A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib in Combination With Topical Corticosteroids in Adult Patients With Moderate to Severe Atopic Dermatitis BREEZE-AD7
Phase: PHASE3
Conditions: Atopic Dermatitis
Sponsor: Eli Lilly and Company

Protocol I4V-MC-JAIY(a) 
 
A Multicenter, Randomized, Doubles-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the 
Efficacy and Safety of Baricitinib in Combination with Topical Corticosteroids in Adult Patients 
with Moderate to Severe Atopic Dermatitis 
 
NCT03733301 
 
Approval Date: 18-Dec-2018 
 

I4V-MC-JAIY(a) Clinical Protocol
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Protocol I4V-MC-JAIY(a)
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy 
and Safety of Baricitinib in Combination with Topical 
Corticosteroids in Adult Patients with ModeratetoSevere 
Atopic Dermatitis
BREEZE-AD7
EudraCT number 2018-001726-26
Confidential Information
The information contained in this document is confidential andis 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.
Approval Date: 18-Dec-2018 GMT
Baricitinib (LY3009104)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approvedby Lilly on 05 July 2018.
Amendment (a) Electronically Signed and Approvedby Lilly onDate Provided Below.

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Table of Contents
Section
Page
Protocol I4V-MC-JAIY(a) A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and 
Safety of Baricitinib in Combination with Topical Corticosteroids in 
Adult Patients with Moderate to Severe Atopic Dermatitis 
BREEZE-AD7 ....................................................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................17
3.1.
Background..................................................................................................................17
3.2.
Study Rationale............................................................................................................18
3.3.
Benefit/Risk Assessment..............................................................................................19
4.
Objectives and Endpoints..................................................................................................21
5.
Study Design.....................................................................................................................23
5.1.
Overall Design .............................................................................................................23
5.1.1.
Period 1:  Screening .............................................................................................23
5.1.2.
Period 2:  Double–Blind, Placebo-Controlled Treatment ......................................24
5.1.3.
Period 3:  Post-Treatment Follow-up....................................................................24
5.2.
Number of Participants.................................................................................................26
5.3.
End of Study Definition ...............................................................................................26
5.4.
Scientific Rationale for Study Design...........................................................................27
5.5.
Justification for Dose ...................................................................................................27
5.5.1.
Dose Adjustment for Renal Impairment ...............................................................28
6.
Study Population...............................................................................................................29
6.1.
Inclusion Criteria..........................................................................................................29
6.2.
Exclusion Criteria ........................................................................................................32
6.3.
Lifestyle Restrictions....................................................................................................38
6.4.
Screen Failures.............................................................................................................38
7.
Treatments........................................................................................................................39
7.1.
Treatments Administered .............................................................................................39
7.1.1.
Packaging and Labeling .......................................................................................39
7.2.
Method of Treatment Assignment ................................................................................39
7.2.1.
Selection and Timing of Doses.............................................................................40
7.2.2.
Dose Adjustment for Renal Impairment ...............................................................40
7.3.
Blinding .......................................................................................................................40

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7.4.
Dosage Modification....................................................................................................41
7.5.
Preparation/Handling/Storage/Accountability...............................................................41
7.6.
Treatment Compliance .................................................................................................41
7.7.
Concomitant Therapy...................................................................................................42
7.7.1.
Permitted Medications and Procedures.................................................................42
7.7.2.
Use of Topical Corticosteroids .............................................................................43
7.7.3.
Prohibited Medications and Procedures................................................................44
7.7.4.
Rescue Therapy....................................................................................................45
7.8.
Treatment after the End of the Study............................................................................46
7.8.1.
Study Extensions..................................................................................................46
7.8.2.
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.................................................................51
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.............................................................52
9.1.3.6.
Dermatology Life Quality Index.....................................................................52
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
9.1.3.9.
PROMIS Itch Questionnaire General Short Form 8a v1.0 ...............................53
9.1.3.10.
PROMIS Itch Questionnaire Activity and Clothing Short 
Form 8a v1.0 ..................................................................................................54

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9.1.3.11.
PROMIS Itch Questionnaire Mood and Sleep Short Form 
8a v1.0............................................................................................................54
9.1.3.12.
PROMIS Itch Questionnaire Scratching Behavior Short 
Form 5a v1.0 ..................................................................................................54
9.1.3.13.
PROMIS Sleep Related Impairment Short Form 8a v1.0.................................54
9.1.3.14.
Neuro-QoL Cognitive Function Short Form v2.0............................................54
9.1.3.15.
Patient Benefit Index ......................................................................................55
9.1.4.
Appropriateness of Assessments ..........................................................................55
9.2.
Adverse Events ............................................................................................................55
9.2.1.
Serious Adverse Events........................................................................................56
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................57
9.2.2.
Adverse Events of Special Interest .......................................................................57
9.2.3.
Complaint Handling.............................................................................................57
9.3.
Treatment of Overdose.................................................................................................58
9.4.
Safety...........................................................................................................................58
9.4.1.
Electrocardiograms ..............................................................................................58
9.4.2.
Vital Signs ...........................................................................................................58
9.4.3.
Physical Examination...........................................................................................58
9.4.4.
Laboratory Tests ..................................................................................................58
9.4.5.
Columbia Suicide Severity Rating Scale...............................................................58
9.4.6.
Self-Harm and Follow-up Supplement Forms.......................................................59
9.4.7.
Chest x-ray and Tuberculosis Testing...................................................................59
9.4.8.
Hepatitis B Virus DNA Monitoring......................................................................59
9.4.9.
Hepatic Safety Monitoring and Data Collection....................................................60
9.4.10.
Safety Monitoring ................................................................................................60
9.5.
Pharmacokinetics .........................................................................................................61
9.6.
Pharmacodynamics ......................................................................................................61
9.7.
Pharmacogenetics.........................................................................................................61
9.7.1.
Blood Samples for Pharmacogenetic Research .....................................................61
9.8.
Biomarkers...................................................................................................................62
9.9.
Medical Resource Utilization and Health Economics ...................................................62
10.
Statistical Considerations ..................................................................................................63
10.1. Sample Size Determination ..........................................................................................63
10.2. Populations for Analyses..............................................................................................63
10.3. Statistical Analyses ......................................................................................................63
10.3.1.
General Statistical Considerations ........................................................................63
10.3.2.
Treatment Group Comparability...........................................................................65
10.3.2.1.
Patient Disposition..........................................................................................65

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10.3.2.2.
Patient Characteristics ....................................................................................65
10.3.2.3.
Concomitant Therapy .....................................................................................66
10.3.2.4.
Treatment Compliance....................................................................................66
10.3.3.
Efficacy Analyses ................................................................................................66
10.3.3.1.
Primary Analyses ...........................................................................................66
10.3.3.2.
Secondary Analyses........................................................................................66
10.3.4.
Safety Analyses....................................................................................................67
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................68
10.3.6.
Other Analyses.....................................................................................................68
10.3.6.1.
Health Outcome Measures..............................................................................68
10.3.6.2.
Subgroup Analyses.........................................................................................68
10.3.7.
Interim Analyses..................................................................................................68
10.3.7.1.
Data Monitoring Committee ...........................................................................68
10.3.7.2.
Adjudication Committee.................................................................................69
11.
References ........................................................................................................................70
12.
Appendices .......................................................................................................................74

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List of Tables
Table
Page
Table JAIY.1.
I4V-MC-JAIY Schedule of Activities ............................................................12
Table JAIY.2.
Objectives and Endpoints...............................................................................21
Table JAIY.3.
Treatment Regimens......................................................................................39
Table JAIY.4.
Criteria for Temporary Interruption of Investigational Product.......................47

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List of Figures
Figure
Page
Figure JAIY.5.1. Illustration of study design for Clinical Protocol I4V-MC-JAIY. ...................26

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................75
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.
Protocol Amendment I4V-MC-JAIY(a) Summary A Multicenter, 
Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to 
Evaluate the Efficacy and Safety of Baricitinib in Combination with 
Topical Corticosteroids in Adult Patients with Moderate to Severe 
Atopic Dermatitis ..........................................................................................88

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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 Combination with Topical Corticosteroids in Adult Patients with Moderate to Severe Atopic 
Dermatitis - BREEZE-AD7
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 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 (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 (I4V-MC-JAHG) was effective at reducing disease severity in patients with 
moderate to severe AD (Guttman-Yassky et al. 2018).  The mechanism of action, combined with demonstration of 
clinical benefits in inflammatory diseases involving joints, kidneys, and skin, provides the rationale for evaluating 
baricitinib in moderate–to-severe AD.
Objectives/Endpoints:
Objectives
Endpoints
Primary
To test the hypothesis that baricitinib 4-mg QD + 
TCS or baricitinib 2-mg QD + TCS is superior to 
placebo + TCS 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.
Key Secondary
These are prespecified objectives that will be adjusted for multiplicity
To compare the efficacy of baricitinib 2-mg QD + 
TCS or baricitinib 4-mg QD + TCS to placebo + TCS
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 EASI75 at 16 weeks

Proportion of patients achieving EASI90 at 16 weeks

Percent change from baseline in EASI score at 
16 weeks

Proportion of patients achieving SCORAD75 at 
16 weeks.

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Objectives
Endpoints
To compare the efficacy of baricitinib 2-mg QD + 
TCS or baricitinib 4-mg QD + TCS to placebo + TCS
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 2 days, 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 
16 weeks.
Other Secondary Objectives
These are prespecified objectives that will not be adjusted for multiplicity.
To compare the efficacy of baricitinib 2-mg QD + 
TCS or baricitinib 4-mg QD + TCS to placebo + TCS
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 16 weeks

Proportion of patients achieving IGA of 0 at 16 weeks

Mean change from baseline in SCORAD at 16 weeks

Proportion of patients achieving SCORAD90 at 
16 weeks

Mean change from baseline in body surface area 
affected at 16 weeks

Proportion of patients developing skin infections 
requiring antibiotic treatment by Week 16

Mean gram quantity of background TCS used over 16 
weeks (tube weights)
To compare the efficacy of baricitinib 2-mg QD + 
TCS or baricitinib 4-mg QD + TCS to placebo + TCS
in AD during the 16-week, double-blind,
placebo-controlled treatment period as assessed by 
patient-reported outcome/QoL measures.

Percent change from baseline in Itch NRS at 2 days, 
1 week, 4 weeks, and 16 weeks

Mean change from baseline in Itch NRS at 2 days, 1 
week, 4 weeks, and 16 weeks

Mean change from baseline in the total score of the 
POEM at 16 weeks

Mean change in PGI-S-AD scores at 16 weeks

Mean change from baseline in the HADS at 16 weeks

Mean change in DLQI scores at 16 weeks

Mean change in WPAI scores at 16 weeks

Mean change in EQ-5D-5L scores at 16 weeks.

Mean number of days without use of background TCS 
over 16 weeks
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; 
TCS = topical corticosteroids; WPAI = Work Productivity and Activity Impairment.
Summary of Study Design:
Study I4V-MC-JAIY (JAIY) is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, outpatient study evaluating the efficacy and safety of baricitinib 4-mg once daily (QD) plus topical 
corticosteroids (TCS) and 2-mg QD plus TCS, as compared to placebo plus TCS in adult patients with moderate to 
severe AD.  The study population will include patients aged 18 years or older who have moderate to severe AD and 
a history of inadequate response to existing topical therapies.

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The study duration will be up to 25 weeks over 3 study periods:

Period 1:  Screening Period lasting from 8 to 35 days prior to Week 0 (baseline, Visit 2).

Period 2:  Double-Blinded Treatment Period, lasting from Week 0 (baseline, Visit 2) through Week 16 
(Visit 8) inclusive:
o
At completion of the double-blind treatment period, eligible patients will be provided the option to 
participate in the long-term extension study I4V-MC-JAHN (JAHN).  Those not eligible or who 
chose not to participate will proceed to the post-treatment follow-up period.

