Clinical trial NCT03334422
Conditions: Atopic Dermatitis
Keywords: eczema atopic eczema
Sponsor: Eli Lilly and Company
Start date: 2017-11-27; Completion date: 2018-12-12
Enrollment: 615 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of baricitinib as monotherapy in participants with moderate to severe atopic dermatitis.

Detailed description:

Arms: arm 1: 4mg Baricitinib administered orally once daily. Placebo 1 mg and 2 mg administered orally every day to match arm 2: 2mg Baricitinib administered orally once daily. Placebo 1 mg and 4 mg administered orally every day to match. arm 3: 1mg Baricitinib administered orally once daily. Placebo 2 mg and 4 mg administered orally every day to match. arm 4: Placebo administered orally once daily.
Interventions: intervention 1: Baricitinib intervention 2: Placebo
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally

Protocol documents:
Prot_000.pdf: 
 
I4V-MC-JAHM(b) Clinical Protocol 
 
 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the 
Efficacy and Safety of Baricitinib in Patients with Moderate to Severe Atopic Dermatitis 
 
NCT03334422 
 
Approval Date: 22-Jan-2018 
 
 


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Protocol I4V-MC-JAHM(b)
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy 
and Safety of Baricitinib in Patients with Moderate to Severe
Atopic Dermatitis
BREEZE-AD2
EudraCT Number: 2017-000871-10
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
baricitinib (LY3009104), unless such persons are bound by a confidentiality agreement with 
Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Baricitinib (LY3009104)
Study I4V-MC-JAHM is a Phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group, outpatient, 25-week study designed to evaluate the 
efficacy and safety of baricitinib 1-mg, 2-mg, and 4-mg in patients with moderate to severe 
atopic dermatitis.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly:  29 Jun 2017
Amendment (a) Electronically Signed and Approved by Lilly: 15 Dec 2017
Amendment (b) Electronically Signed and Approved by Lilly on approval date provided 
below.  
Approval Date: 22-Jan-2018 GMT


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Table of Contents
Section
Page
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................13
3.
Introduction ......................................................................................................................18
3.1.
Background..................................................................................................................18
3.2.
Study Rationale............................................................................................................19
3.3.
Benefit/Risk Assessment..............................................................................................19
4.
Objectives and Endpoints..................................................................................................20
5.
Study Design.....................................................................................................................22
5.1.
Overall Design .............................................................................................................22
5.1.1.
Period 1:  Screening .............................................................................................22
5.1.2.
Period 2:  Double Blind Placebo-Controlled Treatment ........................................23
5.1.3.
Period 3:  Post-Treatment Follow-Up...................................................................23
5.2.
Number of Participants.................................................................................................25
5.3.
End of Study Definition ...............................................................................................25
5.4.
Scientific Rationale for Study Design...........................................................................25
5.5.
Justification for Dose ...................................................................................................26
5.5.1.
Dose Adjustment for Renal Impairment ...............................................................26
6.
Study Population...............................................................................................................27
6.1.
Inclusion Criteria..........................................................................................................27
6.2.
Exclusion Criteria ........................................................................................................29
6.3.
Lifestyle Restrictions....................................................................................................35
6.4.
Screen Failures.............................................................................................................35
7.
Treatments........................................................................................................................36
7.1.
Treatments Administered .............................................................................................36
7.1.1.
Packaging and Labeling .......................................................................................36
7.1.2.
Medical Devices...................................................................................................37
7.2.
Method of Treatment Assignment ................................................................................37
7.2.1.
Selection and Timing of Doses.............................................................................37
7.2.2.
Dose Adjustment for Renal Impairment ...............................................................37
7.3.
Blinding .......................................................................................................................38
7.4.
Dosage Modification....................................................................................................38
7.5.
Preparation/Handling/Storage/Accountability...............................................................39
7.6.
Treatment Compliance .................................................................................................39
7.7.
Concomitant Therapy...................................................................................................39


