Clinical trial NCT03733301
Conditions: Atopic Dermatitis
Keywords: eczema atopic eczema
Sponsor: Eli Lilly and Company
Start date: 2018-11-16; Completion date: 2019-08-22
Enrollment: 329 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of baricitinib in combination with topical corticosteroids (TCS) in participants with moderate to severe atopic dermatitis.

Detailed description:

Arms: arm 1: 4 mg Baricitinib administered orally once daily in combination with topical corticosteroids (TCS). Placebo administered orally once daily to match 2 mg Baricitinib. arm 2: 2 mg Baricitinib administered orally once daily in combination with TCS. Placebo administered orally once daily to match 4 mg Baricitinib. arm 3: Placebo administered orally once daily in combination with TCS.
Interventions: intervention 1: Baricitinib intervention 2: Topical corticosteroid intervention 3: Placebo
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered as standard-of-care. intervention 3: Administered orally.

Protocol documents:
Prot_000.pdf: 
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


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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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Task Force on Atopic Dermatitis. Dermatology. 1993;186(1):23-31.


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Taylor PC, Keystone EC, van der Heijde D, Weinblatt ME, del Carmen Morales L, Gonzaga JR, 
Yakushin S, Ishii T, Emoto K, Beattie S, Arora V, Gaich CL, Rooney T, Schlichting D, 
Macias WL, de Bono S, Tanaka. Baricitinib versus placebo or adalimumab in rheumatoid 
arthritis. N Engl J Med. 2017;376:652-662.
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.


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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

SAP_001.pdf: 
Statistical Analysis Plan I4V-MC-JAIY Version 2 
 
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: 12-Aug-2019 
 


I4V-MC-JAIY Statistical Analysis Plan Version 2
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1.
Statistical Analysis Plan for US and Japan: 
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
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Baricitinib (LY3009104) Atopic Dermatitis
Study I4V-MC-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 atopic dermatitis.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I4V-MC-JAIY
Phase 3
Statistical Analysis Plan Version 1 electronically signed and approved by Lilly:
01 April 01, 2019
Statistical Analysis Plan Version 2 electronically signed and approved by Lilly on date 
provided below.
Approval Date: 12-Aug-2019 GMT


I4V-MC-JAIY Statistical Analysis Plan Version 2
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan for US and Japan:  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.................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................7
4.
Study Objectives.................................................................................................................8
4.1.
Primary Objective ..........................................................................................................8
4.2.
Secondary Objectives.....................................................................................................8
4.2.1.
Key Secondary Objectives .....................................................................................8
4.2.2.
Other Secondary Objectives ...................................................................................8
4.3.
Exploratory Objectives.................................................................................................10
5.
Study Design.....................................................................................................................12
5.1.
Summary of Study Design............................................................................................12
5.2.
Method of Assignment to Treatment ............................................................................13
6.
A Priori Statistical Methods ..............................................................................................15
6.1.
Determination of Sample Size ......................................................................................15
6.2.
General Considerations ................................................................................................15
6.2.1.
Analysis Populations............................................................................................15
6.2.2.
Definition of Baseline and Postbaseline Measures................................................16
6.2.3.
Analysis Methods.................................................................................................18
6.2.4.
Derived Data........................................................................................................20
6.3.
Covariate Adjustment...................................................................................................21
6.4.
Handling of Dropouts or Missing Data.........................................................................21
6.4.1.
Nonresponder Imputation.....................................................................................22
6.4.2.
Mixed Model for Repeated Measures...................................................................23
6.4.3.
Modified Last Observation Carried Forward ........................................................23
6.4.4.
Placebo Multiple Imputation ................................................................................23
6.4.5.
Tipping Point Analyses ........................................................................................25
6.5.
Multicenter Studies ......................................................................................................27
6.6.
Multiple Comparisons/Multiplicity...............................................................................27
6.7.
Patient Disposition .......................................................................................................30
6.8.
Patient Characteristics ..................................................................................................31
6.8.1.
Demographics......................................................................................................31


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6.8.2.
Baseline Disease Characteristics ..........................................................................31
6.8.3.
Historical Illness and Pre-existing Conditions ......................................................32
6.9.
Treatment Compliance .................................................................................................33
6.10. Rescue Therapy............................................................................................................33
6.11. Previous and Concomitant Therapy..............................................................................34
6.11.1.
Background TCS..................................................................................................34
6.12. Efficacy Analyses ........................................................................................................35
6.12.1.
Primary Outcome and Methodology.....................................................................42
6.12.2.
Secondary and Exploratory Efficacy Analyses .....................................................42
6.12.3.
Sensitivity Analyses.............................................................................................43
6.13. Health Outcomes/Quality-of-Life Analyses..................................................................43
6.14. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................62
6.15. Safety Analyses............................................................................................................62
6.15.1.
Extent of Exposure...............................................................................................62
6.15.2.
Adverse Events ....................................................................................................63
6.15.2.1.
Common Adverse Events ...............................................................................64
6.15.2.2.
Serious Adverse Event Analyses.....................................................................64
6.15.2.3.
Other Significant Adverse Events...................................................................64
6.15.2.4.
Criteria for Notable Patients ...........................................................................65
6.15.3.
Clinical Laboratory Evaluation.............................................................................65
6.15.4.
Vital Signs and Other Physical Findings...............................................................66
6.15.5.
Special Safety Topics, including Adverse Events of Special 
Interest.................................................................................................................67
6.15.5.1.
Abnormal Hepatic Tests .................................................................................68
6.15.5.2.
Hematologic Changes.....................................................................................69
6.15.5.3.
Lipids Effects .................................................................................................70
6.15.5.4.
Renal Function Effects ...................................................................................71
6.15.5.5.
Elevations in Creatine Phosphokinase (CPK)..................................................71
6.15.5.6.
Infections........................................................................................................71
6.15.5.7.
Major Adverse Cardiovascular Events (MACE) and 
Other Cardiovascular Events...........................................................................74
6.15.5.8.
Venous and Pulmonary Artery Thromboembolic (VTE) 
Events ............................................................................................................75
6.15.5.9.
Arterial Thromboembolic (ATE) Events.........................................................76
6.15.5.10. Malignancies ..................................................................................................76
6.15.5.11. Allergic Reactions/Hypersensitivities .............................................................76
6.15.5.12. Gastrointestinal Perforations...........................................................................77
6.15.5.13. Columbia Suicide Severity Rating Scale.........................................................77


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6.15.5.14. Self-Harm Supplement Form and Self-Harm Follow-up 
Form...............................................................................................................77
6.16. Subgroup Analyses.......................................................................................................77
6.17. Protocol Deviations......................................................................................................79
6.18. Interim Analyses and Data Monitoring.........................................................................79
6.18.1.
Interim Analysis Plan...........................................................................................80
6.19. Planned Exploratory Analyses......................................................................................80
6.20. Annual Report Analyses...............................................................................................80
6.21. Clinical Trial Registry Analyses...................................................................................80
7.
Unblinding Plan................................................................................................................81
8.
References ........................................................................................................................82


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Table of Contents
Table
Page
Table JAIY.5.1. Geographic Regions for Stratification............................................................14
Table JAIY.6.1. Imputation Techniques for Various Variables ................................................22
Table JAIY.6.2. Seed Values for Multiple Imputation .............................................................25
Table JAIY.6.3. Seed Values for Imputation............................................................................27
Table JAIY.6.4. Description and Derivation of Primary, Secondary and Exploratory 
Efficacy Outcomes ........................................................................................37
Table JAIY.6.5. Description of Primary, Secondary and Exploratory Efficacy 
Analyses........................................................................................................40
Table JAIY.6.6. Description and Derivation of Health Outcomes and Quality-of-Life 
Measures .......................................................................................................44
Table JAIY.6.7. Description of Health Outcomes and Quality-of-Life Measures 
Analyses........................................................................................................57
Table JAIY.6.8. Categorical Criteria for Abnormal Treatment-Emergent Blood 
Pressure and Pulse Measurement, and Categorical Criteria for 
Weight Changes for Adults............................................................................67


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Table of Contents
Figure
Page
Figure JAIY.5.1. Illustration of study design for Clinical Protocol I4V-MC-JAIY. ...................13
Figure JAIY.6.1. Illustration of graphical multiple testing procedure with initial α 
allocation and weights. ..................................................................................30


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3.
Revision History
Statistical Analysis Plan (SAP) Version 1 is based on Protocol I4V-MC-JAIY(a). Statistical 
Analysis Plan Version 2 was approved prior to unblinding.  A summary of changes between 
Version 1 and Version 2 are as follows:
Section
Summary of Changes
4.3. Exploratory 
objectives

Updated the time frame for the objective of frequency of patient-reported “no itch”
and “no pain” by starting from Week 0.

Added new exploratory analyses on Hospital Anxiety Depression (HADS), 
Dermatology Life Quality Index (DLQI), Atopic Dermatitis Sleep Scale (ADSS),
and Patient-Oriented Eczema Measure (POEM).

Added new exploratory analyses on early responders.
6.11.1. Background TCS

Updated the weight of dispensed topical corticosteroids (TCS) tube to align with 
JAHL SAP.
6.2.2. Definition on 
Baseline and 
Postbaseline Measures

Updated the derivations of itch weekly scores.
6.2.3. Analysis Methods

Updated the structures of covariance matrix in mixed model repeated measures 
(MMRM) model.
6.6. Multiple 
Comparisons

Updated the graphical testing procedure.
6.16 Subgroup Analysis

Added subgroup analyses for East Asia vs. other.
Table 6.6

Updated the endpoints on the number days of itch-free and pain-free days.
Table 6.7

Updated analyses on the number of itch-free and pain-free days.

Change the type of analysis of covariance (ANCOVA) (modified last observation 
carried forward [mLOCF]) analyses on PROMIS from “exploratory analyses” to 
“sensitivity analyses.”


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4.
Study Objectives
4.1.
Primary Objective
The primary objective of this study is to test the hypothesis that baricitinib 4 mg once daily (QD)
plus topical corticosteroids (TCS) or baricitinib 2 mg QD plus TCS is superior to placebo plus 
TCS in the treatment of patients with moderate to severe atopic dermatitis (AD), as assessed by 
the proportion of patients achieving the validated Investigator’s Global Assessment for AD 
(vIGA-AD, referred to throughout the SAP as IGA) of 0 or 1 with a ≥2-point improvement at 
Week 16.
In particular, the associated estimand for this objective is to measure the effect of therapy with 
baricitinib as assessed by the proportion of patients with a response of IGA 0 or 1 at Week 16 
assuming treatment response disappears after patients are rescued or discontinue from the study 
or treatment.  See Sections 6.4.1 and 6.12.1 on how this estimand handles outcomes after the 
occurrence of any intercurrent event through nonresponder imputation (NRI).
4.2.
Secondary Objectives
4.2.1. Key Secondary Objectives
These are prespecified objectives that will be adjusted for multiplicity. 
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 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.

Proportion of patients achieving a 4-point 
improvement from baseline 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 
4.2.2. Other Secondary Objectives
These are prespecified objectives that will not be adjusted for multiplicity. 


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Objectives
Endpoints
To test the hypothesis that baricitinib 2 mg QD + 
TCS or baricitinib 4 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 4
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 signs and 
symptoms of AD.

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 BSA 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

Proportion of patients achieving a 4-point 
improvement from baseline in Skin Pain NRS at 16 
weeks

Mean change from baseline in the total score of the 
POEM at 16 weeks

Mean change in the PGI-S-AD scores at 16 weeks

Mean change from baseline in HADS at 16 weeks

Mean change in the DLQI scores at 16 weeks

Mean change in the WPAI scores at 16 weeks

Mean change in the EQ-5D-5L scores at 16 weeks

Mean number of days without use of background 
TCS over 16 weeks


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4.3.
Exploratory Objectives
The exploratory objectives of this study are the following:
Objectives/Endpoints

Frequency of patient-reported “no itch” (Itch NRS score = 0) days from daily diaries from Week 0 to 
Week 16

Frequency of patient-reported “no pain” (Skin Pain NRS score = 0) days from daily diaries from Week 0
to Week 16

Mean change from baseline in PIQ – Itch Interference 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

Patient Benefit Index score at 16 weeks – 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

Proportion of patients achieving PBI global score ≥1 at 16 weeks

Mean change from baseline in the score of Item 1 of the ADSS at 1 week and 16 weeks

Proportion of patients achieving a ≥1-point improvement in the score of Item 1 of the ADSS for those 
with baseline Item 1 score ≥1

Proportion of patients achieving a ≥1-point improvement in the score of Item 2 of the ADSS for those 
with baseline Item 2 score ≥1

Proportion of patients achieving a ≥2-point improvement in the score of Item 2 of the ADSS for those 
with baseline Item 2 score ≥2

Mean change from baseline in the score of Item 3 of the ADSS at 1 week and 16 weeks

Proportion of patients achieving a ≥1-point improvement in the score of Item 3 of the ADSS for those 
with baseline Item 3 score ≥1

To evaluate changes from baseline in immunoglobulin E levels during the study

To evaluate changes from baseline in eosinophil levels during the study

To assess time to 4-point Itch NRS improvement during the first 14 days after initiation of treatment

To assess time to 4-point improvement in Skin Pain during the first 14 days after the initiation of 
treatment

Proportion of patients achieving a ≥4-point improvement in DLQI total score for those with baseline 
DLQI total score ≥4

Proportion of patients achieving DLQI total score 0 or 1

Proportion of patients achieving a ≥4-point improvement in POEM total score for those with baseline 
total score ≥4

Proportion of patients achieving HADS Anxiety Score <8 for those with baseline HADS Anxiety Score
≥8

Proportion of patients achieving HADS Depression Score <8 for those with baseline HADS Depression
Score ≥8

Proportion of patients achieving improvement with HADS Anxiety Score or HADS Depression Score <8 
for those with baseline HADS Anxiety Score ≥8 or HADS Depression Score ≥8

Mean change from baseline in HADS subscale scores


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
Proportion of patients achieving ≥4-point improvement in Itch NRS or IGA≤1 at Week 16 for those with 
≥3-point improvement in Itch NRS or IGA≤2 at Week 4

Proportion of patients achieving ≥ 4-point improvement in Itch NRS or IGA≤1 at any time between 
Week 8 and Week 16 for those with ≥3-point improvement in Itch NRS or IGA≤2 at Week 4

Proportion of patients achieving [≥4-point improvement in Itch NRS and IGA≤2] or [IGA≤1] at Week 16 
for those with ≥3-point improvement in Itch NRS or IGA≤2 at Week 4

Proportion of patients achieving [≥4-point improvement in Itch NRS and IGA≤2] or [IGA≤1] at any time 
between Week 8 and Week 16 for those with ≥3-point improvement in Itch NRS or IGA≤2 at Week 4


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5.
Study Design
5.1.
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 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 
I4V-MC-JAHN (JAHN).
Approximately 300 patients ≥18 years of age who have responded inadequately to topical 
therapy will be randomized at 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.
Study JAIY will consist of 3 periods:  

Period 1:  Screening period is between 8 and 35 days prior to Week 0 (Visit 2)

Period 2:  Double-Blind, Placebo-Controlled Treatment period from Week 0 (Visit 2) 
through Week 16 (Visit 8)

Period 3:  Post-Treatment Follow-Up period from last treatment visit at Week 16 (Visit 8) 
or Early Termination Visit (ETV) to approximately 28 days after the last dose of 
investigational product
Figure JAIY.5.1 illustrates the study design.  The blinding procedure is described in the Protocol.


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Figure JAIY.5.1.
Illustration of study design for Clinical Protocol I4V-MC-JAIY.
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 once daily dose who have renal impairment (defined as eGFR 
<60 mL/min/1.73 m2), the baricitinib dose will be 2 mg once daily.
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 to 72 hours after Visit 1 (post-PPD).
d
Occurs approximately 28 days after the last dose of investigational product.  Not required for those patients 
entering the long-term extension study JAHN.
5.2.
Method of Assignment to Treatment
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 [EU], Japan [JPN], rest-of-world [ROW]) 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 
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.
This study will be conducted internationally in multiple sites.  Table JAIY.5.1 describes how 
regions will be defined for stratification.  Regions may be combined for statistical analyses in the 


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case when one of the region strata fails to meet the required minimum number of 30 patients.  
The 2 region strata with the least number of patients will then be pooled. 
Table JAIY.5.1.
Geographic Regions for Stratification
Region
Countries
Europe
Germany, Italy, Poland, Spain, Austria
Japan
Japan
Rest of World
Taiwan, Australia, Korea, Argentina


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6.
A Priori Statistical Methods
6.1.
Determination of Sample Size
Study JAIY will aim to enroll approximately 300 patients ≥18 years of age.  The proposed 
sample size will ensure a 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´s 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 2 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.
6.2.
General Considerations
This plan describes a priori statistical analyses for efficacy, health outcomes, and safety that will 
be performed.  
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (Lilly).  The 
statistical analyses will be performed using SAS® Version 9.4 or higher. 
Not all displays described in this SAP will necessarily be included in the clinical study report 
(CSR).  Not all displays will necessarily be created as a “static” display.  Some may be 
incorporated into interactive display tools instead of or in addition to a static display.  Any 
display described in this SAP and not included in the CSR will be available upon request.
Statistical tests of treatment effects and confidence intervals (CIs) will be performed at a 2-sided 
significance level of 0.05, unless otherwise stated (e.g., graphical multiple testing strategy in 
Section 6.6).
Data collected at ETVs will be mapped to the closest scheduled visit number for that patient if it 
falls within the visit window as discussed in Section 6.2.2.  For by-visit summaries, only visits in 
which a measure was scheduled to be collected will be summarized.  Any unscheduled visit data 
will be included at the patient-level listings.  However, the data will still be used in other 
analyses, including shift analyses for safety analytes, change from baseline using modified last 
observation carried forward (mLOCF) for efficacy analyses, and other categorical analyses 
including safety.  
6.2.1. Analysis Populations
Intent-to-treat (ITT) population:  The ITT population analysis set is defined as all randomized 
patients. 
Per-protocol Set (PPS):  PP subset of the ITT analysis set will include those patients who do 
not have any significant or important protocol violations.  Qualifications for and identification of 


