
Investigators should make every attempt to conduct efficacy and safety assessments immediately 
before administering any rescue treatment. An unscheduled visit can be used for this purpose if 
necessary.  All patients requiring rescue during the first 16 weeks of the study will be considered 
nonresponders for the primary endpoint at Visit 8 (Week 16), will have to be discontinued from 
the study at Week 16, and may be eligible to enroll into the open-label Study JAIX.
Rescue Therapy after Week 16
No rescue therapies are allowed after Week 16.
Only patients who achieved an IGA score of 0 or 1 at Week 16 will remain in the study beyond 
Week 16.  After Week 16, if patients experience worsening of their AD the use of low-potency 
TCS (for example, hydrocortisone 2.5% ointment) is permitted as concomitant therapy.  If after 
starting low-potency TCS a patient reaches clear or almost clear skin, TCS should be 
discontinued.  If lesions return, patients can be retreated with low-potency TCS.  
Patients requiring more than low-potency TCS will be considered nonresponders and will be 
discontinued from the study.  The use of TCNIs or crisaborole is not allowed after Week 16.
7.8.
Treatment after the End of the Study
7.8.1.
Continued Access
After the conclusion of the study, continued access to baricitinib will not be provided to patients.  
Patients will be referred to their local treatment centers for AD therapy as clinically indicated.

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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1.
Temporary Interruption from Investigational Product
In some circumstances, it may be necessary to temporarily interrupt treatment as a result of AEs
or abnormal laboratory values that may have an unclear relationship to investigational product.  
For example, investigational product should be temporarily interrupted if the patient experiences 
a cardiovascular AE considered to be related to study treatment, is graded as moderate (Grade 2
according to Common Terminology Criteria for Adverse Events Version 3.0), and that does not 
resolve promptly with supportive care.  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 JAIW.4.  
For the abnormal laboratory findings and clinical events (regardless of relatedness) listed in 
Table JAIW.4, specific guidance is provided for temporarily interrupting treatment and 
determining 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 JAIW.4 may be restarted at the discretion of 
the investigator.
Table JAIW.4.
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 × 103/µL or <2.00 GI/L)
WBC count 2500 cells/µL
(≥2.50 × 103/µL or ≥2.50 GI/L)
ANC <1000 cells/L
(<1.00 × 103/µL or <1.00 GI/L)
ANC ≥1200 cells/µL
(≥1.20 × 103/µL or ≥1.20 GI/L)
Lymphocyte count <500 cells/µL
(<0.50 × 103/µL or <0.50 GI/L)
Lymphocyte count 750 cells/µL
(≥0.75 × 103/µL or ≥0.75 GI/L)
Platelet count <75,000/µL
(<75 × 103/µL or <75 GI/L)
Platelet count 100,000/µL
(≥100 × 103/µL or ≥100 GI/L)
eGFR <50 mL/min/1.73 m2 (from serum creatinine) 
eGFR 60 mL/min/1.73 m2
ALT or AST >5 × ULN
ALT and AST return to <2 × 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
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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For specific guidance on temporary interruption of investigational product after use of a 
prohibited medication, please refer to Section 7.7.1.
Lastly, investigational product should be temporarily interrupted for suicidal ideation or any 
suicide-related behaviors as assessed by the following patient responses on the C-SSRS:  

A “yes” answer to Question 4 (Active Suicidal Ideation with Some Intent to Act, Without 
Specific Plan) or

A “yes” answer to Question 5 (Active Suicidal Ideation with Specific Plan and Intent) on 
the “Suicidal Ideation” portion of the C-SSRS or

A “yes” answer to any of the suicide-related behaviors (actual attempt, interrupted 
attempt, aborted attempt, preparatory act or behavior) on the “Suicidal Behavior” portion 
of the C-SSRS.  
Note:  Before resumption of investigational product, it is recommended that a patient be 
assessed by a psychiatrist or appropriately trained professional to assist in deciding whether 
the patient should remain on investigational product and ultimately continue participation in 
the study.  A patient does not necessarily have to have investigational product interrupted if 
they have self-injurious behavior that would be classified as non-suicidal self-injurious 
behavior.  
8.1.2.
Permanent Discontinuation from Investigational Product
Investigational product should be permanently discontinued if the patient requests to discontinue 
investigational product.
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a patient meets 1 of the following conditions after consultation with the 
Lilly-designated medical monitor:

ALT or AST >8 × ULN

ALT or AST >5 × ULN for >2 weeks

ALT or AST >3 × ULN and total bilirubin level (TBL) >2 × ULN or 
international normalized ratio >1.5

ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, and/or rash

ALP >3 × ULN

ALP >2.5 × ULN and TBL >2 × ULN

ALP >2.5 × ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, and/or rash
Note:  Patients who are discontinued from investigational product because of a 
hepatic event or liver test abnormality should have additional hepatic safety data 
collected via the hepatic safety eCRF.

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Investigational product should be permanently discontinued if any of the following laboratory 
abnormalities are observed:

white blood cell count <1000 cells/µL (1.00 × 103/µL or 1.00 GI/L)

absolute neutrophil count <500 cells/µL (0.50 × 103/µL or 0.50 GI/L)

lymphocyte count <200 cells/µL (0.20 × 103/µL or 0.20 GI/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 JAIW.4) 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 (except for successfully treated basal or squamous cell skin 
carcinoma)

HBV DNA is detected with a value above limit of quantitation or 2 sequential 
tests return a value below the limit of quantitation (see Section 9.4.8)

certain prohibited medications are taken per Section 7.7.1

development of a VTE 
Note:  Patients who develop a VTE may have additional follow-up and testing 
recommended (see Section 9.4.10. and Appendix 6).
If a patient develops multiple risk factors for a VTE during the conduct of the study as described 
in Exclusion Criterion [23], the investigator may consider study discontinuation if he/she 
believes the risk outweighs the benefits of continuing therapy.  It is recommended that the 
investigator consult with Lilly (or its designee) before discontinuing therapy for this reason.  
If a patient discontinues investigational product for any reason, the patient is encouraged to
remain in the study through Week 16 (Visit 8) and follow the regular visit schedule to provide 
the primary efficacy and safety data.  Patients discontinuing from the investigational product 
prematurely for any reason should complete AE and other follow-up procedures per Section 2
(Schedule of Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety) of this protocol.

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8.1.3.
Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the patient to continue on 
study treatment.  If the investigator and the sponsor clinical research physician agree it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
sponsor clinical research physician to allow the inadvertently enrolled patient to continue in the 
study with or without treatment with investigational product. Safety follow up is as outlined in 
Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety) of this 
protocol.
8.2.
Discontinuation from the Study
Patients may choose to withdraw from the study for any reason at any time, and the reason for 
early withdrawal will be documented.
Some 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

participation in the study needs to be stopped for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and good clinical 
practice

investigator decision
o
The investigator decides that the patient should be discontinued from the 
study.
o
If the patient, for any reason, requires treatment with another therapeutic 
agent (not allowed as part of rescue therapy [Section 7.7.3]) that has been 
demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs before introduction of the new 
agent.

patient decision
o
The patient requests to be withdrawn from the study.
Patients discontinuing from the study prematurely for any reason should complete AE and other 
safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety) of this protocol.
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.

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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 and Appendix 4 list the laboratory tests that will be performed for this study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1.
Primary Efficacy Assessments
Eczema Area and Severity Index scores
The EASI assesses extent of disease at 4 body regions and measures 4 clinical signs: 
(1) erythema, (2) induration/papulation, (3) excoriation, and (4) lichenification, each on a scale 
of 0 to 3. The EASI confers a maximum score of 72. The EASI evaluates 2 dimensions of AD: 
disease extent and clinical signs (Hanifin et al. 2001).  
9.1.2.
Secondary Efficacy Assessments
9.1.2.1.
Validated Investigator’s Global Assessment for Atopic Dermatitis (vIGA-
AD)
The IGA used in this study, the vIGA-AD (referred to as the IGA throughout the protocol), measures 
the IGA of the patient’s overall severity of their AD, on the basis of a static, numeric 5-point 
scale from 0 (clear skin) to 4 (severe disease).  The score is based on an overall assessment of the 
degree of erythema, papulation/induration, oozing/crusting, and lichenification.
9.1.2.2.
Eczema Area and Severity Index scores
The EASI assesses extent of disease at 4 body regions and measures 4 clinical signs: 
(1) erythema, (2) induration/papulation, (3) excoriation, and (4) lichenification, each on a scale 
of 0 to 3. The EASI confers a maximum score of 72. The EASI evaluates 2 dimensions of AD: 
disease extent and clinical signs (Hanifin et al. 2001).  
BSA affected by AD will be derived from data collected as part of the EASI assessment.
9.1.2.3.
SCORing Atopic Dermatitis
The SCORing Atopic Dermatitis (SCORAD index uses the rule of nines to assess disease extent 
and evaluates 6 clinical characteristics to determine disease severity: (1) erythema, 
(2) edema/papulation, (3) oozing/crusts, (4) excoriation, (5) lichenification, and (6) dryness. The 
SCORAD index also assesses subjective symptoms of pruritus and sleep loss. These 3 aspects 
(extent of disease, disease severity, and subjective symptoms) combine to give a maximum 
possible score of 103 (Stalder et al. 1993; Kunz et al. 1997; Schram et al. 2012).

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9.1.2.4.
Hospital Anxiety Depression Scale
The Hospital Anxiety Depression Scale (HADS) is a 14-item self-assessment scale that 
determines the levels of anxiety and depression that a patient is experiencing over the past week.
The HADS utilizes a 4-point Likert scale (for example, 0 to 3) for each question and is intended 
for ages 12 to 65 years (Zigmond and Snaith 1983; White et al. 1999).  Scores for each domain 
(anxiety and depression) can range from 0 to 21, with higher scores indicating greater anxiety or 
depression (Zigmond and Snaith 1983; Snaith 2003).
9.1.3.
Health Outcomes and Quality-of-Life Measures
The patient self-reported questionnaires will be administered via either an electronic patient diary 
or via an electronic tablet.  Questionnaires will have been translated into the native language of 
the country and/or region and linguistically validated.
9.1.3.1.
Patient-Oriented Eczema Measure
The POEM is a simple, 7-item, patient-administered scale that assesses disease severity in 
children and adults.  Patients respond to questions about the frequency of 7 symptoms (itching, 
sleep disturbance, bleeding, weeping/oozing, cracking, flaking, and dryness/roughness) over the 
last week.  Response categories include “No days,” “1-2 days,” “3-4 days,” “5-6 days,” and 
“Every day,” with corresponding scores of 0, 1, 2, 3, and 4, respectively.  Scores range from 0-28 
with higher total scores indicating greater disease severity (Charman et al. 2004).
9.1.3.2.
Itch Numeric Rating Scale
The Itch Numeric Rating Scale (NRS) is a patient-administered, 11-point horizontal scale 
anchored at 0 and 10, with 0 representing “no itch” and 10 representing “worst itch imaginable.”  
Overall severity of a patient’s itching is indicated by selecting the number that best describes the 
worst level of itching in the past 24 hours (Naegeli et al. 2015; Kimball et al. 2016).
9.1.3.3.
Atopic Dermatitis Sleep Scale
The Atopic Dermatitis Sleep Scale (ADSS) is a 3-item, patient-administered questionnaire 
developed to assess the impact of itch on sleep including difficulty falling asleep, frequency of 
waking, and difficulty getting back to sleep the previous night.  Patient’s rate their difficulty 
falling asleep and difficulty getting back to sleep, items 1 and 3, respectively, using a 5-point 
Likert-type scale with response options ranging from 0 “not at all” to 4 “very difficult.”  Patients 
report their frequency of waking the previous night, item 2, by selecting the number of times 
they woke up each night, ranging from 0 to 29 times.  The ADSS is designed to be completed 
each day with respondents thinking about sleep “last night.” Each item is scored individually.  
9.1.3.4.
Skin Pain Numeric Rating Scale
Skin Pain NRS is a patient-administered, 11-point horizontal scale anchored at 0 and 10, with 
0 representing “no pain” and 10 representing “worst pain imaginable.” Overall severity of a 
patient’s skin pain is indicated by selecting the number that best describes the worst level of skin 
pain in the previous 24 hours.