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7.7.1.
Prohibited Medications and Procedures................................................................39
7.7.2.
Permitted Medications and Procedures.................................................................40
7.7.3.
Rescue Therapy....................................................................................................41
7.8.
Treatment after the End of the Study............................................................................42
7.8.1.
Study Extensions..................................................................................................42
7.8.2.
Continued Access.................................................................................................43
8.
Discontinuation Criteria ....................................................................................................44
8.1.
Discontinuation from Study Treatment.........................................................................44
8.1.1.
Temporary Interruption from Study Treatment .....................................................44
8.1.2.
Permanent Discontinuation from Study Treatment ...............................................45
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................47
8.2.
Discontinuation from the Study....................................................................................47
8.3.
Lost to Follow-Up........................................................................................................48
9.
Study Assessments and Procedures ...................................................................................49
9.1.
Efficacy Assessments...................................................................................................49
9.1.1.
Primary Efficacy Assessments .............................................................................49
9.1.2.
Secondary Efficacy Assessments..........................................................................49
Eczema Area and Severity Index Scores .........................................................49
9.1.2.1.
SCORing Atopic Dermatitis ...........................................................................49
9.1.2.2.
Hospital Anxiety Depression Scale .................................................................49
9.1.2.3.
9.1.3.
Health Outcomes and Quality-of-Life Measures...................................................50
Patient-Oriented Eczema Measure ..................................................................50
9.1.3.1.
Itch Numeric Rating Scale..............................................................................50
9.1.3.2.
Nocturnal Sleep–Wake and Itch Patterns ........................................................50
9.1.3.3.
Atopic Dermatitis Sleep Scale ........................................................................50
9.1.3.4.
Skin Pain Numeric Rating Scale .....................................................................50
9.1.3.5.
Patient Global Impression of Severity.............................................................51
9.1.3.6.
Dermatology Life Quality Index .....................................................................51
9.1.3.7.
European Quality of Life–5 Dimensions–5 Levels..........................................51
9.1.3.8.
Work Productivity and Activity Impairment 
9.1.3.9.
Questionnaire–Atopic Dermatitis....................................................................51
9.1.4.
Appropriateness of Assessments ..........................................................................52
9.2.
Adverse Events ............................................................................................................52
9.2.1.
Serious Adverse Events........................................................................................53
Suspected Unexpected Serious Adverse Reactions..........................................53
9.2.1.1.
9.2.2.
Adverse Events of Special Interest .......................................................................54
9.2.3.
Complaint Handling.............................................................................................54
9.3.
Treatment of Overdose.................................................................................................54


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9.4.
Safety...........................................................................................................................54
9.4.1.
Electrocardiograms ..............................................................................................54
9.4.2.
Vital Signs ...........................................................................................................55
9.4.3.
Physical Exam .....................................................................................................55
9.4.4.
Laboratory Tests ..................................................................................................55
9.4.5.
Columbia Suicide Severity Rating Scale...............................................................55
9.4.6.
Self-Harm and Follow-up Supplement Forms.......................................................55
9.4.7.
Chest x-ray and Tuberculosis Testing...................................................................56
9.4.8.
Hepatitis B Virus DNA Monitoring......................................................................56
9.4.9.
Hepatic Safety Monitoring and Data Collection....................................................56
9.4.10.
Safety Monitoring ................................................................................................57
9.5.
Pharmacokinetics .........................................................................................................58
9.6.
Pharmacodynamics ......................................................................................................59
9.7.
Pharmacogenomics ......................................................................................................59
9.7.1.
Blood Samples for Pharmacogenetic Research .....................................................59
9.8.
Biomarkers...................................................................................................................60
9.9.
Medical Resource Utilization and Health Economics ...................................................60
10.
Statistical Considerations ..................................................................................................61
10.1. Sample Size Determination ..........................................................................................61
10.2. Populations for Analyses..............................................................................................61
10.3. Statistical Analyses ......................................................................................................61
10.3.1.
General Statistical Considerations ........................................................................61
10.3.2.
Treatment Group Comparability...........................................................................64
Patient Disposition..........................................................................................64
10.3.2.1.
Patient Characteristics ....................................................................................64
10.3.2.2.
Concomitant Therapy .....................................................................................64
10.3.2.3.
Treatment Compliance....................................................................................64
10.3.2.4.
10.3.3.
Efficacy Analyses ................................................................................................64
Primary Analyses ...........................................................................................64
10.3.3.1.
Secondary Analyses........................................................................................65
10.3.3.2.
10.3.4.
Safety Analyses....................................................................................................65
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................66
10.3.6.
Other Analyses.....................................................................................................66
Health Outcome Measures..............................................................................66
10.3.6.1.
Subgroup Analyses.........................................................................................66
10.3.6.2.
10.3.7.
Interim Analyses ..................................................................................................67
Data Monitoring Committee ...........................................................................67
10.3.7.1.
Adjudication Committee.................................................................................67
10.3.7.2.