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significant or important protocol violations will be determined while the study remains blinded, 
prior to database lock.
Follow-up population:  The follow-up population is defined as patients who entered the follow-
up period.
Unless otherwise specified, the efficacy and health outcome analyses will be conducted on the 
ITT population (Gillings and Koch 1991), which seeks to preserve the benefits of randomization 
and avoid selection bias.  Patients will be analyzed according to the treatment to which they were 
randomized.  In addition, the analyses of primary and key secondary endpoints will be repeated 
using the PPS population.  
Safety population:  The safety population is defined as 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.  
Safety analyses will be performed using the safety population.  Patients will be analyzed 
according to the treatment regimen to which they were assigned.  Analyses of the safety 
endpoints, many of which are incidence based, will include all patients in the safety population, 
unless specifically stated otherwise. 
In the rare situation where a patient is Lost to Follow-up at the first postbaseline visit, but some 
safety data exists (e.g., unscheduled laboratory assessments) after first dose of study drug, a 
listing of the data or a patient profile may be provided, when requested. 
6.2.2. Definition of Baseline and Postbaseline Measures
The baseline value for efficacy and health outcomes variables measured at scheduled visits is 
defined as the last non-missing measurement on or prior to the date of first study drug 
administration (expected at Week 0, Visit 2).
The baseline value for the daily diary assessments (Itch NRS, ADSS, Skin Pain NRS, PGI-S-
AD) is the mean of the non-missing assessments in the 7 days prior to the date of first study drug 
administration (expected at Week 0, Visit 2).  
If there are less than 4 non-missing assessments in the baseline diary window, the interval lower 
bound can be extended up to 7 additional days, one day at a time, to obtain the most recent 4 
non-missing values.  If there are not at least 4 non-missing assessments in the baseline period, 
the baseline mean is missing.
Baseline for the safety analyses is defined as the last non-missing scheduled (planned) 
measurement on or prior to the date of first study drug administration for continuous measures 
by-visit analyses and all non-missing measurements on or prior to the date of first study drug 
administration for all other analyses.  
Postbaseline measurements are collected after study drug administration through Week 16 
(Visit 8) or early discontinuation visit.  Efficacy data collected at scheduled visits (e.g., eCOA, 
ClinRO) will be used in all analyses unless it is missing.  If an assessment is missing at a 
scheduled visit, an unscheduled post-baseline assessment can be used provided it falls within the 


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window interval as follows:  a ±2 day window is used for Visit 3 (Week 1), Visit 4 (Week 2), 
and Visit 5 (Week 4); and a ±4 day window is used to Visit 6 (Week 8), Visit 7 (Week 12), and 
Visit 8 (Week 16).  If there is more than 1 unscheduled visit within the defined visit window and 
no scheduled visit assessment is available, the unscheduled visit closest to the scheduled visit 
date will be used.  If two unscheduled visits of equal distance are available, then the latter of the 
two will be used.
Postbaseline daily diary endpoints will be the mean of weekly visit windows (diary windows) 
anchored on day of first dose (Day 1) for Weeks 1 through 14 as follows:  Week 1 
(Days 1 through7), Week 2 (Days 8 through 14), Week 3 (Days 15 through 21), …, Week 14 
(Days 92 through 98). 
Week 16 Daily Diary Window Construction
The following sequential steps will be used to determine the Week 16 diary window.  The 
general goal is to anchor on the scheduled Week 16 visit (or a proximal unscheduled visit) if 
such a visit exists or to use an interval based on days in study for cases where a scheduled 
Week 16 or a proximal surrogate does not exist.
Step 1: If the Week 16 scheduled visit exists, the Week 16 diary interval is the 7 days prior to 
the Week 16 date provided that window has at least 4 non-missing observations.  If there are less 
than 4 non-missing observations, the diary window’s lower bound will be extended 1 day at a 
time (up to day 99) to a maximum of 14 days prior to the Week 16 date until 4 non-missing 
observations are obtained.  If, after extending this diary window’s lower bound to 14 days, there 
are less than 4 non-missing observations then go to Step 2.
Step 2: If the Week 16 scheduled visit does not exist, the 7 days prior to the last visit (scheduled 
or unscheduled) occurring after Day 105, will constitute the Week 16 diary window provided 
that window contains at least 4 non-missing observations.  If there are less than 4 non-missing 
observations, the diary window’s lower bound will be extended 1 day at a time (up to Day 99) to 
a maximum of 14 days prior to the unscheduled visit date until 4 non-missing observations are 
obtained.  If, after extending this diary window’s lower bound to 14 days, there are less than 4 
non-missing observations then go to Step 3.
Step 3: If neither a Week 16 scheduled visit is available nor an unscheduled visit to act as a 
surrogate for the Week 16 diary window, then the Week 16 window will be Day 106 to Day 112. 
If there are less than 4 non-missing observations, the dairy window’s lower bound will be 
extended 1 day at a time to Day 99 until 4 non-missing observations are obtained.
If the steps above do not detect a window with at least 4 non-missing observations, then the 
Week 16 window is 7 days from either the Week 16 visit, the surrogate visit or Days 106 through 
112 and the mean is missing and subject to imputation rules.
Week 15 Daily Diary Window Construction
The lower boundary of the Week 15 diary window is defined as Day 99. The upper bound of the 
Week 15 diary window is the minimum of either Day 105 or the lower bound of the Week 16 


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diary window -1.  Consequently, Week 15 may be less than 4 days if the Week 16 scheduled 
visit is before Day 112.  Moreover, as Week 15 diary window cannot exceed 7 days, there could 
be daily assessments between Weeks 15 and 16 diary windows that do not fall into a diary 
window.  If after constructing the diary windows, there are fewer than 4 non-missing values the 
mean for Week 15 is missing and subject to imputation rules.
Handling of Duplicate Diary Records
If there is more than one diary record on a particular date, the first record on that particular date 
will be used in the analysis.
Note, as some analyses require use of the primary censoring rule, assessments collected on the 
day of rescue or afterwards will be excluded from the weekly visit interval calculation when 
implementing the rule for daily diary.  If, after exclusion of these records, there are less than 4 
non-missing assessments, the weekly interval which implements the primary censoring rule will 
be missing.  The post-study follow-up weekly score for daily diaries will be calculated as the 
mean of the 7 days prior to the follow-up visit which occur after last dose of study treatment.  
Postbaseline measures for the safety analyses are defined as the non-missing scheduled (planned) 
measurements after the date of first study drug administration for continuous measures by-visit 
analyses and all non-missing measurements after the date of first study drug administration for 
all other analyses.  
6.2.3. Analysis Methods
The main analysis method of categorical efficacy variables and health outcomes variables will 
use a logistic regression analysis with region, baseline disease severity (IGA), baseline value and 
treatment group in the model, except for the analysis on IGA.  For IGA, the logistic regression 
model will include region, baseline disease severity (IGA), and treatment group.  Firth’s 
correction will be used in order to accommodate (potential) sparse response rates.  The p-value 
for the odds ratio from the logistic regression model will be used for statistical inference, unless 
Firth’s correction still results in quasi-separation.  In that case, Fisher’s exact test will be used for 
statistical inference.  The difference in percentages and 100(1-alpha)% CI of the difference in 
percentages using the Newcombe-Wilson method without continuity correction will be reported.  
The p-value from the Fisher’s exact test will also be produced as a secondary analysis.  
The main analysis method for all continuous efficacy and health outcomes variables will use 
mixed model repeated measures (MMRM) analysis.  The MMRM model will use a restricted 
maximum likelihood (REML) estimation.  The model will include treatment, region, baseline 
disease severity (IGA), visit, and treatment-by-visit-interaction as fixed categorical effects and 
baseline and baseline-by-visit-interaction as fixed continuous effects.  For daily diary 
assessments, the model for analyses up to Week 16 will include all weekly assessments.  An 
unstructured (co)variance structure will be used to model the between- and within-patient errors.  
If this analysis fails to converge, the heterogeneous autoregressive [ARH(1)], followed by the 
heterogeneous compound symmetry (CSH), followed by the heterogeneous Toeplitz (TOEPH), 
followed by autoregressive [AR(1)], followed by compound symmetry (CS) will be used.  The 


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Kenward-Roger method will be used to estimate the degrees of freedom.  Treatment least 
squares means (LSM) will be estimated within the framework of the MMRM using type 3 sums 
of squares.  Differences in LSM between each dose of baricitinib and placebo (and associated p-
values, standard errors and 95% CI) will be used for statistical inference.  The LSM difference, 
standard error, p-value and 95% CI will be reported.  
Treatment comparisons for continuous efficacy and health outcomes variables may also be made 
using analysis of covariance (ANCOVA) for primary and key secondary objectives.  When an 
ANCOVA model is used, the model includes region, baseline disease severity, treatment group, 
and baseline value.  Treatment LSM will be estimated within the framework of the ANCOVA 
using type 3 sums of squares.  Reported differences in LSM and associated p-values, standard 
errors and 95% CI will be used for statistical inference.  Treatment-by-region interaction will 
also be added to the model for sensitivity purposes and is discussed in Section 6.5.
Beginning on Day 14 a Cox proportional hazard (CPH) model of time (in days) to first 
observance of a 4-point itch reduction with effects for treatment, region, baseline mean itch, and 
disease severity will be used to test for treatment differences from placebo.  For this analysis, 
daily itch scores will be compared to the baseline to determine if a 4-point itch reduction has 
been achieved in patients with a baseline itch of at least 4.  The baseline for Itch NRS is defined 
in Section 6.2.2.  Beginning on Day 14, the day on which the first time itch NRS is reduced by at 
least 4 will be modeled. If any significant difference between any baricitinib dose and placebo is 
observed then the same analyses will be run on Day 13. This process of evaluating at the next 
lowest day will proceed until no significant differences are observed.  No adjustments for 
multiple tests and multiple comparisons will be used.  This analysis uses the Primary Censoring 
Rule for patients who are rescued or permanently discontinue study drug (see Section 6.4).  
Missing daily itch data will be replaced using NRI rule which means missing data is replaced 
with a non-response which would entail replacing missing values with a time to event of 
>14 days, censored; >13 days, censored, etc., depending on the window being used.  If the model 
assumptions for the CPH model do not hold, a log-rank test will be used.
Restricted mean survival time will be evaluated at Days 2, 3, 4 and 5 as an exploratory analysis.  
The model will include terms for baseline disease severity (IGA), baseline itch, region, and 
treatment group.
Fisher’s exact test will be used to test for differences between each baricitinib dose and placebo 
in proportions of patients experiencing adverse events (AEs), discontinuation from study drug, 
and for other categorical safety data.  Continuous vital signs, body weight, and other continuous 
safety variables, including laboratory variables will be analyzed by an ANCOVA with treatment 
group and baseline value in the model.  The significance of within-treatment group changes from 
baseline will be evaluated by testing whether or not the treatment group LSM changes from 
baseline are different from zero; the standard error for the LSM change will also be displayed.  
Differences in LSM will be displayed, with the p-value associated with the LSM comparison to 
placebo and a 95% CI on the LSM difference also provided.  In addition to the LSMs for each 
group, the within-group p-value for the change from baseline will be displayed.  


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Confusion table will be used to calculate the proportions of responder patients defined at week 
16, and at any time between Weeks 8 and 16, for those with improvement on itch NRS or IGA at 
early week. The confusion table will generate the Positive Prediction Value (PPV) and Negative 
Prediction Value (NPV), which can access the performance of predicting late week responders 
using early week data. All missing values will be treated by NRI method.   
6.2.4. Derived Data

Age (year), derived using first dose date as the reference start date and July 1st of birth 
year and truncated to a whole-year (integer) age.  Patients whose derived age is less than 
18 will have the required minimum age of 18 at informed confirmed; reporting for age, 
age groups, and lab ranges, however will be based on their derived age.

Age group (<65, ≥65 years old)

Age group (<65, ≥65 to <75, ≥75 to <85, ≥85 years old)

Body Mass Index (BMI) (kg/m2) = Weight (kg)/((Height (cm)/100)2)

BMI category (<25 kg/m2, ≥25 to <30 kg/m2, ≥30 kg/m2)

The duration of AD from diagnosis (years) = [(Date of informed consent – Date of AD 
diagnosis )+1]/ 365.25.
o
If year of onset is missing, duration of AD will be set as missing.  Otherwise, 
unknown month will be taken as January, and unknown day will be taken as 
01.  The duration of AD will be rounded to 1 decimal place.

Duration of AD (years) category (0 to <2 years, 2 to < 5 years, 5 to <10 years, 10 to 
<20 years, ≥20 years)

Diagnosis age (years), derived using diagnosis date as the reference start date and July 1
of birth year and truncated to a whole-integer age.

Diagnosis age group (<18, ≥18 to <50, ≥50 years old)

Change from baseline = postbaseline measurement at Visit x – baseline measurement.  
o
If a baseline value is missing, it will not be imputed and the change from 
baseline will not be calculated.

Percent change from baseline at Visit x: 
((Post-baseline measurement at Visit x - Baseline measurement)/Baseline 
measurement)*100.
o
If a baseline value is missing, it will not be imputed and percent change from 
baseline will not be calculated.  

Weight (kg) = weight (lbs) * 0.454.

Weight category (<60 kg, ≥60 to <100 kg, ≥100 kg)

Height (cm) = height (in) * 2.54.

Cyclosporine inadequate efficacy (yes, no)
o
Set yes if the reason for discontinuation is inadequate response.

Cyclosporine intolerance (yes, no)
o
Set yes if the reasons for discontinuation are:  intolerance to medication or 
contraindication (Physician indicated cyclosporine was used and a 
contraindication was noted).

Cyclosporine contraindication [ineligible] (yes, no)


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o
Set to yes if cyclosporine never used because of a contraindication

Cyclosporine inadvisable (yes, no)

Set to yes if the following reasons were selected for either not using the medication or 
discontinuing the medication:
o
Reason for not using medication:  Physician decision, concern about side 
effects, unfavorable benefit risk, contraindication. 
o
Reasons for discontinuation:  inadequate response, intolerance to medication, 
or contraindication.

TCNI inadequate efficacy (yes, no)
o
Set yes if the reason for discontinuation is inadequate response.

TCNI intolerance (yes, no)
o
Set yes if the reasons for discontinuation are:  intolerance to medication or 
contraindication (Physician indicated TCNI was used and a contraindication 
was noted).

TCNI contraindication / [ineligible](yes, no)
o
Set to yes if TCNI never used because of a contraindication

TCNI inadvisable (yes, no)

Set to yes if the following reasons were selected for either not using the medication or 
discontinuing the medication:
o
Reason for not using medication:  Physician decision, concern about side 
effects, unfavorable benefit risk, contraindication. 
o
Reasons for discontinuation:  inadequate response, intolerance to medication, 
or contraindication.
6.3.
Covariate Adjustment
The randomization to treatment groups at Week 0 (Visit 2) is stratified by disease severity (IGA) 
and geographic region as described in Section 5.1.  Unless otherwise specified, the statistical 
analysis models will adjust for these stratification variables.  The covariates used in the logistic 
model for categorical data will include the parameter value at baseline.  The covariates used in 
the ANCOVA model for continuous data will include the parameter value at baseline.  Inclusion 
of baseline in the model ensures treatment LSM are estimated at the same baseline value.  When 
an MMRM analysis is performed, baseline value and baseline-by-visit interactions will be 
included as covariates.  
6.4.
Handling of Dropouts or Missing Data
Intercurrent events (ICH E9 R1) are events which occur after the treatment initiation and make it 
impossible to measure a variable or influence how it would be interpreted.  
Depending on the estimand being addressed, different methods will be used to handle missing 
data as a result of intercurrent events.  Intercurrent events can occur through the following: 

application of one of the censoring rules (including after permanent study drug 
discontinuation or after rescue therapy) 

discontinuation 


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
missing an intermediate visit prior to discontinuation or rescue

lost to follow-up. 
Non-censor intercurrent events are events that are not due to the application of any censoring 
rule, i.e., the last 3 items in the list above. 
Note that as efficacy and health outcome data can accrue after a patient permanently discontinues 
study drug or begins rescue therapy, specific general censoring rules to the data will be applied 
to all efficacy and health outcome observations subsequent to these events depending on the 
estimand being addressed.  These specific censoring rules are described below. 
The primary censoring rule will censor efficacy and health outcome data after permanent study 
drug discontinuation or after rescue therapy.  This censoring rule will be applied to all 
continuous and categorical efficacy and health outcome endpoints.  This censoring rule is 
equivalent to using all the data up to rescue.
A secondary censoring rule will only censor efficacy and health outcome data after permanent 
study drug discontinuation.  This sensitivity analysis will include all observed values up to study 
drug discontinuation.  The secondary censoring rule will be applied to primary and key 
secondary efficacy and health outcome endpoints as sensitivity analyses.  
Table JAIY.6.1 describes the planned imputation methods for efficacy and health outcome 
endpoints with associated censoring rules.  Sections 6.4.1 through 6.4.5 summarize the 
methodology of each imputation rule. 
Table JAIY.6.1.
Imputation Techniques for Various Variables
Efficacy and Health Outcome Endpoints
Imputation Method
IGA(0,1), EASI75, 4-point Itch NRS improvement, EASI90, 
SCORAD75
NRIab, pMIa, Tipping pointa
EASI percent change, ADSS Item 2 change, Skin Pain NRS 
change
MMRMab, mLOCFa, pMIa
All remaining categorical measures
NRIa
All remaining continuous efficacy and health outcome 
measures 
MMRMa, mLOCFa
Abbreviations:  ADSS = Atopic Dermatitis Sleep Scale; EASI = Eczema Area and Severity Index score; 
IGA = Investigator’s Global Assessment for AD; mLOCF = modified last observation carried forward; 
MMRM = mixed model repeated measures; NRI = nonresponder imputation, NRS = Numeric Rating Scale; 
pMI = placebo multiple imputation; SCORAD = SCORing Atopic Dermatitis.
a
Analyses utilizing the primary censoring rule.
b
Analyses utilizing the secondary censoring rule.
6.4.1. Nonresponder Imputation
A nonresponder imputation (NRI) method imputes missing values as non-responses and can be 
justified based on the composite strategy for handling intercurrent events (ICH E9 R1).  This 
imputation procedure assumes the effects of treatments disappear after the occurrence of an 
intercurrent event defined by the associated censoring rule.  