Period 3:  Post-Treatment Follow-Up Period, spanning the period from the last treatment visit at Week 16 
(Visit 8) 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 once daily (QD), baricitinib 2-mg QD, or 
baricitinib 4-mg QD.  Use of TCS as a background therapy is allowed during the study.  The study duration will be 
up to 25 weeks (Screening Period:  up to 5 weeks prior to randomization; Double-Blinded Treatment Period:  
16 weeks; Follow-up Period:  approximately 4 weeks after the last dose of investigational product).
Number of Patients
This study will include approximately 300 patients with AD who will be randomized in a 1:1:1 ratio to receive 
placebo QD, baricitinib 2-mg QD or baricitinib 4-mg QD (100 patients in each treatment group).
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, and region in the model.  The proportions and 95% confidence interval (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, region, baseline severity, 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.
Fisher exact test will be used for all adverse events (AEs), 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 JAIY.1.
I4V-MC-JAIY Schedule of Activities
Screening
Double-Blind, Placebo-Controlled
Post-treatment 
Follow-up
Period 1
Period 2
Period 3
Visit Number
1
2
3
4
5
6
7
8
801a
Weeks from Randomization
0
1
2
4
8
12
16 or ET
Days from Randomization
0
7
14
28
56
84
112
Visit Tolerance Interval (days)
-8 to -35
±2
±2
±2
±4
±4
±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 use)
X
Previous and current AD treatments
X
Weight
X
X
X
X
X
X
X
Height
X
Vital signs (BP and pulse rate)
X
X
X
X
X
X
X
X
X
Physical examination
X
Symptom-directed physical examinationb
X
X
X
X
X
X
X
X
12-lead ECG (single)
X
Chest x-rayc (posterior–anterior view)
X
TB testd
X
Read PPD if applicable (48-72 hours post 
PPD)
Xe
Pre-existing Conditions
X
Adverse Events
X
X
X
X
X
X
X
X
Concomitant Medication
X
X
X
X
X
X
X
X
X
ePRO (patient diary) dispensed
X
X
X
X
X
X
X
Xg
ePRO (patient diary) returnedf
X
X
X
X
X
X
X
Xg

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Screening
Double-Blind, Placebo-Controlled
Post-treatment 
Follow-up
Period 1
Period 2
Period 3
Visit Number
1
2
3
4
5
6
7
8
801a
Weeks from Randomization
0
1
2
4
8
12
16 or ET
Days from Randomization
0
7
14
28
56
84
112
Visit Tolerance Interval (days)
-8 to -35
±2
±2
±2
±4
±4
±4
28 ± 4 after last 
dose
Randomization
X
IWRS
X
X
X
X
X
X
X
X
X
IP dispensed
X
X
X
X
X
X
IP returned and compliance assessed 
X
X
X
X
X
X
Dispense background TCSh
X
X
X
X
X
X
X
Weigh (tube with cap) and record returned 
background TCSh
X
X
X
X
X
X
X
Scales
IGA
X
X
X
X
X
X
X
X
X
EASI
X
X
X
X
X
X
X
X
X
SCORAD
X
X
X
X
X
X
X
X
X
Health Outcome Measures and Other 
Questionnairesi
POEM
X
X
X
X
X
X
X
X
X
DLQI
X
X
X
X
X
X
X
X
HADS
X
X
X
X
X
X
EQ-5D-5L
X
X
X
X
X
X
X
X
WPAI-AD
X
X
X
X
X
X
X
X
Itch NRS
X
X
X
X
X
X
X
X
X
Skin Pain NRS
X
X
X
X
X
X
X
X
X
ADSS
X
X
X
X
X
X
X
X
X
PGI-S-AD
X
X
X
X
X
X
X
X
X
PIQ – Generalj
X
X
X
X
X
X
X
X
X
PIQ – Activity and Clothingj
X
X
X
X
X
X
X
X
X
PIQ – Mood and Sleepj
X
X
X
X
X
X
X
X
X
PIQ – Scratching Behaviorj
X
X
X
X
X
X
X
X
X

I4V-MC-JAIY(a) Clinical Protocol
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Screening
Double-Blind, Placebo-Controlled
Post-treatment 
Follow-up
Period 1
Period 2
Period 3
Visit Number
1
2
3
4
5
6
7
8
801a
Weeks from Randomization
0
1
2
4
8
12
16 or ET
Days from Randomization
0
7
14
28
56
84
112
Visit Tolerance Interval (days)
-8 to -35
±2
±2
±2
±4
±4
±4
28 ± 4 after last 
dose
PROMIS – Sleep-Related Impairmentj
X
X
X
X
X
X
X
X
X
Neuro-QoL – Cognitive Functionj
X
X
X
Patient Benefit Indexj
X
X
X
C-SSRSk/Self-Harm Supplement Form
X
X
X
X
X
X
X
X
X
Self-Harm Follow-up Forml
X
X
X
X
X
X
X
X
X
Laboratory Assessment
Clinical Chemistrym
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
Lipids (fasting)n
X
X
Xo
X
Serum Pregnancyp
X
FSHq
X
TSH
X
HIV
X
HCV antibodyr
X
HBV testing
X
HBV DNAs
X
X
Urinalysis
X
X
X
X
X
X
X
Urine Pregnancyp
X
X
X
X
X
X
X
Pharmacogenetics:  blood
X
Serum immunoglobulins
X
X
X
Exploratory storage samples (serum and
plasma)
X
X
X
RNA and biomarkers:  blood
X
X
X

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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; DNA = deoxyribonucleic acid; EASI = Eczema Area and Severity 
Index; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EQ-5D-5L = the European Quality of Life–5 Dimensions–5 Levels; ET = early 
termination; ePRO = electronic patient-reported outcomes (device); ETV = early termination visit; 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; IP = investigational product; IWRS = interactive web-response system; 
Neuro-QoL = Quality of Life in Neurological Disorders; NRS = numeric rating scale ; PBI = Patient Benefit Index; PGI-S-AD = Patient Global Impression of 
Severity–Atopic Dermatitis;  PIQ = Pain Impact Questionnaire; POEM = Patient-Oriented Eczema Measure; PPD = purified protein derivative; PROMIS = 
Patient-Reported Outcomes Measurement Information System; RNA = ribonucleic acid; SCORAD = SCORing Atopic Dermatitis; TB = tuberculosis; TCS = 
topical corticosteroids; TSH =thyroid-stimulating hormone; WPAI-AD = Work Productivity and Activity Impairment–Atopic Dermatitis.
a
Patients who have discontinued IP, but remain in the study for more than 28 days without IP can combine their Visit 8/ET visit with their Visit 801 (follow-up 
visit).
b
The symptom-directed physical examination may be repeated at the investigator’s discretion any time a patient presents with physical complaints.
c
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.
d
TB test(s) including PPD, QuantiFERON®-TB Gold, and T SPOT®.  See Exclusion Criterion [39] 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 
centrally (recommended/preferred) or locally; 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 screening.)
e
If PPD testing was chosen to test for TB, then the patient must return and have the PPD test read 48 to 72 hours after Visit 1 (post-PPD).  
f
ePRO devices will need to be collected from screen fail patients.
g
For patients not entering Study JAHN, their JAIY patient diary will continue to be dispensed at the final visit and returned at Visit 801.
h
Only as required based on clinical symptoms.
i
The following measures (POEM, DLQI, EQ-5D-5L, WPAI-AD, PIQ, PROMIS, Neuro-QoL, and PBI) should be completed prior to any clinical assessments 
being performed on days when study visits occur.
j
These will be conducted in the countries where translations are available.
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 only required if triggered by the Self-Harm Supplement Form.
m Clinical chemistry will include the following value calculated by the central laboratory from serum creatinine:  estimated glomerular filtration rate (eGFR, 
calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] Creatinine 2009 equation).
n
Fasting lipid profile:  Patients should not eat or drink anything except water for 12 hours prior to sample collection.  If a patient attends these visits in a 
nonfasting state, this will not be considered a protocol violation.
o
Only required for patients completing an ETV prior to completion of Visit 7 (Week 12).

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p
For all women of child-bearing 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.
q
For female patients ≥40 and <60 years of age who have had a cessation of menses for at least 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 (Section 9.4.8).

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3.
Introduction
3.1.
Background
Atopic dermatitis (AD), also known as 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).  Atopic dermatitis 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); 36% of patients have reported
that they often or always scratch until their skin bleeds (Langenbruch et al. 2014).  Pruritus from 
AD can worsen during night time, resulting in sleep disturbances; 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, sleep quality and latency were significantly 
associated with poor quality of life (QoL) (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 Food and Drug Administration (FDA)-approved systemic 
treatments for patients with moderate to severe AD, with the exception of systemic 
corticosteroids, and in the European Union, only cyclosporine had been approved for the 
treatment of patients with severe AD (Bieber and Straeter 2015).  In 2017, Dupixent (dupilumab) 
injection, an IgG4 monoclonal antibody that inhibits interleukin (IL)-4 and IL-13, was approved 
by the FDA and the European Medicines Agency (EMA) for this patient population.  A recently 
completed Phase 2 study (I4V-MC-JAHG [JAHG]) evaluated the safety and efficacy of 
baricitinib (a Janus kinase [JAK] inhibitor) in AD and results showed significant improvement in 
disease severity compared to placebo and no new safety concerns were identified
(Guttman-Yassky et al. 2018).
In addition to AD, baricitinib has also been studied in Phase 3 in patients with rheumatoid 
arthritis (RA) and in Phase 2 in patients with diabetic nephropathy, moderate to severe psoriasis, 
and systemic lupus erythematosus.
Through 13 February 2018, baricitinib has been studied in approximately 548 healthy volunteers 
and 4673 patients have received baricitinib in clinical studies.  Of these, more than 2700 patients 
have been treated with baricitinib for more than a year and more than 2100 patients have been 
treated with baricitinib for more than 2 years at doses of 2-mg once daily (QD) and/or 4-mg QD 
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 

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daily for 24 weeks, 8-mg daily for 76 weeks, and lower doses up to 4-mg daily for up to 
approximately 5 years.
3.2.
Study Rationale
The underlying cause of AD is not completely understood.  Loss of function mutations in the 
gene for filaggrin (filament aggregating protein), 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 T cell activation caused by genetic and environmental factors, leading to significant 
skin infiltration by T cells and dendritic cells.  The cytokine thymic stromal lymphopoietin 
(TSLP) is thought to act as a master switch that triggers the initiation and maintenance of AD 
(Moniaga et al. 2013; Ziegler et al. 2013).  Overexpression of TSLP in keratinocytes, the most 
prevalent cell type in the skin, triggers robust itch-evoked scratching 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 in the skin, TSLP also enhances maturation and differentiation of 
dendritic cells and naive CD4+ T cells and induces production of Th2-related cytokines involved 
in AD pathogenesis (Wilson et al. 2013; Divekar and Kita 2015).  Thymic stromal lymphopoietin
and other key cytokines involved in AD pathogenesis, such as IL-13, IL-5, IL-22, and IL-31, 
signal through receptors associated with intracellular JAK1/JAK2/tyrosine kinase 2 (TYK2) 
signaling (Ziegler et al. 2013; Nomura and Kabashima 2015).
Janus kinases are a family of tyrosine kinases that mediate cytokine receptor signaling through 
phosphorylation and activation of signal transducers and activators of transcription (STAT) 
proteins.  There are 4 known JAK family members:  JAK1, JAK2, JAK3, and TYK2 (Clark et al. 
2014).  The relative affinity of JAK inhibitors for different members of the JAK kinase family 
allows for differentiation of JAK inhibitors in relation to their enzymatic inhibitory profile.  In 
vitro assays indicate that baricitinib is a selective inhibitor of JAKs with potency and selectivity 
for JAK1/2 and less 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 signaling through a JAK1/JAK2 heterodimer intracellularly (or a 
JAK1/JAK2/TYK2), such as IL-6, TSLP, IL-13, or IL-31 (Vaddi and Luchi 2012).
The recently completed Phase 2 study of baricitinib in AD, JAHG, met its primary objective of 
proportion of patients achieving a 50% improvement from baseline in Eczema Area and Severity 
Index (EASI) scores compared to placebo (Guttman-Yassky et al. 2018).  Baricitinib also showed 
statistically significant improvements for other disease severity analyses as well as multiple 
different patient-reported outcome (PRO) scales compared to placebo, further validating the 
hypothesis that JAK1/JAK2 signaling plays a key role in AD pathogenesis.
To comprehensively evaluate the efficacy of baricitinib in patients with AD, both as a 
monotherapy and in combination with background TCS, several Phase 3 studies have been 
initiated.  Two multiregional Phase 3 studies (I4V-MC-JAHL [BREEZE-AD1] and 
I4V-MC-JAHM [BREEZE-AD2]) will evaluate the safety and efficacy of baricitinib 
monotherapy as compared to placebo, in adult patients with moderate to severe AD.  A