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9.1.3.5.
Patient Global Impression of Severity
The Patient Global Impression of Severity–Atopic Dermatitis (PGI-S-AD) is a single-item 
question asking the patient how they would rate their overall AD symptoms over the past 
24 hours.  The 5 categories of responses range from “no symptoms” to “severe.”
9.1.3.6.
Dermatology Life Quality Index
The Dermatology Life Quality Index (DLQI) is a simple, patient-administered, 10-item, 
validated, quality-of-life questionnaire that covers 6 domains including symptoms and feelings, 
daily activities, leisure, work and school, personal relationships, and treatment. The recall period 
of this scale is over the “last week.” Response categories include “not at all,” “a little,” “a lot,” 
and “very much,” with corresponding scores of 0, 1, 2, and 3, respectively, and unanswered (“not 
relevant”) responses scored as 0 as applicable. Scores range from 0-30 with higher scores 
indicating greater impairment of quality of life. A DLQI total score of 0 to 1 is considered as 
having no effect on a patient’s health-related quality of life (Hongbo et al. 2005), and a 4-point 
change from baseline is considered as the minimal clinically important difference threshold 
(Khilji et al. 2002; Basra et al. 2015).
9.1.3.7.
European Quality of Life–5 Dimensions–5 Levels
The European Quality of Life–5 Dimensions–5 Levels (EQ-5D-5L) is a standardized measure of 
health status that provides a simple, generic measure of health for clinical and economic 
appraisal.  The EQ-5D-5L consists of 2 components:  a descriptive system of the respondent’s 
health and a rating of his or her current health state using a 0 to 100 mm Visual Analog Scale 
(VAS).  The descriptive system comprises the following 5 dimensions:  mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression.  Each dimension has 5 levels:  no problems, 
slight problems, moderate problems, severe problems, and extreme problems.  The respondent is 
asked to indicate his or her health state by checking in the box associated with the most 
appropriate statement in each of the 5 dimensions.  It should be noted that the numerals 1 to 
5 have no arithmetic properties and should not be used as an ordinal score.  The VAS records the 
respondent’s self-rated health on a vertical VAS where the endpoints are labeled “best 
imaginable health state” and “worst imaginable health state.”  This information can be used as a 
quantitative measure of health outcome.  The EQ-5D-5L health states, defined by the EQ-5D-5L 
descriptive system, may be converted into a single summary index by applying a formula that 
essentially attaches values (also called weights) to each of the levels in each dimension 
(Herdman et al. 2011; EuroQol Group 2015 [WWW]).
9.1.3.8.
Work Productivity and Activity Impairment Questionnaire–Atopic 
Dermatitis
The Work Productivity and Activity Impairment Questionnaire–Atopic Dermatitis (WPAI-AD) 
records impairment due to AD during the past 7 days.  The WPAI-AD consists of 6 items 
grouped into 4 domains: absenteeism (work time missed), presenteeism (impairment at 
work/reduced on-the-job effectiveness), work productivity loss (overall work 
impairment/absenteeism plus presenteeism), and activity impairment. Scores are calculated as 
impairment percentages (Reilly et al. 1993), with higher scores indicating greater impairment 
and less productivity.

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9.1.4.
Appropriateness of Assessments
All assessments utilized in this study are standard, widely used, and generally recognized as 
reliable, accurate, and relevant with the exception of ADSS and Skin Pain NRS, which are 
currently being developed and validated according to regulatory guidances.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed, study site personnel will record via eCRF the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs. Investigators should record their assessment of the 
potential relatedness of each AE to investigational product, via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.  
A “reasonable possibility” means that there is a cause-and-effect relationship between the 
investigational product, study device, and/or study procedure and the AE.  
The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF, clarifying if possible the circumstances leading 
to any dosage modifications, or discontinuations of treatment.
9.2.1.
Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following outcomes:

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
death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention 
to prevent 1 of the other outcomes listed in the definition above.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug 
abuse.
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  The SAE reporting to the sponsor begins after the patient has signed the ICF and has 
received investigational product.  However, if an SAE occurs after signing the ICF, 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 
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 
hepatic safety eCRF.
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements, any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he or 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 Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs. Lilly has procedures that will be followed for the recording 

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and expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidances.
9.2.2.
Adverse Events of Special Interest
AEs of special interest will include the following:

infections (including TB, herpes zoster, or opportunistic infections)

malignancies

hepatic events (see Section 9.4.9)

major adverse cardiovascular events (MACE) (see Section 9.4.11)

thrombotic events (such as deep vein thrombosis and pulmonary embolism) (see 
Section 9.4.10).
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 to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
Refer to the IB.
9.4.
Safety
Any clinically significant findings from 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 study treatment 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 Visit 1 and read by a qualified 
physician (the investigator or qualified designee) at the site to determine whether the patient 
meets entry criteria.
ECGs may be obtained at additional times, when deemed clinically necessary.
9.4.2.
Vital Signs
For each patient, vital signs should be measured according to the Schedule of Activities 
(Section 2).

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9.4.3.
Physical Exam
For each patient, a complete physical examination (excluding pelvic and rectal examinations) 
will be performed at Visit 1 (Screening).  A symptom-directed physical examination will be 
performed at other visits as specified in the Schedule of Activities (Section 2).  A complete
physical examination may be repeated at the investigator’s discretion at any time a patient 
presents with physical complaints.
9.4.4.
Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). With the exception of laboratory test results that may unblind 
the study, Lilly or its designee will provide the investigator with the results of laboratory tests 
analyzed by a central vendor, if a central vendor is used for the clinical trial.
9.4.5.
Columbia Suicide Severity Rating Scale
The C-SSRS captures the occurrence, severity, and frequency of suicidal ideation and/or 
behavior during the assessment period.  The scale includes suggested questions to solicit the type 
of information needed to determine if suicidal ideation and/or behavior occurred.  The C-SSRS is 
administered by an appropriately trained health care professional with at least 1 year of patient 
care/clinical experience.  The tool was developed by the National Institute of Mental Health trial 
group for the purpose of being a counterpart to the Columbia Classification Algorithm of Suicide 
Assessment categorization of suicidal events.  For this study, the scale has been adapted (with 
permission from the scale authors) to include only the portion of the scale that captures the 
occurrence of the 11 preferred ideation and behavior categories.
The nonleading AE collection should occur before the collection of the C-SSRS. If a 
suicide-related event is discovered during the C-SSRS but was not captured during the 
nonleading AE collection, sites should not change the AE form. If an event is serious or leads to 
discontinuation, this is an exception, and the SAE and/or AE leading to discontinuation should 
be included on the AE form, and the process for reporting SAEs should be followed.
9.4.6.
Self-Harm and Follow-Up Supplement Forms
Suicide-related events (behavior and/or ideations) will be assessed and evaluated at every visit 
with the administration of the C-SSRS and the Self-Harm Supplement Form.  The Self-Harm 
Supplement Form is a single question to enter the number of suicidal behavior events, possible 
suicide behaviors, or nonsuicidal self-injurious behaviors.  If the number of behavioral events is 
greater than zero, it will lead to the completion of the self-harm follow-up form.  The self-harm 
follow-up form is a series of questions that provides a more detailed description of the behavior 
cases.
9.4.7.
Chest X-Ray and Tuberculosis Testing
A posterior–anterior view chest x-ray will be obtained locally at screening (Visit 1), unless 
results from a chest x-ray obtained within 6 months before the study are available.  The chest 
x-ray will be reviewed by the investigator or his or her designee to exclude patients with active 

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TB infection.  In addition, patients will be tested at screening (Visit 1) for evidence of active or 
latent TB as described in the exclusion criteria, Section 6.2.
Investigators should follow local guidelines for monitoring patients for TB if a patient is at high 
risk for acquiring TB or reactivation of latent TB.
9.4.8.
Hepatitis B Virus DNA Monitoring
Patients who are HBcAb positive and HBV DNA negative (undetectable) at Visit 1 will require 
measurement of HBV DNA per Schedule of Activities, regardless of their hepatitis B surface 
antibody 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 as specified in the Schedule of 
Activities (Section 2).

If the patient has 2 or more test results with a value “below limit of quantitation”
or a test result above the limit of quantitation, the patient will be permanently 
discontinued from investigational product (see Section 8.1.2) and should be 
referred to a hepatology specialist.  
9.4.9.
Hepatic Safety Monitoring and Data Collection
If a study patient experiences elevated ALT ≥3 × ULN, ALP ≥2 × ULN, or elevated TBL 
≥2 × 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 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.
Criteria for discontinuation 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:

elevation of serum ALT to ≥5 × ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2 × ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2 × ULN on 2 or more consecutive blood tests

patient discontinued from treatment due to a hepatic event or abnormality of liver 
tests

hepatic event considered to be an SAE

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See Appendix 4 and Appendix 5 for a description of hepatic laboratory values that warrant 
patient exclusion from the study, temporary or permanent discontinuation of investigational 
product, or additional safety collection via the hepatic eCRF.
9.4.10. VTE Assessment
If a patient develops the signs and symptoms of a deep vein thrombosis or pulmonary embolism, 
appropriate local laboratory tests and imaging should be performed, as necessary, for diagnosis 
of the event.  For confirmed cases, additional laboratory testing should be performed as outlined 
in Appendix 6. All suspected VTE events will be independently adjudicated by a blinded 
Clinical Event Committee (see Section 10.3.6.3).
9.4.11. 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 (an advisory group for this study formed to protect 
the integrity of data [refer to Interim Analyses section, Section 10.3.6]) can conduct additional 
analyses of the safety data.
The Lilly clinical research physician 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
trial. These reports will be reviewed to ensure completeness and accuracy but will not be
unblinded to Lilly during the clinical trial.  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 trial and minimize any potential for bias
while providing for appropriate safety monitoring.
Investigators will monitor vital signs and carefully review findings that may be associated with 
cardiovascular and VTEs. AE reports and vital signs will be collected at each study visit. The 
cardiovascular monitoring plan includes the following:

regular monitoring of lipid levels

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
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), VTEs, 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.
9.5.
Pharmacokinetics
Not applicable.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Pharmacogenetics
9.7.1.
Blood Samples for Pharmacogenetic Research
A 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, 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 only be used for investigations related to 
disease and drug or class of drugs under study in the context of this clinical program.
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to baricitinib and to 
investigate genetic variants thought to play a role in AD or other inflammatory skin diseases.  
Assessment of variable response may include evaluation of AEs or differences in efficacy.
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 site personnel.
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and/or (ethical review boards/investigational review 
boards) impose shorter time limits, at a facility selected by Lilly.  This retention period enables 
use of new technologies, response to regulatory questions, and investigation of variable response 
that may not be observed until later in the development of baricitinib or after baricitinib becomes 
commercially available.