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All categorical endpoints will utilize the NRI method after applying the primary censoring rule to 
patients who permanently discontinued study drug or were rescued (described in Section 6.4).  
Additionally, all primary and key secondary categorical endpoints will utilize NRI after applying 
the secondary censoring rule as sensitivity analyses.  For analyses which utilize either of the 
censoring methods, randomized patients without at least 1 post-baseline observation will be 
defined as nonresponders for all visits.  
6.4.2. Mixed Model for Repeated Measures
Mixed Model for Repeated Measures analyses will be performed on continuous endpoints to 
mitigate the impact of missing data.  This approach assumes missing observations are missing-at-
random (missingness is related to observed data) and borrows information from patients in the 
same treatment arm taking into account both the missingness of data through the correlation of 
the repeated measurements.
Essentially MMRM estimates the treatment effects had all patients remained on their initial 
treatment throughout the study.  For this reason, the MMRM implies a different estimand 
(hypothetical strategy [ICH E9 R1]) than the one used for NRI on categorical outcomes.  
All continuous endpoints will utilize MMRM after applying the primary censoring rule.  As 
sensitivity analyses, all secondary continuous endpoints will also utilize MMRM after applying 
the secondary censoring rule (Table JAIY.6.1).  
6.4.3. Modified Last Observation Carried Forward
For continuous measure, a modified last observation carried forward (mLOCF) imputation 
technique replaces missing data with the most recent non-missing post-baseline assessment.  The 
specific modification to the LOCF is data after an intercurrent event will not be carried forward 
thus the mLOCF is applied after the specified censoring rule is implemented.  The mLOCF 
assumes the effect of treatment remain the same after the event that caused missing data as it was 
just prior to the missing data event.  Analyses using mLOCF require a nonmissing baseline and 
at least 1 postbaseline measure otherwise the data is missing for analyses purposes. Analyses 
using mLOCF help ensure the number of randomized patients who were assessed post-baseline 
is maximized and is reasonable for this data as data directly prior to an intercurrent event (such 
as initiation of rescue therapy or drop out) is likely a non-efficacious response.
All continuous efficacy and health outcomes endpoints will use with mLOCF imputation 
methodology with an ANCOVA as sensitivity analyses to the MMRM analyses.
6.4.4. Placebo Multiple Imputation
The Placebo Multiple Imputation (pMI) methodology will be used as a sensitivity analysis for 
the analysis of the primary efficacy endpoint (IGA 0 or 1 at Week 16) as well as the key 
secondary endpoints at Week 16.  In these sensitivity analyses the primary censoring rule will be 
applied.
The pMI assumes that the statistical behavior of drug- and placebo- treated patients after the 
occurrence of intercurrent events will be the same as if patients were treated with placebo.  Thus, 


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in the effectiveness context, pMI assumes no pharmacological benefit of the drug after the 
occurrence of intercurrent events but is a more conservative approach than mLOCF because it 
accounts for uncertainty of imputation, and therefore does not underestimate standard errors, and 
it limits bias.  In the efficacy context pMI is a specific form of a missing not at random analysis 
and expected to yield a conservative estimate of efficacy.  
In the pMI analysis, multiple imputations are used to replace missing outcomes for drug- and 
placebo-treated patients who have an intercurrent event using multiple draws from the posterior 
predictive distribution estimated from the placebo arm.  The binary outcomes will then be 
derived from the imputed data. 
Data are processed sequentially by repeatedly calling SAS® PROC MI to impute missing 
outcomes at visits t=1,.., T.
1. Initialization:  Set t=0 (baseline visit)
2. Iteration:  Set t=t+1.  Create a data set combining records from drug- and placebo-treated 
patients with columns for covariates X and outcomes at visits 1,..,t with outcomes for all 
drug-treated patients set to missing at visit t and set to observed or imputed values at 
visits 1,..,t-1.
3. Imputation:  Run Bayesian regression in SAS® PROC MI on this data to impute missing 
values for visit t using previous outcomes for visits 1 to t-1 and baseline covariates.  Note 
that only placebo data will be used to estimate the imputation model since no outcome is 
available for drug-treated patients at visit t.
4. Replace imputed data for all drug-treated patients at visit t with their observed values, 
whenever available up to permanent study drug discontinuation and/or rescue (if 
censoring on rescue).  If t < T then go to Step 2, otherwise proceed to Step 5.
5. Repeat steps 1-4, m times with different seed values to create m imputed complete data 
sets.
Analysis:  For continuous endpoints, fit its treatment response model (MMRM) for each 
completed data set.  For the primary and secondary key efficacy endpoints [IGA (0,1), EASI75, 
EASI90, SCORAD75, and 4-point improvement from baseline in Itch NRS], the binary 
outcomes will be derived from the imputed data for each patient before fitting the logistic 
regression model.  
The number of imputed data sets will be m=100 and a 6-digit seed value will be pre-specified for 
each analysis.  Within the program, the seed will be used to generate the m seeds needed for 
imputation.  The initial seed values are given in Table JAIY.6.2.


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Table JAIY.6.2.
Seed Values for Multiple Imputation
Analysis
Seed value
Proportion of patients achieving IGA of 0 or 1 with a ≥2-point improvement from baseline at 
Week 16 using the primary censoring rule
123450
Percent change from baseline in EASI score at 16 weeks using the primary censoring rule.  
EASI75 and EASI90 will leverage imputation from EASI and therefore do not need a new 
seed number.
123451
Proportion of patients achieving SCORAD75 at 16 week using the primary censoring rule,
with data up to rescue
123452
Proportions of patients achieving a 4-point improvement from baseline in Itch NRS at 
Week 16 using the primary censoring rule
123453
Mean change from baseline in Skin Pain NRS at Week 16 using the primary censoring rule
123454
Mean change from baseline in the score of Item 2 of the ADSS at Week 16 using the 
primary censoring rule
123455
Abbreviations:  ADSS = Atopic Dermatitis Sleep Scale; EASI = Eczema Area and Severity Index score; 
IGA = Investigator’s Global Assessment for AD; NRS = Numeric Rating Scale; SCORAD = SCORing Atopic 
Dermatitis.
The final inference on treatment difference is conducted from the multiple datasets using Rubin’s 
combining rules, as implemented in SAS® PROC MIANALYZE. 
6.4.5. Tipping Point Analyses
To investigate the missing data mechanism, sensitivity analyses using multiple imputation (MI) 
under the missing not at random assumption will be provided for the following primary and key 
secondary objectives as given in Table JAIY.6.3. 
All patients in the ITT population will be included. Data after the occurrence of intercurrent 
events (after application of the primary censoring rule) will be set to missing.
Within each analysis, a most extreme case will be considered, in which all missing data for 
patients randomized to baricitinib 2 mg or 4 mg will be imputed using the worst possible result 
and all missing data for patients randomized to placebo will be imputed with the best possible 
result.  Treatment differences will be analyzed using logistic regression or ANCOVA 
(Section 6.1) as appropriate.  
For continuous variables, the following process will be used to determine the tipping point:
1. To handle intermittent missing visit data, a Markov chain Monte Carlo method (SAS®
Proc MI with MCMC option) will be used to create a monotone missing pattern. 
2. A set of Bayesian regressions (using SAS® Proc MI with MONOTONE option) will be 
used for the imputation of monotone dropouts.  Starting from the first visit with at least 
1 missing value, the regression models will be fit sequentially with treatment as a fixed 
effect and values from the previous visits as covariates.  


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3. A delta score is added to all imputed scores at the primary time point for patients in the 
baricitinib treatment groups, thus worsening the imputed value.  The delta score is capped 
for patients based on the range of the outcome measure being analyzed.
4. Treatment differences between baricitinib and placebo are analyzed for each imputed 
dataset using ANCOVA (Section 6.1).  Results across the imputed datasets are 
aggregated using SAS® Proc MIANALYZE in order to compute a p-value for the 
treatment comparisons for the given delta value.
5. Steps 3 and 4 are repeated, and the delta value added to the imputed baricitinib scores is 
gradually increased.  The tipping point is identified as the delta value which leads to a 
loss of statistical significance (aggregated p-value >0.05) when evaluating baricitinib 
relative to the placebo group.
As a reference, for each delta value used in Steps 3 through 5, a fixed selection of delta values 
(ranging from slightly negative to slightly positive) will be added to imputed values in the 
placebo group, and Step 4 will be performed for the combination.  This will result in a 2-d table, 
with the columns representing the delta values added to the imputed placebo responses, and the 
rows representing the delta values added to the imputed baricitinib responses.  Separate 2-d 
tables will compare each baricitinib dose group to placebo.
A similar process will be used for the categorical variables:
1. Missing responses in the baricitinib groups will be imputed with a range of low response 
probabilities, including probabilities of 0, 0.1, and 0.2.
2. For missing responses in the placebo group, a range of responses probabilities (for 
example, probability = 0, 0.2 … 1) will be used to impute the missing values.  Multiple 
imputed datasets will be generated for each response probability.
3. Treatment differences between baricitinib and placebo are analyzed for each imputed 
dataset using logistic regression (Section 6.1).  Results across the imputed datasets are 
aggregated using SAS® Proc MIANALYZE in order to compute a p-value for the 
treatment comparisons for the given response probability.  If the probability values do not 
allow for any variation between the multiple imputed datasets (for example, all missing 
responses in the placebo and baricitinib groups are imputed as responders and 
nonresponders, respectively), then the p-value from the single imputed dataset will be 
used.
The tipping point is identified as the response probability value within the placebo group that 
leads to a loss of statistical significance when evaluating baricitinib relative to placebo. 
For tipping point analyses the number of imputed data sets will be m=100 and the seed values to 
start the pseudorandom number generator of SAS Proc MI (same values for MCMC option and 
for MONOTONE option) are given in Table JAIY.6.3. 


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Table JAIY.6.3.
Seed Values for Imputation
Analysis
Seed value
Proportion of patients achieving IGA (0,1) with ≥2-point improvement at Week 16; 
primary censoring rule
123470
Proportion of patients achieving EASI75 at Week 16; primary censoring rule
Proportion of patients achieving EASI90 at Week 16; primary censoring rule
123471
Proportions of patients achieving a 4-point improvement from baseline in Itch NRS at 
Week 16, primary censoring rule
123472
Proportion of patients achieving SCORAD75 at Week 16; primary censoring rule
123473
6.5.
Multicenter Studies 
This study will be conducted by multiple investigators at multiple sites internationally.  The 
countries will be categorized into geographic regions, as described in Section 5.2.
For the analysis of the primary endpoint, treatment-by-region interaction will be added to the 
logistic regression model as a sensitivity analysis and results from this model will be compared 
to the primary model (without the interaction effect).  If the treatment-by-region interaction is 
significant at a 2-sided α level of 0.1, the nature of this interaction will be inspected as to 
whether it is quantitative (i.e., the treatment effect is consistent in direction across all regions but 
not in size of treatment effect) or qualitative (the treatment is beneficial in some but not all 
regions).  If the treatment-by-region interaction effect is found to be quantitative, results from the 
primary model will be presented.  If the treatment-by-region interaction effect is found to be 
qualitative, further inspection will be used to identify in which regions baricitinib is found to be 
more beneficial.
6.6.
Multiple Comparisons/Multiplicity
The primary and key secondary endpoints will be adjusted for multiplicity in order to control the 
overall family-wise Type I error rate at a 2-sided alpha level of 0.05.  
The following is a list of primary and key secondary endpoints to be tested.
Primary Null Hypotheses: 

Null Hypotheses[IGA0-1]:  Proportion of baricitinib 4-mg patients achieving IGA of 0 or 
1 with a ≥2-point improvement from baseline at Week 16 is equal to the proportion of 
placebo patients achieving IGA of 0 or 1 with a ≥2-point improvement from baseline at 
Week 16

Null Hypotheses[IGA0-1]:  Proportion of baricitinib 2-mg patients achieving IGA of 0 or 
1 with a  ≥2-point improvement from baseline at Week 16 is equal to the proportion of 
placebo patients achieving IGA of 0 or 1 with a ≥2-point improvement from baseline at 
Week 16 


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Key Secondary Null Hypotheses:

Null Hypotheses[EASI75]:  Proportion of baricitinib 4-mg patients achieving EASI75 is 
equal to the proportion of placebo patients achieving EASI75 at Week 16

Null Hypotheses[ITCH W16]:  Proportion of baricitinib 4-mg patients achieving a 4-
point improvement in Itch NRS is equal to the proportion of placebo patients achieving a 
4-point improvement in Itch NRS at Week 16 among patients with baseline Itch NRS 
score ≥4

Null Hypotheses[EASI PCFB]:  Percent change from baseline in EASI score for 
baricitinib 4-mg patients is equal to the percent change from baseline in EASI score for 
placebo patients at Week 16 

Null Hypotheses[ITCH W4]:  Proportion of baricitinib 4-mg patients achieving a 4-point 
improvement in Itch NRS is equal to the proportion of placebo patients achieving a 4-
point improvement in Itch NRS at Week 4 among patients with baseline Itch NRS score 
≥4  

Null Hypotheses[SCORAD75]:  Proportion of baricitinib 4-mg patients achieving 
SCORAD75 is equal to the proportion of placebo patients achieving SCORAD75 at 
Week 16

Null Hypotheses[EASI 90]:  Proportion of baricitinib 4-mg patients achieving EASI90 is 
equal to the proportion of placebo patients achieving EASI90 at Week 16 

Null Hypotheses[PAIN NRS]:  Mean change from baseline in Skin Pain NRS for 
baricitinib 4-mg patients is equal to the mean change from baseline in Skin Pain NRS for 
placebo patients at Week 16

Null Hypotheses[ADSS2 W16]:  Mean change from baseline in the score of Item 2 of the 
ADSS for baricitinib 4-mg patients equal to the mean change from baseline in the score 
of Item 2 of the ADSS for placebo patients at Week 16

Null Hypotheses[ITCH W2]:  Proportion of baricitinib 4-mg patients achieving a 4-point 
improvement in Itch NRS is equal to the proportion of placebo patients achieving a 4-
point improvement in Itch NRS at Week 2 among patients with baseline Itch NRS score 
≥4 

Null Hypotheses[ADSS2 W1]:  Mean change from baseline in the score of Item 2 of the 
ADSS for baricitinib 4-mg patients is equal to the mean change from baseline in the score 
of Item 2 of the ADSS for placebo patients at Week 1

Null Hypotheses[ITCH W1]:  Proportion of baricitinib 4-mg patients achieving a 4-point 
improvement in Itch NRS is equal to the proportion of placebo patients achieving a 4-
point improvement in Itch NRS at Week 1 among patients with baseline Itch NRS score 
≥4 

Null Hypotheses[ITCH D2]:  Proportion of baricitinib 4-mg patients achieving a 4-point 
improvement in Itch NRS is equal to the proportion of placebo patients achieving a 4-
point improvement in Itch NRS at Day 2 among patients with baseline Itch NRS score ≥4 

Null Hypotheses[EASI75]:  Proportion of baricitinib 2-mg patients achieving EASI75 is 
equal to the proportion of placebo patients achieving EASI75 at Week 16 

Null Hypotheses[ITCH W16]:  Proportion of baricitinib 2-mg patients achieving a 4-
point improvement in Itch NRS is equal to the proportion of placebo patients achieving a 
4-point improvement in Itch NRS at Week 16 among patients with baseline Itch NRS 
score ≥4 


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
Null Hypotheses[EASI PCFB]:  Percent change from baseline in EASI score for 
baricitinib 2-mg patients is equal to the percent change from baseline in EASI score for 
placebo patients at Week 16 

Null Hypotheses[ITCH W4]:  Proportion of baricitinib 2-mg patients achieving a 4-point 
improvement in Itch NRS is equal to the proportion of placebo patients achieving a 4-
point improvement in Itch NRS at Week 4 among patients with baseline Itch NRS score 
≥4 

Null Hypotheses[SCORAD75]:  Proportion of baricitinib 2-mg patients achieving 
SCORAD75 is equal to the proportion of placebo patients achieving SCORAD75 at 
Week 16

Null Hypotheses[EASI90]:  Proportion of baricitinib 2-mg patients achieving EASI90 is 
equal to the proportion of placebo patients achieving EASI90 at Week 16 

Null Hypotheses[PAIN NRS]:  Mean change from baseline in Skin Pain NRS for 
baricitinib 2-mg patients is equal to the mean change from baseline in Skin Pain NRS for 
placebo patients at Week 16

Null Hypotheses[ADSS2 W16]:  Mean change from baseline in the score of Item 2 of the 
ADSS for baricitinib 2-mg patients is equal to the mean change from baseline in the score 
of Item 2 of the ADSS for placebo patients at Week 16 

Null Hypotheses [ITCH W2]:  Proportion of baricitinib 2-mg patients achieving a 4-point 
improvement in Itch NRS is equal to the proportion of placebo patients achieving a 4-
point improvement in Itch NRS at Week 2 among patients with baseline Itch NRS score 
≥4 

Null Hypotheses[ADSS2 W1]:  Mean change from baseline in the score of Item 2 of the 
ADSS for baricitinib 2-mg patients is equal to the mean change from baseline in the score 
of Item 2 of the ADSS for placebo patients at Week 1 

Null Hypotheses[ITCH W1]:  Proportion of baricitinib 2-mg patients achieving a 4-point 
improvement in Itch NRS is equal to the proportion of placebo patients achieving a 4-
point improvement in Itch NRS at Week 1 among patients with baseline Itch NRS score 
≥4 

Null Hypotheses[ITCH D2]:  Proportion of baricitinib 2-mg patients achieving a 4-point 
improvement in Itch NRS is equal to the proportion of placebo patients achieving a 4-
point improvement in Itch NRS at Day 2 among patients with baseline Itch NRS score ≥4 
The multiple testing strategy for the primary and the major secondary endpoint will be 
implemented through the graphical testing procedure depicted by Figure JAIY.6.1. 