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long-term extension study I4V-MC-JAHN(JAHN; discussed in Sections5.1.2and 7.8.1) follows 
studies JAHL, JAHM, and this study (I4V-MC-JAIY[JAIY]), and includes a randomized 
treatment withdrawal and downtitration substudy.  Study I4V-MC-JAIN (BREEZE-AD4) is a 
multiregional Phase3 study evaluating the safety and efficacy of baricitinib in combination with 
TCS in patients with moderatetosevere AD who have experienced failure of cyclosporine, or 
are intolerant to, or have a contraindication to, cyclosporine.
This study, JAIY(BREEZE-AD7), is designed in the same patient population asstudies JAHL 
and JAHM. However,JAIYwill assess baricitinib in combination with TCS, and will provide 
additional information on timing and impact of baricitinib on patient-reported itch, a hallmark of 
AD.  
3.3. Benefit/Risk Assessment
CCI
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 

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CCI
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
More information about the known and expected benefits, risks, serious adverse events (SAEs), 
and reasonably anticipated adverse events (AEs) of baricitinib are to be found in the 
investigator’sbrochure (IB).

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4.
Objectives and Endpoints
Table JAIY.2 shows the objectives and endpoints of the study.
Table JAIY.2.
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
To test the hypothesis that baricitinib 4-mg QD + 
TCS or baricitinib 2-mg QD + TCS is superior to 
placebo + TCS 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.
Key Secondary Objectives
These are prespecified objectives that will be adjusted for multiplicity
To compare the efficacy of baricitinib 2-mg QD + 
TCS or baricitinib 4-mg QD + TCS to placebo + 
TCS 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 EASI75 at 16 weeks

Proportion of patients achieving EASI90 at 16 weeks

Percent change from baseline in EASI score at 
16 weeks

Proportion of patients achieving SCORAD75 at 
16 weeks.
To compare the efficacy of baricitinib 2-mg QD + 
TCS or baricitinib 4-mg QD + TCS to placebo + 
TCS 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 2 days, 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 
16 weeks.
Other Secondary Objectives
These are prespecified objectives that will not be adjusted for multiplicity.
To compare the efficacy of baricitinib 2-mg QD + 
TCS or baricitinib 4-mg QD + TCS to placebo + 
TCS 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 16 weeks

Proportion of patients achieving IGA of 0 at 16 weeks

Mean change from baseline in SCORAD at 16 weeks

Proportion of patients achieving SCORAD90 at 
16 weeks

Mean change from baseline in body surface area 
affected at 16 weeks

Proportion of patients developing skin infections 
requiring antibiotic treatment by Week 16.

Mean gram quantity of background TCS used over 16 
weeks (tube weights)

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Objectives
Endpoints
To compare the efficacy of baricitinib 2-mg QD + 
TCS or baricitinib 4-mg QD + TCS to placebo + 
TCS in AD during the 16-week, double-blind, 
placebo-controlled treatment period as assessed by 
patient-reported outcome/QoL measures.

Percent change from baseline in Itch NRS at 2 days, 
1 week, 4 weeks, and 16 weeks

Mean change from baseline in Itch NRS at 2 days, 1 
week, 4 weeks, and 16 weeks

Mean change from baseline in the total score of the 
POEM at 16 weeks

Mean change in PGI-S-AD scores at 16 weeks

Mean change from baseline in the HADS at 16 weeks

Mean change in DLQI scores at 16 weeks

Mean change in WPAI scores at 16 weeks

Mean change in EQ-5D-5L scores at 16 weeks

Mean number of days without use of background TCS 
over 16 weeks
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 PIQ – General score

Mean change from baseline in PIQ – Activity and Clothing score

Mean change from baseline in PIQ – Mood and Sleep score

Mean change from baseline in PIQ – Scratching Behavior score

Mean change from baseline in PROMIS – Sleep-Related Impairment score

Mean change from baseline in Neuro-QoL – Cognitive Function score

Mean change from baseline in Patient Benefit Index score – global score plus the following subscales:
o
Reducing social impairments
o
Reducing psychological impairments
o
Reducing impairments due to therapy
o
Reducing physical impairments
o
Having confidence in healing.

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

To evaluate changes from baseline in IgE levels during the study

To evaluate changes from baseline in eosinophil levels during the study
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; Neuro-QoL = Quality of Life in Neurological Disorders; NRS = numeric rating scale; PIQ = Pain 
Impact Questionnaire; PROMIS = Patient-Reported Outcomes Measurement Information System; 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; TCS = topical corticosteroids; 
WPAI = Work Productivity and Activity Impairment.

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5.
Study Design
5.1.
Overall Design
Study JAIY is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, outpatient study evaluating the efficacy and safety of baricitinib 2-mg QD and 
4-mg QD, in combination with TCS, as compared to placebo in combination with TCS, in adult 
patients with moderate to severe AD.  The study is divided into 3 periods, a 5-week Screening 
period, a 16-week Double-Blinded Treatment period, and a 4-week Post-Treatment Follow-Up 
period.  For those patients who complete the 16-week treatment period, there is an option to 
participate in the long-term extension Study JAHN.
Approximately 300 patients ≥18 years of age who have responded inadequately to topical 
therapy will be randomized in a 1:1:1 ratio to receive placebo QD, baricitinib 2-mg QD, or 
baricitinib 4-mg QD in combination with TCS (100 patients in each treatment group).  Patients 
will be stratified at randomization according to disease severity (Investigator’s Global 
Assessment [IGA] 3 vs. 4) and geographic region.
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, and Appendix 5 list the specific laboratory tests that will be 
performed for this study. Laboratory samples listed in Appendix 4, Appendix 5, and Appendix 6
are collected when possible in the event of specific AEs.  Study governance considerations are 
described in detail in Appendix 3.  Section 10.3.7.1 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 prior to Visit 2 (Week 0).  At 
Visit 1, the patient will sign the informed consent form (ICF) prior to any study assessments, 
examinations, or procedures being performed (Appendix 3).  All screening procedures will be 
performed according to the Schedule of Activities (Section 2).  Patients who receive a purified 
protein derivative (PPD) skin test at Visit 1 will need to return within 48 to 72 hours later to read 
the skin test.  Prior to 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 
PRO assessments will be the average score of the 7 days prior to randomization; thus, the 
minimum screening window was set at 8 days.
All patients who have not previously received the herpes zoster vaccine by screening will be 
encouraged (per local guidelines) to do so prior to randomization.  Refer to the exclusion 
criterion [28] in Section 6 for additional information regarding herpes zoster vaccinations.  In 
addition, investigators should review the vaccination status of their patients and follow the local 

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guidelines for vaccination of those >18 years of age with nonlive vaccines intended to prevent 
infectious disease prior to entering patients into the study.
Patients who meet all of the inclusion and none of the exclusion criteria (Section 6) will continue 
to Visit 2.
5.1.2. Period 2:  Double–Blind, Placebo-Controlled Treatment
At Visit 2 (Week 0, baseline), study eligibility for each patient will be reviewed, based on all 
inclusion and exclusion criteria (Section 6), and laboratory test results.  Patients who meet all 
criteria will proceed to randomization and begin the 16-week 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 at the clinic.
Patient will be randomized at a 1:1:1 ratio into 1 of the 3 treatment groups (placebo QD, 
baricitinib 2-mg QD, or baricitinib 4-mg QD).  Investigational product will be administered daily 
for 16 weeks (treatment period Visits 2 through 8; Section 7).  All patients will be required to use 
emollients daily.  Daily diaries will continue to be utilized throughout the treatment period.  
Download of this data will be required at study visits.  TCS will be dispensed at V2 and used on 
affected areas as described in section 7.7.2. Topical calcineurin inhibitors (TCNIs) is also 
allowed, but TCNI use should be limited to problem areas (e.g. face and skin folds).  The use of 
higher potency TCS and systemic therapies for the treatment of AD are not allowed, except as 
part of rescue therapy for patients not responding to treatment.  Details of background topical 
therapy, as well as rescue therapy and rescue criteria are included in Section 7.7.  Assessments of 
disease severity will be performed by the investigator at all study visits including unscheduled 
and early termination visits (ETVs).
The primary efficacy endpoint and final visit in the treatment period will be at Week 16 (Visit 8).  
Patients who complete through the Week 16 study visit may be eligible for inclusion in the 
long-term extension study JAHN (up to 2 additional years of treatment).
If a patient discontinues investigational product for any reason, the patient should remain in the 
study through Week 16 (Visit 8).  If the patient refuses and wishes to withdraw consent, an ETV 
should be performed as soon as logistically possible.
5.1.3. Period 3:  Post-Treatment Follow-up
Patients who complete the study through Visit 8 (Week 16) and do not enter the long-term 
extension study will have a post-treatment follow-up visit (Visit 801) approximately 28 days 
after the last dose of investigational product.
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.

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Patients who have discontinued investigational product, but remain in the study for more than 
28 days without investigational product will have an ETV if they chose to discontinue early; 
however, a separate follow-up visit (V801) is not required.
Patients should not initiate new systemic AD treatment during this period.  However, if patients 
or investigators must initiate treatment, patients should complete an unscheduled visit prior to the 
first dose of the new therapy.
Figure JAIY.5.1 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; eGFR = estimated glomerular filtration rate; 
PPD = purified protein derivative; QD = once daily; TCS = topical corticosteroids; 
V = visit; W = week.
a
Applicable to patients taking topical treatments (excluding emollients) or 
systemic treatments for AD at the time of screening.
b
For patients randomized to the 4-mg QD dose who have renal impairment 
(defined as eGFR <60 mL/min/1.73 m2), the baricitinib dose will be 2-mg QD.
c
Patients for whom PPD skin test for the evaluation of tuberculosis infection was 
performed at V1 must return and PPD test must be read 48-72 hours after Visit 1 
(post-PPD).
d
Occurs approximately 28 days after the last dose of IP.  Not required for those 
patients entering the long-term extension study JAHN.
Figure JAIY.5.1.
Illustration of study design for Clinical Protocol I4V-MC-JAIY.
5.2.
Number of Participants
Approximately 300 participants will be enrolled; approximately 420 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.

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5.4.
Scientific Rationale for Study Design
This study will enroll moderate to severe AD patients with a history of inadequate response to 
existing topical therapies for whom a systemic treatment such as baricitinib may therefore be 
appropriate.
Topical corticosteroids are the first-line anti-inflammatory treatment, even for patients treated 
with systemic treatments.  For this reason, this study will assess the efficacy of baricitinib in 
combination with background mild-to-moderate potency TCS, used as determined appropriate by 
the investigator.
During the screening period (Period 1), a washout of systemic and topical treatments for AD was 
incorporated prior to randomization to minimize confounding effects of patients receiving a wide 
range of different background treatments prior to study entry as well as potential safety issues 
related to the use of other therapies, including rebound effects after discontinuation of systemic 
therapies.  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 16 weeks of treatment.
In consideration of the disease severity, all patients in Study JAIY are eligible for rescue to 
higher potency 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 (Section 7.7.4).
Investigator’s Global Assessments 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).  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 (e.g., moderate to severe).  The scale that will be 
used in this study, the validated Investigator’s Global Assessment of Atopic Dermatitis 
(vIGA-AD, referred to throughout the protocol as IGA), has been developed internally and 
assesses AD severity using a 5-point scale.
The 16-week efficacy endpoint was chosen because it is likely that a robust clinical effect will be 
observed with baricitinib within this timeframe based on the Phase 2 study results in AD and 
from previous studies in another inflammatory skin condition.
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 AD Phase 3 studies are baricitinib 2-mg, and 4-mg QD.  These doses 
were chosen primarily based on the recently completed Phase 2 AD study, JAHG, and are 
additionally supported by pharmacokinetics (PK), safety, and efficacy data for baricitinib in 
Phase 2 and Phase 3 RA studies and a Phase 2 psoriasis study.