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11.
References ........................................................................................................................68
12.
Appendices .......................................................................................................................72


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List of Tables
Table
Page
Table JAHM.1.
I4V-MC-JAHM Schedule of Activities..........................................................13
Table JAHM.2.
Objectives and Endpoints...............................................................................20
Table JAHM.3.
Treatment Regimens......................................................................................36
Table JAHM.4.
Criteria for Temporary Interruption of Investigational Product.......................44


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List of Figures
Figure
Page
Figure JAHM.1. Illustration of study design for Clinical Protocol I4V-MC-JAHM. .................24


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................73
Appendix 2.
Clinical Laboratory Tests...............................................................................77
Appendix 3.
Study Governance Considerations..................................................................79
Appendix 4.
Hepatic Monitoring Tests For Treatment-Emergent Abnormality...................83
Appendix 5.
Liver Function Testing and Hepatic Safety Monitoring..................................84
Appendix 6.
American Academy of Dermatology:  Criteria for the Diagnosis and 
Assessment of Atopic Dermatitis ...................................................................85
Appendix 7.
Classification of Potency for Topical Corticosteroids.....................................86
Appendix 8.
Protocol Amendment I4V-MC-JAHM(b) Summary - A Multicenter, 
Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to 
Evaluate the Efficacy and Safety of Baricitinib in Patients with 
Moderate to Severe Atopic Dermatitis ...........................................................87


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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 Patients with Moderate to Severe Atopic Dermatitis
Rationale:
Atopic dermatitis (AD) is a pruritic, chronic or chronically relapsing, highly symptomatic inflammatory skin disease 
characterized by excessive T cell activation leading to significant skin infiltration by T-cells and dendritic cells 
(Bieber 2010).  Presentation is varied, but includes skin manifestations and pruritus, with associated sleep 
disturbances and subsequent skin infections.  The course of disease includes relapses of varying duration and 
severity.
Baricitinib is an orally available, selective Janus kinase (JAK) inhibitor with potency and selectivity for JAK1 and 
JAK2 and less potency for JAK3 or tyrosine kinase 2 (TYK2) (Fridman et al. 2010).  The pathogenesis of AD is 
thought to be modulated through thymic stromal lymphopoietin (TSLP), interleukin (IL)-13, IL-4, IL-5, IL-22, and 
IL-31, many of which activate receptors with downstream signaling through intracellular JAK1/JAK2/TYK2
(Nomura and Kabashima 2015).  This activity profile suggests that baricitinib may 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.  The mechanism of action, combined with demonstration of clinical benefit in inflammatory 
diseases involving joints, kidneys, and skin, provides the rationale for evaluating baricitinib in moderate to severe 
AD.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary
To test the hypothesis that baricitinib 4-mg QD or 
baricitinib 2-mg QD is superior to placebo in the 
treatment of patients with moderate to severe AD.

Proportion of patients achieving IGA of 0 or 1 with 
a ≥2-point improvement at Week 16.
Key Secondary 
These are prespecified objectives that will be adjusted for multiplicity
To test the hypothesis that baricitinib 1-mg QD is 
superior to placebo in the treatment of patients with 
moderate to severe AD.

Proportion of patients achieving IGA of 0 or 1 with 
a ≥2-point improvement at Week 16.


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Objectives
Endpoints
To compare the efficacy of baricitinib 1-mg QD, 
2-mg QD, or 4-mg QD to placebo in AD during the 
16-week double-blind placebo-controlled treatment 
period as measured by improvement in signs and 
symptoms of AD.

Proportion of patients achieving 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 1-mg QD, 
2-mg QD, or 4-mg QD to placebo in AD during the 
16-week double-blind placebo-controlled treatment 
period as assessed by patient-reported outcome 
measures.

Proportions of patients achieving a 4-point 
improvement in Itch NRS at 1 week, 2 weeks, 
4 weeks, and 16 weeks

Mean change from baseline in the score of Item 2 of
the ADSS at 1 week and 16 weeks

Mean change from baseline in Skin Pain NRS at
16 weeks.
Other Secondary Objectives
These are prespecified objectives that will not be adjusted for multiplicity.
To test the hypothesis that baricitinib 1-mg QD, 2-mg 
QD, or 4-mg QD is superior to placebo in the 
treatment of patients with moderate to severe AD

Proportion of patients achieving IGA of 0 or 1 with 
a ≥2-point improvement at Week 4.
To compare the efficacy of baricitinib 1-mg QD, 
2-mg QD, or 4-mg QD to placebo in AD during the 
16-week double-blind placebo-controlled period as 
measured by improvement in signs and symptoms of 
AD.