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Figure JAIY.6.1.
Illustration of graphical multiple testing procedure with initial α 
allocation and weights.
For Japan, the same testing strategy will be used, however, the proportion of patients achieving 
EASI75 and IGA of 0 or 1 at Week 16 are considered co-primary. Both endpoints have to meet 
statistical significance compared with placebo in order to demonstrate a superiority of a given 
baricitinib dose (baricitinib 4-mg and/or baricitinib 2-mg) compared with placebo.
There will be no adjustment for multiple comparisons for any other analyses.
6.7.
Patient Disposition
An overview of patient populations will be summarized by treatment group.  Frequency counts 
and percentages of patients excluded prior to randomization by primary reason for exclusion will 
be provided for patients who failed to meet study entry requirements during screening.
Patient disposition through Week 16 will be summarized using the ITT population.  Frequency 
counts and percentages of patients who complete the study treatment visits or discontinue early 
from the study along with whether they completed follow-up, did not complete follow-up or 


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enrolled into the extension will be summarized separately by treatment group for patients who 
are not rescued and for patients who are rescued, along with their reason for study 
discontinuation.  Frequency counts and percentages of patients who complete the treatment or 
discontinue treatment early will also be summarized separately by treatment group for patients 
who are not rescued and for patients who are rescued, along with their reason for treatment 
discontinuation.  
A listing of patient disposition will be provided for all randomized patients, with the extent of 
their participation in the study and the reason for discontinuation.  A listing of all randomized 
patients with their treatment assignment will also be provided.
6.8.
Patient Characteristics
Patient characteristics including demographics and baseline characteristics will be summarized 
descriptively by treatment group for the ITT population.  Historical illnesses and pre-existing 
conditions will be summarized descriptively by treatment group for the ITT population.  No 
formal statistical comparisons will be made among treatment groups unless otherwise stated.
6.8.1. Demographics
Patient demographics will be summarized as described above.  The following demographic 
information will be included:

Age

Age group (<65 vs. ≥65)

Age group (<65, ≥65 to <75, ≥75 to <85, ≥85)

Gender (male, female)

Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Multiple)

Region (as defined in Table JAIY.5.1)

Country 

Weight (kg)

Weight category (<60 kg, ≥60 to <100 kg, ≥100 kg)

Height (cm)

BMI (kg/m2) 

BMI category (<25 kg/m2, ≥25 to <30 kg/m2, ≥30 kg/m2)
A listing of patient demographics will also be provided for the ITT population. 
6.8.2. Baseline Disease Characteristics
The following baseline disease information will be categorized and presented for baseline AD 
clinical characteristics, baseline health outcome measures, and other baseline demographic and 
disease characteristics as described above: 

Duration since AD diagnosis (years) 

Duration since AD diagnosis category (0 to <2 years, 2 to <5 years, 5 to <10 years, 10 to 
<20 years, ≥20 years)


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
Age at Diagnosis (years) 

Age Group at Diagnosis (<18 years, ≥18 to <50 years, ≥50 years)

Habits (Alcohol:  Never, Current, Former; Tobacco:  Never, Current, Former)

Skin Infections treated with a pharmacological agent within past year (yes, no, unknown; 
number if yes)

Atopic Dermatitis Flares within past year (yes, no, unknown; number if yes)

Validated Investigator’s Global Assessment for AD (IGA) score

Eczema Area and Severity Index (EASI) score

SCORing Atopic Dermatitis (SCORAD)

Body Surface Area (BSA) affected by AD

Hospital Anxiety Depression Scale (HADS) subscales

Patient-Oriented Eczema Measure (POEM)

Itch Numerical Rating Scale (NRS)

Atopic Dermatitis Sleep Scale (ADSS) Item 2 

Dermatology Life Quality Index (DLQI)

Skin Pain NRS

Patient Global Impression of Severity (PGI-S-AD)

Prior therapy (topical therapy only; systemic therapy) 

Prior use of Cyclosporine (yes, no)

Cyclosporine inadequate response (yes, no)

Cyclosporine intolerance (yes, no)

Cyclosporine contraindication [ineligible] (yes, no)

Cyclosporine inadvisable (yes no)

Prior use of TCNI (yes, no)

TCNI inadequate response (yes, no)

TCNI intolerance (yes, no)

TCNI contraindication [ineligible] (yes, no)

TCNI inadvisable (yes, no)

Vaccine (yes, no)

Baseline renal function status:  impaired (eGFR <60 mL/min/1.73 m2) or not impaired 
(eGFR ≥60 mL/min/1.73 m2)

Immunoglobulin E (IgE):  intrinsic(<200 kU/I) or extrinsic (≥200 kU/I)
6.8.3. Historical Illness and Pre-existing Conditions
Historical illnesses are defined as those conditions recorded in the Pre-existing Conditions and 
Medical History electronic case report form (eCRF) or from the Prespecified Medical History:  
Comorbidities eCRF with an end date prior to the informed consent date.  The number and 
percentage of patients with selected historical diagnoses will be summarized by treatment group 
using the ITT population.  Historical diagnoses will be categorized using the Medical Dictionary 
for Regulatory Activities (MedDRA®, most current available version) algorithmic standardized 
MedDRA queries (SMQs) or similar pre-defined lists of preferred terms (PTs) of interest.
Preexisting conditions are defined as those conditions with a start date prior to the first dose of 
the study drug and stop dates that are at or after the informed consent date or have no stop date 


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(i.e., are ongoing). For events occurring on the day of the first dose of study treatment, the date 
and time of the onset of the event will both be used to determine if the event was pre-existing. 
Conditions with a partial or missing start date (or time if needed) will be assumed to be ‘not pre-
existing’ unless there is evidence, through comparison of partial dates, to suggest otherwise.  
Pre-existing conditions will be categorized using the MedDRA SMQs or similar pre-defined lists 
of PTs of interest.  Frequency counts and percentages of patients with selected pre-existing 
conditions will be summarized by treatment group using the ITT population.
6.9.
Treatment Compliance
Patient compliance with study medication will be assessed from Week 0 (Visit 2) to Week 16 
(Visit 8) or Early Termination using the ITT population.
All patients are expected to take 2 tablets daily from a package as described in the protocol.  
Each bottle contains 36 tablets.  A patient is considered noncompliant if he or she misses >20% 
of the prescribed doses during the study, unless the patient’s study drug is withheld by the 
investigator.  For patients who had their treatment temporarily interrupted by the investigator, the 
period of time that dose was withheld will be taken into account in the compliance calculation. 
Compliance in the period of interest up to Visit x will be calculated as follows: 
Compliance = total number of tablets dispensed – total number of tablets returned
expected number of total tablets
where 

Total number of tablets dispensed:  sum of tablets dispensed in the period of interest prior 
to Visit x; 

Total number of tablets returned:  sum of the tablets returned in the period of interest 
prior to and including Visit x;

Expected number of tablets:  number of days in the period of interest*number of tablets 
taken per day = [(date of last dose – date of first dose + 1) – number of days of temporary 
drug interruption]*number of tablets taken per day 
Patients who are significantly noncompliant (compliance <80%) through Week 16 will be 
excluded from the PPS population.
Descriptive statistics for percent compliance and non-compliance rate will be summarized for the 
ITT population by treatment group for Week 0 through Week 16.  Sub-intervals of interest, such 
as compliance between visits, may also be presented.  The number of expected doses, tablets 
dispensed, tablets returned, and percent compliance will be listed by patient for Week 0 through 
Week 16. 
6.10. Rescue Therapy
Rescue therapy with additional topical and systemic therapies is available starting after 2 weeks 
of treatment (Visit 4), for patients who are experiencing worsening and unacceptable symptoms 
of AD despite treatment with IP and moderate-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 


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of triamcinolone 0.1% cream (moderate-potency TCS) on large surfaces may be considered for 
rescue to high- or ultra-high-potency TCS.  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, 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. 
The initial rescue therapy will be the first non-missing record before the last dose date from the
CRF page Concomitant Therapy: Rescue Therapy.
A summary of the initial rescue therapy and the reason for requiring initial rescue will be 
produced, as well as a summary of the proportion of patients initially rescued at each study visit.  
A summary of all rescue medications will be provided.
6.11. Previous and Concomitant Therapy
Summaries of previous and concomitant medications will be based on the ITT population. 
At screening, previous and current AD treatments are recorded for each patient.  Concomitant 
therapy for the treatment period is defined as therapy that starts before or during the treatment 
period and ends during the treatment period or is ongoing (has no end date or ends after the 
treatment period).  Should there be insufficient data to make this comparison (for example, the 
concomitant therapy stop year is the same as the treatment start year, but the concomitant therapy 
stop month and day are missing), the medication will be considered as concomitant for the 
treatment period.  
Summaries of previous medications will be as follows:

Previous AD therapies
Summaries of concomitant medications, with sponsor and non-sponsor provided background 
TCS included, will be as follows:

General Concomitant medications excluding rescue medicine
6.11.1. Background TCS
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 7.7.3 in the protocol.
The dispensed weight of sponsor-provided TCS tubes for the two different potencies (low and 
moderate) varies between countries due to different supply regions.  Average weights of full 
tubes were used to determine the dispensed weights for each region.  Returned tubes were 
weighed with cap (without the carton) to determine the amount of TCS in grams (g) used at each 
visit. 


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For low potency TCS, the dispensed tube weight with cap (without the carton) in Japan is 13.5g.  
For countries supplied by European distributors (Austria, Germany, Italy, Poland, and Spain), the 
dispensed weight of low potency TCS is 21g.  The remaining countries, supplied by US 
distributors (Argentina, Australia, Korea, and Taiwan), the weight of low potency TCS is 40g. 
For moderate potency TCS, the dispensed tube weight with cap (without the carton) in Japan is 
13.5g.  For countries supplied by European distributors, the dispensed weight of moderate 
potency TCS is 38g.  The remaining countries, supplied by US distributors, the weight of 
moderate potency TCS is 40g.The total amount of background TCS, provided by sponsor, will 
be summarized in grams by potency (low and moderate) and both potencies, between visits 
(Week 0 through Week 1, Week 1 through Week 2, Week 2 through Week 4, Week 4 through 
Week 8, Week 8 through 12, Week 12 through Week 16), and throughout the entire 16-week 
treatment period.  If a returned tube is not weighed or not returned, then the tube can be 
classified as partially used, fully used, unused, or unknown.  Partially used rescue medication 
tubes will be defined as 50% used whereas fully used and unused tubes will be defined as 100% 
and 0% used respectively.  When drug accountability is not performed for a particular tube of 
rescue medication or an answer of ‘unknown’ is given for a tube which is not returned, that 
particular tube will not be included in the analysis. The main analysis on the total amount of 
background TCS throughout the entire 16-week treatment period will apply censoring rule #1.  
After patients who get rescued or discontinue IP, whichever is earlier, it is assumed that they 
would use the same amount of TCS as they did before.  Analysis will be done via analysis of 
variance (ANOVA), with geographic region, baseline disease severity and treatment as factors in 
the model.  The secondary analysis will apply censoring rule #2 with the same assumptions as 
described above.
Whether any background TCS is used or not used for each patient is also collected on the diary 
device in each day starting from the first dose date throughout the study.
The total number of days that the patients did not use background TCS will be summarized by 
both potencies throughout the entire 16-week treatment period.  The main analysis applies 
censoring rule #1.  After patients who are rescued or discontinue IP, it is assumed that
background TCS would be applied each day.  In case of missing values in the daily diary, it will 
be assumed that background TCS has been used.  Analysis will be done via ANOVA, with 
geographic region, baseline disease severity and treatment as factors in the model.  A secondary 
analysis will apply censoring rule #2, with the same assumptions for missing values as described 
above.
6.12. Efficacy Analyses
The general methods used to summarize efficacy data, including the definition of baseline value 
for assessments are described in Section 6.2.  The censoring rules applied to data as well as 
imputation methods are described in Section 6.4.
Table JAIY.6.4 provides the descriptions and derivations of the primary, secondary, and 
exploratory efficacy outcomes.


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Table JAIY.6.5 provides the detailed analyses including analysis type, method and imputation, 
population, time point, and comparisons for efficacy analyses.


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Table JAIY.6.4.
Description and Derivation of Primary, Secondary and Exploratory Efficacy Outcomes
Measure
Description
Variable
Derivation / Comment
Imputation Approach if 
Missing Components
Validated 
Investigator’s 
Global 
Assessment 
for AD (IGA)
The validated Investigator’s global 
assessment of the patient’s overall 
severity of their AD, based on a static, 
numeric 5-point scale from 0 (clear) to 
4 (severe).  The score is based on an 
overall assessment of the degree of 
erythema, papulation/induration, 
oozing/crusting, and lichenification.
IGA score
Single item.  Range: 0 to 4
0 represents “clear”
4 represents “severe”
Single item, missing if 
missing.
Change from baseline in 
IGA score
Change from baseline: observed IGA 
score – baseline IGA score
Missing if baseline or 
observed value is missing.

IGA [0,1] with 
≥2-point 
improvement

IGA [0]

Observed score of 0 or 1 and change 
from baseline ≤2

Observed score of 0

Missing if baseline or 
observed value is 
missing.

Single item, missing if 
missing.


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Eczema Area 
and Severity 
Index (EASI) 
The EASI assesses objective physician 
estimates of 2 dimensions of atopic 
dermatitis – disease extent and clinical 
signs (Hanifin et al 2001) – by scoring 
the extent of disease (percentage of skin 
affected: 0 = 0%; 1 = 1-9%; 2 = 10-29%; 
3 = 30-49%; 4 = 50-69%; 5 = 70-89%; 
6 = 90-100%) and the severity of 4 
clinical signs (erythema, 
edema/papulation, excoriation, and 
lichenification) each on a scale of 0 to 3 
(0 = none, absent; 1 = mild; 
2 = moderate; 3 = severe) at 4 body sites 
(head and neck, trunk, upper limbs, and 
lower limbs).  Half scores are allowed 
between severities 1, 2 and 3.  Each 
body site will have a score that ranges 
from 0 to 72, and the final EASI score 
will be obtained by weight-averaging 
these 4 scores.  Hence, the final EASI 
score will range from 0 to 72 for each 
time point. 
EASI score 
Derive EASI region score for each of 
head and neck, trunk, upper limbs, and 
lower limbs as follows: 
EASIregion = (Erythema + 
edema/papulation +  Excoriation + 
Lichenification) *(value from percentage 
involvement), where erythema, 
edema/papulation, excoriation, and 
lichenification are evaluated on a scale 
of 0 to 3 and value from percentage 
involvement is on a scale of 0 to 6.  
Then total EASI score is as follows: 
EASI = 0.1*EASIhead and neck + 
0.3*EASItrunk + 0.2*EASIupper limbs + 
0.4*EASIlower limbs 
N/A – partial assessments 
cannot be saved.   
 Change from baseline 
in EASI score 
 Percent change from 
baseline EASI score 
100 ൈܱܾݏ݁ݎݒ݁݀ݏܿ݋ݎ݁െܤܽݏ݈݁݅݊݁
ܤܽݏ݈݁݅݊݁
 
Change from baseline: observed EASI 
score – baseline EASI score 
% change from baseline: 
Missing if baseline or 
observed value is missing. 
EASI50 
% Improvement in EASI score from 
baseline ≥ 50%: 
% change from baseline ≤ -50 
Missing if baseline or 
observed value is missing. 
EASI75 
% Improvement in EASI score from 
baseline ≥75%: 
% change from baseline ≤-75 
Missing if baseline or 
observed value is missing. 
EASI90 
% Improvement in EASI score from 
baseline ≥90%: 
% change from baseline ≤-90 
Missing if baseline or 
observed value is missing. 
Body Surface 
Area (BSA) 
Affected by 
AD 
Body surface area affected by AD will 
be assessed for 4 separate body regions 
and is collected as part of the EASI 
assessment:  head and neck, trunk 
(including genital region), upper 
extremities, and lower extremities 
BSA score 
Use the percentage of skin affected for 
each region (0 to 100%) in EASI as 
follows: 
BSA Total = 0.1*BSAhead and neck + 
0.3*BSAtrunk + 0.2* BSAupper limbs + 
N/A – partial assessments 
cannot be saved.   


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(including the buttocks).  Each body 
region will be assessed for disease extent 
ranging from 0% to 100% involvement.  
The overall total percentage will be 
reported based off of all 4 body regions 
combined, after applying specific 
multipliers to the different body regions 
to account for the percent of the total 
BSA represented by each of the 4 
regions. 
0.4*BSAlower limbs 
Change from baseline in 
BSA score 
Change from baseline: observed BSA 
score – baseline BSA score 
Missing if baseline or 
observed value is missing. 
SCORing 
Atopic 
Dermatitis 
(SCORAD) 
The SCORing Atopic Dermatitis 
(SCORAD) index uses the rule of nines 
to assess disease extent (head and neck 
9%; upper limbs 9% each; lower limbs 
18% each; anterior trunk 18%; back 
18%; and genitals 1%).  It evaluates 6 
clinical characteristics to determine 
disease severity:  (1) erythema, 
(2) edema/papulation, (3) oozing/crusts, 
(4) excoriation, (5) lichenification, and 
(6) dryness on a scale of 0 to 3 
(0=absence, 1=mild, 2=moderate, 
3=severe).  The SCORAD index also 
assesses subjective symptoms of pruritus 
and sleep loss in the last 72 hours on 
visual analogue scales (VAS) of 0 to 10 
where 0 is no itch or sleep loss and 10 is 
worst imaginable itch or 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). 
SCORAD score 
SCORAD = A/5 + 7B/2 + C, where  
A is extent of disease, range 0-100 
B is disease severity, range 0-18 
C is subjective symptoms, range 0-20 
 
Missing if components A 
and B are missing or if 
component C is missing.  
Partial assessments 
performed by physician 
cannot be saved and partial 
assessments performed by 
subject cannot be saved.  
 Change from baseline 
in SCORAD score 
 Percent change from 
baseline in SCORAD 
score 
100 ൈܱܾݏ݁ݎݒ݁݀ݏܿ݋ݎ݁െܤܽݏ݈݁݅݊݁
ܤܽݏ݈݁݅݊݁
 
Change from baseline: observed 
SCORAD score – baseline SCORAD 
score 
% change from baseline: 
Missing if baseline or 
observed value is missing. 
SCORAD75 
% Improvement in SCORAD from 
baseline ≥75%: 
% change from baseline ≤-75 
Missing if baseline or 
observed value is missing. 
SCORAD90 
% Improvement in SCORAD from 
baseline ≥90%: 
% change from baseline ≤-90 
Missing if baseline or 
observed value is missing. 


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Table JAIY.6.5.
Description of Primary, Secondary and Exploratory Efficacy Analyses
Measure
Variable
Analysis Method
(Section 6.2.3)
Population
(Section 6.2.1)
Comparison/Time Point
Analysis Type
Validated 
Investigator’s 
Global 
Assessment 
for AD (IGA)
Proportion of patients achieving IGA 
[0,1] with a ≥2-point improvement
Logistic regression 
using NRI
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Primary analysis
PPS
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity analysis
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 4
Secondary analysis
Logistic regression 
using pMI and 
Tipping Point
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity analysis 
Proportion of patients achieving IGA [0]
Logistic regression 
using NRI
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Secondary analysis
Eczema Area 
and Severity 
Index (EASI)
EASI score
Change from baseline in EASI score
Percent change from baseline in EASI 
score
MMRM
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Key secondary 
analysis
PPS
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity analysis
ANCOVA using 
mLOCF
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity analysis
pMI and Tipping 
Point
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity analysis 
Proportion of patients achieving 
EASI50
Logistic regression 
using NRI
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Secondary analysis
Proportion of patients achieving 
EASI75
Proportion of patients achieving 
EASI90
Logistic regression 
using NRI
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Key secondary 
analysis
PPS
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity analysis
pMI and Tipping 
Point
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity analysis 
Body Surface 
Area (BSA) 
Affected by 
AD
BSA score
Change from baseline in BSA score
MMRM
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Secondary analysis
ANCOVA using 
mLOCF
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity analysis 


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Measure
Variable
Analysis Method
(Section 6.2.3)
Population
(Section 6.2.1)
Comparison/Time Point
Analysis Type
SCORing 
Atopic 
Dermatitis 
(SCORAD)
SCORAD score
Change from baseline in SCORAD 
score
Percent change from baseline in 
SCORAD score
MMRM
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Secondary analysis
ANCOVA using 
mLOCF
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity analysis
Proportion of patients achieving 
SCORAD75
Logistic regression 
using NRI
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Key secondary 
analysis
PPS
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity analysis
Logistic regression 
using pMI
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity analysis 
Proportion of patients achieving 
SCORAD90
Logistic regression 
using NRI
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Secondary analysis
pMI and Tipping 
Point
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity analysis
Skin 
Infections
Proportion of patients developing skin 
infections requiring antibiotic treatment
Fisher’s exact
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Secondary analysis
Abbreviations:  ANCOVA = analysis of covariance; Bari = baricitinib; ITT = intent-to-treat; mLOCF = modified last observation carried forward; 
MMRM = mixed model repeated measures; NRI = nonresponder imputation; PBO = placebo; pMI=placebo multiple imputation; PPS = per protocol set.
Notes: (1) for all other post-baseline visits not mentioned in the table, but collected for the measures as specified in the protocol, the analyses will be made as 
exploratory analyses. 
           (2) All primary and key secondary analyses will be performed for Japan population. Other key secondary and exploratory analysis may be performed for 
Japan population.