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In the Phase 2 Study JAHG, both the 2-mg and 4-mg doses showed benefit on the primary and 
major secondary endpoints (Eczema Area and Severity Index [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 (Guttman-Yassky et al. 2018).  However, the 4-mg dose appeared to demonstrate a 
more rapid benefit (at 4 weeks) on the more stringent endpoints (improvement of at least 75% in 
EASI score [EASI75], improvement of at least 90% in EASI score [EASI90], and IGA 0 or 1) 
compared to 2-mg dose particularly in the subgroup of patients with baseline EASI scores ≥16.  
The 4-mg dose resulted in statistically significant improvement in these endpoints at Week 4 and 
this level of response was maintained through Week 16.  A similar trend between the baricitinib 
4-mg and 2-mg doses was observed in patients with RA.  Although in Study JAHG, the 4-mg 
dose seemed to perform better than the 2-mg dose on more stringent endpoints, on other 
endpoints, including an improvement of at least 50% in EASI score [EASI50], and EASI change 
from baseline, 2-mg and 4-mg doses showed similar efficacy compared to placebo.  Therefore, 
both doses will be tested in Study JAIY.  
5.5.1. Dose Adjustment for Renal Impairment
Baricitinib exposure increases with decreased renal function.  Based on PK simulations of 
baricitinib exposures for the mild and moderate categories of renal function (stratified as 
estimated glomerular filtration rate [eGFR] 60 to <90 mL/min/1.73 m2 and eGFR 30 to 
<60 mL/min/1.73 m2, respectively), dose adjustment is not required for patients with eGFR 
≥60 mL/min/1.73 m2.  Patients with eGFR <60 mL/min/1.73 m2 who are randomized to the 
4-mg dose will receive a dose of 2-mg QD, which will ensure that exposures do not exceed those 
of the 4-mg QD dose in patients with eGFR ≥60 mL/min/1.73 m2.  For patients randomized to 
the 2-mg dose, there will be no dose adjustment based on renal function.  The dose adjustment 
for renal impairment will be managed by interactive web-response system (IWRS) to ensure 
maintenance of the treatment blind.  This study will not enroll patients with screening 
eGFR <40 mL/min/1.73 m2.  See Section 8.1.1 for eGFR thresholds that trigger interruption of 
investigational product.
The procedure of dose adjustment based on renal function (eGFR) during the study is detailed in 
Section 7.2.2.

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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 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 at least 18 years of age 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 prior to screening, as defined by the 
American Academy of Dermatology:  Guidelines of care for the management 
of AD; Section 1.  Diagnosis and assessment of atopic dermatitis (Appendix 
7).
[4]
have moderate to severe AD, including all of the following:
a.
Eczema Area and Severity Index (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 preceding screening 
as defined by at least 1 of the following:
a.
inability to achieve good disease control defined as mild disease or better 
(e.g., IGA ≤2) after use of at least a moderate potency TCS for at least 
4 weeks, or for the maximum duration recommended by the product 
prescribing information (e.g., 14 days for super-potent TCS), whichever 
is shorter.  Topical corticosteroids may be used with or without TCNIs.

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b. Patients who failed systemic therapies intended to treat AD within 
6 months preceding screening, such as cyclosporine, methotrexate, 
azathioprine, and mycophenolate mofetil will also be considered as a 
surrogate for having inadequate response to topical therapy.
[6]
agree to discontinue use of the following excluded medications/treatments for 
at least 4 weeks prior to randomization (Visit 2) and throughout the study:
a.
oral systemic corticosteroids 
b. systemic immunomodulators, including, but not limited to, cyclosporine, 
methotrexate, mycophenolate mofetil, and azathioprine
c.
any other systemic therapy used to treat AD or symptoms of AD 
(approved or off-label use)
[7] agree to discontinue the use of following excluded medications for at least 
2 weeks prior to randomization (Visit 2):
a.
TCS or topical immune modulators (e.g., tacrolimus or pimecrolimus)
b. Topical phosphodiesterase type 4 (PDE-4) inhibitor (crisaborole)
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
(Section 7.7.1) for the treatment of allergic conditions other than AD.  
Use of antihistamines for the treatment of itch is not allowed during the 
study.
d. phototherapy, includes therapeutic phototherapy (psoralen plus ultraviolet
A, ultraviolet B), excimer laser as well as self-treatment with tanning 
beds.
[8]
have applied emollients daily for at least 14 days prior to 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 prior to screening as determined by the 
investigator.  Sedating antihistamines (see above) are not permitted.
Patient Characteristics
[10] Male or nonpregnant, nonbreastfeeding female patients
Patients of child-bearing potential who are abstinent (if this is complete 
abstinence, as their preferred and usual lifestyle) 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 
the opposite sex.

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Total abstinence is defined as refraining from intercourse during the entirety 
of the study and for at least 1 week following the last dose of investigational 
product.  Periodic abstinence such as calendar, ovulation, symptothermal, 
postovulation methods and withdrawal are not acceptable methods of 
contraception.
Otherwise, patients and their partners of child-bearing potential must agree to 
use 2 effective methods of contraception, where at least 1 form is highly 
effective for the entirety of the study and for at least 1 week following the last 
dose of investigational product.
The following contraception methods are considered acceptable (the patient, 
and their partner, should choose 2, and 1 must be highly effective [defined as 
<1% failure rate per year when used consistently and correctly]):

Highly effective birth control methods:
o
Combined (estrogen- and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation:  oral, 
intravaginal, or transdermal
o
Progestogen-only hormonal contraception associated with inhibition of 
ovulation:  oral, intravaginal, or implantable
o
Intrauterine device/intrauterine hormone-releasing system
o
Vasectomized partner (with appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate).

Effective birth control methods:
o
Male or female condom with spermicide.  It should be noted that the 
use of male and female condoms as a double barrier method is not
considered acceptable due to the high failure rate when these methods 
are combined.
o
Diaphragm with spermicide
o
Cervical sponge
o
Cervical cap with spermicide
o
Oral contraceptives that do not inhibit ovulation
Note:  When local guidelines concerning highly effective or effective 
methods of birth control differ from the above, the local guidelines must 
be followed.
a.
Females of non–child-bearing potential are not required to use birth 
control and they are defined as:

women ≥60 years of age or women who are congenitally sterile, or

women ≥40 and <60 years of age who have had a cessation of menses for 
≥12 months and a follicle-stimulating hormone (FSH) test confirming 
nonchildbearing potential (≥40 mIU/mL or ≥40 IU/L), or women who are 
surgically sterile (i.e., 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 (e.g., psoriasis or lupus erythematosus) that would interfere with 
evaluations of the effect of study medication on AD.
[12] have had an important side effect to TCS (e.g., intolerance to treatment, 
hypersensitivity reactions, significant skin atrophy, and systemic effects), as 
assessed by the investigator or treating physician that would prevent further 
use.
[13] patients who, in the opinion of the investigator, 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 may interfere with participation in the study.
[14] a history of eczema herpeticum within 12 months prior to screening.
[15] a history of 2 or more episodes of eczema herpeticum in the past.
[16] 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 previous screen failure and at least 2 weeks after resolution of the 
infection.
[17] have any serious concomitant illness that is anticipated to require the use of 
systemic corticosteroids or otherwise interfere with study participation or 
require active frequent monitoring (e.g., unstable chronic asthma).
[18] have been treated with the following therapies:
a.
monoclonal antibody (e.g., ustekinumab, omalizumab, and dupilumab) or 
fusion proteins that target inflammatory pathways (e.g., etanercept) for 
less than 5 half-lives prior to randomization.
b. received prior treatment with any oral JAK inhibitor (e.g., tofacitinib and
ruxolitinib) <4 weeks prior to randomization
c.
received any parenteral corticosteroid administered by intramuscular or 
intravenous injection within 6 weeks prior to 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 prior to 
planned randomization (Visit 2).
Note:  Intranasal or inhaled steroid use is allowed during the trial.

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e.
probenecid at the time of randomization (Visit 2) that cannot be 
discontinued for the duration of the study
Medical Conditions in General
[19] are largely or wholly incapacitated permitting little or no self-care, such as 
being bed-ridden.
[20] 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.  Reassessment of blood pressure during the screening period 
is allowed.
[21] have had any major surgery within 8 weeks prior to screening or will require 
major surgery during the study that in the opinion of the investigator in 
consultation with Lilly or its designee, would pose an unacceptable risk to the 
patient if participating in the trial.
[22] are immunocompromised and, in the opinion of the investigator, at an 
unacceptable risk for participating in the study.
[23] have experienced any of the following within 12 weeks of screening:  VTE, 
myocardial infarction (MI), unstable ischemic heart disease, stroke, or New 
York Heart Association Stage III/IV heart failure.
[24] have a history of recurrent (≥2) VTE or are considered at high risk of VTE as 
deemed by the investigator.
[25] have a history or presence of cardiovascular, respiratory, hepatic, 
gastrointestinal, endocrine, hematological, neurological, or neuropsychiatric 
disorders or any other serious and/or unstable illness that in the opinion of the 
investigator, could constitute an unacceptable risk when taking investigational 
product or interfere with the interpretation of data.
[26] have a history of 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 less than 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.
[27] have a current or recent clinically serious viral, bacterial, fungal, or parasitic 
infection, including but not limited to the following:

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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 prior to screening.
b. a history of disseminated/complicated herpes zoster (e.g., 
multidermatomal involvement, ophthalmic zoster, central nervous system 
involvement, or postherpetic 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 did not 
receive appropriate and documented prophylaxis for TB.
f.
evidence of active TB or have previously had evidence of active TB and 
did not receive appropriate and documented treatment.
g. clinically serious infection or received intravenous antibiotics for an 
infection, within the past 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.
[28] have been exposed to a live vaccine within 12 weeks prior to 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:  Patients eligible for herpes zoster vaccine, who have not received it 
prior to screening will be encouraged (per local guidelines) to do so prior to 
randomization; vaccination with the live herpes zoster vaccine can occur 
during the screening period but must take place >4 weeks prior to 
randomization and start of IP.  
Vaccination with the non-live herpes zoster vaccine requires at least 
2 injections administered 8 weeks apart and, therefore, cannot be completed 
during the 5 week screening period.  Patients who have initiated vaccination 
with non-live herpes zoster vaccine before the trial should plan to receive the 
second dose at least 4 weeks prior to randomization.  
[29] have a history of chronic alcohol abuse, intravenous drug abuse, or other illicit 
drug abuse within the 2 years prior to screening.
[30] 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:
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

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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, and preparatory act or behavior) on the “Suicidal 
Behavior” portion of the C-SSRS;
and the ideation or behavior occurred within 2 months prior to Visit 1.
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.
[31] have donated more than a single unit of blood within 4 weeks prior to 
screening or intend to donate blood during the course of the study.
Other Exclusions
[32] are unable or unwilling to make themselves available for the duration of the 
study and/or are unwilling to follow study restrictions/procedures.
[33] 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.
[34] have participated within the last 30 days in a clinical study involving an 
investigational product.  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) should have passed.
[35] have previously been randomized in this study or any other study 
investigating baricitinib, or who have experienced hypersensitivity to the 
active substance or to any of the excipients.
[36] 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.
[37] are Lilly or Incyte employees or their designee.
Diagnostic Assessments
[38] 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.
[39] have evidence of active TB or latent TB
a.
have evidence of active TB, defined in this study as the following:

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
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.