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Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome-wide association studies, and candidate gene studies.  Regardless of 
technology utilized, genotyping data generated will be used only for the specific research scope 
described in this section.
9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, 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 AD, mechanism of action of baricitinib, and/or research 
method or in validating diagnostic tools or assay(s) related to AD.
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 site personnel.
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and ethical review boards impose shorter time limits, at a 
facility selected by Lilly.  This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in the development of baricitinib or after baricitinib becomes commercially available.
9.9.
Medical Resource Utilization and Health Economics
Health Economics will be evaluated in this study utilizing the EQ-5D-5L and WPAI-AD (see 
Section 9.1.3).  Medical Resource Utilization parameters will not be evaluated in this study.

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10. Statistical Considerations
10.1. Sample Size Determination
Study JAIW will aim to enroll approximately 450 patients aged ≥18 years.  The proposed sample
size will ensure approximately 68% power to detect any difference between the baricitinib 2-mg
and placebo treatment groups, assuming a 10% placebo and 20% baricitinib 2-mg response rate 
for the primary endpoint EASI75 using a Chi-squared test with a 2-sided ɑ level of 0.05. The 
assumptions are based on what was observed in the Phase 3 monotherapy Studies JAHL and 
JAHM.    
Sample size and power estimates were obtained from nQuery® Advisor 7.0.
10.2. Populations for Analyses
Unless otherwise specified, the efficacy and health outcome analyses will be conducted on the 
intent-to-treat population, defined as all randomized patients, even the patients who do not 
receive the correct treatment or otherwise did not follow the protocol.  Patients will be analyzed 
according to the treatment to which they were assigned.  Significant protocol violations will be 
described in the SAP.
Unless otherwise specified, safety analyses will be performed on all randomized patients who 
receive at least 1 dose of investigational product and who did not discontinue from the study for 
the reason “Lost to Follow-up” at the first postbaseline visit.
Further details of other populations will be described in the SAP.  Patients will be analyzed 
according to the dosing regimen to which they were assigned in the Double-Blinded Treatment 
Period.
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee. A detailed 
SAP describing the statistical methodologies will be developed by Lilly or its designee.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol and the justification for making the change will be described 
in the clinical study report.  Additional exploratory analyses of the data will be conducted as 
deemed appropriate.
All tests of treatment effects will be conducted at a 2-sided ɑ level of 0.05, unless otherwise 
stated. Treatment comparisons of discrete efficacy variables between baricitinib and placebo 
will be made using a logistic regression analysis with IGA baseline disease severity, baseline 
score and treatment group in the model. Region may be added as an additional factor if there is a 
sufficient number of patients for rest-of-world and stratification has not resulted in empty strata. 
This will be finalized in the SAP.  If appropriate, treatment by region interaction may be added 

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to the model of the primary and key secondary variables as a sensitivity analysis.  If this 
interaction is significant at a 2-sided 0.1 level, further inspection will be used to assess whether 
the interaction is quantitative (that is, the treatment effect is consistent in direction but not size of 
effect) or qualitative (the treatment is beneficial for some but not all regions).  The percentages, 
difference in percentages, and 95% CI of the difference in percentages will be reported. The 
p-value from the Fisher’s exact test will also be produced.
When evaluating continuous measures over time, a restricted maximum likelihood-based 
MMRM will be used.  The model will include treatment, baseline disease severity (IGA), 
baseline score, visit, and treatment-by-visit interaction as fixed categorical effects and baseline 
score and baseline score-by-visit interaction as fixed continuous effects. Geographic region may 
be added as an additional factor if appropriate.  An unstructured (co)variance structure will be 
used to model the between- and within-patient errors. If this analysis fails to converge, other 
structures will be tested. The Kenward–Roger method will be used to estimate the degrees of 
freedom. Type III sums of squares for the LSMs will be used for the statistical comparison; 95%
CI will also be reported. Contrasts will be set up within the model to test treatment groups at 
specific time points of interest. Further details on the use of MMRM will be described in the 
SAP.  
Treatment comparisons of continuous efficacy and health outcome variables may also be made 
using ANCOVA with baseline disease severity (IGA), treatment group, and baseline score in the 
model.  Geographic region may be added as an additional factor if appropriate.  Type III tests for 
LSM will be used for statistical comparison between treatment groups.  The LSM difference, 
standard error, p-value, and 95% CI may also be reported.  The method used to handle missing 
data will be specified in the SAP.
Fisher’s exact test will be used for the 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 and baseline value in the model. Shift tables for categorical safety analyses (for 
example, “high” or “low” laboratory results) will also be produced.
Missing Data Imputation:
1. NRI:  All patients who discontinue the study or the study treatment at any time for any 
reason will be defined as nonresponders for the NRI analysis for categorical variables 
such as IGA 0/1 or EASI 50/75/90 after discontinuation and onward.  Patients who 
receive rescue therapy will be analyzed as nonresponders after rescue and onward.  An 
additional analysis will be performed that includes all available data whether rescue 
medication was given or not.
2. Continuous variables such as EASI and SCORAD scores will be assumed to be missing 
after rescue or discontinuation, and then an MMRM analysis will be performed.  An 
additional analysis will be performed that includes all available data whether rescue 
medication was given or not.

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3. Last observed carried forward:An additional analysis will be performed that uses the 
last observed value on or before discontinuation/dropout or rescue therapy.  This will 
then be analyzed using a logistic model for categorical variables or ANCOVA for 
continuous variables as described above.
Additional sensitivityanalyses for the primary and key secondary endpoints such as tipping point 
analyses as well as placebo multiple imputationwill be done.  Details of these methods are in 
Appendix 9,and any changes to these details will be finalized in the SAP.
Adjustment for Multiple Comparisons:
The following is a list of primary and keysecondary hypothesesto be tested:
PrimaryNull Hypothesis: 
 ,,:  Proportion of baricitinib 2-mg patients achieving EASI75is less than or equal to 
the proportion of placebopatientsachievingEASI75at Week 16
Key Secondary Null Hypotheses: 
 ,,:  Proportion of baricitinib 2-mg patients achieving IGA of 0 or 1 and ≥2-point 
improvement from baseline at Week 16is less than or equal to the proportion of placebo
patients achieving IGA of 0 or 1 and ≥2-point improvement from baseline at Week 16
 ,,:  Proportion of baricitinib 2-mg patients achieving EASI90 is less than or equal to 
the proportion of placebopatients achieving EASI90at Week 16
 ,,:  Mean percent change from baseline in EASI score forbaricitinib 2-mg is less 
than or equal to the mean percent change from baseline in EASI score for placebo at 
Week 16
 ,,:  Proportion of baricitinib 2-mg patients achieving SCORAD75is less than or 
equal to the proportion of placebopatients achieving SCORAD75at Week16
 ,,:  Proportion of baricitinib 2-mg patients achieving a 4-point improvement in 
ItchNRSis less than or equal to the proportion of placebopatients achieving a 4-point 
improvement in Itch NRS at Week 16
 ,,
 :  Proportion of baricitinib 2-mg patients achieving a 4-point improvement in 
ItchNRSis less than or equal to the proportion of placebopatients achieving a 4-point 
improvement in Itch NRS at Week 4
 ,,
 :  Proportion of baricitinib 2-mg patients achieving a 4-point improvement in 
ItchNRSis less than or equal to the proportion of placebopatients achieving a 4-point 
improvement in Itch NRS at Week 2
 ,,
 :  Proportion of baricitinib 2-mg patients achieving a 4-point improvement in 
ItchNRSis less than or equal to the proportion of placebopatients achieving a 4-point 
improvement in Itch NRS at Week 1
 , ,:  Mean change from baseline in the score of Item 2of the ADSS forbaricitinib 
2-mg is less than or equal to the mean change from baseline in the score of Item 2of the 
ADSSfor placebo at Week 16
  ,,:  Mean change from baseline in the score of Item 2of the ADSS forbaricitinib 
2-mg is less than or equal to the mean change from baseline in the score of Item 2of the 
ADSS for placebo at Week 1

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 , ,:  Mean change from baseline in Skin Pain NRSforbaricitinib 2-mg is less than or 
equal to the mean change from baseline in Skin Pain NRSfor placebo at Week 16
 ,,:  Proportion of baricitinib 1-mg patients achieving EASI75is less than or equal to 
the proportion of placebopatients achieving EASI75at Week 16
 ,,:  Proportion of baricitinib 1-mg patients achieving IGA of 0 or 1 and ≥2-point 
improvement from baseline at Week 16is less than or equal to the proportion of placebo
patients achieving IGA of 0 or 1 and ≥2-point improvement from baseline at Week 16
 ,,:  Proportion of baricitinib 1-mg patients achieving EASI90 is less than or equal to 
the proportion of placebopatients achieving EASI90at Week 16
 ,,:  Mean percent change from baseline in EASI score forbaricitinib 1-mg is less 
than or equal to the mean percent change from baseline in EASI score for placebo at 
Week 16
 ,,:  Proportion of baricitinib 1-mg patients achieving SCORAD75is less than or
equal to the proportion of placebopatients achieving SCORAD75at Week 16
 ,,:  Proportion of baricitinib 1-mg patients achieving a 4-point improvement in 
ItchNRSis less than or equal to the proportion of placebopatients achieving a 4-point 
improvement in Itch NRS at Week 16
 ,,
 :  Proportion of baricitinib 1-mg patients achieving a 4-point improvement in 
ItchNRSis less than or equal to the proportion of placebopatients achieving a 4-point 
improvement in Itch NRS at Week 4
  ,, :  Proportion of baricitinib 1-mg patients achieving a 4-point improvement in 
ItchNRSis less than or equal to the proportion of placebopatients achieving a 4-point 
improvement in Itch NRS at Week 2
  ,, :  Proportion of baricitinib 1-mg patients achieving a 4-point improvement in 
ItchNRSis less than or equal to the proportion of placebopatients achieving a 4-point 
improvement in Itch NRS at Week 1
 , ,:  Mean change from baseline in the score of Item 2of the ADSS forbaricitinib 
1-mg is less than or equal to the mean change from baseline in the total score of the 
ADSS for placebo at Week 16
  ,,:  Mean change from baseline in the score of Item 2of the ADSS forbaricitinib 
1-mg is less than or equal to the mean change from baseline in the total score of the 
ADSS for placebo at Week 1
 , ,:  Mean change from baseline in Skin Pain NRSforbaricitinib 1-mg is less than or 
equal to the mean change from baseline in Skin Pain NRSfor placebo at Week 16
Multiplicityadjustedanalyses will be performed on theseprimary andkeysecondary null 
hypotheses to control the overall family-wise TypeI error rate at a 2-sided α level of 0.05. The 
graphical multiple testing procedure described in Bretz et al. (2011), whichis a closed testing 
procedure, will be used;therefore,it strongly controls the family-wise error rate across all 
endpoints (Alosh et al. 2014). FigureJAIW.2depicts the graphical testing scheme (including 
testing order, interrelationships, TypeI error allocation, and the associated propagation)and is 
further described inAppendix 10.  Further details of the specific graphical testing scheme 