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6.12.1. Primary Outcome and Methodology
The validated Investigator’s Global Assessment for AD (IGA) uses the clinical characteristics of 
erythema, papulation/induration, oozing/crusting and lichenification to produce a single-item 
score ranging from 0 to 4.  The primary analysis of the study is to test the null hypotheses that 
neither baricitinib 4 mg nor baricitinib 2 mg is superior to placebo when evaluating the 
proportion of patients achieving IGA of 0 or 1 at Week 16 in the ITT population.  The analysis 
assumes that treatment response disappears after patients are rescued or permanently discontinue 
from treatment.  This will serve as the primary estimand.  In this estimand, missing data due to 
the application of the primary censoring rule and the occurrence of other non-censor intercurrent 
events will be imputed using the NRI method described in Section 6.4.1.  
A supplemental estimand is to test the null hypotheses that neither baricitinib 4 mg nor 
baricitinib 2 mg is superior to placebo when evaluating the proportion of patients achieving IGA 
of 0 or 1 at Week 16 in the ITT population.  This analysis assumes the treatment response 
disappears after patients permanently discontinue from treatment.  In this supplemental estimand, 
missing data due to the application of the secondary censoring rule and the occurrence of other 
non-censor intercurrent events will be imputed using the NRI method described in Section 6.4.1.
A logistic regression analysis as described in Section 6.2.3 will be used for the comparisons.  
The odds ratio, the corresponding 95% CIs and p-value, as well as the treatment differences and 
the corresponding 95% CIs, will be reported. 
Multiplicity controlled analyses will be performed on the primary and key secondary (see 
Section 4.2.1) objectives to control the overall Type I error rate at a 2-sided alpha level of 0.05.  
A graphical approach will be used to perform the multiplicity controlled analyses as described in 
Section 6.6.
6.12.2. Secondary and Exploratory Efficacy Analyses
For secondary analysis, the null hypotheses is that neither baricitinib 4 mg nor baricitinib 2 mg is 
superior to placebo in the ITT population.  These analyses assume treatment response disappears 
after patients are rescued or permanently discontinued from treatment and will serve as the 
primary estimand.  In this estimand, missing data due to the application of the primary censoring 
rule and the occurrence of other non-censor intercurrent events will be imputed using the method 
described in Table JAIY.6.1.
A supplemental estimand for secondary endpoints is to test the null hypotheses that neither 
baricitinib 4 mg nor baricitinib 2 mg is superior to placebo in the ITT population.  These 
analyses assume the treatment response disappears after patients permanently discontinue from 
treatment.  In this supplemental estimand, missing data due to the application of the secondary 
censoring rule and the occurrence of other non-censor intercurrent events will be imputed using 
the method described in Table JAIY.6.1.
A list of exploratory endpoints are provided in Section 4.2.2.  There will be no adjustment for 
multiple comparisons for exploratory endpoints.  The secondary and exploratory efficacy 


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endpoints are detailed in Table JAIY.6.4 and analyses are provided in Table JAIY.6.5.  Health 
outcomes analyses are described in Section 6.13.
6.12.3. Sensitivity Analyses
Sensitivity analyses are included to demonstrate robustness of analyses methods using different 
missing data imputations, censoring rules, populations and analyses assumptions.  Sensitivity 
analyses for select outcomes have been previously described and include the following:

Analyses of key endpoints using the per-protocol analysis set (Section 6.2.1)

Analyses of key endpoints using the secondary censoring rule (Section 6.2)

Placebo multiple imputation (Section 6.4.4)

Tipping point analysis (Section 6.4.5)

The addition of a treatment-by-region interaction to the logistic regression model for the 
primary outcome (Section 6.5)

Analysis of continuous outcomes with ANCOVA (Section 6.2.3), with missing data 
imputed using mLOCF (Section 6.4.3). 
6.13. Health Outcomes/Quality-of-Life Analyses
The general methods used to summarize health outcomes and quality-of-life measures, including 
the definition of baseline value for assessments are described in Section 6.1.
Health outcomes and quality-of-life measures will generally be analyzed according to the 
formats discussed in Section 6.12.
Table JAIY.6.6 includes the descriptions and derivations of the health outcomes and quality-of-
life measures. 
Table JAIY.6.7 provides the detailed analyses including analysis type, method and imputation, 
population, time point, and comparisons for health outcomes and quality-of-life measures.


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Table JAIY.6.6. 
Description and Derivation of Health Outcomes and Quality-of-Life Measures 
Measure 
Description 
Variable 
Derivation / Comment 
Imputation 
Approach if 
Missing 
Components 
Itch Numeric Rating Scale 
(NRS) 
 
 
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).  Refer to Section 6.2.2 for details on 
how to calculate the weekly score which will be 
used in the continuous analysis.  
Itch NRS score 
Single item; range 0-10.  Refer to 
Section 6.2.2 on how to derive the 
visit score.   
Refer to 
Section 6.2.2 on 
how to derive 
the weekly visit 
score.  
 Change from 
baseline in Itch 
NRS 
 Percent change 
from baseline in 
Itch NRS 
Change from baseline: observed 
Itch score – baseline Itch score 
% change from baseline: 
100
ൈܱܾݏ݁ݎݒ݁݀ݏܿ݋ݎ݁െܤܽݏ݈݁݅݊݁
ܤܽݏ݈݁݅݊݁
 
Missing if 
baseline or 
observed value 
is missing. 
4-point Itch 
improvement in 
subgroup of 
patients with 
baseline Itch NRS 
≥4  
Change from baseline ≤-4 and 
baseline ≥4 
Missing if 
baseline is 
missing or <4 or 
observed value 
is missing. 
 Itch-free days 
(Itch NRS = 0) 
The number of itch-free days 
during intervals starting on the 
day of the first study drug 
administration.  This will be 
calculated for the following 
intervals: baseline to Week 4, 
Week 4 to Week 8, Week 8 to 
Week 12 and Week 12 to Week 
16.   Day 1 is defined as the day 
of first study drug administration 
therefore the baseline to Week 4 
assessment is based on Day 1 to 
Day 28, Week 4 to Week 8 is 
based on Day 29 to Day 56, etc. 
Missing if 
observed value 
is missing.  


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Measure
Description
Variable
Derivation / Comment
Imputation 
Approach if 
Missing 
Components
Skin Pain Numeric Rating 
Scale (NRS)
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  
Refer to Section 6.2.2 for details on how to 
calculate the weekly score which will be used in 
the continuous analysis.  
Skin Pain NRS 
score
Single item; range 0 to 10.  Refer 
to Section 6.2.2 on how to derive 
the visit score.  
Refer to 
Section 6.2.2 on 
how to derive 
the visit score.  
Change from 
baseline in Skin 
Pain NRS
Change from baseline: observed 
skin pain score – baseline skin 
pain score
Missing if 
baseline or 
observed value 
is missing.
Skin Pain-free days 
(Skin Pain NRS = 
0)
The number of skin pain-free 
days during intervals starting on 
the day of the first study drug 
administration.  This will be 
calculated for the following 
intervals: baseline to Week 4, 
Week 4 to Week 8, Week 8 to 
Week 12 and Week 12 to Week 
16.  Thus, if Day 1 is defined as 
the day of first study drug 
administration, the baseline to 
Week 4 assessment is based on 
Day 1 to Day 28, Week 4 to 
Week 8 is based on Day 29 to 
Day 56, etc.
Missing if 
observed value 
is missing.


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Measure
Description
Variable
Derivation / Comment
Imputation 
Approach if 
Missing 
Components
Atopic Dermatitis Sleep 
Scale (ADSS)
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.    

Item 1 score of 
ADSS

Item 2 score of 
ADSS

Item 3 score of 
ADSS
Single items: Item 1, range 0 to 4; 
Item 2, range 0 to 29; Item 3, 
range 0 to 4.  Refer to 
Section 6.2.2 on how to derive the 
visit score.  
Refer to 
Section 6.2.2 on 
how to derive 
the weekly visit 
score.  

Change from 
baseline in 
score of Item 1 
of ADSS

Change from 
baseline in 
score of Item 2 
of ADSS

Change from 
baseline in 
score of Item 3 
of ADSS
Change from baseline: observed 
ADSS item score – baseline 
ADSS item score
Missing if 
baseline or 
observed value 
is missing.


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Measure
Description
Variable
Derivation / Comment
Imputation 
Approach if 
Missing 
Components
Patient- Oriented Eczema 
Measure (POEM)
The POEM is a simple, 7-item, patient-
administered scale that assesses disease severity 
in children and adults.  Patients respond to 
questions about the frequency of 7 symptoms 
(itching, sleep disturbance, bleeding, 
weeping/oozing, cracking, flaking, and 
dryness/roughness) over the last week.  
Response categories include “No days,” “1-2 
days,” “3-4 days,” “5-6 days,” and “Every day” 
with corresponding scores of 0, 1, 2, 3, and 4, 
respectively.  Scores range from 0-28 with 
higher total scores indicating greater disease 
severity (Charman et al. 2004).  
POEM score
POEM total score: sum of 
questions 1 to 7, Range 0 to 28. 
If a single 
question is left 
unanswered, 
then that 
question is 
scored as 0.  If 
more than one 
question is 
unanswered, 
then the tool is 
not scored.  If 
more than one 
response is 
selected, then 
the response 
with the highest 
score is used.
Change from 
baseline in POEM 
score
Change from baseline: observed 
POEM score – baseline POEM 
score
Missing if 
baseline or 
observed value 
is missing.
4-point 
improvement in 
POEM score in 
subgroup of 
patients with 
baseline ≥4 
Change from baseline ≤-4 and 
baseline ≥4
Missing if 
baseline is 
missing or <4 or 
observed value 
is missing.


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Measure
Description
Variable
Derivation / Comment
Imputation 
Approach if 
Missing 
Components
Patient Global Impression of 
Severity–Atopic Dermatitis 
(PGI-S-AD)
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.”  
PGI-S-AD score
Single item.  Range 1 to 5.  Refer 
to Section 6.2.2 on how to derive 
the visit score.  
Refer to 
Section 6.2.2 on 
how to derive 
the visit score.  
Change from 
baseline in PGI-S-
AD
Change from baseline: observed 
PGI-S-AD score – baseline PGI-
S-AD score
Missing if 
baseline or 
observed value 
is missing.
Hospital Anxiety Depression 
Scale (HADS)
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 and depression) can range 
from 0 to 21, with higher scores indicating 
greater anxiety or depression (Zigmond and 
Snaith 1983; Snaith 2003).
HADS score for 
anxiety and 
depression 
domains
Anxiety domain score is sum of 
the seven anxiety questions, range 
0 to 21;
Depression domain score is sum 
of the seven depression questions, 
range 0 to 21. 
N/A – partial 
assessments 
cannot be saved.  
Change from 
baseline in HADS 
total score, anxiety 
and depression 
domain
Change from baseline: observed 
HADS domain score – baseline 
HADS domain score
Missing if 
baseline or 
observed value 
is missing.
Dermatology Life Quality 
Index (DLQI)
The Dermatology Life Quality Index (DLQI) is 
a simple, patient-administered, 10-item, 
validated, quality-of-life questionnaire that 
covers 6 domains including symptoms and 
feelings, daily activities, leisure, work and 
school, personal relationships, and treatment.  
The recall period of this scale is over the “last 
week.”  Response categories include  “a little,” 
“a lot,” and “very much,” with corresponding 
Symptoms and 
feelings domain
Sum of questions 1 and 2, range 0 
to 6.
N/A – partial 
assessments 
cannot be saved.  
Daily activities 
domain
Sum of questions 3 and 4, range 0 
to 6.
N/A – partial 
assessments 
cannot be saved.  
Leisure domain
Sum of questions 5 and 6, range 0 
to 6.
N/A – partial 
assessments 
cannot be saved.  


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Measure
Description
Variable
Derivation / Comment
Imputation 
Approach if 
Missing 
Components
scores of 1, 2, and 3, respectively, and “not at 
all,” or unanswered (“not relevant”) responses 
scored as 0.  Scores range from 0-30 with 
higher scores indicating greater impairment of 
quality of life.  A DLQI total score of 0 to 1 is 
considered as having no effect on a patient’s 
health-related 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).
Work and school 
domain
Sum of questions 7 and 7B (if it is 
answered), range 0 to 3. 
Responses of “yes” and “no” on 
Question 7 are given scores of 3 
and 0 respectively.  If Question 7 
is answered “no” then Question 
7b is answered with “a lot”, “a 
little”, “not at all” getting scores 
of 2, 1, 0 respectively.  
N/A – partial 
assessments 
cannot be saved.  
Personal 
relationships 
domain
Sum of questions 8 and 9, range 0 
to 6.
N/A – partial 
assessments 
cannot be saved.  
Treatment domain 
Question 10, range 0 to 3.
N/A – partial 
assessments 
cannot be saved.  
DLQI total score
DLQI total score: sum of all six 
DLQI domain scores, range 0 to 
30.
N/A – partial 
assessments 
cannot be saved.  
Change from 
baseline in DLQI
Change from baseline: observed 
DLQI score – baseline DLQI 
score
Missing if 
baseline or 
observed value 
is missing.
4-point 
improvement in 
DLQI total score in 
subgroup of 
patients with 
baseline ≥4 
Change from baseline ≤4 and 
baseline ≥4
Missing if 
baseline is 
missing or <4 or 
observed value 
is missing.
DLQI (0,1)
A DLQI (0,1) response is defined 
as a post-baseline DLQI total 
score of 0 or 1
Missing if the 
DLQI total score 
is missing


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Measure
Description
Variable
Derivation / Comment
Imputation 
Approach if 
Missing 
Components
Work Productivity and 
Activity Impairment: Atopic 
Dermatitis (WPAI-AD)
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.  
Employment status
Question (Q)1
Single item, 
missing if 
missing.
Change in 
employment status 
Employed at baseline and 
remained employed: Q1 = 1 at 
post-baseline visit and at baseline 
visit.
Not employed at baseline and 
remain unemployed: Q1 = 0 at 
post-baseline visit and at baseline 
visit.
Missing if 
baseline or
observed value 
is missing.
Percentage of 
absenteeism
Percent work time missed due to 
problem: (Q2/(Q2 + Q4))*100
If Q2 or Q4 is 
missing, then 
missing.
Change from 
baseline in 
absenteeism
Change from baseline: observed 
absenteeism – baseline 
absenteeism
Missing if 
baseline or 
observed value 
is missing.
Percentage of 
presenteeism
Percent impairment (reduced 
productivity while at work) while 
working due to problem: 
(Q5/10)*100
If Q5 is missing, 
then missing.
Change from 
baseline in  
presenteeism
Change from baseline: observed 
presenteeism – baseline 
absenteeism
Missing if 
baseline or 
observed value 
is missing.
Overall work 
impairment
Percent overall work impairment 
(combines absenteeism and 
presenteeism) due to problem: 
(Q2/(Q2+Q4) + [(1-
Q2/(Q2+Q4))*(Q5/10)])*100
If Q2, Q4, or Q5 
is missing, then 
missing.


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Measure
Description
Variable
Derivation / Comment
Imputation 
Approach if 
Missing 
Components
Change from 
baseline in work 
impairment
Change from baseline: observed 
work impairment – baseline work 
impairment
Missing if 
baseline or 
observed value 
is missing.
Percentage of 
impairment in 
activities 
Percent activity impairment 
(performed outside of work) due 
to problem:  (Q6/10)*100
If Q6 is missing, 
then missing.
Change from 
baseline in 
impairment in 
activities
Change from baseline: observed 
impairment in activities –
baseline impairment in activities
Missing if 
baseline or 
observed value 
is missing.
European Quality of Life–5 
Dimensions–5 Levels (EQ-
5D-5L)
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 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 

EQ-5D mobility 

EQ-5D self-care

EQ-5D usual 
activities

EQ-5D pain/ 
discomfort

EQ-5D anxiety/ 
depression
Five health profile dimensions, 
each dimension has 5 levels: 
1 = no problems
2 = slight problems
3 = moderate problems
4 = severe problems
5 = extreme problems  
It should be noted that the 
numerals 1 to 5 have no 
arithmetic properties and should 
not be used as a primary score.
Each dimension 
is a single item, 
missing if 
missing. 
EQ-5D VAS
Single item.  Range 0 to 100.
0 represents “worst health you 
can imagine” 
100 represents “best health you 
can imagine”
Single item, 
missing if 
missing.
Change from
baseline in EQ-5D
VAS
Change from baseline: observed 
EQ-5D VAS score – baseline EQ-
5D VAS score
Missing if 
baseline or 
observed value 
is missing.
EQ-5D-5L UK
Population-based
index score (health
Derive EQ-5D-5L UK
Population-based index score
according to the link by using the 
N/A – partial 
assessments 
cannot be saved 


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Measure
Description
Variable
Derivation / Comment
Imputation 
Approach if 
Missing 
Components
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]).
state index)
UK algorithm to produce a 
patient-level index score between 
-0.59 and 1.0 (continuous 
variable).
on the eCOA 
tablet.  
Change from
baseline in EQ-5D-
5L UK Population-
based index score
Change from baseline: observed 
EQ-5D-5L UK score – baseline 
EQ-5D-5L UK score
Missing if 
baseline or 
observed value 
is missing.
EQ-5D-5L US
Population-based
index score (health
state index)
Derive EQ-5D-5L US
Population-based index score
according to the link by using the 
US algorithm to produce a 
patient-level index score between 
-0.11 and 1.0 (continuous 
variable).
N/A – partial 
assessments 
cannot be saved 
on the eCOA 
tablet.  
Change from
baseline in
EQ-5D-5L US
Population-based
index score
Change from baseline: observed 
EQ-5D-5L US score – baseline 
EQ-5D-5L US score
Missing if 
baseline or 
observed value 
is missing.
PROMIS Itch Questionnaire 
(PIQ)
PIQ – Itch Interference:  consists of 8 items 
assessing the impact of itch on various aspects 
of life.
PIQ – Activity and Clothing:  consists of 8 
items assessing activity and clothing related 
quality of life impairment from itch in adults 
“in the past 7 days”.
PIQ – Mood and Sleep:  consists of 8 items 
assessing mood and sleep related quality of life 
impairment from itch and impact of itch “in the 
past 7 days”.
PIQ – Scratching Behavior:  consists of 5 items 
assessing quality of life impairment from 
scratching behavior and the physical 
PIQ – Itch
Interferencea
8 items.  Each range 1 to 5.
1=Never, 2=Rarely, 
3=Sometimes, 4=Often, 
5=Almost always (continuous 
variable).  Total raw scores are 
converted to T-Scores with higher 
scores representing greater impact
because of itch.
Calculation is 
made by 
HealthMeasures 
Scoring Service, 
powered by 
Assessment 
CenterSM
Change from
baseline in PIQ –
Itch Interference
Change from baseline: observed 
PIQ Itch Interference score –
baseline PIQ Itch Interference
score
Missing if
Baseline or
observed value
is missing.
PIQ – Activity and
Clothing
8 items.  Each range 1 to 5.
1=Never, 2=Rarely, 
Score is 
calculated by 