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.
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:

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 

PPD test is positive and the patient has no medical history or chest 
x-ray findings consistent with active TB, the patient may have a 
QuantiFERON®-TB Gold test or T-SPOT® TB test (as available and if 
compliant with local TB guidelines).  If the test results are not 
negative, the patient will be considered to have latent TB (for purposes 
of this study); or

QuantiFERON®-TB Gold test or T-SPOT® TB test (as available and if 
compliant with local TB guidelines) may be used instead of the PPD 
test.  If the test results are positive, the patient will be considered to 
have latent TB.  If the test is not negative, the test may be repeated 
once within approximately 2 weeks of the initial value.  If the repeat 
test results are again not negative, the patient will be considered to 
have latent TB (for purposes of this study). Patients who have an 
indeterminate QuantiFERON®-TB Gold test (not negative), may either 
repeat the QuantiFERON®-TB Gold test or have T-SPOT TB test. 
Purified protein derivative testing after an indeterminate 
QuantiFERON®-TB Gold test is not allowed.  
Exception:  A patient who has evidence of latent TB may be enrolled if 
he or she completes at least 4 weeks of appropriate treatment prior to 
randomization and agrees to complete the remainder of treatment while in 
the trial.

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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.
[40] have a positive test for HBV infection defined as:
a.
positive for hepatitis B surface antigen (HBsAg), or
b. positive for hepatitis B core antibody (HBcAb) and positive hepatitis B 
virus deoxyribonucleic acid (HBV DNA).
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.
[41] have HCV infection (positive for anti-hepatitis C antibody with confirmed 
presence of HCV ribonucleic acid (RNA)
Note:  Patients who have documented anti-HCV treatment for a past HCV
infection AND are HCV RNA negative may be enrolled in the study.
[42] have evidence of HIV infection and/or positive HIV antibodies.
[43] 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.
[44] have any of the following specific abnormalities on screening laboratory tests:
a.
AST or ALT ≥2x upper limit of normal (ULN)
b. alkaline phosphatase (ALP) ≥2x ULN
c.
total bilirubin ≥1.5x ULN
d. hemoglobin <10.0 g/dL (100.0 g/L)
e.
total white blood cell count <2500 cells/µL (<2.50x103/µL or 
<2.50 GI/L)

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f.
neutropenia (absolute neutrophil count [ANC] <1200 cells/µL) 
(<1.20x103/µL or <1.20 GI/L)
g. lymphopenia (lymphocyte count <750 cells/µL) (<0.75x103/µL or 
<0.75 GI/L)
h. thrombocytopenia (platelets <100,000/µL) (<100x103/µL or <100 GI/L)
i.
eGFR <40 mL/min/1.73 m2 (Chronic Kidney Disease Epidemiology 
Collaboration equation [CKD-EPI] Creatinine 2009 equation).
Note:  For cases with any of the aforementioned laboratory abnormalities 
(Exclusion Criteria [43] and [44]), 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.
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 2-mg, and baricitinib 4-mg administered 
orally once a day.  Table JAIY.3 shows the treatment regimens.
Table JAIY.3.
Treatment Regimens
Regimen
Investigational Product Supplied
Dose
Baricitinib 4-mg QDa
Baricitinib 4-mg tablets
2 tablets per day
Placebo to match 2-mg tablets
Baricitinib 2-mg QD
Baricitinib 2-mg tablets
2 tablets per day
Placebo to match 4-mg tablets
Placebo QD
Placebo to match 4-mg tablets
2 tablets per day
Placebo to match 2-mg tablets
Abbreviation:  QD = once daily.
a
The baricitinib dose for patients randomized to the 4-mg QD treatment group who have renal impairment 
(defined as eGFR <60 mL/min/1.73 m2) will be 2-mg QD.
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

at the end of the study, returning all unused medication to Lilly, or its designee, 
unless the sponsor and sites have agreed all unused medication is to be destroyed 
by the site, as allowed by local law
7.1.1. Packaging and Labeling
The sponsor (or its designee) will provide the following investigational products:

tablets containing 4-mg of baricitinib

tablets containing 2-mg of baricitinib

placebo tablets to match baricitinib 4-mg tablets and 2-mg tablets
Patients are required to take 2 tablets daily from packages assigned by the IWRS.  
Clinical trial materials will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized in a 1:1:1 ratio (placebo:  
baricitinib 2-mg:  baricitinib 4-mg) to double-blind treatment at Visit 2 (Week 0).  
Randomization will be stratified by geographic region (Europe, Japan, rest-of-world) and disease 
severity at baseline (IGA 3 vs. 4).  Assignment to treatment groups will be determined by a 
computer-generated random sequence using an IWRS.  The IWRS will be used to assign 

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packages containing double-blind investigational product tablets to each patient according to the 
study schedule of activities. Site personnel will confirm that they have located the correct 
packages by entering a confirmation number found on the packages into the IWRS.
7.2.1. Selection and Timing of Doses
The investigational product should be taken once daily 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.  
7.2.2. Dose Adjustment for Renal Impairment
The rationale of dose adjustment for patients with documented renal impairment (defined as 
screening eGFR ≥40 to <60 mL/min/1.73 m2) is detailed in Section 5.5.1.
The dose adjustment for renal impairment will be managed by IWRS to ensure maintenance of 
the treatment blind.  The eGFR value from the screening visit (Visit 1) will be entered into IWRS 
at Visit 2, and IWRS will assign the treatment doses accordingly.
Patients with documented renal impairment (defined as screening eGFR ≥40 to 
<60 mL/min/1.73 m2), who are randomized to the 4-mg active treatment arm will receive a dose 
of 2-mg QD by the IWRS.  For patients randomized to the 2-mg dose, there will be no dose 
adjustment based on renal function.
No dose adjustment will be made for patients with screening eGFR ≥60 mL/min/1.73 m2.  These 
patients who are randomized to active treatment will receive their assigned dose, either 
baricitinib 4-mg or 2-mg, respectively.
During the study, for patients with documented renal impairment when the subsequent eGFR 
falls <30 mL/min/1.73 m2, investigational product will be withheld until their eGFR becomes 
≥40 mL/min/1.73 m2, whereupon the investigational product dosing may resume.  For patients 
with screening eGFR ≥60 mL/min/1.73 m2, when the subsequent eGFR falls to 
<40 mL/min/1.73 m2, investigational product will be withheld until their eGFR becomes 
≥50 mL/min/1.73 m2, whereupon the investigational product dosing may resume (Section 8.1.1).
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 until after 
completion of the Double-Blinded Treatment Period.  It is expected that the need for unblinding 
a patient’s treatment prior to completion of the Double-Blinded Treatment Period will be 
extremely rare.  Every effort should be made to preserve the blind unless there is a compelling 
reason that knowledge of the specific treatment would alter the medical care of the patient.  In 
case of an emergency, the investigator has the sole responsibility for determining if unblinding of 

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a patient’s treatment assignment is warranted for medical management of the event.  Patient 
safety must always be the first consideration in making such a determination.  Where feasible 
and when timing of the emergent situation permits, the investigator should attempt to contact the 
Lilly medical monitor before unblinding a subject’s treatment assignment.  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 10.3.7.1.
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 8) 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).

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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 7.7.4.
7.7.1. 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 containing pharmacological agents with antipruritic or antiseptic
properties 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 prior to the 
procedures to allow adequate assessment of skin dryness

Background TCS therapy with moderate-potency and/or low-potency TCS (e.g., 
triamcinolone 0.1% cream and/or hydrocortisone 2.5% ointment) are to be used on active 
lesions, as described in Section 7.7.2

Topical calcineurin inhibitors (e.g., tacrolimus and pimecrolimus), or topical 
PDE-4 inhibitor (i.e., crisaborole, where approved) are permitted in place of TCS 
on areas where application of TCS is considered inappropriate by the investigator; 
use should be limited to problem areas (e.g., face, neck, skin folds, genital areas, 
etc.) as described in Section 7.7.2
In addition, the following therapies are permitted during the study:

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, desloratadin, fexofenadine, levocetirizine, loratadine, mizolastine, and 
rupatadine are allowed for treatment of allergic conditions other than AD.  Use of 
antihistamines for treatment of itch is not allowed during the study

Single intra-articular or soft tissue (bursa, tendons, and ligaments) corticosteroid 
injection is allowed during the 16-week double-blind, placebo-controlled period

Intranasal or inhaled steroid use is allowed

Topical anesthetics and topical and systemic anti-infective medications are 
allowed

Nonlive vaccinations are allowed; however, vaccination while receiving 
baricitinib may reduce efficacy of the vaccine

ophthalmic drugs containing antihistamines, corticosteroids or other immunosuppressants
are allowed 

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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.
7.7.2.Use of Topical Corticosteroids
A washout period of 14 days is required for all TCS prior to randomization at Visit 2.
At baseline (Week 0, Visit 2), patients will receive triamcinolone 0.1% cream (or 
equivalent-potency TCS) and hydrocortisone 2.5% ointment (or equivalent-potency TCS).  See 
“Choice of Background Topical Corticosteroid” below.  Triamcinolone 0.1% cream 
(moderate-potency TCS) should be applied at least once daily to affected areas until lesions are 
under control (clear or almost clear).  Patients should then switch to hydrocortisone 2.5% ointment 
(low-potency TCS) and treat previously affected areas once-daily for 7 days and then stop.  
Hydrocortisone 2.5% ointment (low-potency TCS) may also be used to replace triamcinolone 0.1% 
cream (moderate-potency TCS) on areas of thin skin (face, neck, folds, and genital areas) and areas 
with skin atrophy.
If lesions reappear during the course of the study, the patients should resume the once-daily 
applications of triamcinolone 0.1% cream (moderate-potency TCS) or hydrocortisone 2.5% 
ointment (low-potency TCS) as described above.
Patients whose lesions persist or worsen despite the use of emollients and low- and/or 
moderate-potency TCS and/or patients who require daily applications on large surfaces may be 
considered for topical rescue with high- or ultra-high-potency TCS (Section 7.7.4 for details).
On the days of study visits, topical therapy including TCS should not be applied before the patient 
has undergone all study procedures and clinical evaluations in order to allow adequate assessment 
of skin dryness. Inability to follow this guidance for use of TCS will not be considered a protocol 
violation.
Choice of Background Topical Corticosteroid
Where possible, triamcinolone cream 0.1% and/or hydrocortisone 2.5% ointment will be 
supplied by the sponsor for use as background TCS.  In the event of these specific TCS being 
unavailable, an alternate, equivalent-potency TCS may be provided by the sponsor (see below).  
Topical corticosteroid use, when supplied by the sponsor, should be recorded via weight of 
returned tubes as indicated in the Schedule of Activities (Section 2).  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 by the sites.  Refer to Appendix 8 for guidance on potency 
equivalence.  

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
Where possible, TCS use when supplied by the site should also be recorded via weight of 
returned tubes, as indicated in the Schedule of Activities (Section 2); however, where this 
is not practical, this information does not need to be recorded, and will not be considered 
a protocol violation.  

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.
Choice of High- and Ultra-High-Potency Topical Corticosteroids for Rescue
The use and choice of specific high- or ultra-high-potency TCS for rescue is at the discretion of 
the investigator and it will not be provided by the sponsor.  The weights of returned tubes of the 
high- and ultra-high-potency TCS are not required.
Other Topical Treatments
Investigators may also select to use TCNIs and/or crisaborole in countries where approved, in 
place of TCS.  If TCNIs or crisaborole are prescribed, use should be limited to problem areas 
(e.g., face, neck, skin folds, genital areas, etc.).
Use of all topical treatments for AD must be recorded in the CRF.
7.7.3. Prohibited Medications and Procedures
Prohibited Medications and Procedures Not Requiring 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, the prohibited therapy must be discontinued.  