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(including testing order, interrelationships, Type I error allocation, and the associated 
propagation) will be prespecified and finalized in the SAP.  These details may be revised when 
newer information is obtained on the endpoints that are being tested.  However, the graphical 
testing scheme will be finalized before primary database lock, which will occur after the last 
patient in the study completes Visit 8 (Week 16) or is permanently discontinued from the study.  
Figure JAIW.2.
Study I4V-MC-JAIW scheme structure.
Abbreviations:  H = null hypothesis.
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
All patients who discontinue from the study or the study treatment will be identified, along with 
their reason for discontinuation. Reasons for discontinuation from the study will be summarized 
by treatment group.
10.3.2.2. Patient Characteristics
Demographic and baseline characteristics will be summarized descriptively by treatment group. 
Descriptive statistics including number of patients, mean, standard deviation, median, minimum, 
and maximum will be provided for continuous measures, and frequency counts and percentages 
will be tabulated for categorical measures. No formal statistical comparisons will be made 
among treatment groups unless otherwise stated.

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10.3.2.3. Concomitant Therapy
Concomitant medications will be descriptively summarized by treatment group in terms of 
frequencies and percentages using the safety population. The medications will be coded 
accordingly.
10.3.2.4. Treatment Compliance
Treatment compliance with the randomly assigned study medication will be evaluated at every
clinic visit through the counts of returned investigational product tablets. A patient will be 
considered significantly noncompliant if he or she misses more than 20% of the prescribed doses 
during the study, unless the patients investigational product is withheld by the investigator for 
safety reasons (that is, compliance <80%).  Similarly, a patient will be considered significantly 
noncompliant if he or she is judged by the investigator to have intentionally or repeatedly taken 
more than the prescribed amount of medication (that is, compliance ≥120%).
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary efficacy measure is the categorical outcome of EASI75 at Week 16 for baricitinib 2-
mg.  EASI75 is defined as having an improvement of at least 75% from baseline.  Primary 
analysis will be conducted using a logistic regression as described above with treatment and 
stratification variables, which include baseline disease severity (IGA), baseline score and region, 
as appropriate in the model.  NRI for missing data as described above will be used.
Additional analysis of the primary efficacy outcome will include analyzing the outcome as 
observed, that is, whether rescue medication was given.
10.3.3.2. Secondary Analyses
The following secondary categorical outcomes will be analyzed in a similar manner as the 
primary, that is, using the same logistic regression model.  This applies to both baricitinib 2-mg 
vs placebo, and baricitinib 1-mg vs placebo unless stated otherwise.  NRI will be used for these 
analyses unless otherwise noted.

IGA score of 0 or 1 (clear or almost clear skin) and ≥2-point improvement from 
baseline at Week 16. Besides NRI, this outcome will also be analyzed using 
observed cases, that is, whether rescue medication was given.

EASI75 at Week 16 for baricitinib 1-mg vs placebo. EASI75 is defined as having an 
improvement of at least 75% from baseline.

EASI90 at Week 16.  EASI90 is defined as having an improvement of at least 
90% from baseline.

SCORAD75 at Week 16.  SCORAD75 is defined as having an improvement of at 
least 75% from baseline.

SCORAD90 at Week 16.  SCORAD90 is defined as having an improvement of at 
least 90% from baseline.

4-point improvement in Itch NRS at 1 week, 2 weeks, 4 weeks, and 16 weeks.

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The following continuous measures will be analyzed with the MMRM model described above 
unless otherwise noted. Contrasts within the MMRM model will be used to assess treatment 
differences for time points of interest as specified above in the list of objectives.

Mean change from baseline in the following outcome measures:
o
ADSS Item 2 score
o
EASI score
o
SCORAD score
o
BSA
o
Itch NRS
o
POEM total score
o
PGI-S-AD
o
HADS
o
DLQI total score
o
WPAI-AD
o
EQ-5D-5L
The EASI total score and SCORAD total score will also be analyzed as observed, that is, not 
assuming missing values after rescue medication is given.
10.3.4. Safety Analyses
All safety data will be descriptively summarized by treatment groups and analyzed using the 
safety population.
TEAEs are defined as AEs that first occurred or worsened in severity after the first dose of study 
treatment. The number of TEAEs as well as the number and percentage of patients who 
experienced at least 1 TEAE will be summarized using Medical Dictionary for Regulatory 
Activities for each system organ class (or a body system) and each preferred term by treatment 
group. SAEs and AEs that lead to discontinuation of investigational product will also be 
summarized by treatment group. Fisher’s exact test will be used to perform comparisons 
between each baricitinib dose and the placebo group.
All clinical laboratory results will be descriptively summarized by treatment group. Individual 
results that are outside of 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 by treatment group and analyzed using
ANCOVA with treatment and baseline value in the model. 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.
Observed values and changes from baseline (predose or screening if missing) for vital signs and
physical characteristics will be descriptively summarized by treatment group and time point.  
Change from baseline to postbaseline in vital signs and body weight will be analyzed using 
ANCOVA with treatment and baseline value in the model.

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The incidence and average duration of investigational product interruptions will be summarized 
and compared descriptively among treatment groups. Various techniques may be used to 
estimate the effects of investigational product interruptions on safety measures. Further analyses 
may be performed and will be planned in the SAP.
Data collected after initiation of rescue therapy will be summarized as appropriate.
10.3.5. Other Analyses
10.3.5.1. Health Outcome Measures
The health outcome measures will be analyzed using methods described for continuous or
categorical data as described for efficacy measures in Section 10.3.3.
10.3.5.2. Subgroup Analyses
To assess whether the treatment effect is similar across subgroups for the primary efficacy 
outcome, a logistic model will be used and will include treatment, stratification variables (IGA 
(3,4) at baseline, baseline disease severity and region) as appropriate, the subgroup variable (for 
example, sex), and the subgroup-by-treatment interaction.  If the interaction is statistically 
significant at level of 0.10, the nature of the interaction will be explored, that is, within each 
subgroup the treatment effect will be estimated.  Similarly, for the continuous variables of EASI, 
the MMRM model will include additional variables for subgroup and the subgroup-by-treatment 
interaction.
Subgroups to be evaluated will include geographic region (as appropriate), baseline severity, sex, 
age, race, previous therapy, etc.  Further definitions for the levels of the subgroup variables, the 
analysis methodology, and any additional subgroup analyses will be defined in the SAP. 
Because this study is not powered for subgroup analyses, all subgroup analyses will be treated as 
exploratory.
10.3.6. Interim Analyses
10.3.6.1. Data Monitoring Committee
A DMC will monitor the overall safety 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 compounds.  DMC membership will 
include, at a minimum, specialists with expertise in dermatology, statistics, and other appropriate 
specialties.
The DMC will be authorized to review unblinded results of analyses by treatment group before
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. While 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, no 
information regarding efficacy will be communicated. Moreover, the study will not be stopped 
for positive efficacy results nor will it be stopped for futility. Hence, no ɑ is spent.  Details of 

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the DMC, including its operating characteristics, will be documented in a DMC charter and 
DMC analysis plan.
10.3.6.2. Unblinded Study Team for Early Regulatory Submission
Besides DMC members, a limited number of preidentified individuals may gain access to the 
limited unblinded data, as specified in the unblinding plan, before the interim or final database 
lock to initiate or for preparation of regulatory documents.  The study may be terminated 
prematurely on the basis of futility following the Week 16 interim analysis. Although this is an 
interim analysis with respect to the entire study, it is the only and final analysis for the primary 
and all key secondary endpoints. Therefore, all the ɑ is allocated for this interim analysis only 
and no other ɑ is allocated for other endpoints assessed beyond Week 16.  Information that may 
unblind the study during the analyses will not be reported to study sites or blinded study team 
until the study has been unblinded.
Unblinding details will be specified in a separate unblinding plan document.
10.3.6.3. 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), 
VTEs, and noncardiovascular deaths.  Details of membership, operations, recommendations from 
the Committee, and the communication plan will be documented in the Charter.

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12.
Appendices

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Appendix 1.
Abbreviations and Definitions
Term
Definition
AD
atopic dermatitis
ADSS
Atopic Dermatitis Sleep Scale
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
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received.
BMI
body mass index
BSA
body surface area
C-SSRS
Columbia Suicide Severity Rating Scale
CSR
clinical study report
DLQI
Dermatology Life Quality Index
DMC
data monitoring committee
EASI
Eczema Area and Severity Index
ECG
electrocardiogram
eCOA
electronic clinical outcome assessment
eCRF
electronic case report form
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
Enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ePRO
electronic patient-reported outcome
EQ-5D-5L
European Quality of Life–5 Dimensions–5 Levels
ETV
early termination visit
GCP
good clinical practice
HADS
Hospital Anxiety Depression Scale
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IB
investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IGA
Investigator’s Global Assessment
IL
interleukin
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.