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Measure
Description
Variable
Derivation / Comment
Imputation 
Approach if 
Missing 
Components
manifestations of itch in adults “in the past 7 
days”. 
3=Sometimes, 4=Often, 
5=Almost always (continuous 
variable).  Total raw scores are 
converted to T-Scores with higher 
scores representing greater impact
because of itch.
HealthMeasures 
Scoring Service, 
powered by 
Assessment 
CenterSM
Change from
baseline in PIQ –
Activity and
Clothing
Change from baseline: observed 
PIQ Activity and Clothing score –
baseline PIQ Activity and 
Clothing score
Missing if
Baseline or
observed value
is missing.
PIQ – Mood and
Sleep
8 items.  Each range 1 to 5.
1=Never, 2=Rarely, 
3=Sometimes, 4=Often, 
5=Almost always (continuous 
variable).  Total raw scores are 
converted to T-Scores with higher 
scores representing greater impact
because of itch.
Score is 
calculated by 
HealthMeasures 
Scoring Service, 
powered by 
Assessment 
CenterSM
Change from
baseline in PIQ –
Mood and Sleep
Change from baseline: observed 
PIQ Mood and Sleep score –
baseline PIQ Mood and Sleep
score
Missing if
Baseline or
observed value
is missing.
PIQ – Scratching
Behavior
5 items.  Each range 1 to 5.
Response options for the 
frequency of scratching 
behaviors:  1=Never, 2=Rarely, 
3=Sometimes, 4=Often, 
5=Almost always
The response options for the 
worry related to scratching items:  
1=Not at all, 2=A little bit, 
3=Somewhat, 4=Quite a bit, 
5=Very much (continuous 
variable).  Total raw scores are 
converted to T-Scores with higher 
Score is 
calculated by 
HealthMeasures 
Scoring Service, 
powered by 
Assessment 
CenterSM


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Measure
Description
Variable
Derivation / Comment
Imputation 
Approach if 
Missing 
Components
scores representing more 
scratching behavior.  
Change from
baseline in PIQ –
Scratching
Behavior
Change from baseline: observed 
PIQ Scratching Behavior score –
baseline PIQ Scratching Behavior
score
Missing if
Baseline or
observed value
is missing.
PROMIS – Sleep Related 
Impairment 
The Sleep Related Impairment Short Form 
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.  
PROMIS sleep
related impairment
8 items.  Each range 1 to 5.
1=Not at all; 2=A little bit; 
3=Somewhat; 4=Quite a bit; to 
5=Very much (continuous 
variable).  Total raw scores are 
converted to T-Scores with higher 
scores representing greater sleep 
impairment.
Score is 
calculated by 
HealthMeasures 
Scoring Service, 
powered by 
Assessment 
CenterSM
Change from
baseline in
PROMIS sleep
related impairment  
Change from baseline: observed 
PROMIS Sleep Related 
Impairment score – baseline 
PROMIS Sleep Related 
Impairment score
Missing if
Baseline or
observed value
is missing.
Neuro-QoL – Cognitive 
Function
The Cognitive Function Short Form 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 “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 
Neuro-QoL –
Cognitive Function
The total raw scores are 
converted to T-Scores with higher 
scores indicating better 
(desirable) self-reported health.  
Score is 
calculated by 
HealthMeasures 
Scoring Service, 
powered by 
Assessment 
CenterSM
Change from
baseline in Neuro-
QoL – Cognitive
Function  
Change from baseline: observed 
Neuro-QoL – Cognitive Function  
score – baseline Neuro-QoL –
Cognitive Function  score
Missing if
Baseline or
observed value
is missing.


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Measure
Description
Variable
Derivation / Comment
Imputation 
Approach if 
Missing 
Components
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.
Patient Benefit Index (PBI)
The Patient Benefit Index (PBI) measures 
patient-defined treatment objectives and 
benefits.  It consists of 2 questionnaires.  Before 
therapy, patients complete the standardized 
“Patient Needs Questionnaire” (PNQ) 
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” 
(PBQ).  
Subscales of the Patient Benefit Index are:

Reducing social impairments subscale 
score:  item 11, 13, 14, 15, 16, 17

Reducing psychological impairments 
subscale score:  item 6, 7, 9, 10, 12

Reducing impairments due to therapy 
subscale score:  item 18, 19, 20, 21

Reducing physical impairments 
subscale score:  item 1, 2, 3, 4, 5

Having confidence in healing subscale 
score:  item 8, 22, 23

Patient
Benefit Index
(PBI) global
score

Subscale
scores
25 items.  0=not at all, 
1=somewhat; 2=moderately; 
3=quite; 4=very; 
PBI global score is calculated for 
each patient by weighing the 
achievement values of the 
treatment objectives by their 
importance to the individual 
patient. 
For score calculation, both 
“does/did not apply” and question 
unanswered will be treated as 
missing values.  The global score 
is calculated using only these 
item pairs, for which the patient 
has given a response other than 
“does/did not apply to me” in 
both PNQ and PBQ. 
Subscale scores are calculated in 
the same manner as the global 
score.
PBI global score 
and subscales 
may only be 
computed if the 
patient has 
provided at least 
75% valid data 
in each of the 
PNQ and PBQ 
respectively.
In this context, 
the responses 
“not at all” and 
“does/did not 
apply” count as 
valid data. 
Thus a treatment 
goal is regarded 
missing if the 
patient has not 
responded to the 
item in the PNQ 
and/or in the 
PBI.


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Measure
Description
Variable
Derivation / Comment
Imputation 
Approach if 
Missing 
Components

PBI global
score ≥1
PBI global score at least 1
Missing if 
observed value 
is missing
a
PIQ – Itch Interference here is the same as PIQ – General in the protocol. 


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Table JAIY.6.7.
Description of Health Outcomes and Quality-of-Life Measures Analyses
Measure
Variable
Analysis Method
(Section 6.2.3)
Population
(Section 6.2.1)
Comparison/Time Point
Analysis Type
Itch Numeric 
Rating Scale 
(NRS)
Itch NRS score
Change from baseline in Itch NRS 
score
MMRM
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 1, …, 16
Secondary 
Analysis
ANCOVA using 
mLOCF 
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Day 2, Week 1,…, 16
Secondary 
Analysis at Day 2; 
Sensitivity 
Analysis for others
pMI
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 1, …, 16
Sensitivity 
Analysis
Percent change from baseline Itch score
MMRM
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 1, …,16
Secondary 
Analysis
ANCOVA using 
mLOCF
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Day 2, Week 1, …, 16
Secondary 
Analysis at Day 2; 
Sensitivity 
Analysis for others
Proportion of patients achieving a 4-
point improvement in Itch NRS in 
subgroup of patients who had baseline 
Itch NRS ≥4
Logistic regression 
using NRI
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Day 2, Week 1,…, 16
Key Secondary 
Analysis at Day 2, 
Week 1, 2 and 16
PPS
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity 
analysis
Logistic regression 
using pMI and 
Tipping Point
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity 
analysis 
Number of Itch-free (Itch NRS = 0) 
Days
Two-sample t-test
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 0 to Week 4, …, 
Week 12 to 16
Exploratory 
Analysis
Skin Pain Numeric 
Rating Scale 
(NRS)
Skin Pain NRS score
Change from baseline in Skin Pain 
NRS score
MMRM
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 1,…, 16
Key Secondary 
Analysis at Week 
16
PPS
Bari 4 mg or Bari 2 mg vs 
PBO; Week 1,…, 16
Sensitivity 
analysis


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Measure
Variable
Analysis Method
(Section 6.2.3)
Population
(Section 6.2.1)
Comparison/Time Point
Analysis Type
ANCOVA using 
mLOCF
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 1,…, 16
Sensitivity 
Analysis
pMI
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 1,…, 16
Sensitivity 
analysis 
Number of Skin Pain-free (Skin pain 
NRS = 0) Days
Two-sample t-test
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 0 to Week 4,…, 
Week 12 to 16
Exploratory 
Analysis 
Proportion of patients achieving a 4-
point improvement in Skin Pain NRS in 
subgroup of patients with baseline Skin 
Pain NRS ≥4
Logistic regression 
using NRI
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 1,…, 16
Other Secondary 
Analysis
Atopic Dermatitis 
Sleep Scale 
(ADSS)
ADSS item scores
Change from baseline in ADSS item 
scores
MMRM
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 1,…, 16
Key Secondary 
Analysis at Week 
1 and 16
PPS
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity 
analysis
ANCOVA using 
mLOCF
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 1,…, 16
Sensitivity 
Analysis 
pMI
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity 
analysis 
Patient-Oriented 
Eczema Measure 
(POEM)
POEM score
Change from baseline in POEM score
MMRM
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; at each post-baseline 
visit
Secondary 
Analysis
ANCOVA using 
mLOCF
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity 
Analysis
Proportion of patients achieving a 4-
point improvement in subgroup of 
patients with baseline POEM ≥4
Logistic regression 
using NRI
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; at each post-baseline 
visit
Secondary 
Analysis
Patient Global 
Impression of 
Severity–Atopic 
Dermatitis (PGI-S-
AD)
PGI-S-AD score
Change from baseline in PGI-S-AD 
score
MMRM
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; at each post-baseline 
visit
Secondary 
Analysis
ANCOVA using 
mLOCF
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity 
Analysis


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Measure
Variable
Analysis Method
(Section 6.2.3)
Population
(Section 6.2.1)
Comparison/Time Point
Analysis Type
Hospital Anxiety 
Depression Scale 
(HADS)
HADS domain scores
Change from baseline in HADS 
domain
MMRM
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 2, 4, 8,16
Secondary 
Analysis
ANCOVA using 
mLOCF
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity 
Analysis
Dermatology Life 
Quality Index 
(DLQI)
DLQI total score
Change from baseline in DLQI
Observed and change from baseline 
in domain scores
-Symptoms and feelings
-Daily activities
-Leisure 
-Work and school
-Personal relationships
    -Treatment
MMRM
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Secondary 
Analysis
ANCOVA using 
mLOCF
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity 
Analysis
Proportion of patients achieving a 4-
point improvement in DLQI total score 
in subgroup of patients with baseline 
DLQI ≥4
Logistic regression 
using NRI
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 1, 2, 4, 8, 16
Other Secondary 
Analysis
Proportion of patients achieving DLQI 
(0,1)
Logistic regression 
using NRI
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 1, 2, 4, 8, 16
Other Secondary 
Analysis
Work Productivity 
and Activity 
Impairment:  
Atopic Dermatitis 
(WPAI-AD)
Observed and Change from baseline in 
employment status 
Descriptive statistics 
(observed)
ITT
No comparisons; Week 16
Secondary 
Analysis
Observed and Change from baseline in:
absenteeism
presenteeism 
overall work impairment
impairment in activities
MMRM 
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; at each post-baseline 
visit
Secondary 
Analysis
ANCOVA using 
mLOCF
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; at each post-baseline 
visit
Sensitivity 
Analysis 


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Measure
Variable
Analysis Method
(Section 6.2.3)
Population
(Section 6.2.1)
Comparison/Time Point
Analysis Type
European Quality 
of Life–5 
Dimensions–5 
Levels (EQ-5D-
5L)
Observed values in
EQ-5D mobility 
EQ-5D self-care
EQ-5D usual activities
EQ-5D pain/ discomfort
EQ-5D anxiety/ depression
Logistic Regression 
using NRI
ITT
Bari 4 mg or Bari 2 mg vs 
PBO: at each post-baseline 
visit
Exploratory 
Analysis
Observed and Change from baseline in
EQ-5D VAS
EQ-5D-5L UK Population-based
index score
EQ-5D-5L US Population-based
index score
MMRM
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Secondary 
Analysis
ANCOVA using 
mLOCF
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Sensitivity 
Analysis
PROMIS
Observed and Change from baseline in:

PIQ – Itch Interference score

PIQ – Activity and Clothing 
score

PIQ – Mood and Sleep score

PIQ – Scratching Behavior 
score

PROMIS – Sleep-Related 
Impairment score
MMRM
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 1, 2, 4, 8, 12, 16
Exploratory 
Analysis
ANCOVA using 
mLOCF
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 1, 2, 4, 8, 12, 16
Sensitivity 
Analysis
Neuro-QoL –
Cognitive Function 
score
Observed and Change from baseline in:
Neuro-QoL – Cognitive Function score
ANCOVA using 
mLOCF
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Exploratory 
Analysis


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Measure
Variable
Analysis Method
(Section 6.2.3)
Population
(Section 6.2.1)
Comparison/Time Point
Analysis Type
PBI

PBI global score

Reducing social impairments 
subscale score

Reducing psychological 
impairments subscale score

Reducing impairments due to 
therapy subscale score

Reducing physical 
impairments subscale score

Having confidence in healing 
subscale score
ANOVAa
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Exploratory 
Analysis
PBI
Proportion of patients achieving PBI 
global score ≥1 at Week 16
Logistic regression 
using NRI
ITT
Bari 4 mg or Bari 2 mg vs 
PBO; Week 16
Exploratory 
Analysis
Abbreviations:  ANCOVA = analysis of covariance; ANOVA= analysis of variance; Bari = baricitinib; ITT = intent-to-treat; mLOCF = modified last observation 
carried forward; MMRM = mixed model repeated measures; NRI = nonresponder imputation; PBO = placebo; pMI=placebo multiple imputation; PPS = per 
protocol set.
Notes:  for all other post-baseline visits not mentioned in the table, but collected for the measures as specified in the protocol, the analyses are made as 
exploratory analyses.
Notes:  all the key secondary are performed for Japan population. Other secondary and exploratory analyses may be performed for Japan population.
a
ANOVA model includes region, baseline disease severity (IGA) and treatment as factors in the model.


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6.14. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods
Pharmacokinetic (PK), Pharmacodynamic (PD) and Biomarker analyses to address secondary 
and exploratory objectives of this study will be described by Lilly in separate PK/PD and 
Biomarker analysis plans.
6.15. Safety Analyses
The general methods used to summarize safety data, including the definition of baseline and 
postbaseline are described in Section 6.2.
Safety analyses will include data from first dose of the study treatment to after rescue, unless 
otherwise stated, and patients will be analyzed according to the investigational product to which 
they were randomized at Visit 2.  A sensitivity approach to the safety analyses will use data 
censored at last dose of the study drug for patients rescued to systemic therapy.  These analyses 
will be conducted for treatment-emergent adverse events (TEAEs), serious adverse events 
(SAEs), AEs leading to permanent study drug discontinuation and special topics excluding 
deaths and malignancies.  Additional analyses may be conducted using data after rescue to 
systemic therapy for some safety topics such as systemic TEAEs, and SAEs.  Safety analyses 
will use the safety population defined in Section 6.2.1.
Safety topics that will be addressed include the following:  AEs including TEAEs and SAEs, 
clinical laboratory evaluations, vital signs and physical characteristics, Columbia Suicide 
Severity Rating Scale (C-SSRS), the Self-Harm Supplement Form, safety in special groups and 
circumstances, including adverse events of special interest (AESI) (see Section 6.15.5), and 
investigational product interruptions.
Unless otherwise specified, by-visit summaries will include planned on-treatment visits.  For 
tables that summarize events (such as AEs, categorical lab abnormalities, shift to maximum 
value), post-last dose follow-up data will be included.  Follow-up data is defined as all data 
occurring up to 30 days (planned maximum follow-up time) after last dose of treatment including 
rescue, regardless of study period.  
For selected safety assessments other than events, descriptive statistics may be presented for the 
last measure observed during post-treatment follow-up (up to 30 days after the last dose of 
treatment including rescue, regardless of study period).  
6.15.1. Extent of Exposure
Duration of exposure (in days) will be calculated as follows:

Duration of exposure to investigational product (including exposure after the initiation of 
rescue therapy):  date of last dose of study drug including rescue – date of first dose of 
study drug + 1.
Last dose of study drug including rescue is calculated as last date on study drug. See the
compound level safety standards for more details.


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Total patient-years (PY) of exposure to study drug will be reported for each treatment group for
overall duration of exposure.  Descriptive statistics will be provided for patient-days of exposure 
and the frequency of patients falling into different exposure ranges in addition to cumulative 
exposures will be summarized.  
Exposure ranges will be summarized as follows:  

≥28 days, ≥56 days, ≥84 days, and ≥112 days

>0 to <28 days, ≥28 days to <56 days, ≥56 days to <84 days, ≥84 days to <112 days, and 
≥112 days
Overall exposure for a treatment group will be summarized in total PY which is calculated 
according to the following formula:

Exposure in PY (PYE) = sum of duration of exposure in days (for all patients in treatment 
group) / 365.25
6.15.2. Adverse Events
Adverse events are recorded in the eCRFs.  Each AE will be coded to system organ class (SOC) 
and preferred term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) 
version that is current at the time of database lock.  Severity of AEs is recorded as mild, 
moderate, or severe.
A TEAE is defined as an event that either first occurred or worsened in severity after the first 
dose of study treatment and on or prior to the last visit date during the analysis period.  The 
analysis period is defined as the treatment period plus up to 30 days off-drug follow-up time.  
Adverse events are classified based upon the MedDRA PT.  The MedDRA Lowest Level Term 
(LLT) will be used in defining which events are treatment-emergent.  The maximum severity for 
each LLT during the baseline period up to first dose of the study medication will be used as 
baseline.  If an event with missing severity is preexisting during the baseline period, and persists 
during the treatment period, then the baseline severity will be considered mild for determining 
treatment-emergence (that is, the event is treatment-emergent if the severity is coded moderate or 
severe postbaseline and not treatment-emergent if the severity is coded mild postbaseline).  If an 
event occurring postbaseline has a missing severity rating, then the event is considered 
treatment-emergent unless the baseline rating is severe, in which case the event is not treatment-
emergent.  The day and time for events where onset is on the day of the first dose of study 
treatment will both be used to distinguish between pretreatment and posttreatment to derive 
treatment-emergence.  Should there be insufficient data for AE start date to make this 
comparison (for example, the AE start year is the same as the treatment start year, but the AE 
start month and day are missing), the AE will be considered treatment-emergent.
In general, summaries will include the number of patients in the safety population (N), frequency 
of patients reporting the event (n), and relative frequency (that is, percentage; n/N*100).  For any 
events that are gender-specific based on the displayed PT, the denominator used to compute the 
percentage will only include patients from the appropriate gender.