High potency TCS (defined as any TCS with higher than moderate strength as 
defined in Appendix 8) except when given as rescue therapy as described in 
Section 7.7.4.

topical antihistamines or sedating, systemic antihistamines including, but not limited to, 
alimemazine, chlorphenamine, clemastine, cyproheptadine, diphenhydramine, 
hydroxyzine, ketotifen, and promethazine

Prescription allergen immunotherapy

phototherapy including psoralen and ultraviolet A (PUVA), ultraviolet B, tanning 
booth and excimer laser

bleach baths 
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 [BCG] or herpes zoster), 
(see Exclusion Criterion [28])

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o
For BCG vaccination, investigational product should be temporarily 
interrupted for 12 weeks.
o
For live herpes zoster vaccination, investigational product should be 
temporarily interrupted for 4 weeks.  

probenecid:  if a patient is inadvertently started on probenecid, 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 
investigational product should be permanently discontinued
Prohibited Medications Requiring Permanent Discontinuation of Investigational Product

systemic corticosteroids

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)

other JAK inhibitors (e.g., tofacitinib and ruxolitinib)

systemic immunosuppressive/immunomodulatory substances, including, but not 
limited to, cyclosporine, methotrexate, mycophenolate mofetil, interferon γ, 
azathioprine, or biologic agents
Note:  In the event that these prohibited medications were inadvertently used, agreement and 
documentation to continue investigational product must be sought from sponsor.
7.7.4. Rescue Therapy
For patients who are experiencing worsening and unacceptable symptoms of AD despite 
treatment with investigational product and moderate-potency TCS, rescue therapy with 
additional topical and systemic therapies is available starting after 2 weeks of treatment (Visit 4).  
Use of rescue medications should be limited to patients where control of symptoms cannot be 
achieved with increased emollient use and background TCS (low potency and moderate 
potency).  Prior to rescue, control of AD symptoms should be attempted by avoiding 
exacerbating factors, intensifying emollient applications, and using only the permitted study 
treatments, including background TCS therapy (e.g., triamcinolone 0.1% cream and/or 
hydrocortisone 2.5% ointment) (Section 7.7.2).
Rescue with High- and Ultra-High-Potency TCS
Patients whose lesions persist or worsen despite the use of emollients and background TCS 
therapy (e.g., triamcinolone 0.1% cream and/or hydrocortisone 2.5% ointment) and/or patients 
who require prolonged applications of triamcinolone 0.1% cream (moderate-potency TCS) on 
large surfaces may be considered for rescue to high- or ultra-high-potency TCS (Appendix 8 for 
TCS potency).
High- or ultra-high-potency TCS may be used once daily for up to 14 consecutive days or less, or
based on the maximum duration recommended in the prescribing information.

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It is recommended that if a patient reaches “clear” to “almost clear” skin after topical rescue, 
then moderate-, high-, or ultra-high-potency TCS should be stopped, and low-potency TCS (e.g., 
hydrocortisone 2.5% ointment) should be used once daily for an additional 7 days, then stopped.
Patients rescued with high- or ultra-high-potency TCS will continue to take investigational 
product and use of topical rescue therapy will be documented in the eCRF.
Rescue with Systemic Therapies
If topical rescue therapy as described above fails to sufficiently control AD symptoms, then oral 
systemic medications may be used as rescue (e.g., corticosteroids, cyclosporine, and 
methotrexate); however, investigational product will be required to be permanently discontinued 
for the remainder of the 16-week study duration.  If these medications are needed for other 
medical conditions (e.g., asthma flare), they will still be treated as rescue medications.  These 
patients are still eligible to enter the long-term extension study (JAHN), if they complete the 
schedule of study visits through Visit 8 (Week 16) and are also able to complete a minimum 
4-week washout from oral systemic rescue medications (which can occur during the screening 
period for Study JAHN).  
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.
7.8.
Treatment after the End of the Study
7.8.1. Study Extensions
Patients who complete this study through Visit 8 may be eligible to participate in Study JAHN, if 
enrollment criteria for Study JAHN are met.
7.8.2. Continued Access
After the conclusion of the study, continued access to baricitinib will not be provided to patients 
who are not eligible for or who do not choose to participate in Study JAHN.  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 the study treatment, is graded as moderate
(Grade 2 according to Common Terminology Criteria for Adverse Events [CTCAE] 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 JAIY.4.
For the abnormal laboratory findings and clinical events (regardless of relatedness) listed in 
Table JAIY.4, specific guidance is provided for temporarily interrupting treatment and when 
treatment may be restarted.  Retest frequency and timing of follow-up laboratory tests to monitor 
the abnormal finding is at the discretion of the investigator.  Investigational product that was 
temporarily interrupted because of an AE or abnormal laboratory value not specifically covered 
in Table JAIY.4 may be restarted at the discretion of the investigator.  If laboratory abnormalities 
leading to temporary interruption of investigational product are identified from Visit 2 laboratory 
tests, investigational product must still be interrupted, even though the abnormal laboratory 
results are unrelated to investigational product.
Table JAIY.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
(<2.00x103/µL or <2.00 GI/L)
WBC count 2500 cells/µL
(≥2.50x103/µL or ≥2.50 GI/L)
ANC <1000 cells/L
(<1.00x103/µL or <1.00 GI/L)
ANC ≥1200 cells/µL
(≥1.20x103/µL or ≥1.20 GI/L)
Lymphocyte count <500 cells/µL
(<0.50x103/µL or <0.50 GI/L)
Lymphocyte count 750 cells/µL
(≥0.75x103/µL or ≥0.75 GI/L)
Platelet count <75,000/µL
(<75x103/µL or <75 GI/L)
Platelet count 100,000/µL
(≥100x103/µL or ≥100 GI/L)
eGFR <40 mL/min/1.73 m2 (from serum creatinine) for 
patients with screening eGFR ≥60 mL/min/1.73 m2
eGFR 50 mL/min/1.73 m2
eGFR <30 mL/min/1.73 m2 (from serum creatinine) for 
patients with screening eGFR ≥40 to <60 mL/min/1.73 m2
eGFR 40 mL/min/1.73 m2
ALT or AST >5x ULN
ALT and AST return to <2x 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
Clinical features of VTE (such as deep vein thrombosis or 
pulmonary embolism) are presenta
After evaluation and institution of appropriate 
treatment of VTEb

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Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; eGFR = estimated glomerular filtration rate; IP = investigational product; ULN = upper limit 
of normal; VTE = venous thromboembolic event; WBC = white blood cell.
a
Evaluate promptly and institute appropriate treatment.  Upon evaluation if VTE is ruled out and no other 
temporary or permanent discontinuation criteria are met, then IP may be resumed.  
b
After evaluation and institution of treatment if the investigator deems that the patient is still at significant risk, or 
if this would constitute a second VTE for the patient, then IP should be discontinued permanently.
Although temporary interruption of investigational product is not a requirement at times of 
increased potential risk of VTE (e.g., surgery, significant air travel, or other situations involving 
prolonged immobilization) we recommend following appropriate VTE prophylaxis guidelines to 
help manage the VTE risk under these circumstances.  
For specific guidance on temporary interruption of investigational product after use of a 
prohibited medication, please refer to Section 7.7.3 (Prohibited Medications and Procedures).
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:  Prior to 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 subject should remain on investigational product and ultimately continued 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 nonsuicidal 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 >8x ULN

ALT or AST >5x ULN for more than 2 weeks

ALT or AST >3x ULN and total bilirubin level (TBL) >2x ULN or international 
normalized ratio (INR) >1.5

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
ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, and/or rash

ALP >3x ULN

ALP >2.5x ULN and TBL >2x ULN

ALP >2.5x 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 due to a hepatic 
event or liver test abnormality should have additional hepatic safety data collected via 
the hepatic safety eCRF.
Investigational product should be permanently discontinued if any of the following laboratory 
abnormalities are observed:

white blood cell count <1000 cells/µL (1.00x103/µL or 1.00 GI/L)

ANC <500 cells/µL (0.50x103/µL or 0.50 GI/L)

lymphocyte count <200 cells/µL (0.20x103/µL or 0.20 GI/L)

hemoglobin <6.5 g/dL (<65.0 g/L)
NOTE:  Temporary interruption rules (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 JAIY.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)

hepatitis B virus DNA is detected with a value above limit of quantitation or 
2 sequential tests return a value of below the limit of quantitation (Section 9.4.8)

develop a second VTE

certain prohibited medications are taken per Section 7.7.3 (Prohibited 
Medications and Procedures)
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 (GCP)

investigator decision
o
The investigator decides that the patient should be discontinued from the 
study
o
If the patient, for any reason, requires treatment with another therapeutic agent 
(not allowed as part of rescue therapy [Section 7.7.4]) that has been 
demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

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
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 investigator’s 
global assessment of the patient’s overall severity of their AD, based on 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. Secondary Efficacy Assessments
9.1.2.1.
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).
Body surface area affected by AD will be derived from data collected as part of the EASI 
assessment.
9.1.2.2.
SCORing Atopic Dermatitis
The 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).
9.1.2.3.
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 (e.g., 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 

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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 and in countries where the questionnaires have been translated into the 
native language of the 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 to 
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 last 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 last 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 past 24 hours.
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, 

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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 lot,” and “very 
much,” with corresponding scores of 1, 2, and 3, respectively, and unanswered (“not relevant”) 
responses scored as 0.  Scores range from 0 to 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 QoL (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 ticking (or placing a cross) 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.
9.1.3.9.
PROMIS Itch Questionnaire General Short Form 8a v1.0
Patient-Reported Outcomes Measurement Information System (PROMIS) is a set of 
person-centered measures that evaluates and monitors physical, mental, and social health in 
adults and children.  It can be used with the general population and with individuals living with 
chronic conditions.  The Itch General Short Form 8a (PIQ – General) within the PROMIS itch 
item bank consists of 8 items assessing the impact of itch on various aspects of life.  Response 

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options range from 1=Never, 2=Rarely; 3=Sometimes; 4=Often; to 5=Almost always; total raw 
scores are converted to T-Scores with higher scores representing greater impact because of itch.
9.1.3.10. PROMIS Itch Questionnaire Activity and Clothing Short Form 8a v1.0
The Activity and Clothing Short Form 8a (PIQ – Activity and Clothing) within the PROMIS itch 
item bank consists of 8 items assessing activity and clothing related quality of life impairment 
from itch in adults “in the past 7 days”.  Response options range from 1=Never, 2=Rarely; 
3=Sometimes; 4=Often; to 5=Almost always; total raw scores are converted to T-Scores with 
higher scores representing greater impact on activity and clothing because of itch.  
9.1.3.11. PROMIS Itch Questionnaire Mood and Sleep Short Form 8a v1.0
The Mood and Sleep Short Form 8a (PIQ – Mood and Sleep) within the PROMIS Itch item bank 
consists of 8 items assessing mood and sleep related quality of life impairment from itch and 
impact of itch “in the past 7 days”.  Response options range from 1=Never, 2=Rarely; 
3=Sometimes; 4=Often; to 5=Almost always; total raw scores are converted to T-Scores with 
higher scores representing greater impact on mood and sleep because of itch.  
9.1.3.12. PROMIS Itch Questionnaire Scratching Behavior Short Form 5a v1.0
The Scratching Behavior Short Form 5a (PIQ – Scratching Behavior) within the PROMIS Itch 
item bank consists of 5 items assessing quality of life impairment from scratching behavior and 
the physical manifestations of itch in adults “in the past 7 days”.  Response options for the 
frequency of scratching behaviors range from 1=Never, 2=Rarely, 3=Sometimes; 4=Often, to 
5=Almost always.  The response options for the worry related to scratching items range from 
1=Not at all; 2=A little bit; 3=Somewhat; 4=Quite a bit; to 5=Very much.  Total raw scores are 
converted to T-Scores with higher scores representing more scratching behavior.  
9.1.3.13. PROMIS Sleep Related Impairment Short Form 8a v1.0
The Sleep Related Impairment Short Form 8a (PROMIS – Sleep Impairment [PROMIS 2015])
within the PROMIS bank consists of 8 items measuring self-reported perceptions of alertness, 
sleepiness, and tiredness during usual waking hours, and the perceived functional impairments 
during wakefulness associated with sleep problems or impaired alertness “in the past 7 days”.  
Response options range from 1=Not at all; 2=A little bit; 3=Somewhat; 4=Quite a bit; to 5=Very 
much.  Total raw scores are converted to T-Scores with higher scores representing greater sleep 
impairment.
9.1.3.14. Neuro-QoL Cognitive Function Short Form v2.0
Neuro-QoL is a set of self-reported measures that assess the health-related quality of life 
(HRQOL) of adults and children with neurological disorders and is comprised of item banks and 
scales that evaluate symptoms, concerns, and issues that are relevant across disorders along with 
instruments that assess areas most relevant for specific patient populations (NINDS 2015).  The 
Cognitive Function Short Form v2.0 (Neuro-QoL – Cognitive Function) domain within 
Neuro-QoL bank consists of 8 items measuring Executive Function (perceived difficulties in 
applications of mental health function related to planning, organizing, calculating, remembering 
and learning) “in the past 7 days” and General Concerns (perceived difficulties in everyday 
cognitive abilities such as memory, attention, and decision making) using the lead-in phrase 