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Investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IWRS
interactive web-response system
JAK
Janus kinase
LSM
least squares mean
MACE
major adverse cardiovascular events
MI
myocardial infarction
MMRM
mixed-effects model of repeated measures
NRI
nonresponder imputation
NRS
Numeric Rating Scale
PDE-4 inhibitor
phosphodiesterase type 4 inhibitor
pMI
placebo multiple imputation
POEM
Patient-Oriented Eczema Measure
PPD
purified protein derivative
QD
once daily
RA
rheumatoid arthritis
SAE
serious adverse event
SAP
statistical analysis plan
SCORAD
SCORing Atopic Dermatitis
SUSAR
suspected unexpected serious adverse reaction
TB
Tuberculosis
TBL
total bilirubin level
TCNI
topical calcineurin inhibitor
TCS
topical corticosteroids
TEAE
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, which does not necessarily have to have a causal relationship 
with this treatment.
TSH
thyroid-stimulating hormone
TSLP
thymic stromal lymphopoietin
TYK2
tyrosine kinase 2
ULN
upper limit of normal
VAS
Visual Analog Scale
vIGA-AD
validated Investigator’s Global Assessment for Atopic Dermatitis
VTE
venous thromboembolic event (deep vein thrombosis or pulmonary embolism)
WPAI-AD
The Work Productivity and Activity Impairment–Atopic Dermatitis

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Appendix 2.
Clinical Laboratory Tests
Hematologya,b
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
Mean cell hemoglobin concentration
Alanine aminotransferase (ALT)
Leukocytes (WBC)
Aspartate aminotransferase (AST)
Platelets
Blood urea nitrogen (BUN)
Absolute counts of:
Creatinine
Neutrophils, segmented
Cystatin C
Neutrophils, juvenile (bands)
Uric acid
Lymphocytes
Calcium
Monocytes
Glucose
Eosinophils
Albumin
Basophils
Total protein
Estimated glomerular filtration rate (eGFR)e
Urinalysisa,b,d
Creatine phosphokinase (CPK)
Color
Specific gravity
Other Testsa
pH
Hepatitis B Surface antigen (HBsAg)f
Protein
Anti-Hepatitis B Core antibody (HBcAb)f
Glucose
HBV DNAk
Ketones
Anti-Hepatitis B Surface antibody (HBsAb)f
Bilirubin
Human immunodeficiency virus (HIV)f
Urobilinogen
Hepatitis C antibodyf,g
Blood
Thyroid-stimulating hormone (TSH)
Leukocyte esterase
Exploratory storage samples (serum, plasma and mRNA)
Nitrite
Pregnancy Testh
Follicle-stimulating hormonef,i
Lipidsa,c
Serum immunoglobulin (IgE)
Total cholesterol
QuantiFERON®-TB Gold or T-SPOT® TB j
Low-density lipoprotein
PPD (local testing)
High-density lipoprotein
Triglycerides
Abbreviations: FSH = follicle-stimulating hormone; HBV = hepatitis B virus; PPD = purified protein derivative;
RBC = red blood cell; TB = tuberculosis; WBC = white blood cell.
a
Assayed by sponsor-designated laboratory.
b
Unscheduled or repeat blood chemistry, hematology, and urinalysis panels may be performed at the discretion of 
the investigator, as needed.
c
Fasting lipid profile. Patients should not eat or drink anything except water for 12 hours prior to test.  If a patient 
attends these visits in a nonfasting state, this will not be considered a protocol violation.
d
Microscopic examination of sediment performed only if abnormalities are noted on the routine urinalysis.

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e
eGFR for serum creatinine calculated by the central laboratory using the Chronic Kidney Disease Epidemiology 
Collaboration Creatinine 2009 equation.
f
Test required at Visit 1 only to determine eligibility of patient for the study.
g
A positive hepatitis C antibody result will be confirmed with an alternate hepatitis C method.
h
For all women of childbearing potential, a serum pregnancy test will be performed at Visit 1 and a local urine 
pregnancy test will be performed at Visit 2 and at all subsequent study visits after Visit 3.  If required per local 
regulations and/or institutional guidelines, pregnancy testing can occur at other times during the study treatment 
period.
i
To confirm postmenopausal status for women ≥40 and <60 years of age who have had a cessation of menses, an
FSH test will be performed. Nonchildbearing potential is defined as an FSH ≥40 mIU/mL and a cessation of
menses for at least 12 months.
j
The QuantiFERON®-TB Gold test is the preferred alternative to the PPD test for the evaluation of TB infection,
and it may be used instead of the PPD test or T-SPOT® TB test and may be read locally. If the 
QuantiFERON-TB Gold test is indeterminate, 1 retest is allowed.  If the retest is indeterminate, then the patient 
is excluded from the study.
k
HBV DNA testing will be done in those patients who are HBcAb+ at screening.

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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 the following:

that the patient understands the potential risks and benefits of participating in 
the study.

that informed consent is given by each patient.  This includes obtaining the 
appropriate signatures and dates on the informed consent form (ICF) prior to 
the performance of any protocol procedures and prior to the administration of 
investigational product.

answering any questions the patient may have throughout the study and 
sharing in a timely manner any new information that may be relevant to the
patient’s willingness to continue his or her participation in the trial.
Appendix 3.1.2.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Council for Harmonisation (ICH)
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Eli Lilly and 
Company (Lilly) before the study may begin at the investigative site(s).  Lilly or its 
representatives must approve the ICF, including any changes made by the ERBs, before it is used 
at the investigative site(s). All ICFs must be compliant with the ICH guideline on Good Clinical 
Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current investigator’s brochure and updates during the course of the study

ICF

relevant curricula vitae.
Appendix 3.1.3.
Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines

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
applicable laws and regulations.
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.4.
Investigator Information
Physicians with a specialty in dermatology will participate as investigators in this clinical trial.
Appendix 3.1.5.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.6.
Final Report Signature
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 clinical study report (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 CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

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 evaluate CRF data and use standard computer edits to detect errors in 
data collection

conduct a quality review of the database.

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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
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Electronic patient-reported outcome (ePRO) measures (for example, a rating scale) and 
electronic clinical outcome assessments (eCOAs) are entered into an ePRO/eCOA instrument at 
the time that the information is obtained.  In these instances where there is no prior written or 
electronic source data at the site, the ePRO/eCOA instrument record will serve as the source.
If ePRO/eCOA records are stored at a third-party site, investigator sites will have continuous 
access to the source documents during the study and will receive an archival copy at the end of 
the study for retention.
Any data for which the ePRO/eCOA instrument record will serve to collect source data will be 
identified and documented by each site in that site’s study file.
Case report form data will be encoded and stored in InForm.  Data managed by a central vendor, 
such as laboratory test data, will be stored electronically in the central vendor’s database system.  
Data will subsequently be transferred from the central vendor to the Lilly data warehouse.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system.  Data will subsequently be transferred from the central 
vendor to the Lilly data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.

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Appendix 4.
Hepatic Monitoring Tests for
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly, 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
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cell; WBC = white blood cell.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Appendix 5.
Liver Function Testing and Hepatic Safety 
Monitoring
Liver Function Testing and Hepatic Safety Monitoring
Analyte
Exclusion
Criteria
Additional 
Hepatic 
Testing
Hepatic eCRF 
Reporting
Temporary 
Interruption of 
IP
Permanent Discontinuation 
of IP after Consultation 
with the Lilly-Designated 
Medical Monitor
Protocol 
Section
Section 6.2
Section 9.4.9
Section 9.4.9
Section 8.1.1
Section 8.1.2
ALT/AST
≥2x ULN
ALT only 
≥3x ULN
ALT only
≥5x ULN on ≥2 
consecutive 
tests
≥5x ULN

>8x ULN

>5x ULN for >2 
weeks

>3x ULN AND TBL 
>2x ULN or INR >1.5

>3x ULN with 
symptomsa
ALP
≥2x ULN
≥2x ULN
≥2x ULN on ≥2 
consecutive 
tests
No applicable 
criteria

>3x ULN

>2.5x ULN AND TBL 
>2x ULN 

>2.5x ULN with 
symptomsa
TBL
≥1.5x ULN
≥2x ULN
≥2x ULN
(excluding 
Gilbert’s 
syndrome)
No applicable 
criteria

ALT or AST >3x 
ULN AND TBL >2x 
ULN

ALP >2.5x ULN AND 
TBL >2x ULN
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; IP = investigational product; TBL = total bilirubin level; ULN = upper 
level of normal.
a
Fatigue, nausea, vomiting, right upper-quadrant pain or tenderness, fever, and/or rash.

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Appendix 6.
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 7.
American Academy of Dermatology:  Criteria 
for the Diagnosis and Assessment of Atopic Dermatitis
Features to be considered in diagnosis of patients with atopic dermatitis:
Essential Features—Must be present:

pruritus

eczema (acute, subacute, chronic)
o
typical morphology and age-specific patterns*
o
chronic or relapsing history
*Patterns include:
1)
facial, neck, and extensor involvement in infants and children
2)
current or previous flexural lesions in any age group
3)
sparing of the groin and axillary regions
Important Features—Seen in most cases, adding support to the diagnosis:

early age of onset

atopy
o
personal and/or family history
o
Immunoglobulin E reactivity

xerosis
Associated Features—These clinical associations help to suggest the diagnosis of atopic 
dermatitis but are too nonspecific to be used for defining or detecting atopic dermatitis for 
research and epidemiologic studies:

atypical vascular responses (for example, facial pallor, white dermographism, delayed blanch 
response)

keratosis pilaris/pityriasis alba/hyperlinear palms/ichthyosis

ocular/periorbital changes

other regional findings (for example, perioral changes/periauricular lesions)

perifollicular accentuation/lichenification/prurigo lesions
Exclusionary Features—It should be noted that a diagnosis of atopic dermatitis depends on 
excluding conditions, such as:

scabies

seborrheic dermatitis

contact dermatitis (irritant or allergic)

ichthyoses

cutaneous T-cell lymphoma

psoriasis

photosensitivity dermatoses

immune deficiency diseases

erythroderma of other causes
Source: Eichenfield et al. 2014.

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Appendix 8.
Classification of Potency for Topical 
Corticosteroids
Potency
Class
Topical Corticosteroid
Formulation
Ultra high
I
Clobetasol propionate
Cream 0.05%
Diflorasone diacetate
Ointment 0.05%
High
II
Amcinonide
Ointment 0.1%
Betamethasone dipropionate
Ointment 0.05%
Desoximetasone
Cream or ointment 0.025%
Fluocinonide
Cream, ointment or gel 0.05%
Halcinonide
Cream 0.1%
III
Betamethasone dipropionate
Cream 0.05%
Betamethasone valerate
Ointment 0.1%
Diflorasone diacetate
Cream 0.05%
Triamcinolone acetonide
Ointment 0.1%
Moderate
IV
Desoximetasone
Cream 0.05%
Fluocinolone acetonide
Ointment 0.025%
Fludroxycortide
Ointment 0.05%
Hydrocortisone valerate
Ointment 0.2%
Triamcinolone acetonide
Cream 0.1%
V
Betamethasone dipropionate
Lotion 0.02%
Betamethasone valerate
Cream 0.1%
Fluocinolone acetonide
Cream 0.025%
Fludroxycortide
Cream 0.05%
Hydrocortisone butyrate
Cream 0.1%
Hydrocortisone valerate
Cream 0.2%
Triamcinolone acetonide
Lotion 0.1%
Low
VI
Betamethasone valerate
Lotion 0.05%
Desonide
Cream 0.05%
Fluocinolone acetonide
Solution 0.01%
VII
Dexamethasone sodium phosphate
Cream 0.1%
Hydrocortisone 
Lotion, cream, or ointment 2.5%
Hydrocortisone acetate
Cream 1%
Methylprednisolone acetate
Cream 0.25%
Source:  WHO (1997) and Tadicherla et al. 2009.