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In an overview table, the number and percentage of patients in the safety population who 
experienced death, an SAE, any TEAE, discontinuation from the study due to an AE, permanent 
discontinuation from study drug due to an AE, or a severe TEAE will be summarized by 
treatment group.  
The number and percentage of patients with TEAEs will be summarized by treatment group in 
2 formats by MedDRA PT:

nested within SOC with decreasing frequency in SOC, and events ordered within each 
SOC by decreasing frequency in the baricitinib 4-mg group;

with events ordered by decreasing frequency in the baricitinib 4-mg group.
6.15.2.1. Common Adverse Events
Common TEAEs are defined as TEAEs that occurred in ≥2% (before rounding) of patients in 
any treatment group including placebo.  The number and percentage of patients with common 
TEAEs will be summarized by treatment using MedDRA PT ordered by decreasing frequency in 
the baricitinib 4-mg group.  
The number and percentage of patients with TEAEs will be summarized by maximum severity 
by treatment using MedDRA PT ordered by decreasing frequency in the baricitinib 4-mg group
for the common TEAEs.  For each patient and TEAE, the maximum severity for the MedDRA 
level being displayed is the maximum postbaseline severity observed from all associated LLTs 
mapping to that MedDRA PT.  
6.15.2.2. Serious Adverse Event Analyses
Consistent with the International Conference on Harmonisation (ICH) E2A guideline (1994) and 
21 Code of Federal Regulations (CFR) 312.32 (a) (2010), a SAE is any AE that results in any 
one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threating experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect
The number and percentage of patients who experienced any SAE will be summarized by 
treatment using MedDRA PT nested within SOC.  Events will be ordered by decreasing 
frequency in the baricitinib 4-mg group within decreasing frequency in SOC.  The SAEs will 
also be summarized by treatment using MedDRA PT without SOC.
An individual listing of all SAEs will be provided.  A listing of deaths, if any, regardless of when 
they occurred during the study, will also be provided.
6.15.2.3. Other Significant Adverse Events
Other significant AEs to be summarized will provide the number and percentage of patients who:

permanently discontinued study drug because of an AE or death


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
temporarily interrupted study drug because of AE
by treatment using MedDRA PT nested within SOC.  Events will be ordered by decreasing 
frequency in the baricitinib 4-mg group within decreasing frequency in SOC.  
A summary of temporary interruptions of study drug will also be provided, showing the number 
of patients who experienced at least one temporary interruption and the number of temporary 
interruptions per patient with an interruption.  Further, the duration of each temporary 
interruption (in days), the cumulative duration of dose interruption (in days) using basic 
descriptive statistics and the reason for dose interruption will be provided.  
A listing of all AEs leading to permanent discontinuation from the study drug or from the study 
will be provided.  A listing of all temporary study drug interruptions, including interruptions for 
reasons other than AEs, will be provided.
6.15.2.4. Criteria for Notable Patients
Patient narratives will be provided for all patients who experience certain “notable” events prior 
to data cutoff for the submission.  See compound level safety standards for list of criteria.  
6.15.3. Clinical Laboratory Evaluation
For the categorical laboratory analyses (shift and treatment emergent), the analysis period is 
defined as the treatment period plus up to 30 days off-drug follow-up time.  The analysis period 
for the continuous laboratory analyses (e.g., change from baseline by time point) is defined as the 
treatment period excluding off-drug follow-up time.
All laboratory tests will be presented using the International Système (SI) and US conventional 
(CN) units.  The performing central laboratory reference ranges will be used to define the low 
and high limits. Results pertaining to the 4 key hepatic laboratory assessments (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], total bilirubin, and alkaline 
phosphatase [ALP]) will be included as a separate analysis to address the risk of liver injury as a 
special safety topic (see Section 6.15.5.1).
There is one special circumstance for laboratory values to be derived based on regularly 
scheduled, protocol-specified analytes.  The low-density lipoprotein/high-density lipoprotein 
(LDL/HDL) ratio will be derived as the ratio of LDL cholesterol to HDL cholesterol.  There are 
no central lab reference ranges for the LDL/HDL ratio.
The following will be conducted for the laboratory analytes collected quantitatively:

Box plots:  Values at each visit (starting from randomization) and change from last 
baseline to each visit and to last postbaseline measure will be displayed in box plots for 
patients who have both a baseline and at least 1 postbaseline visit.  The last non-missing 
observation in the treatment period will be used as the last observation.  Individual 
measurements outside of reference limits will also be displayed using distinct symbols 
overlaying the box plot.  Original-scale data will be used for the display but for some 
analytes (for example, immunoglobulins) a logarithmic scale may be used to aid in 
viewing the measures of central tendency and dispersion.  Unplanned measurements will 


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be excluded.  Descriptive summary statistics will be included below the box plot along 
with p-values resulting from between treatment comparison in change from last baseline 
to last observation.  An ANCOVA model with explanatory term for treatment and the 
baseline value as a covariate will be used.  These box plots will be used to evaluate trends 
over time and to assess a potential impact of outliers on central tendency summaries.  

Treatment-emergent high/low analyses:  The number and percentage of patients with 
treatment-emergent high and low laboratory results at any time will be summarized by 
treatment group.  Planned and unplanned measurements will be included.  A treatment-
emergent high result is defined as a change from a value less than or equal to the high 
limit at all baseline visits to a value greater than the high limit at any time during the 
treatment period.  A treatment-emergent low result is defined as a change from a value 
greater than or equal to the low limit at all baseline visits to a value less than the low limit 
at any time during the treatment period.  The Fisher’s exact test will be used for the 
treatment comparisons.  Number at risk (NAR) for the treatment-emergent high result is 
defined as the number of patients with a value less than or equal to the high limit at all 
baseline visits.  NAR for the treatment-emergent low result is defined as the number of 
patients with a value greater than or equal to the low limit at all baseline visits for the 
treatment-emergent low result.
A listing of abnormal findings will be provided for laboratory analyte measurements, including 
qualitative measures. The listing will include but not limited to patient ID, treatment group, 
laboratory collection date, analyte name, and analyte finding.  If needed by the safety 
physician/scientist, for analytes measured qualitatively, the number and percentage of patients
with treatment-emergent abnormal laboratory results at any time will be summarized by 
treatment.  Planned and unplanned measurements will be included.  A treatment-emergent 
abnormal result is defined as a change from normal at all baseline visits to abnormal at any time 
postbaseline.
Note that additional analyses of certain laboratory analytes will be discussed within sub-sections 
of Section 6.15.5 pertaining to Special Safety topics (Section 6.15.5.1 for hepatic analytes, 
Section 6.15.5.2 for analytes related to hematological changes, Section 6.15.5.3 for analytes 
related to lipids, Section 6.15.5.4 for analytes related to renal function, and Section 6.15.5.5 for 
CPK).
6.15.4. Vital Signs and Other Physical Findings
For the treatment-emergent categorical analyses (shift and treatment emergent), the analysis 
period is defined as the treatment period plus up to 30 days off-drug follow-up time.  The 
analysis period for the continuous analyses (e.g., change from baseline by time point) is defined 
as the treatment period excluding off-drug follow-up time.
Vital signs and physical characteristics include systolic blood pressure (SBP), diastolic blood 
pressure (DBP), pulse, weight, and BMI.  Original-scale data will be analyzed.  When these 
parameters are analyzed as continuous numerical variables, unplanned measurements will be 


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excluded.  When these parameters are analyzed as categorical outcomes and/or treatment-
emergent abnormalities, planned and unplanned measurements will be included.  
The planned analyses described for the laboratory analytes in Section 6.15.3 will be used to 
analyze the vital signs and physical characteristics.
Table JAIY.6.8 defines the low and high baseline values as well as the criteria used to define 
treatment-emergence based on post-baseline values.  The blood pressure and pulse rate criteria 
are consistent with the document Selected Reference Limits for Pulse/Heart Rate, Arterial Blood 
Pressure (Including Orthostasis), and Electrocardiogram Numerical Parameters for Use in 
Analyses of Phase 2-4 Clinical Trials Version 1.3 approved on April 29, 2015 as recommended 
by the Lilly Cardiovascular Safety Advisory Committee (CVSAC).
Table JAIY.6.8.
Categorical Criteria for Abnormal Treatment-Emergent Blood 
Pressure and Pulse Measurement, and Categorical Criteria for 
Weight Changes for Adults
Parameter
(Units of Measure)
Low
High
Systolic Blood Pressure 
(mm Hg) 
≤90 (low limit) and decrease from 
lowest value during baseline ≥20 if >90 
at each baseline visit
≥140 (high limit) and increase from highest 
value during baseline ≥20 if <140 at each 
baseline visit
Diastolic Blood Pressure 
(mm Hg) 
≤50 (low limit) and decrease from 
lowest value during baseline ≥10 if >50 
at each baseline visit
≥90 (high limit) and increase from highest 
value during baseline ≥10 if <90 at each 
baseline visit
Pulse 
(beats per minute)
<50 (low limit) and decrease from 
lowest value during baseline ≥15 if ≥50 
at each baseline visit
>100 (high limit) and increase from highest 
value during baseline ≥15 if ≤100 at each 
baseline visit
Weight 
(kilograms)
(Loss) decrease ≥7% from lowest value 
during baseline
(Gain) increase ≥7% from highest value 
during baseline
6.15.5. Special Safety Topics, including Adverse Events of Special 
Interest
In addition to general safety parameters, safety information on specific topics of special interest 
will also be presented.  Additional special safety topics may be added as warranted.  The topics 
outlined in this section include the protocol-specified AESI.
In general, for topics regarding safety in special groups and circumstances, patient profiles 
and/or patient listings, where applicable, will be provided when needed to allow medical review 
of the time course of cases/events, related parameters, patient demographics, study drug 
treatment and meaningful concomitant medication use.  In addition to the safety topics for which 
provision or review of patient data is specified, these will be provided when summary data are 
insufficient to permit adequate understanding of the safety topic.


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6.15.5.1. Abnormal Hepatic Tests
Analyses for abnormal hepatic tests will involve 4 laboratory analytes:  ALT, AST, total 
bilirubin, and ALP.  In addition to the analyses described in Section 6.15.3, this section describes 
specific analyses for this topic.  
First, the number and percentage of patients with the following abnormal elevations in hepatic 
laboratory tests at any time will be summarized between treatment groups:

The percentages of patients with an ALT measurement ≥3×, 5×, and 10× the central 
laboratory upper limit of normal (ULN) during the treatment period will be summarized 
for all patients with a postbaseline value and for subsets based on various levels of 
baseline.
o
The analysis of 3× ULN will contain 4 subsets:  patients whose non-missing 
maximum baseline value is ≤1× ULN, patients whose maximum baseline is 
>1× ULN but <3× ULN, patients whose maximum baseline value is ≥3× ULN, 
and patients whose baseline values are missing.
o
The analysis of 5× ULN will contain 5 subsets:  patients whose non-missing 
maximum baseline value is ≤1× ULN, patients whose maximum baseline is 
>1× ULN but <3× ULN, patients whose maximum baseline is ≥3× ULN but 
<5× ULN, patients whose maximum baseline value is ≥5× ULN, and patients 
whose baseline values are missing.
o
The analysis of 10× ULN will contain 6 subsets:  patients whose non-missing 
maximum baseline value is ≤1× ULN, patients whose maximum baseline is 
>1× ULN but <3× ULN, patients whose maximum baseline is ≥3× ULN but 
<5× ULN, patients whose maximum baseline is ≥5× ULN but <10× ULN, 
patients whose maximum baseline value is ≥10× ULN, and patients whose 
baseline values are missing.

The percentages of patients with an AST measurement ≥3×, 5×, and 10× the central 
laboratory ULN during the treatment period will be summarized for all patients with a 
postbaseline value and for subsets based on various levels of baseline.  Analyses will be 
constructed as described above for ALT.  

The percentages of patients with a total bilirubin measurement ≥2× the central laboratory 
ULN during the treatment period will be summarized for all patients with a postbaseline 
value and subset into 4 subsets:  patients whose non-missing maximum baseline value is 
≤1× ULN, patients whose maximum baseline is >1× ULN but <2× ULN, patients whose 
maximum baseline value is ≥2× ULN, and patients whose baseline values are missing.

The percentages of patients with an ALP measurement ≥1.5× the central laboratory ULN 
during the treatment period will be summarized for all patients with a postbaseline value 
and subset into 4 subsets:  patients whose non-missing maximum baseline value is 
≤1× ULN, patients whose maximum baseline is >1× ULN but <1.5× ULN, patients 
whose maximum baseline value is ≥1.5× ULN, and patients whose baseline values are 
missing.


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Information collected from additional hepatic safety data collection forms will be provided in 
patient profiles.
Second, to further evaluate potential hepatotoxicity, an Evaluation of Drug-Induced Serious 
Hepatotoxicity (eDISH) plot using maximum postbaseline ALT divided by ULN vs. maximum 
postbaseline total bilirubin divided by ULN will be created that includes all patients from the 
safety populations for the studies included in the submission (any phase, any medication).  Each 
subject with at least 1 postbaseline ALT and total bilirubin contributes 1 point to the plot.  The 
measurements do not need to be taken at the same blood draw.  Symbols may be used to indicate 
randomized treatment.
When criteria are met for hepatic evaluation and completion of the hepatic safety CRF, 
investigators are required to answer a list of questions (see Compound level safety standards).  A 
listing of the collected information will be generated together with a graphical patient profile.  
This includes demographics, disposition, and a display of study drug exposure, AEs, medications, 
and the liver-related measurements over time will be provided for these patients and any 
additional patients meeting ALT or AST measurement greater than or equal to 5× ULN (on a 
single measurement) or ALP measurement greater than or equal to 2× ULN (on a single 
measurement).
6.15.5.2. Hematologic Changes
Hematologic changes will be defined based on clinical laboratory assessments.  Common 
Terminology Criteria for Adverse Events (CTCAEs) will be applied for selected laboratory tests 
and are described in the compound level safety standards.  These CTCAE grading schemes are 
consistent with both Version 3.0 and Version 4.03 of the CTCAE guidelines (CTCAE 2003, 
2010).  
Treatment-emergent laboratory abnormalities occurring at any time during the treatment period 
and shift tables of baseline to maximum grade during the treatment period will be tabulated.  
Planned and unplanned measurements will be included.  Treatment-emergence will be 
characterized using the following 5 criteria (as appropriate to the grading scheme):

any increase in postbaseline CTCAE grade from worst baseline grade

increase to Grade 1 or above at worst postbaseline

increase to Grade 2 or above at worst postbaseline

increase to Grade 3 or above at worst postbaseline

increase to Grade 4 at worst postbaseline.
Shift tables will show the number and percentage of patients based on baseline to maximum 
during the treatment period, with baseline depicted by the most extreme grade during the 
baseline period.  With each shift table, a shift table summary displaying the number and 
percentage of patients with maximum postbaseline results will be presented by treatment group 
for each treatment period within the following categories:

decreased:  postbaseline category < baseline category

increased:  postbaseline category > baseline category


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
same:  postbaseline category = baseline category
A laboratory-based treatment-emergent outcome related to increased platelet count will be 
summarized in similar fashion.  Treatment-emergent thrombocytosis as a laboratory-based 
abnormality will be defined as an increase in platelet count from a maximum baseline value 
≤600 billion/L to any postbaseline value >600 billion/L (Lengfelder et al. 1998).  Planned and 
unplanned measurements will be included.  
A listing of patients with treatment-emergent thrombocytosis may be provided for safety review.
6.15.5.3. Lipids Effects
Lipid effects will be assessed through analysis of elevated total cholesterol, elevated LDL 
cholesterol, decreased HDL cholesterol, and elevated triglycerides as described in Section 6.15.3
and with TEAEs potentially related to hyperlipidemia.
Categorical analyses will be performed using National Cholesterol Education Program (NCEP) 
Adult Treatment Panel (ATP) III guidelines (2002) as shown in the compound level safety 
standards.  The grade-like categories shown in this table are ordered from traditionally most 
desirable to least desirable for the purposes of these analyses.
Shift tables will show the number and percentage of patients based on baseline to the least 
desirable category during the treatment period, with baseline depicted by the least desirable 
category during the baseline period.  With each shift table, a shift table summary displaying the 
number and percentage of patients with the least desirable postbaseline results will be presented 
by treatment group for each treatment period within the following categories:

decreased:  postbaseline category more desirable than baseline category,

increased:  postbaseline category less desirable than baseline category,

same:  postbaseline category = baseline category.
Treatment-emergent laboratory abnormalities related to elevated total cholesterol, elevated 
triglycerides, elevated LDL cholesterol, and decreased and increased HDL cholesterol occurring 
at any time during the treatment period will be tabulated using the NCEP categories shown in the 
compound level safety standards.  
Treatment-emergent elevated total cholesterol will be characterized as follows:

increase to categories ‘Borderline high’ or ‘High’

increase to category ‘High.’ 
Treatment-emergent elevated triglycerides will be characterized as 

increase to categories ‘Borderline high,’ ‘High,’ or ‘Very high’ 

increase to categories ‘High’ or ‘Very high’ 

increase to category ‘Very high.’
Treatment-emergent elevated LDL cholesterol will be characterized as 

increase to categories ‘Borderline high,’ ‘High,’ or ‘Very high’ 


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
increase to categories ‘High’ or ‘Very high’ 

increase to ‘Very high’
Treatment-emergent abnormal HDL cholesterol will be characterized as

decreased HDL
o
decrease to categories ‘Normal’ or ‘Low’
o
decrease to category ‘Low’

increased HDL
o
increase to categories ‘Normal’ or ‘High’
o
increase to category ‘High’
The percentages of patients with treatment-emergent potential hyperlipidemia will be summarize 
by treatment, ordered by decreasing frequency in the baricitinib 4-mg group using a predefined 
MedDRA list of PTs that is a subset of the narrow scope PTs in the MedDRA SMQ 
‘Dyslipidemia’ (code 200000026) [see Compound level safety standards].  
6.15.5.4. Renal Function Effects
Effects on renal function will be assessed through analysis of elevated creatinine.
CTCAEs will be applied for laboratory tests related to renal effects as shown in the compound 
level safety standards.  This CTCAE grading scheme is consistent with both Version 3.0 and 
Version 4.03 of the CTCAE guidelines.  Shift tables will show the number and percentage of 
patients based on baseline to maximum during the treatment period, with baseline depicted by 
highest grade during the baseline period.  Treatment-emergent laboratory abnormalities related to 
elevated creatinine occurring at any time during the analysis period will be tabulated.  Refer to 
the Compound level safety standards for details.
6.15.5.5. Elevations in Creatine Phosphokinase (CPK)
Elevations in creatine phosphokinase (CPK) will be addressed using CTCAE criteria as 
described in the compound level safety standards.  This CTCAE grading scheme is consistent
with both Version 3.0 and Version 4.03 of the CTCAE guidelines.  Analyses will be the same as 
the CTCAE analyses specified for laboratory tests related to renal function events in 
Section 6.15.5.2.
A listing of elevated CPK (CTCAE grade of 3 or above) will be provided for medical safety 
review.
Treatment-emergent adverse events potentially related to muscle symptoms may be analyzed, 
based on reported AEs.  The Muscle Symptoms special search category is a pre-defined 
MedDRA search criteria list that contains the narrow scope terms from the Rhabdomyolysis / 
myopathy SMQ (code 20000002) plus selected terms from the Musculoskeletal SOC.  These 
terms are shown in the compound level safety standards.  
6.15.5.6. Infections
Infections will be defined using all the PTs from the Infections and Infestations SOC as defined 
in MedDRA.  Serious infection will be defined as all the infections that meet the SAE criteria. 