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“how much difficulty do you currently have…”.  The response options for the Executive 
Function items range from 1=Very Often (several times a day); 2=Often (once a day); 
3=Sometimes (2-3 times); 4=Rarely (once); to 5=Never).  The response options for the General 
Concerns items range from 1=Cannot do; 2=A lot; 3=Somewhat; 4=A little, to 5=None.  The 
total raw scores and are converted to T-Scores with higher scores indicating better (desirable) 
self-reported health.  
9.1.3.15. Patient Benefit Index
The Patient Benefit Index (PBI) measures patient-defined treatment objectives and benefits, 
particularly in the course of a treatment (Augustin et al. 2009; Blome et al. 2011). It consists of 
2 questionnaires. Before therapy, patients complete the standardized “Patient Needs 
Questionnaire” indicating individual importance of treatment objectives. This reflects their 
personal preferences with respect to therapeutic benefit. During the study, patients rate the 
extent to which the treatment objectives have been achieved in the “Patient Benefit 
Questionnaire”. Response options range from 0=not at all, 1=somewhat; 2=moderately; 3=quite; 
4=very; to 5=does/did not apply to me. A global score is calculated for each patient by weighing 
the achievement values of the treatment objectives by their importance to the individual patient. 
Moreover, the PBI will be supplemented by 6 rating scales assessing the following areas:  
physical well-being, emotional well-being, performance capacity on the job and in everyday 
living, social contacts, leisure activities, and quality of life. Patients with PBI ≥1 are considered 
having at least minimum patient-relevant treatment benefit.
9.1.4. Appropriateness of Assessments
All assessments utilized in this study are standard, widely used, and generally recognized as 
reliable, accurate, and relevant except 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 or stabilizes with
appropriate diagnostic evaluation; for events that are not anticipated to resolve or stabilize, the 
patient should be followed until the treating physician (in consultation with the sponsor) 
determines that appropriate followup has been completed.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.

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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.  In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs. 
Investigators should record the following via eCRF for each AE:  time of onset, time of 
termination, severity, and their assessment of the potential relatedness of each AE to 
investigational product.
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:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (i.e., 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.

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Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method (e.g. investigator space portal, telephone, 
or fax).  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.  Investigators can contact 
the sponsor via telephone at any time using the qualified medical personnel or Lilly affiliate
medical contact details which are provided in the site study file.  
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 
and expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidances.
9.2.2. Adverse Events of Special Interest
Adverse events of special interest will include the following:

infections (including TB, herpes zoster, or opportunistic infections)

malignancies (except for successfully treated basal or squamous cell carcinoma)

hepatic events (Section 9.4.9)

major adverse cardiovascular events (MACE) (Section 9.4.10)

thrombotic events (such as deep vein thrombosis [DVT] and pulmonary 
embolism)
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.

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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.
Electrocardiograms 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).
9.4.3. Physical Examination
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 

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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 prior to 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 where 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 0, 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 prior to the study are available.  The chest 
x-ray will be reviewed by the investigator or his or her designee to exclude patients with active 
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 at Week 16 (Visit 8) or early termination visit, regardless of their 
hepatitis B surface antibody (HBsAb) status.
The following actions should be taken in response to HBV DNA test results:

If a single result is obtained with a value “below limit of quantitation,” the test 
should be repeated within approximately 2 weeks.  If the repeat test result is 
“target not detected,” monitoring will resume for those patients enrolling in the 
long-term extension study, JAHN.

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 (Section 8.1.2) and should be referred 
to a hepatology specialist.  

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9.4.9. Hepatic Safety Monitoring and Data Collection
If a study patient experiences elevated ALT ≥3x ULN, ALP ≥2x ULN, or elevated TBL
≥2x ULN, liver testing (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, 
ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator and in 
consultation with the study medical monitor.  Monitoring of ALT, AST, TBL, and ALP should 
continue until levels normalize or return to approximate baseline levels.
Discontinuation criteria of investigational products, either temporary interruption or permanent 
discontinuation, due to abnormal ALT, AST, TBL, or ALP, are detailed in Section 8.1.
Additional safety data should be collected via the hepatic eCRF if 1 or more of the following 
conditions occur:

elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥ 2x ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2x 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
See Appendix 4 and Appendix 5 for a description of hepatic laboratory values that warrant 
exclusion from the study, temporary or permanent discontinuation of investigational product, or 
additional safety collection via the hepatic eCRF.
9.4.10. 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 10.3.7]) 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 

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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 events and VTE (Appendix 6).  Adverse event reports and vital signs will be 
collected at each study visit.  The cardiovascular monitoring plan includes the following:

regular monitoring of lipid levels

potential MACE (cardiovascular death, MI, and stroke), other cardiovascular 
events (such as hospitalization for unstable angina, hospitalization for heart 
failure, serious arrhythmia, resuscitated sudden death, cardiogenic shock, 
coronary revascularization such as coronary artery bypass graft or percutaneous 
coronary intervention), venous thrombotic events 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, and excretion, the mechanism of action of the drug, the disease 
etiology, and/or the molecular subtype of the disease being treated.  In the event of an 
unexpected AE, the samples may be genotyped and analysis may be performed to evaluate a 
genetic association with response to baricitinib.  These investigations may be limited to targeted 
exome sequencing approach of known targets involved in drug metabolism or, if appropriate, 
genome-wide association studies may be performed to identify regions of the genome associated 
with the variability observed in drug response.  Samples will 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.

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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 (ERBs)/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.
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 (PD), mechanism of action, variability of patient response 
(including safety), and clinical outcome.  Sample collection is incorporated into clinical studies 
to enable examination of these questions through measurement of biomolecules including DNA, 
RNA, proteins, lipids, and other cellular elements.
Blood samples for nonpharmacogenetic biomarker research will be collected at the times
specified in the Schedule of Activities (Section 2) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
baricitinib, pathways associated with 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 ERBs 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 
(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 JAIY will aim to enroll approximately 300 patients ≥18 years of age.  The proposed 
sample size will ensure an 89% power to detect an absolute difference of 20% between the 
baricitinib 4-mg and placebo treatment groups and the baricitinib 2-mg and placebo treatment 
groups, each using a 2-sided alpha of 0.025 and a Fisher exact test, assuming a 10% placebo 
response rate for the primary endpoint.  The assumptions are based on what was observed in the 
Phase 2 study (JAHG).  The proposed end point of IGA 0 or 1 represents patients whose AD is 
clear or almost clear from a baseline of moderate or severe disease.  The anticipated effect size 
represents 3 times more patients achieving this benefit compared to placebo, which, in discussion 
with therapeutic experts, is of a magnitude that is considered clinically relevant.
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 if the patient does 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.
Safety analyses will be done 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 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 (CSR).  Additional exploratory analyses of the data will be conducted 
as deemed appropriate.
All tests of treatment effects will be conducted at a 2-sided alpha 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 region, disease severity, and treatment 
group in the model.  The percentages, difference in percentages, and 95% confidence interval 

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(CI) of the difference in percentages will be reported.  Treatment-by-region interaction will be 
added to the logistic regression 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 (i.e., 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 
p-value from the Fisher exact test will also be produced.
When evaluating continuous measures over time, a restricted maximum likelihood-based 
mixed-effects model of repeated measures (MMRM) will be used.  The model will include 
treatment, region, baseline severity, 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 (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 least squares 
means (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 analysis of covariance (ANCOVA) with region, disease severity, treatment group, and 
baseline value in the model.  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 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 (e.g., 
“high” or “low” laboratory results) will also be produced.
Missing data imputation:
1. Nonresponder imputation (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. MMRM:  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.
3. Last observed carried forward (LOCF):  An additional analysis will be performed that 
uses the last observed value on or prior to discontinuation or rescue therapy.  This will 

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then be analyzed using a logistic model for categorical variables or ANCOVA for 
continuous variables as described above.
Additional sensitivity analyses for the primary and key secondary endpoints such as tipping point 
analyses as well as a reference based multiple imputation method may be done and will be 
specified in the SAP.
Adjustment for Multiple Comparisons:
Multiplicity controlled analyses will be performed on the primary and major secondary endpoints 
to control the overall family-wise Type I error rate at a 2-sided α level of 0.05.  The graphical 
multiple testing procedure described in Bretz et al. (2011) will be used.  The graphical approach 
is a closed testing procedure; hence it strongly controls the family-wise error rate across all 
endpoints (Alosh et al. 2014).  Details of the specific graphical testing scheme (including testing 
order, interrelationships, Type I error allocation, and the associated propagation) will be 
prespecified in the SAP.
The following is a list of primary and key secondary endpoints to be tested:
Primary:

proportion of baricitinib 4-mg patients achieving IGA of 0 or 1 and ≥2-point 
improvement from baseline at Week 16.

proportion of baricitinib 2-mg patients achieving IGA of 0 or 1 and ≥2-point 
improvement from baseline at Week 16.
Key Secondaries:
Evaluated for  2-mg and 4-mg:

proportion of patients achieving EASI75 at 16 weeks

proportion of patients achieving EASI90 at 16 weeks

percent change from baseline in EASI score at 16 weeks

proportion of patients achieving SCORAD75 at 16 weeks

proportions of patients achieving a 4-point improvement in Itch NRS at 2 days, 
1 week, 2 weeks, 4 weeks, and 16 weeks

mean change from baseline in the score of Item 2 from the ADSS at 1 week and 
16 weeks

mean change from baseline in skin pain NRS at 16 weeks
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, 

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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.
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 patient’s 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 binary outcome of response defined as IGA score of 0 or 1 
(clear or almost clear skin) and ≥2-point improvement from baseline at Week 16.  Primary 
analysis will be conducted using a logistic regression as described above with treatment and the 
stratification variables (disease severity and region) in the model.  Nonresponder imputation 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 or not rescue medication was used.
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, but with respective baseline scores as 
further covariate included.  Nonresponder imputation will be used for these analyses unless 
otherwise noted.

EASI75 at Week 16.  EASI75 is defined as having an improvement of at least 
75% from baseline.  Besides NRI, this outcome will also be analyzed using 
observed cases, that is, whether rescue medication was given or not.