Proportion of patients achieving 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.
To compare the efficacy of baricitinib 1-mg QD, 
2-mg QD, or 4-mg QD to placebo 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 1 week 
and 16 weeks

Mean change from baseline in Itch NRS at 4 weeks 
and 16 weeks

Mean change from baseline in the total score of the 
POEM at 16 weeks

Mean change in PGI-S-AD scores at 16 weeks

Mean change from baseline in 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.


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Abbreviations:  AD = atopic dermatitis; ADSS = Atopic Dermatitis Sleep Scale; DLQI = Dermatology Life Quality 
Index; EASI = Eczema Area and Severity Index; EQ-5D-5L = the European Quality of Life–5 Dimensions–
5 Levels;  HADS = Hospital Anxiety Depression Scale; IGA = Investigator’s Global Assessment; NRS = 
numeric rating scale; QD = once daily; PGI-S-AD = Patient Global Impression of Severity–Atopic Dermatitis; 
POEM = Patient-Oriented Eczema Measure; QoL = quality of life; SCORAD = SCORing Atopic Dermatitis; 
WPAI = Work Productivity and Activity Impairment.
Summary of Study Design:
Study I4V-MC-JAHM (JAHM) 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), 2-mg QD, 
and 1-mg QD as compared to placebo in adult patients with moderate to severe AD.  The study population will 
include patients aged 18 years or older who have moderate to severe AD and a history of inadequate response or 
intolerance to existing topical therapies.
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, 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 4 treatment groups:  placebo once daily (QD), baricitinib 1-mg QD, 
baricitinib 2-mg QD, or baricitinib 4-mg QD.  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 600 patients with AD who will be randomized 2:1:1:1 to placebo QD or 1 of 
3 dose groups of baricitinib (1-mg QD, 2-mg QD, or 4-mg QD) (240 patients in the placebo arm; 120 patients in 
each baricitinib 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.


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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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Abbreviations:  AD = atopic dermatitis; ADSS = Atopic Dermatitis Sleep Scale; BP = blood pressure; C-SSRS = Columbia Suicide Severity Rating Scale 11 
categories suicidal ideation/suicidal behavior; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; 
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; HIV = human immunodeficiency virus; IGA = 
Investigator’s Global Assessment; IP = investigational product; IWRS = interactive web-response system; NRS = numeric rating scale ; PGI-S-AD = Patient 
Global Impression of  Severity–Atopic Dermatitis;  PK = pharmacokinetic; POEM = Patient-Oriented Eczema Measure; PPD = purified protein derivative; 
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 [38] for description of TB testing.  In countries where the 
QuantiFERON-TB Gold test or T-SPOT is available, either test may be used instead of the PPD TB test.  The QuantiFERON-TB Gold test may be performed 
locally or centrally; the T-SPOT must be performed locally.  (Note:  Exception:  Patients with a history of active or latent TB who have documented evidence 
of appropriate treatment, have no history of re-exposure since their treatment was completed, and have a screening chest x-ray with no evidence of active TB 
may be enrolled if other entry criteria are met.  Such patients would not be required to undergo the protocol-specific TB testing but must have a chest x-ray at 
screening.)
e
If PPD testing was chosen to test for TB, then the patient must return and PPD test read 48 to 72 hours after Visit 1 (post-PPD).  
f
Actigraphy devices and ePRO devices will need to be collected from screen fail patients.
g
For patients not entering Study JAHN, their JAHM patient diary will continue to be dispensed at the final visit and returned at Visit 801.
h
Only required if patient met rescue criteria.
i
The following measures (POEM, DLQI, PGI-S-AD, Itch NRS, Skin Pain NRS, ADSS, EQ-5D-5L, WPAI-AD) should be completed prior to any clinical 
assessments being performed on days when study visits occur.
j
Suicidal ideation and behavior subscales excerpt – Adapted for the assessment of 11 preferred ideation and behavior categories.
k
The Self-Harm Follow-up Form is only required if triggered by the Self-Harm Supplement Form.
l
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).
m 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.
n
Only required for patients completing an ETV prior to completion of Visit 7 (Week 12).
o
For all women of childbearing potential, a serum pregnancy test (central laboratory) will be performed at Visit 1.  Urine pregnancy tests (local laboratory) will 
be performed at Visit 2 and at all subsequent study visits after Visit 3.  If required per local regulations and/or institutional guidelines, pregnancy testing can 
occur at other times during the study treatment period.