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Appendix 9.
Multiple Imputation
Placebo Multiple Imputation
The placebo multiple imputation (pMI) method will be used as a sensitivity analysis for the 
analysis of the primary efficacy endpoint, EASI75, as well as the key secondary endpoints at 
Week 16 (Visit 8). In the main analysis, all patients who either permanently discontinue study 
treatment or discontinue from the study for any reason at any time or who are rescued will be 
considered missing after discontinuation or rescue.  The secondary (“as observed”) analysis will 
be conducted for the primary endpoint, IGA (0,1) with ≥2-point improvement, and 4-point 
improvement from baseline in Itch Numeric Rating Scale (NRS) at Week 16.  In this analysis, all 
patients who either permanently discontinue study treatment or discontinue from the study for 
any reason at any time will be considered to be missing after discontinuation.  
The pMI assumes that the statistical behavior of drug- and placebo- treated patients after 
discontinuing study medication becomes that of placebo-treated patients.  Multiple imputations 
are used to replace missing outcomes (IGA, EASI, SCORing Atopic Dermatitis (SCORAD), 
Itch NRS, Atopic Dermatitis Sleep Scale (ADSS) Item 2, and Skin Pain NRS scores) for drug-
and placebo-treated patients who discontinued using multiple draws from the posterior predictive 
distribution estimated from the placebo arm.  The binary outcomes of IGA (0,1), EASI75, 
EASI90, SCORAD75, and 4-point improvement from baseline in Itch NRS will then be derived 
from the imputed data.
Data are processed sequentially by repeatedly calling SAS® PROC MI to impute missing 
outcomes at visits t=1,.., T.
1. Initialization:  Set t=0 (baseline visit)
2. Iteration:  Set t=t+1. Create a data set combining records from drug- and placebo-treated 
patients with columns for covariates X and outcomes at visits 1,..,t with outcomes for all 
drug-treated patients set to missing at visit t and set to observed or imputed values at 
visits 1,..,t-1.
3. Imputation:  Run Bayesian regression in SAS PROC MI on this data to impute missing 
values for visit t using previous outcomes for visits 1 to t-1 and baseline covariates.  Note 
that only placebo data will be used to estimate the imputation model since no outcome is 
available for drug-treated patients at visit t.
4. Replace imputed data for all drug-treated patients at visit t with their observed values, 
whenever available up to permanent study drug discontinuation and/or rescue (if 
censoring on rescue). If t < T then go to Step 2, otherwise proceed to Step 5.
5. Repeat steps 1-4, m times with different seed values to create m imputed complete data 
sets.

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Analysis:  For each completed data set use the model as would have been applied had the data 
been complete for the continuous outcome.For the primary and secondary key efficacy 
endpoints of IGA (0,1), EASI75, EASI90, SCORAD75, and 4-point improvement from baseline 
in Itch NRS, the binary outcomes will be derived from the imputed data for each patient before 
fitting into the analysis model.A logistic regression model will be applied.  
The number of imputed data sets will be m=100 and a 6-digit seed value will be prespecified for 
each analysis.  Within the program, the seed will be used to generate the mseeds needed for 
imputation.  The initial seed values are given below:  
Analysis
Seed value
Proportion of patients achieving IGA of 0 or 1 with a ≥2-point improvement from 
baseline at Week16, with data up to rescue
123450
Proportion of patients achieving EASI75 at 16weeks, with data up to rescue
123451
Proportion of patients achieving EASI90 at 16weeks, with data up to rescue
123451
Mean percent change from baseline in EASI score at 16weeks, with data up to rescue
123451
Proportion of patients achieving SCORAD75 at 16week, with data up to rescue
123452
Proportions of patients achieving a4-point improvement from baseline in Itch NRS at 
Week 16, with data up to rescue
123453
Mean change from baseline in Skin Pain NRS at Week 16, with data up to rescue
123454
Mean change from baseline in the score of Item2 of the ADSS at Week 16, with data up 
to rescue
123455
Proportion of patients achieving IGA of 0 or 1 with a ≥2-point improvement from 
baseline at Week16, including data after rescue
123456
Proportion of patients achieving EASI75 at 16weeks, including data after rescue
123457
Proportions of patients achieving a 4-point improvement from baseline in Itch NRS at 
Week 16, including data after rescue
123458
The final inference on treatment difference is conducted from the multiple datasets using Rubin’s 
combining rules, as implemented in SAS PROC MI ANALYZE.  
Thus, in the effectiveness context, pMI assumes no pharmacological benefit of the drug after 
dropout but is a more reasonable approach than modified last observed carried forward because 
unlike modified last observed carried forward it accounts for uncertainty of imputation, and 
therefore does not underestimate standard errors, and it limits bias by taking into account 
study/placebo effects.In the efficacy context pMI is a specific form of a missing not at random 
analysis expected to yield a conservative estimate of efficacy.
Tipping Point Analyses
To investigate the missing data mechanism,sensitivity analysis using multiple imputation (MI) 
under the missing not at random assumption will be provided for the following primary and 
major secondary objectives:
EASI75 at Week 16, baricitinib 2-mg compared to placebo.
IGA (0,1) with ≥2-point improvement at Week 16, baricitinib 2-mg compared to placebo,

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
Itch NRS 4-point improvement from baseline to Week 16, baricitinib 2-mg compared to 
placebo.
All available data will be included in the analyses, excluding data that occurs after rescue or after 
permanent discontinuation of study drug.  All patients in the intent-to-treat population are 
included.
Within each analysis, a most extreme case will be considered, in which all missing data for 
patients randomized to baricitinib 1-mg or 2-mg will be imputed using the worst possible result 
and all missing data for patients randomized to placebo will be imputed with the best possible 
result.  Treatment differences will be analyzed using logistic regression or analysis of covariance
(ANCOVA) (Section 10.3.1) as appropriate.  
For continuous variables, the following process will be used to determine the tipping point:
1. To handle intermittent missing visit data, a Markov chain Monte Carlo method (SAS 
Proc MI with MCMC option) will be used to create a monotone missing pattern.  
2. A set of Bayesian regressions (using SAS Proc MI with MONOTONE option) will be 
used for the imputation of monotone dropouts.  Starting from the first visit with at least 
1 missing value, the regression models will be fit sequentially with treatment as a fixed 
effect and values from the previous visits as covariates.  
3. A delta score is added to all imputed scores at the primary time point for patients in the 
baricitinib treatment groups, thus worsening the imputed value.  The delta score is capped 
for patients based on the range of the outcome measure being analyzed.
4. Treatment differences between baricitinib and placebo are analyzed for each imputed 
dataset using ANCOVA.  Results across the imputed datasets are aggregated using SAS 
Proc MI ANALYZE to compute a p-value for the treatment comparisons for the given 
delta value.
5. Steps 3 and 4 are repeated, and the delta value added to the imputed baricitinib scores is 
gradually increased.  The tipping point is identified as the delta value which leads to a 
loss of statistical significance (aggregated p-value >0.05) when evaluating baricitinib 
relative to the placebo group.
As a reference, for each delta value used in Steps 3-5, a fixed selection of delta values (ranging 
from slightly negative to slightly positive) will be added to imputed values in the placebo group, 
and Step 4 will be performed for the combination.  This will result in a 2-d table, with the 
columns representing the delta values added to the imputed placebo responses, and the rows 
representing the delta values added to the imputed baricitinib responses.  Separate 2-d tables will 
compare each baricitinib dose group to placebo.
A similar process will be used for the categorical variables:
1. Missing responses in the baricitinib groups will be imputed with a range of low response 
probabilities, including probabilities of 0, 0.1, and 0.2.

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2. For missing responses in the placebo group, a range of responses probabilities (for 
example, probability=0, 0.2 … 1) will be used to impute the missing values.  Multiple 
imputed datasets will be generated for each response probability.
3. Treatment differences between baricitinib and placebo will be analyzed for each imputed 
dataset using logistic regression.  Results across the imputed datasets will be aggregated 
using SAS Proc MI ANALYZE to compute a p-value for the treatment comparisons for 
the given response probability.  If the probability values do not allow for any variation 
between the multiple imputed datasets (for example, all missing responses in the placebo 
and baricitinib groups are imputed as responders and nonresponders, respectively), then 
the p-value from the single imputed dataset will be used.
The tipping point is identified as the response probability value within the placebo group that 
leads to a loss ofstatistical significance when evaluating baricitinib relative to placebo.  
For tipping point analyses the number of imputed data sets will be m=100 and the seed values to 
start the pseudorandom number generator of SAS Proc MI (same values for MCMC optionand 
for MONOTONE option) will be: 
Analysis
Seed value
Proportion of patients achieving IGA of 0, 1 or 2 at Week16, with data up to rescue
123461
Proportion of patients achieving EASI75 at 16weeks, with data up to rescue
123462
Proportions of patients achieving a 4-point improvement from baseline in Itch NRS at 
Week 16, including data after rescue
123463

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Appendix 10. Adjustment for Multiple Comparisons
The primary hypothesis H2,1,0 will be tested at a 2-sided α=0.05.  If the initial null hypothesis is
not rejected, no further testing will be conducted as the α for that test is considered “spent” and 
cannot be passed to other endpoints.  If H2,1,0 is rejected, then α will be propagated to H2,2,0.    
The testing process will continue with α propagated according to the weights on the 
corresponding edges displayed in Figure JAIW.2, as long as each hypothesis in the sequence can 
be rejected at its allocated α level.  Each time a hypothesis is rejected, the graph will be updated 
to reflect the reallocation of α, which is considered “recycled” by Alosh et al. 2014.  This 
iterative process of updating the graph and reallocating α will be repeated until all hypotheses 
have been tested or when no remaining hypotheses can be rejected at their corresponding α 
levels.
There will be no adjustment for multiple comparisons for any other analyses.  Any changes to 
the details of the adjustment for multiple comparisons will be finalized in the statistical analysis 
plan prior to primary database lock.  