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 (4 domains)
o
EQ-5D-5L (VAS, health state index)
o
PIQ – General
o
PIQ – Activity and Clothing
o
PIQ – Mood and Sleep
o
PIQ – Scratching Behavior
o
PROMIS – Sleep-Related Impairment
o
Neuro-QoL - Cognitive Function
o
Patient Benefit Index.
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.
Treatment-emergent adverse events 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 MedDRA 
(Medical Dictionary for Regulatory Activities) for each system organ class (or a body system) 
and each preferred term by treatment group.  Serious adverse events and AEs that lead to 
discontinuation of investigational product will also be summarized by treatment group.  Fisher 
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 adverse events of special interest, will be 

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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.
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. Pharmacokinetic/Pharmacodynamic Analyses
Not applicable.  
10.3.6. Other Analyses
10.3.6.1. 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.
10.3.6.2. 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, the 
subgroup variable (e.g., sex) and the subgroup by treatment interaction.  If the interaction is 
statistically significant at =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 region, baseline severity, sex, age, race, prior 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.  As this study is not powered for 
subgroup analyses, all subgroup analyses will be treated as exploratory.
10.3.7. Interim Analyses
10.3.7.1. Data Monitoring Committee
A DMC will oversee the conduct of this trial.  The DMC will consist of members external to 
Lilly.  This DMC will follow the rules defined in the DMC charter, focusing on potential and 
identified risks for this molecule and for this class of compounds.  Data Monitoring Committee 
membership will include, at a minimum, specialists with expertise in dermatology, statistics, and 
other appropriate specialties.

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The DMC will be authorized to review unblinded results of analyses by treatment group prior to 
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 alpha is spent.  Details 
of the DMC, including its operating characteristics, will be documented in a DMC charter and 
DMC analysis plan.
Besides DMC members, a limited number of pre-identified individuals may gain access to the 
limited unblinded data, as specified in the unblinding plan, prior to the final database lock for 
preparation of regulatory documents.  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.
10.3.7.2. Adjudication Committee
A blinded Clinical Event Committee will adjudicate potential MACE (cardiovascular death, MI, 
and stroke), other cardiovascular events (such as hospitalization for unstable angina, 
hospitalization for heart failure, serious arrhythmia, resuscitated sudden death, cardiogenic 
shock, coronary revascularization such as coronary artery bypass graft or percutaneous coronary 
intervention), venous thrombotic events, 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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Tuttle KR, Brosius FC, Adler SG, Kretzler M, Mehta RL, Tumlin JA, Liu J, Silk ME, Cardillo 
TE, Duffin KL, Haas JV, Macias WL, Janes JM. Baricitinib in diabetic kidney disease: Results 
from a Phase 2, multicenter, randomized, double-blind, placebo-controlled study. Paper 
presented at: Annual Meeting of the American Diabetes Association; 5–9 June 2015; Boston, 
MA.
Vaddi K, Luchi M. JAK inhibition for the treatment of rheumatoid arthritis: a new era in oral 
DMARD therapy. Expert Opin Investig Drugs. 2012;21(7):961-973.
White D, Leach C, Sims R, Atkinson M, Cottrell D. Validation of the Hospital Anxiety and 
Depression Scale for use with adolescents. Br J Psychiatry. 1999;175(5):452-454.
Wilson SR, Thé L, Batia LM, Beattie K, Katibah GE, McClain SP, Pellegrino M, Estandian DM, 
Bautista DM. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to 
induce itch. Cell. 2013;155(2):285-295.
Yano C, Saeki H, Ishiji T, Ishiuji Y, Sato J, Tofuku Y, Nakagawa H. Impact of disease severity 
on sleep quality in Japanese patients with atopic dermatitis. J Dermatol Sci. 
2013;72(2):195-197.
Ziegler SF, Roan F, Bell BD, Stoklasek TA, Kitajima M, Han H. The biology of thymic stromal 
lymphopoietin (TSLP). Adv Pharmacol. 2013;66:129-155.
Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand. 
1983;67:361-370.

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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.
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANC
absolute neutrophil count
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BCG
Bacillus Calmette-Guérin
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.
BSA
body surface area
CI
confidence interval
C-SSRS
Columbia Suicide Severity Rating Scale
CSR
clinical study report
DLQI
Dermatology Life Quality Index
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DVT
deep vein thrombosis
EASI
Eczema Area and Severity Index
ECG
electrocardiogram
eCOA
electronic clinical outcome assessment
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the 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.
EQ-5D-5L
European Quality of Life–5 Dimensions–5 Levels
ERB
ethical review board
ETV
early termination visit
FDA
the Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
good clinical practice

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HADS
Hospital Anxiety Depression Scale
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
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.
INR
international normalized ratio
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
LOCF
last observed carried forward
LSM
least squares mean
MACE
major adverse cardiovascular events
MI
myocardial infarction
MMRM
mixed-effects model of repeated measures
Neuro-QoL
Quality of Life in Neurological Disorders
NRI
nonresponder imputation
NRS
Numeric Rating Scale
PBI
Patient Benefit Index
PD
Pharmacodynamic(s)
PDE-4 inhibitor
phosphodiesterase type 4 inhibitor
PIQ
Pain Impact Questionnaire
PK
pharmacokinetic(s)
POEM
Patient-Oriented Eczema Measure
PPD
purified protein derivative
PRO/ePRO
patient-reported outcomes/electronic patient-reported outcomes
PROMIS
Patient-Reported Outcomes Measurement Information System
QD
once daily
QoL
quality of life
RA
rheumatoid arthritis
SAE
serious adverse event
SAP
statistical analysis plan
SCORAD
SCORing Atopic Dermatitis
STAT
signal transducer and activator of transcription
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TBL
total bilirubin level
TCNI
topical calcineurin inhibitor

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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
VAS
Visual Analog Scale
ULN
upper limit of normal
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,c
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,d
Serum immunoglobulin (IgA, IgG, IgM, and 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; Ig = immunoglobulin;
mRNA = messenger ribonucleic acid; 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
Microscopic examination of sediment performed only if abnormalities are noted on the routine urinalysis.
d
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.

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e
eGFR for serum creatinine calculated by the central laboratory using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) Creatinine 2009 equation.
f
Test required at Visit 1 only to determine eligibility of patient for the study.
g
A positive hepatitis C antibody (Hep C antibody) result will be confirmed with an alternate hepatitis C method.
h
For all women of child-bearing 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.  Non–child-bearing 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 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 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 Brochure (IB) and updates during the course of the study

informed consent form

relevant curricula vitae
Appendix 3.1.3.
Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party.

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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
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, 

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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 (e.g., 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 ≥3x 
ULN
ALT ≥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; 
eCRF = electronic case report form; 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; fXa = factor Xa; 
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 (eg, facial pallor, white dermographism, delayed blanch response)

keratosis pilaris/pityriasis alba/hyperlinear palms/ichthyosis

ocular/periorbital changes

other regional findings (e.g., 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 LF, Tom WL, Chamlin SL, Feldman SR, Hanifin JM, Simpson EL, Berger TG, 
Bergman JN, Cohen DE, Cooper KD, Cordoro KM, Davis DM, Krol A, Margolis DJ, Paller AS, 
Schwarzenberger K, Silverman RA, Williams HC, Elmets CA, Block J, Harrod CG, Smith Begolka W, 
Sidbury R. Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and 
assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70(2):338-351.

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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] World Health Organization. Model Prescribing Information: Drugs used in skin diseases. 1997; 
Geneva.
Tadicherla S, Ross K, Shenefelt PD, Fenske NA. Topical corticosteroids in dermatology. J Drugs Dermatol.
2009;8(12):1093-1105.

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Appendix 9.
Protocol Amendment I4V-MC-JAIY(a)
Summary A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Phase 3 Study to Evaluate the 
Efficacy and Safety of Baricitinib in Combination with 
Topical Corticosteroids in Adult Patients with Moderate
to Severe Atopic Dermatitis
Overview
Protocol I4V-MC-JAIY A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 
Study to Evaluate the Efficacy and Safety of Baricitinib in Combination with Topical 
Corticosteroids in Adult Patients with Moderate to Severe Atopic Dermatitis  has been amended.  
The new protocol is indicated by amendment (a) and will be used to conduct the study in place of 
any preceding version of the protocol.
Amendment Summary for Protocol I4V-MC-JAIY Amendment (a)
Section # 
Description of Change
Brief Rationale
Section 5.1.2
crisaborole was listed in the description of 
rescue therapies in Period 2.  This was an error, 
crisaborole is not considered a rescue therapy 
and is allowed during the trial (Permitted 
Medications Section 7.7.1). 
Minor error was corrected
Section 5.4
in the scientific rationale for study design
section, intolerance to existing topical therapies 
was listed.  This was an error and was 
corrected to only include inadequate response 
to topic therapies
Minor error was corrected
Section 6.1
leukotriene inhibitors were removed from 
washout
Leukotriene inhibitors are not a prohibited 
medication because evidence suggests little 
impact to AD, so no need for washout
Section 7.7.4
wording on rescue with high and ultra-high 
potency TCS use was updated
Modified for clarity
Section 8.1.2 and 
Appendix 5
Eosinophilia (>5%) was removed from 
permanent discontinuation of IP criteria
Elevated eosinophils are very common in 
patients with moderate to severe AD and do 
not reflect an increased risk for liver events.  

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
5.1.2.
Period 2:  Double–Blind, Placebo-Controlled Treatment
Patient will be randomized at a 1:1:1 ratio into 1 of the 3 treatment groups (placebo QD, 
baricitinib 2-mg QD, or baricitinib 4-mg QD).  Investigational product will be administered daily 
for 16 weeks (treatment period Visits 2 through 8; Section 7).  All patients will be required to use 
emollients daily.  Daily diaries will continue to be utilized throughout the treatment period.  
Download of this data will be required at study visits.  TCS will be dispensed at V2 and used on 
affected areas as described in section 7.7.2. Topical calcineurin inhibitors (TCNIs) is also 
allowed, but TCNI use should be limited to problem areas (e.g. face and skin folds).  The use of 
higher potency TCS, crisaborole, and systemic therapies for the treatment of AD are not allowed, 
except as part of rescue therapy for patients not responding to treatment.  Details of background 
topical therapy, as well as rescue therapy and rescue criteria are included in Section 7.7.  
Assessments of disease severity will be performed by the investigator at all study visits including 
unscheduled and early termination visits (ETVs).
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 whom a systemic treatment such as baricitinib may 
therefore be appropriate.
6.1.
Inclusion Criteria
Type of Patient and Disease Characteristics
[6]
agree to discontinue use of the following excluded medications/treatments for 
at least 4 weeks prior to randomization (Visit 2) and throughout the study:
a.
oral systemic corticosteroids and leukotriene inhibitors
b. systemic immunomodulators, including, but not limited to, cyclosporine, 
methotrexate, mycophenolate mofetil, and azathioprine
c.
any other systemic therapy used to treat AD or symptoms of AD 
(approved or off-label use)
7.7.4.
Rescue Therapy
Rescue with High- and Ultra-High-Potency TCS
High- or ultra-high-potency TCS may be used once daily for up to 14 consecutive days or less, or 
based on the maximum duration recommended in the prescribing information.

I4V-MC-JAIY(a) Clinical Protocol
Page 90
LY3009104
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 >8x ULN

ALT or AST >5x ULN for more than 2 weeks

ALT or AST >3x ULN and total bilirubin level (TBL) >2x ULN or international 
normalized ratio (INR) >1.5

ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, and/or rash, and/or eosinophilia (>5%)

ALP >3x ULN

ALP >2.5x ULN and TBL >2x ULN

ALP >2.5x ULN with the appearance of fatigue, nausea, vomiting, right quadrant 
pain or tenderness, fever, and/or rash, and/or eosinophilia (>5%)
NOTE:  Patients who are discontinued from investigational product due to a hepatic 
event or liver test abnormality should have additional hepatic safety data collected via 
the hepatic safety eCRF.
Appendix 5. Liver Function Testing and Hepatic Safety 
Monitoring
Table footnotes:
a
Fatigue, nausea, vomiting, right upper-quadrant pain or tenderness, fever, and/or rash, and/or eosinophilia (>5%).

PPD
Leo Document ID = 0f04528a-106c-4e12-ae0b-97e05bca33ac
Approver:
Approval Date & Time: 18-Dec-2018 16:23:01 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 18-Dec-2018 16:51:32 GMT
Signature meaning: Approved
PPD