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p
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).
q
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.
r
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 (see Section 9.4.8).
s
See Section 9.5 for details.  At Visit 2 (Week 0) patients will take their investigational product in the clinic and PK samples will be drawn 15 minutes and 
1 hour postdose.  Other Visit 2 baseline laboratory samples should be taken before administration of investigational product.  At Visit 5 (Week 4), patients 
should take their investigational product at home prior to visiting the clinic and samples will be collected 2 to 4 hours after the dose is taken at home.  At 
Visit 6 (Week 8) and Visit 7 (Week 12), patients will be asked to not take their oral investigational product prior to visiting the clinic and a sample will be 
collected at any time predose on the day of the clinic visit.  If the patient has taken his/her oral dose prior to the visit, the sample may be drawn anytime 
postdose, and the inability to collect a predose sample will not be considered a protocol violation.  For Visit 8 (Week 16), patients should take their 
investigational product at home prior to visiting the clinic and samples will be collected 4 to 6 hours after the dose is taken at home.  For the ETV, a sample 
may be drawn anytime if the last dose of investigational product was taken within the last 48 hours.  For visits where PK samples will be collected, the actual 
date and exact 24-hour clock time of sample collection as well as the date and time of the 2 doses prior to the sample being drawn should be recorded. At 
Visit 5 (Week 4) and Visit 8 (Week 16), these 2 doses should be the dose given the morning of the day of sample collection and the dose given the previous 
day.  At Visit 6 (Week 8) and Visit 7 (Week 12), the 2 previous doses should be the dose taken yesterday and the dose taken the day before that.  This 
sampling schedule should be followed as closely as possible; however, failure to take PK samples at these specified times will not be considered a protocol 
violation.  


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3.
Introduction
3.1.
Background
Atopic dermatitis (AD), also known as eczema or atopic eczema, is a common, chronic, 
relapsing, highly symptomatic inflammatory skin disease (Bieber 2010).  Patients with AD may 
present with skin lesions that can be acute with oozing, crusted, eroded vesicles or papules on 
erythematous plaques.  Patients may also present with lesions that have a subacute appearance, 
with thick and excoriated plaques, or chronic appearance, with lichenified, slightly pigmented, 
excoriated plaques (Bieber 2010).  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), with 36% of patients 
reporting that they often or always scratch until their skin bleeds (Langenbruch et al. 2014).  
Pruritus from AD can worsen at night, resulting in sleep disturbances, with approximately 27% 
of adult patients with AD experiencing sleep disturbance as a result of itching (Langenbruch et 
al. 2014).  In adult patients with moderate to severe AD, 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.  In March 2017, Dupixent (dupilumab) injection, a IgG4 monoclonal antibody 
that inhibits interleukin (IL)-4 and IL-13, was approved by the FDA for this patient population.  
In the European Union, only cyclosporine has been approved for the treatment of patients with 
severe AD (Bieber and Straeter 2015).  A recently completed Phase 2 study (I4V-MC-JAHG 
[JAHG]) evaluated the safety and efficacy of baricitinib (Janus kinase [JAK] inhibitor) in AD 
and results showed significant improvement in disease severity compared to placebo and no new 
safety concerns were identified.
In addition to AD, baricitinib has also been studied in Phase 3 in patients with rheumatoid 
arthritis (RA) and in Phase 2 in patients with diabetic nephropathy, moderate to severe psoriasis, 
and systemic lupus erythematosus.
Through 04 June 2016, baricitinib has been studied in more than 450 healthy volunteers and 
4200 patients have received baricitinib in clinical studies.  Of these, more than 2400 patients 
have been treated with baricitinib for more than a year and more than 900 patients have been 
treated with baricitinib for more than 2 years at doses of 2-mg 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 daily for 
24 weeks, 8-mg daily for 76 weeks, and lower doses up to 4-mg daily for up to approximately 
5 years.


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3.2.
Study Rationale
The underlying cause of AD is not completely understood.  Loss of function mutations in 
filaggrin (filament aggregation protein) gene, 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 EASI scores compared to 
placebo.  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.
3.3.
Benefit/Risk Assessment
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’s Brochure (IB).


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4.
Objectives and Endpoints
Table JAHM.2 shows the objectives and endpoints of the study.
Table JAHM.2.
Objectives and Endpoints
Objectives
Endpoints
Primary
To test the hypothesis that baricitinib 4-mg QD or 
baricitinib 2-mg QD is superior to placebo in the 
treatment of patients with moderate to severe AD.