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Appendix 11. Investigator Global Assessment

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Appendix 12. Protocol Amendment I4V-MC-JAIW(c) 
Summary - A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy 
and Safety of Baricitinib in Adult Patients with Moderate to 
Severe Atopic Dermatitis
Overview
Protocol I4V-MC-JAIW, A Multicenter, Randomized, Double Blind, Placebo Controlled, Phase 
3 Study to Evaluate the Efficacy and Safety of Baricitinib in Adult Patients with Moderate to 
Severe Atopic Dermatitis, has been amended.  The new protocol is indicated by amendment (c) 
and will be used to conduct the study in place of any preceding version of the protocol.
Amendment Summary for Protocol I4V-MC-JAIW Amendment (c)
Section # 
Description of Change
Brief Rationale
Section 1, 4, 
5.1.2, 5.1.3, 9.1.1, 
9.1.2.1, 9.1.2.2, 
9.1.2.3, 9.1.2.4, 
10.3.3.1, 10.3.3.2, 
10.3.5.2 and 
Appendix 9
Primary efficacy endpoint was changed
Baricitinib 1-mg was removed as a 
component of the primary objective .
Criteria for patient eligibility for enrollment 
into Study JAIX and language for related 
sections were updated.
IGA (0,1) at week 16 was assigned as a 
key secondary endpoint while EASI75 at 
week 16 became the primary endpoint. 
Both EASI 75 and IGA 0/1 are regulatory 
accepted endpoints for clinical trials in 
Atopic Dermatitis. EASI 75 was already 
included in the study as a key secondary 
endpoint. Based on the available data from 
completed BREEZE studies, there is 
greater power to test EASI 75 compared to 
IGA 0/1, thus exchanging the order of 
testing of IGA 0/1 and EASI 75 will 
optimize the multiplicity testing approach 
of the study.
Based on available data from completed 
BREEZE studies, baricitinib 1-mg was 
removed as a co-primary and will be 
considered with the secondary analyses 
only. 
To allow all patients participating in Study 
JAIW the opportunity to receive IP (2-mg 
QD), the study design has been updated to 
allow “responders” from Study JAIW to 
enter open-label Study JAIX after 

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Section # 
Description of Change
Brief Rationale
Additional exploratory endpoints were 
included.
completing the full treatment period of 
Study JAIW. This change allows all
patients enrolled in Study JAIW to be 
assessed for entering Study JAIX at some 
point at or after JAIW Visit 8 and will 
generate more safety and efficacy data at 
the 2-mg dose.  
Based on results from completed studies 
with similar patient populations, additional 
exploratory endpoints for PROs have been 
included.
Section 5.4 and 
Section 11
Provided information regarding the EASI 
scale and updated the References list.
Incorporated empirical evidence of EASI 
scale reliability to support its’ inclusion as 
the primary efficacy endpoint for this 
study.
Section 10.1, 
10.3.1 and 
Appendix 10
Updated statistical model and estimated 
statistical power calculations.
Hypotheses graphical testing figure was 
updated.
References to the primary endpoint of IGA 
were removed
Given the new primary endpoint for the 
study, the statement and the rationale for 
power calculation needed to be updated.
With the removal of baricitinib 1-mg as a 
co-primary endpoint, null hypothesis 
testing needed to be revised to reflect the 
change in alpha.
References to IGA as the primary 
endpoint were removed to reflect the 
change in primary endpoint.

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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
Objectives/Endpoints:
Objectives
Endpoints
Primary
This is a prespecified objective that will be adjusted for multiplicity.
To test the hypothesis that baricitinib 1-
mg QD or 2-mg QD is superior to 
placebo in the treatment of patients 
with moderate to severe AD

Proportion of patients achieving IGA of 0 or 1 with a 
≥2-point improvement at Week 16 Proportion of patients 
achieving EASI75 at Week 16
Key Secondary
These are prespecified objectives that will be adjusted for multiplicity.
To compare the efficacy of baricitinib 
1-mg QD or 2-mg QD to placebo in AD
during the 16-week, double-blind,
placebo-controlled treatment period as 
measured by improvement in signs and 
symptoms of AD

Proportion of patients achieving IGA of 0 or 1 with a ≥2-point 
improvement at Week 16

Proportion of patients achieving EASI75 at Week 16 (1-mg)

Proportion of patients achieving EASI90 at Week 16 

Mean percent change from baseline in EASI score at Week 16 

Proportion of patients achieving SCORAD75 at Week 16 
Statistical Analysis:
Treatment comparisons of discrete efficacy variables will be made using a logistic regression analysis with 
treatment, and baseline disease severity (IGA), and baseline score in the model.  Region may be added to the model 
if patient numbers allow.  The proportions and 95% CI will be reported.  If a patient needs to use rescue medication, 
the data after rescue onward will be considered missing, and missing data will be imputed using the nonresponder 
imputation (NRI) method.  All patients who discontinue the study or study treatment at any time for any reason will 
be defined as nonresponders for the NRI analysis for categorical variables after discontinuation onward.  Additional
analyses will be done using all observed data whether rescue medication was used or not.
Treatment comparisons of continuous efficacy and health outcome variables will be made using mixed-effects 
model of repeated measures (MMRM) with treatment, baseline disease severity (IGA), visit, and treatment-by-visit
interaction as fixed categorical effects and baseline score and baseline score-by-visit interaction as fixed continuous 
effects.  An unstructured covariance matrix will be used to model the within-patient variance–covariance errors.  
Type III sums of squares for the least squares means (LSMs) will be used for the statistical comparison, and 
contrasts will be set up within the model to compare treatment groups at specific time points of interest.

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4.   Objectives and Endpoints
Table JAIW.2 shows the objectives and endpoints of the study.
Table JAIW.2.
Objectives and Endpoints
Objectives
Endpoints
Primary
This is a prespecified objective that will be adjusted for multiplicity.
To test the hypothesis that baricitinib 1-mg QD or
2-mg QD is superior to placebo in the treatment of 
patients with moderate to severe AD

Proportion of patients achieving IGA of 0 or 1 
with a ≥2-point improvement at Week 16 
Proportion of patients achieving EASI75 at 
Week 16
Key Secondary
These are prespecified objectives that will be adjusted for multiplicity.
To compare the efficacy of baricitinib 1-mg QD or
2-mg QD to placebo in AD during the 16-week,
double-blind, placebo-controlled treatment period as 
measured by improvement in signs and symptoms 
of AD

Proportion of patients achieving IGA of 0 or 1 
with a ≥2-point improvement at Week 16 

Proportion of patients achieving EASI75 at 
Week 16 (1-mg)
Exploratory Objectives/Endpoints

Exploratory objectives evaluating the response to baricitinib treatment regimens on other patient 
reported outcomes will be specified in the SAP. These endpoints may include dichotomous endpoints or 
change from baseline for the following measures: POEM, DLQI, Itch NRS, ADSS, Skin Pain NRS, 
PGI-S-AD, and HADS.
5.1.2    Period 2:  Double-Blind Placebo-Controlled Treatment, 
Weeks 0 to 104
At Week 16, all patients who meet the primary endpoint (IGA 0 or 1) and who have not required 
rescue therapy before Week 16 will be allowed to continue on this study.  All other patients will 
be discontinued from this study and may be eligible to enroll in a separate open-label study 
(Study I4V-MC-JAIX [JAIX; BREEZE-AD6]).  Patients need to complete at least 16 weeks in 
Study JAIW to be eligible to enroll in the open-label extension (Study JAIX).  Patients who 
choose to enroll into the open-label study (Study JAIX) will not be required to complete the 
Study JAIW post-treatment follow up visit.  
Patients who complete week 104 (Visit 15) will have the option to transition to open-label Study 
JAIX if eligibility criteria are met, regardless of responder status, or continue to the 
post-treatment follow-up.
5.1.3
Period 3:  Post-Treatment Follow-Up
Patients who complete the study through Visit 15 (Week 104) will have a post-treatment 
follow-up visit (Visit 801) approximately 28 days after the last dose of investigational product, 
unless the patient is transitioning to open-label Study JAIX.

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Abbreviations:  AD = atopic dermatitis; QD = once daily; V = visit; W = week.
a At Week 16, all patients who meet the primary endpoint achieve an (IGA 0 or 1) and who have 
not required rescue therapy before Week 16 will be allowed to continue in this study.  All other 
patients will be discontinued from this study and may be eligible to enroll in the separate 
open-label Study JAIX.
b    Patients who complete this study will be eligible for assessment to enroll in open-label Study 
JAIX.
c Occurs approximately 28 days after the last dose of investigational product.
Figure JAIW.1.
Illustration of study design for Clinical Protocol I4V-MC-JAIW.
5.4
Scientific Rationale for Study Design
Both EASI score and IGAs are commonly used in clinical trials, both for qualifying patients for 
enrollment and for evaluating treatment efficacy (Langley et al. 2015; Futamura et al. 2016; 
Bożek and Reich, 2017). There is no single “gold standard” disease severity scale for AD. 
However, IGA scales provide clinically meaningful measures to patients and investigators that 
are easily described and that correspond to disease severity categories (for example, moderate to 
severe), and a 75% improvement from Baseline (EASI75) is a commonly used measure of 
treatment effect in AD clinical trials.
The IGA scale that will be used in this trial, the validated Investigator’s Global Assessment of 
Atopic Dermatis (vIGA-AD, referred to throughout the protocol as IGA; Appendix 11), has been 
developed internally and assesses AD severity using a 5-point scale.
The 16-week efficacy endpoint was chosen because it is probable that a robust clinical effect will 
be observed with baricitinib within this time frame on the basis of the Phase 2 study results in 
AD and previous studies in another inflammatory skin condition.  Patients who do not meet the 
primary endpoint of achieve IGA of 0 or 1 at Week 16 will be discontinued from the study.  
Similarly, patients who achieve an IGA of 0 or 1 at Week 16, and experience worsening in their 
disease resulting in an IGA score of ≥3 at any time after Week 16 will also be discontinued from 
the study.  Patients who are discontinued from Study JAIW may be eligible to enroll in open-
label Study JAIX.
9.1.1    Primary Efficacy Assessments
Eczema Area and Severity Index scores: The EASI assesses extent of disease at 4 body 
regions and measures 4 clinical signs:  (1) erythema, (2) induration/papulation, (3) excoriation, 
and (4) lichenification, each on a scale of 0 to 3.  The EASI confers a maximum score of 72.  The 
EASI evaluates 2 dimensions of AD: disease extent and clinical signs (Hanifin et al. 2001).  
Validated Investigator’s Global Assessment for Atopic Dermatitis (vIGA-AD):  The IGA used in 
this study, the vIGA-AD (referred to as the IGA throughout the protocol), measures the IGA of the 
patient’s overall severity of their AD, on the basis of a static, numeric 5-point scale from 0 (clear 
skin) to 4 (severe disease).  The score is based on an overall assessment of the degree of 
erythema, papulation/induration, oozing/crusting, and lichenification.