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The number and percentage of patients with TEAEs of infections, serious infections, and 
infections resulting in permanent study drug discontinuation will be summarized by treatment 
group using MedDRA PTs.  The proportion of patients developing skin infections requiring 
antibiotic treatment by Week 16 will also be summarized on the overview of infections table.
The number and percentage of patients with TEAEs of infections by maximum severity will be 
summarized by treatment group using MedDRA PTs.  
Treatment-emergent infections will be reviewed in context of other clinical and laboratory 
parameters via a listing (details see Compound level safety standards).  
The TEAE infections will be further analyzed in terms of potential opportunistic infection,
herpes zoster and herpes simplex.  Summary of HBV DNA monitoring results and association 
between infection and neutropenia/lymphopenia will also be provided in the context of 
infections. 
Opportunistic infection
To identify potential opportunistic infections (POIs), the following approach will be used: 

identifying the POIs using a list of MedDRA PTs (refer to the compound level safety 
standards).  
Potential opportunistic infections identified through these search approaches may be combined in 
one list for medical assessment and final classification of whether the case met the modified 
Winthrop definitions for opportunistic infections (OIs).
A final listing for OIs will be provided for the CSR and to assist the composition of patient 
narratives.
Herpes zoster
Cases of herpes zoster will be further classified as follows: 

localized or non-multidermatomal-involvement of the primary and/or adjacent 
dermatomes only
o
complicated – documented ocular (cornea or deeper structure; for example, iritis, 
keratitis, retinitis, etc.) or motor nerve involvement (e.g., palsy; post herpetic 
neuralgia [PHN] does not meet criteria for motor nerve involvement).
o
uncomplicated-localized or non-multidermatomal cases that are not complicated

multidermatomal-involvement beyond primary and adjacent dermatomes (that is, >3 
contiguous dermatomes) or involvement of two or more non-contiguous dermatomes
o
complicated-documented ocular (cornea or deeper structure; for example iritis, 
keratitis, retinitis, etc.) or motor nerve involvement  
o
uncomplicated-multidermatomal cases 

disseminated-systemic infection, visceral or widespread cutaneous (e.g., ≥5 dermatomes 
or 3 to 4 dermatomes including at least 1 non-contiguous).


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
Recurrent - >1 infection occurring in an individual patient during the course of 
participation in the baricitinib clinical program.
All herpes zoster will undergo medical review to determine the classification as described above.
A summary of herpes zoster table will be provided.  The summary table will also include event 
maximum severity, seriousness, whether resulting in temporary study drug interruption, whether 
resulting in study drug discontinuation, whether treated with antiviral medication, and event 
outcome.  The incidence rate adjusted for observation time will also be provided (as defined in 
Section 6.15.2).  Of note, in the context of herpes zoster, antiviral medication treatment is 
defined as that the medication was initiated at the event start date, or within 30 days before or 
after the event start date.  The antiviral medication for herpes zoster includes but not limited to 
Aciclovir, Brivudine, Cidofovir, Famciclovir, Foscarnet, Ganciclovir, Penciclovir, Valaciclovir, 
Valganciclovir, Vidarabine (best presented by J05AB, J05AC, J05AE, and J05AH Anatomical 
Therapeutic Classification codes).  Medical representatives will review the concomitant
medication list prior to database lock and make adjustment of the above list if necessary.
If a patient has more than 1 event of herpes zoster, the event with the maximum severity will be 
used in these summary tables.  If more than 1 event of herpes zoster occurs with the same 
severity, the event with the longest duration will be used in the summary table.
Herpes simplex 
A summary analysis of herpes simplex will be provided.  Herpes simplex will be defined based 
on MedDRA PT as listed in the compound level safety standards (both narrow and broad terms 
in the herpes simplex section).  The list needs to be reviewed by medical prior to data locks (final 
and interim).  The summary table will include event maximum severity, seriousness, whether 
resulting in temporary study drug interruption, whether resulting in study drug discontinuation, 
and whether treated with antiviral medication.  
If a patient has more than 1 event of herpes simplex, the event with the maximum severity will 
be used in these summary tables.  If more than 1 event of herpes simplex occurs with the same 
severity, the event with the longest duration will be used in the summary table.
Skin Infections
A summary analysis of skin infections may be provided.  Skin infections may be defined based 
on MedDRA preferred term (see the Compound level safety standards).  
HBV DNA
A listing of patients with detectable hepatitis B virus (HBV) deoxyribonucleic acid (DNA) post 
baseline will be provided.
HBV DNA status post baseline (not detectable, detectable but not quantifiable [i.e., < lower limit 
of detection (LLOD)], quantifiable [i.e., ≥LLOD]) will be summarized by treatment group 
stratified by baseline HBV serology status, specifically:

HBsAb+ / HBcAb+


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
HBsAb- / HBcAb+
Association between infection and neutropenia/lymphopenia
Depending on the number of cases with CTCAE Grade 2 or greater, a summary table will be 
provided for treatment-emergent infections that were preceded or accompanied by neutropenia.  
For this analysis, neutropenia is defined as (1) CTCAE Grade 2 or greater, (2) Grade 3 or greater.  
Infection events with onset date ≤14 days before or after the Grade 2 or greater neutrophil count 
collection date will be considered as infections preceded or accompanied by neutropenia. 
Similar analyses as above will be conducted to evaluate the association between infection and 
lymphopenia. 
6.15.5.7. Major Adverse Cardiovascular Events (MACE) and Other Cardiovascular 
Events
Potential major adverse cardiovascular events (MACE) and other cardiovascular events requiring 
adjudication will be analyzed.  
Categories and subcategories analyzed will include, but are not limited to, the following:

MACE 
o
Cardiovascular death,
o
Myocardial infarction (MI),
o
Stroke,

Other cardiovascular events
o
Transient ischemic attack,
o
Hospitalization for unstable angina,
o
Hospitalization for heart failure,
o
Serious arrhythmia,
o
Resuscitated sudden death,
o
Cardiogenic shock,
o
Coronary interventions (such as coronary artery bypass surgery or percutaneous 
coronary intervention),

Non-cardiovascular death,

All-cause death.
In general, events requiring adjudication are documented by investigative sites using an endpoint 
reporting CRF.  This CRF is then sent to the adjudication center for external adjudication which 
uses an adjudication reporting CRF to document the final assessment of the event as a MACE, as 
some other cardiovascular event, or as no event (according to the Clinical Endpoint Committee 
Charter).  In some cases, however, the investigator may not have deemed that an event had met 
the endpoint criteria but the event was still sent for adjudication as a potential MACE, other 
cardiovascular event, or no event.  These events are included in the adjudication process to 
ensure adequate sensitivity.  In these instances, the adjudication reporting CRF will not have a 
matching endpoint reporting CRF from the investigator.  Events generated from these 


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circumstances will be considered as events sent for adjudication in the absence of an 
investigator’s endpoint reporting form.  
The number and percentage of patients with MACE, other cardiovascular events, non-
cardiovascular death, and all-cause death, as positively adjudicated, will be summarized by 
treatment group based on the categories and subcategories above.  
A listing of the events sent for adjudication will be provided to include data concerning the 
MedDRA PT related to the event, the seriousness of the event, and the event outcome, along 
with the adjudicated result.
6.15.5.8. Venous and Pulmonary Artery Thromboembolic (VTE) Events
Events identified as representative of venous thromboembolic events (VTE) disease will be 
classified as Deep Vein Thrombosis (DVT), pulmonary embolism (PE), or other peripheral 
venous thrombosis and will be analyzed.  The following definitions apply:

DVT:  Clinical diagnosis of a thrombosis in a deep vein above the knee that must be 
confirmed by objective evidence of either:  a filling defect of deep veins of the leg on 
venography or a non-compressible venous segment on ultrasound or confirmation by 
other imaging modality (e.g., Computed tomography [CT], Magnetic Resonance Imaging 
[MRI]).

PE:  Clinical diagnosis of pulmonary embolus that must be confirmed by objective 
evidence of either:  a filling defect of pulmonary arteries by either pulmonary 
angiography or CT angiography or by a high probability Ventilation Perfusion (VQ) 
scan. 

Other Peripheral Venous Thrombosis:  Clinical diagnosis of a venous thrombosis not 
specified by either DVT or PE above.  Other peripheral venous thrombosis disease must 
be confirmed by objective evidence by imaging including venography, ultrasound, CT 
scan, or MRI.  Examples of these would include non-superficial below knee thrombosis, 
portal vein, subclavian vein, or mesenteric vein.  Superficial thrombophlebitis alone is 
not considered a VTE event.
In general, events requiring adjudication are documented by investigative sites using an endpoint 
reporting CRF.  Refer to Section 6.15.5.7 for more details as the process is the same as that of 
MACE. 
The number and percentage of patients with a VTE, DVT/PE, DVT, PE, and other peripheral 
venous thrombosis, as positively adjudicated, will be summarized by treatment group.  Note that 
the below knee thrombosis captured in the “other peripheral venous thrombosis” category will be 
summarized within DVT.  
A listing of the VTE events sent for external adjudication will be provided to include data 
concerning the MedDRA PT related to the event, the seriousness of the event, and the event 
outcome, along with the adjudicated result.


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6.15.5.9. Arterial Thromboembolic (ATE) Events
Refer to the Compound level safety standards.
6.15.5.10.
Malignancies
Malignancies will be identified using terms from the malignant tumors SMQ (SMQ 20000194).  
Malignancies excluding non-melanoma skin cancers (NMSC) and NMSC will be reported 
separately.  
All the cases identified by malignant tumors SMQ will be assessed through medical review to 
determine confirmed NMSC cases. 
First, a listing including all the malignancy cases will be prepared before database lock along 
with the planned NMSC flag according to the current MedDRA version PTs (the list will be 
updated depending on the MedDRA version used for analysis): 

Squamous cell carcinoma of skin (10041834) 

Bowen’s disease (10006059)

Basal cell carcinoma (10004146)

Basosquamous carcinoma (10004178)

Basosquamous carcinoma of skin (10004179)

Squamous cell carcinoma (10041823)

Skin squamous cell carcinoma metastatic (10077314)

Skin cancer (10040808)

Carcinoma in situ of skin (10007390)

Keratoacanthoma (10023347)

Vulvar squamous cell hyperplasia (10079905)

Skin squamous cell carcinoma recurrent (10081136)
This internal review is to occur prior to database lock.  The case review and subsequent summary 
analyses will include all the cases reported in the study database or by LSS report, disregarding 
the length of gap between the last treatment dose date and the event date.  The NMSC flag will 
be confirmed during the internal review process. 
The number and percentage of patients with TEAEs associated malignancies excluding NMSC 
and NMSC will be summarized by treatment group.  
6.15.5.11.
Allergic Reactions/Hypersensitivities
A search will be performed using the MedDRA version 21.1 SMQs to search for relevant events, 
using the following queries:

Anaphylactic reaction SMQ (20000021)

Hypersensitivity SMQ (20000214)

Angioedema SMQ (20000024)
Assessment of the Anaphylactic reaction SMQ includes an algorithmic query.  The algorithmic 
approach comprises one or more events associated with an individual administration of study 
drug, where the events include:


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
A narrow term from the SMQ (Category A of the SMQ); 

Multiple terms from the SMQ, comprising terms from at least two of the following 
categories from the SMQ: 
o
Category B - (Upper Airway/Respiratory signs and symptoms)
o
Category C - (Angioedema/Urticaria/Pruritus/Flush signs and symptoms)
o
Category D - (Cardiovascular/Hypotension signs and symptoms).
Refer to the Compound safety level standards for details.
6.15.5.12.
Gastrointestinal Perforations
Treatment-emergent adverse events related to potential gastrointestinal (GI) perforations will be 
analyzed using reported AEs.  Identification of these events will be based on review of the PTs 
of the MedDRA SMQ 20000107, GI perforations (note that this SMQ holds only narrow terms 
and has no broad terms).  Potential GI perforations identified by the above SMQ search will be 
provided as a listing for internal review.  Each case will be assessed to determine whether it is GI 
perforation. A summary table based on medical review may be provided and treatment 
comparisons will be made using Fisher’s exact test.
6.15.5.13.
Columbia Suicide Severity Rating Scale
Suicidal ideation, suicidal behavior, and self-injurious behavior without suicidal intent, based on 
the C-SSRS, will be listed by patient and visit.  Only patients that show suicidal 
ideation/behavior or self-injurious behavior without suicidal intent during treatment will be 
displayed along with all their ideation and behavior, even if not positive (i.e., if a patient’s 
answers are all ‘no’ for the C-SSRS, then that patient will not be displayed).  A summary of the 
C-SSRS categories during treatment and a shift summary in the C-SSRS categories from 
baseline during treatment will be provided. Refer to the Compound safety level standards for 
details.
6.15.5.14.
Self-Harm Supplement Form and Self-Harm Follow-up Form
The Self-Harm Supplement Form is a single question to enter the number of suicidal behavior 
events, possible suicide behaviors, or nonsuicidal self-injurious behaviors.  If the number of 
behavioral events is greater than zero, it will lead to the completion of the Self-Harm Follow-Up 
Form.  The Self-Harm Follow-Up Form is a series of questions that provides a more detailed 
description of the behavior cases.  A listing of the responses give on the Self-Harm Follow-Up 
Form will be provided.  
6.16. Subgroup Analyses
Subgroup analyses comparing each dose of baricitinib to placebo will be performed on the ITT 
population at Week 16 using the primary censoring rule for the following:

Proportion of patients achieving IGA 0 or 1 

Proportion of patients achieving EASI75 Response Rate 

Proportion of patients achieving Itch NRS 4-point improvement 


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The following subgroups, categorized into disease-related characteristics and demographic 
characteristics, will be evaluated:

Patient Demographic and Characteristics Subgroups: 
o
Gender (male, female)  
o
Age group (<65, ≥65 years old)
o
Age group (<65, ≥65 to <75, ≥75 to <85, ≥85 years old)
o
Baseline weight:  (<60 kg, ≥60 to <100 kg, ≥100 kg)
o
Baseline BMI (<25 kg/m2, ≥25 to <30 kg/m2, ≥30 kg/m2)
o
Race:  (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Multiple)
o
Baseline renal function status:  impaired (eGFR <60 mL/min/1.73 m2) or not 
impaired (eGFR ≥60 mL/min/1.73 m2)

Geographic Region Subgroups: 
o
Region:  (as defined in Table JAIY.5.1)
o
Specific regions (Europe, other)
o
Specific regions (East Asia[Korea, Japan and Taiwan], other)
o
Specific country (Japan, other)
o
Prior systemic therapy use (yes, no)

Baseline Disease-Related Characteristics Subgroup
o
Baseline disease severity (IGA score):  3, 4 
Descriptive statistics will be provided for each treatment and stratum of a subgroup as outlined, 
regardless of sample size.  As all endpoints are categorical, subgroup analyses will be performed 
using logistic regression using Firth’s correction to accommodate (potential) sparse response 
rates.  The model will include the categorical outcome as the dependent variable and baseline 
value (for EASI and itch), baseline severity, treatment, subgroup, and treatment-by-subgroup 
interaction as explanatory variables.  Missing data will be imputed using NRI (Section 6.4.1).  
The treatment-by-subgroup interaction comparing treatment groups will be tested at the 0.1 
significance level.  The p-value from the logistic regression model will be reported for the 
interaction test and the subgroup test, unless the model did not converge.  Response counts and 
percentages will be summarized by treatment for each subgroup category.  The difference in 
percentages and 95% CI of the difference in percentages using the Newcombe-Wilson without 
continuity correction will be reported.  The corresponding p-value from the Fisher’s exact test 
will also be produced.  
In case any level of a subgroup comprises <10% of the overall sample size, only descriptive 
summary statistics will be provided for treatment arms, and no treatment group comparisons will 
be performed within these subgroup levels.  
Additional subgroup analyses on efficacy may be performed as deemed appropriate and 
necessary.


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6.17. Protocol Deviations
Protocol deviations will be tracked by the clinical team, and their importance will be assessed by 
key team members during protocol deviation review meetings.  Out of all important protocol 
deviations (IPDs) identified, a subset occurring during Period 2 with the potential to affect 
efficacy analyses will result in exclusion from the PP population.
Potential examples of deviations include patients who receive excluded concomitant therapy, 
significant non-compliance with study medication (<80% of assigned doses taken, failure to take 
study medication and taking incorrect study medication), patients incorrectly enrolled in the 
study, and patients whose data are questionable due to significant site quality or compliance 
issues.  Refer to a separate document for the important protocol deviations.
Trial Issue Management Plan includes the categories and subcategories of important protocol 
deviations and whether or not these deviations will result in the exclusion of patients from per 
protocol set.
The number and percentage of patients having IPD(s) will be summarized within category and 
subcategory of deviation by treatment group for Period 2 using the ITT population.  Individual 
patient listings of IPDs will be provided.  A summary of reasons patients were excluded from the 
PPS will be provided by treatment group.
6.18. Interim Analyses and Data Monitoring
An interim analyses may be conducted at the time when the last patient completes Visit 8
(Week 16) or ETV.
The baricitinib AD, AA and SLE Phase 3 programs Data Monitoring Committee (DMC) is an 
independent expert advisory group commissioned and charged with the responsibility of 
evaluating cumulative safety at regular intervals. As such, the primary objective of the DMC is 
to monitor the safety of the subjects enrolled in the baricitinib AD, AA and SLE Phase 3 
programs by reviewing the available clinical data at scheduled time points, as described in this 
DMC Charter, as well as on an ad hoc basis, as needed.  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, cardiology, and other appropriate specialties.
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, are documented in the Baricitinib Atopic 


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Dermatitis DMC charter and further details are given in the Interim Analysis Plan in 
Section 6.18.1.
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 interim or 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.
6.18.1. Interim Analysis Plan
The final analyses for this study are considered as the analyses to be presented to the DMC.
6.19. Planned Exploratory Analyses
The planned exploratory analyses are described in Sections 6.12 and 6.13.  Additional 
exploratory analyses may be conducted such as exploring inadequate or super responders and 
their baseline characteristics and will be documented in a supplemental SAP.  Health Technology 
Assessment (HTA) toolkit analyses, which may be produced, will also be documented in the 
supplemental SAP.  
6.20. Annual Report Analyses
Annual report analyses, such as the Development Update Safety Report (DSUR), will be 
documented in a separate document. 
6.21. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include a summary of AEs, provided as a dataset 
which will be converted to an XML file.  Both SAEs and ‘Other’ AE are summarized:  by 
treatment group, by MedDRA PT.

An AE is considered ‘Serious’ whether or not it is a TEAE.

An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious.  For 
each SAE and ‘Other’ AE, for each term and treatment group, the following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).

AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth. 
Similar methods will be used to satisfy the European Clinical Trials Database (EudraCT) 
requirements. 


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7.
Unblinding Plan
A separate JAIY Blinding / Unblinding Plan contains details of how the blind is maintained for
this study. 


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