Proportion of patients achieving IGA of 0 or 1 with 
a ≥2-point improvement at Week 16.
Key Secondary 
These are prespecified objectives that will be adjusted for multiplicity
To test the hypothesis that baricitinib 1-mg QD is 
superior to placebo in the treatment of patients with 
moderate to severe AD.

Proportion of patients achieving IGA of 0 or 1 with 
a ≥2-point improvement at Week 16.
To compare the efficacy of baricitinib 1-mg QD,
2-mg QD, or 4-mg QD to placebo in AD during the 
16-week double-blind placebo-controlled treatment 
period as measured by improvement in signs and 
symptoms of AD.

Proportion of patients achieving 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 1-mg QD,
2-mg QD, or 4-mg QD to placebo in AD during the 
16-week double-blind placebo-controlled treatment 
period as assessed by patient-reported outcome 
measures.

Proportions of patients achieving a 4-point 
improvement in Itch NRS at 1 week, 2 weeks, 
4 weeks, and 16 weeks

Mean change from baseline in the score of Item 2 
of the ADSS at 1 week and 16 weeks.

Mean change from baseline in Skin Pain NRS at 
16 weeks.
Other Secondary Objectives
These are prespecified objectives that will not adjusted for multiplicity.
To test the hypothesis that baricitinib 1-mg QD, 
2-mg QD, or 4-mg QD is superior to placebo in the 
treatment of patients with moderate to severe AD.

Proportion of patients achieving IGA of 0 or 1 with 
a ≥2-point improvement at Week 4
To compare the efficacy of baricitinib 1-mg QD,
2-mg QD, or 4-mg QD to placebo in AD during the 
16-week double-blind placebo-controlled period as 
measured by physician-assessed 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


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Objectives
Endpoints
To compare the efficacy of baricitinib 1-mg QD, 
2-mg QD, or 4-mg QD to placebo 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 
1 week and 16 weeks

Mean change from baseline in Itch NRS at 4 weeks 
and 16 weeks

Mean change from baseline in the total score of the 
POEM at 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.
Exploratory Objectives/Endpoints

Mean change from baseline in nocturnal itch assessed by actigraphy device at 1 week and 4 weeks

Frequency of patient-reported “no itch” (Itch NRS score = 0) days from daily diaries from Week 12 to 
Week 16

Frequency of patient-reported “no pain” (Skin Pain NRS score = 0) days from daily diaries from Week 12 
to Week 16

Mean change from baseline in the score of Item 1 of the ADSS at 1 week and 16 weeks

Mean change from baseline in the score of Item 3 of the ADSS at 1 week and 16 weeks

To evaluate changes from baseline in IgE levels during the study

To evaluate changes from baseline in eosinophil levels during the study

To characterize baricitinib pharmacokinetics in the AD population and explore relationships between 
baricitinib exposure and study endpoints.
Abbreviations:  AD = atopic dermatitis; ADSS = Atopic Dermatitis Sleep Scale; BSA = body surface area; 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; IgE = immunoglobulin E; NRS = numeric rating scale; QD = once daily; QoL = quality of life; 
PGI-S-AD = Patient Global Impression of Severity–Atopic Dermatitis; POEM = Patient-Oriented Eczema 
Measure; SCORAD = SCORing Atopic Dermatitis; WPAI = Work Productivity and Activity Impairment.


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5.
Study Design
5.1.
Overall Design
Study I4V-MC-JAHM (JAHM) is a Phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group, outpatient study evaluating the efficacy and safety of 
baricitinib 1-mg once daily (QD), 2-mg QD, and 4-mg QD as compared to placebo in adult 
patients with moderate to severe AD.  The study is divided into 3 periods, a 5-week Screening 
period, a 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 600 patients ≥18 years of age who have responded inadequately to or who are 
intolerant to topical therapy will be randomized at a 2:1:1:1 ratio to receive placebo QD, 
baricitinib 1-mg QD, baricitinib 2-mg QD, or baricitinib 4-mg QD (240 patients in the placebo 
group; 120 patients in each baricitinib 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.  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 (see Appendix 3).  All screening procedures will 
be performed according to the Schedule of Activities (Section 2).  Patients who receive a purified 
protein derivative (PPD) skin test at Visit 1 will need to return within 48 to 72 hours later to 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 are utilizable to meet inclusion criterion [8].  Additionally, collection of data 
through daily diaries and actigraphy devices will be required throughout the screening period.  
The baseline for the daily PRO and actigraphy 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 [27] in Section 6 for additional information regarding herpes zoster vaccinations.  