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9.1.2.1
Eczema Area and Severity Index scoresValidated Investigator’s Global 
Assessment for Atopic Dermatitis (vIGA-AD)
The IGA used in this study, the vIGA-AD (referred to as the IGA throughout the protocol), measures 
the IGA of the patient’s overall severity of their AD, on the basis of a static, numeric 5-point 
scale from 0 (clear skin) to 4 (severe disease).  The score is based on an overall assessment of the 
degree of erythema, papulation/induration, oozing/crusting, and lichenification.
The EASI assesses extent of disease at 4 body regions and measures 4 clinical signs:  (1) 
erythema, (2) induration/papulation, (3) excoriation, and (4) lichenification, each on a scale of 0 
to 3.  The EASI confers a maximum score of 72.  The EASI evaluates 2 dimensions of AD:  
disease extent and clinical signs (Hanifin et al. 2001).  
BSA affected by AD will be derived from data collected as part of the EASI assessment.
9.1.2.23      SCORing Atopic Dermatitis
9.1.2.34      Hospital Anxiety Depression Scale
10.1 Sample Size Determination
Study JAIW will aim to enroll approximately 450 patients aged ≥18 years.  The proposed sample 
size will ensure at least 90% approximately 68% power to detect any difference between the 
baricitinib 2-mg and placebo treatment groups, assuming a 10% placebo and 250% baricitinib 2-
mg response rate for the primary endpoint EASI75 using a Chi-squared test with a 2-sided ɑ 
level of 0.025.  The assumptions are based on what was observed in the Phase 23 monotherapy
Studyies JAHGL and JAHM.  
Sample size and power estimates were obtained from nQuery® Advisor 7.0 and through 
simulations following adjustments for multiple comparisons.
10.3.1 General Statistical Considerations
All tests of treatment effects will be conducted at a 2-sided ɑ level of 0.05, unless otherwise 
stated. Treatment comparisons of discrete efficacy variables between baricitinib and placebo 
will be made using a logistic regression analysis with IGA baseline disease severity, baseline 
score, and treatment group in the model. Region may be added as an additional factor if there is 
a sufficient number of patients for rest-of-world and stratification has not resulted in empty 
strata. This will be finalized in the SAP.  If appropriate, treatment by region interaction may be 
added to the model of the primary and key secondary variables as a sensitivity analysis.  If this 
interaction is significant at a 2-sided 0.1 level, further inspection will be used to assess whether 
the interaction is quantitative (that is, the treatment effect is consistent in direction but not size of 
effect) or qualitative (the treatment is beneficial for some but not all regions).  The percentages, 
difference in percentages, and 95% CI of the difference in percentages will be reported. The 
p-value from the Fisher’s exact test will also be produced.
When evaluating continuous measures over time, a restricted maximum likelihood-based 
MMRM will be used.  The model will include treatment, baseline disease severity (IGA), 
baseline score, visit, and treatment-by-visit interaction as fixed categorical effects and baseline 

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score and baseline score-by-visit interaction as fixed continuous effects.Geographic region may 
be added as an additional factor if appropriate.  An unstructured (co)variance structure will be 
used to model the between-and within-patient errors. If this analysis fails to converge,other 
structures will be tested. The Kenward–Roger method will be used to estimate the degreesof 
freedom. TypeIII sums of squares for the LSMswill be used for the statistical comparison; 95%
CI will also be reported. Contrasts will be set up within the model to test treatment groups at 
specific time points of interest. Further details on the use of MMRM will be described in the 
SAP.  
Treatment comparisons of continuous efficacy and health outcome variables may also be made 
using ANCOVAwith baselinedisease severity(IGA), treatment group,and baseline valuescore
in the model.  Geographic region may be added as an additional factor if appropriate.  TypeIII 
tests for LSMwill be used for statistical comparison between treatment groups.  The LSM
difference, standard error, p-value, and 95% CI may also be reported.  The method used to 
handle missing data will be specified in the SAP.
Primary Null Hypothesis:  
 ,,:  Proportion of baricitinib 2-mg patients achieving EASI75 is less than or equal to 
the proportion of placebo patients achieving EASI75 at Week 16
 , ,  :  Proportion of baricitinib 2-mg patients achieving IGA of 0 or 1 and ≥2-point 
improvement from baseline at Week 16 is less than or equal to the proportion of placebo 
patients achieving IGA of 0 or 1 and ≥2-point improvement from baseline at Week 16
 , ,  :  Proportion of baricitinib 1-mg patients achieving IGA of 0 or 1 and ≥2-point 
improvement from baseline at Week 16 is less than or equal to the proportion of placebo 
patients achieving IGA of 0 or 1 and ≥2-point improvement from baseline at Week 16
Key Secondary Null Hypotheses: 
 , ,  :  Proportion of baricitinib 2-mg patients achieving EASI75 isless than or equal to 
the proportion of placebo patients achieving EASI75 at Week 16
 , ,  :  Proportion of baricitinib 1-mg patients achieving EASI75 is less than or equal to 
the proportion of placebo patients achieving EASI75 at Week 16
 ,,:  Proportion of baricitinib 2-mg patients achieving IGA of 0 or 1 and ≥2-point 
improvement from baseline at Week 16 is less than or equal to the proportion of placebo 
patients achieving IGA of 0 or 1 and ≥2-point improvement from baseline at Week 16
 , ,:Mean change from baseline in the score of Item 2of the ADSS forbaricitinib 
2-mg is less than or equal to the mean change from baseline in the score of Item 2of the 
ADSS for placebo at Week 16
 , ,:  Mean change from baseline in the score of Item 2of the ADSS forbaricitinib 
2-mg is less than or equal to the mean change from baseline in the score of Item 2of the 
ADSS for placebo at Week 16
 ,,:  Proportion of baricitinib 1-mg patients achieving EASI75 is less than or equal to 
the proportion of placebo patients achieving EASI75 at Week 16

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 ,,:  Proportion of baricitinib 1-mg patients achieving IGA of 0 or 1 and ≥2-point 
improvement from baseline at Week 16 is less than or equal to the proportion of placebo 
patients achieving IGA of 0 or 1and ≥2-point improvement from baseline at Week 16
 , ,:  Mean change from baseline in the score of Item 2of the ADSS forbaricitinib 
1-mg is less than or equal to the mean change from baseline in the total score of the 
ADSS for placebo at Week 16
 , ,:  Mean change from baseline in the score of Item 2of the ADSS forbaricitinib 
1-mg is less than or equal to the mean change from baseline in the total score of the 
ADSS for placebo at Week 16

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Figure JAIW.2.
Study I4V-MC-JAIW scheme structure.
10.3.3.1
Primary Analyses
The primary efficacy measure is the binary outcome of response defined as IGA score of 0 or 1 
(clear or almost clear skin) and ≥2-point improvement from baseline categorical outcome of 
EASI75 at Week 16 for baricitinib 2-mg.  EASI75 is defined as having an improvement of at 
least 75% from baseline.  Primary analysis will be conducted using a logistic regression as 
described above with treatment and stratification variables, which include (IGA baseline disease 
severity, baseline score and region, as appropriate) in the model.  NRI for missing data as 
described above will be used.
Additional analysis of the primary efficacy outcome will include analyzing the outcome as 
observed, that is, whether rescue medication was given.
10.3.3.2
Secondary Analyses
The following secondary categorical outcomes will be analyzed in a similar manner as the 
primary, that is, using the same logistic regression model.  This applies to both baricitinib 2-mg 
vs placebo, and baricitinib 1-mg vs placebo unless stated otherwise.  NRI will be used for these 
analyses unless otherwise noted.

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
EASI75 at Week 16.  EASI75 is defined as having an improvement of at least 
75% from baseline.  IGA score of 0 or 1 (clear or almost clear skin) and ≥2-point 
improvement from baseline at Week 16. Besides NRI, this outcome will also be 
analyzed using observed cases, that is, whether rescue medication was given.

EASI75 at Week 16 for baricitinib 1-mg vs placebo. EASI75 is defined as having an 
improvement of at least 75% from baseline.
10.3.5.2
Subgroup Analyses
To assess whether the treatment effect is similar across subgroups for the primary efficacy 
outcome, a logistic model will be used and will include treatment, stratification variables (IGA 
(3,4) at baseline, baseline disease severity and region) as appropriate, the subgroup variable (for 
example, sex), and the subgroup-by-treatment interaction.  If the interaction is statistically 
significant at level of 0.10, the nature of the interaction will be explored, that is, within each 
subgroup the treatment effect will be estimated.  Similarly, for the continuous variables of EASI, 
the MMRM model will include additional variables for subgroup and the subgroup-by-treatment 
interaction.

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11.  References
Bożek A, Reich, A. Assessment of Intra- and Inter-Rater Reliability of Three Methods for 
Measuring Atopic Dermatitis Severity: EASI, Objective SCORAD, and IGA. Dermatology. 
2017;233(1):16-22.

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Appendix 9.  Multiple Imputation
The placebo multiple imputation (pMI) method will be used as a sensitivity analysis for the 
analysis of the primary efficacy endpoint, IGA (0,1) with ≥2-point improvement EASI75 as well 
as the key secondary endpoints at Week 16 (Visit 8). In the main analysis, all patients who either 
permanently discontinue study treatment or discontinue from the study for any reason at any time 
or who are rescued will be considered missing after discontinuation or rescue.  The secondary 
(“as observed”) analysis will be conducted for the primary endpoint, Eczema Area and Severity 
Index (EASI75) IGA (0,1) with ≥2-point improvement, and 4-point improvement from baseline 
in Itch Numeric Rating Scale (NRS) at Week 16 and will be referred to as the “pMI as observed” 
analysis.  In this analysis, Aall patients who either permanently discontinue study treatment or 
discontinue from the study for any reason at any time will be considered to be missing after 
discontinuation.  
The pMI assumes that the statistical behavior of drug- and placebo- treated patients after 
discontinuing study medication becomes that of placebo-treated patients which is the rationale 
for “pMI as observed”.  The main analysis will be conducted to keep in line with the other 
analyses and to assess the impact of pMI with other imputation methods.  Multiple imputations 
are used to replace missing outcomes (IGA, EASI, SCORing Atopic Dermatitis (SCORAD), 
Itch NRS, Atopic Dermatitis Sleep Scale (ADSS) Item 2, and Skin Pain NRS scores) for drug-
and placebo-treated patients who discontinued using multiple draws from the posterior predictive 
distribution estimated from the placebo arm.  The binary outcomes of IGA (0,1), EASI75, 
EASI90, SCORAD75, and 4-point improvement from baseline in Itch NRS will then be derived 
from the imputed data.
Tipping Point Analyses
To investigate the missing data mechanism, sensitivity analysis using multiple imputation (MI) 
under the missing not at random assumption will be provided for the following primary and 
major secondary objectives:

EASI75 at Week 16, baricitinib 2-mg compared to placebo.

IGA (0,1) with ≥2-point improvement at Week 16, baricitinib 2-mg compared to placebo,

EASI mean percent change from baseline to Week 16, baricitinib 2-mg compared to 
placebo,

Itch NRS 4-point improvement from baseline to Week 16, baricitinib 2-mg compared to 
placebo.
  

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Appendix 10.  Adjustment for Multiple Comparisons
The primary hypothesies H2,1,0 and H1,1,0 will each be tested at a 2-sided α=0.025.  If the initial 
null hypothesies are is not rejected, no further testing will be conducted as the α for that test is 
considered “spent” and cannot be passed to other endpoints.  If H2,1,0 is rejected, then α will be 
propagated to H2,2,0.  In addition, if H1,1,0 is rejected, then α will be split equally and propagated 
to H2,1,0 and H1,2,0.  The testing process will continue in both branches (starting with H2,2,0 and 
H1,2,0 respectively), with α propagated according to the weights on the corresponding edges 
displayed in Figure JAIW.2, as long as each hypothesis in the sequence can be rejected at its 
allocated α level.  Each time a hypothesis is rejected, the graph will be updated to reflect the 
reallocation of α, which is considered “recycled” by Alosh et al. 2014.  This iterative process of 
updating the graph and reallocating α will be repeated until all hypotheses have been tested or 
when no remaining hypotheses can be rejected at their corresponding α levels.

PPD
Leo Document ID = a913b391-57dd-4a5a-aed2-1b334f4cfa69
Approver: 
Approval Date & Time: 10-Oct-2019 09:29:01 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 10-Oct-2019 09:58:01 GMT
Signature meaning: Approved
PPD