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Patients who meet all of the inclusion and none of the exclusion criteria (Section 6) 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 and pharmacokinetic (PK) samples will 
be drawn 15 minutes and 1 hour postdose.  Pharmacokinetic sampling and the related timing of 
dosing for investigational product for each visit are detailed in Section 9.5.
Patient will be randomized at a 2:1:1:1 ratio into 1 of the 4 treatment groups (placebo QD, 
baricitinib 1–mg 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; see Section 7).  All 
patients will be required to use emollients daily.  Daily diaries will continue to be utilized 
throughout the treatment period and through Week 4 for actigraphy devices.  Download of this 
data will be required at study visits.  The use of topical corticosteroids (TCS), topical calcineurin 
inhibitors (TCNIs), 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 rescue 
therapy and criteria are included in Section 7.7.3.  Assessments of disease severity will be 
performed by the investigator at all study visits including unscheduled and 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 will 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 withdraws 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.
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.


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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 JAHM.1 illustrates the study design.  The 4 dosing regimens are described in Section 7.1.  
The blinding procedure is described in Section 7.3.
Abbreviations:  AD = atopic dermatitis; eGFR = estimated glomerular filtration rate; 
PPD = purified protein derivative; QD = once daily; 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 JAHM.1.
Illustration of study design for Clinical Protocol I4V-MC-JAHM.


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5.2.
Number of Participants
Approximately 600 participants will be enrolled; approximately 840 patients will be screened to 
achieve this enrollment.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
This study will enroll moderate to severe AD patients with a history of inadequate response or 
intolerance to existing topical therapies for whom a systemic treatment such as baricitinib may 
therefore be appropriate.
During the screening period (Period 1), a washout of systemic and topical treatments for AD was 
incorporated prior to randomization to minimize confounding effects due to background 
treatment.  The double-blind, placebo-controlled treatment period (Period 2) is designed to 
minimize bias in the evaluation of the efficacy and safety of 3 baricitinib doses, relative to 
placebo, through 16 weeks of treatment.
In consideration of the disease severity, all patients in Study JAHM are eligible for rescue to 
TCS.  Investigators are allowed to rescue patients who are experiencing unacceptable or 
worsening symptoms of AD.  Once rescue medication is used, the patient will be determined to 
be a nonresponder (See Section 7.7.3).
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 trial, 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.
A 2:1:1:1 randomization scheme of placebo, 1-mg baricitinib, 2-mg baricitinib, and 4-mg 
baricitinib was implemented because increased placebo enrollment across treatment groups has 
been reported to decrease placebo response and to also increase statistical power (Mallinckrodt 
2011).
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 our 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.


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5.5.
Justification for Dose
The doses proposed for AD Phase 3 studies are baricitinib 1-mg, 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 PK, safety, and efficacy data for baricitinib in Phase 2 and Phase 3 RA 
studies and a Phase 2 psoriasis study.
In the Phase 2 Study JAHG, both the 2-mg and 4-mg doses showed benefit on the primary and 
major secondary endpoints (EASI, IGA, SCORAD, POEM and DLQI) as compared to placebo,
and both doses had an acceptable safety profile at Week 16.  However, the 4-mg dose appeared 
to demonstrate a more rapid benefit (at 4 weeks) on the more stringent endpoints (EASI75, 
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 EASI-50, and EASI change from baseline, 
2-mg and 4-mg doses showed similar efficacy compared to placebo.  Thus based on available 
data, 3 doses will be included in Phase 3, including a 1-mg dose, to cover the range of exposures 
where clinical responses could be anticipated
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 or 1-mg dose, there will be no dose correction 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 (see 
Appendix 6).
[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, 
or history of intolerance to topical therapy as defined by at least 1 of the 
following:
a.
inability to achieve good disease control defined as mild disease or better
(e.g., IGA ≤2) after use of at least a medium potency TCS for at least 
4 weeks, or for the maximum duration recommended by the product 
prescribing information (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, mycophenolate mofetil will also be considered as a surrogate 
for having inadequate response to topical therapy.
c.
documented history of clinically significant adverse reactions with the use 
of TCS such as skin atrophy, allergic reactions, systemic effects that in the 
opinion of the investigator outweigh the benefits of retreatment.
[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.
sedating antihistamines, including, but not limited to, alimemazine, 
chlorphenamine, clemastine, cyproheptadine, diphenhydramine, 
hydroxyzine, ketotifen, and promethazine
Note:  Patients may use newer, less sedating antihistamines (e.g., fexofenadine, 
loratadine, cetirizine)
d. any other systemic therapy used to treat AD or symptoms of AD
(approved or off-label use)
e.
phototherapy, includes therapeutic phototherapy (psoralen plus 
ultraviolet-A, ultraviolet-B), excimer laser as well as self-treatment with 
tanning beds.
[7]
agree to discontinue use of the following excluded medications for at least 
2 weeks prior to randomization (Visit 2) and throughout the study:
a.
TCS or topical immune modulators (e.g., tacrolimus or pimecrolimus)
b. topical phosphodiesterase type 4 (PDE-4) inhibitor (crisaborole)
[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] are male or nonpregnant, nonbreastfeeding female patients, except
a.
Male patients must agree to use 2 forms of birth control (1 must be highly 
effective, see below) while engaging in sexual intercourse with female 
partners of childbearing potential while enrolled in the study and for at 
least 4 weeks following the last dose of investigational product.


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b. Female patients of childbearing potential must agree to use 2 forms of 
birth control, when engaging in sexual intercourse with a male partner 
while enrolled in the study and for at least 4 weeks following the last dose 
of investigational product.
The following birth control methods are considered acceptable (the patient should choose 2 to be 
used with their male partner, and 1 must be highly effective):
o
highly effective birth control methods:  oral, injectable, or implanted hormonal 
contraceptives (combined estrogen/progesterone or progesterone only, associated 
with inhibition of ovulation); intrauterine device or intrauterine system (e.g., 
progestin-releasing coil); or vasectomized male (with appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate).
o
effective birth control methods:  condom with a spermicidal foam, gel, film, 
cream, or suppository; occlusive cap (diaphragm or cervical/vault caps) with a 
spermicidal foam, gel, film, cream, or suppository; or oral hormonal 
contraceptives.
Note: When local guidelines concerning highly effective or effective methods of birth control 
differ from the above, the local guidelines must be followed.
a.
Females of nonchildbearing potential are not required to use birth control 
and they are defined as:
o
women ≥60 years of age or women who are congenitally sterile, or
o
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).
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] 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.
[13] a history of eczema herpeticum within 12 months prior to screening.
[14] a history of 2 or more episode of eczema herpeticum in the past.


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[15] patients who are currently experiencing a skin infection that requires 
treatment, or is currently being treated, with topical or systemic antibiotics.
Note:  Patients may not be rescreened until at least 4 weeks after the date of their 
previous screen failure and at least 2 weeks after resolution of the infection.
[16] have any serious concomitant illness that is anticipated to require the use of 
systemic corticosteroids or otherwise interfere with study participation or 
require active frequent monitoring (e.g., unstable chronic asthma).
[17] have been treated with the following therapies:
a.
monoclonal antibody (e.g., ustekinumab, omalizumab, dupilumab) for less 
than 5 half-lives prior to randomization.
b. received prior treatment with any oral JAK inhibitor (e.g., tofacitinib, 
ruxolitinib) less than 4 weeks prior to randomization.
c.
received any parenteral corticosteroid administered by intramuscular or 
intravenous injection within 2 weeks prior to study entry (Visit 1) or 
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 2 weeks prior to 
study entry (Visit 1) or within 6 weeks prior to planned randomization 
(Visit 2).
Note:  intranasal or inhaled steroid use is allowed during the trial.
e.
probenecid at the time of randomization (Visit 2) that cannot be 
discontinued for the duration of the study
Medical Conditions in General
[18] are largely or wholly incapacitated permitting little or no self-care, such as 
being bedridden.
[19] have uncontrolled arterial hypertension characterized by a repeated systolic 
blood pressure >160 mm Hg or diastolic blood pressure >100 mm Hg in a 
seated position.
[20] have had any major surgery within 8 weeks 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.
[21] are immunocompromised and, in the opinion of the investigator, at an 
unacceptable risk for participating in the study.
[22] have experienced any of the following within 12 weeks of screening:  venous
thromboembolic event (VTE), myocardial infarction (MI), unstable ischemic 
heart disease, stroke, or New York Heart Association Stage III/IV heart 
failure.


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[23] have a history of recurrent (≥ 2) VTE or are considered at high risk of VTE as 
deemed by the investigator.  
[24] have a history or presence of cardiovascular, respiratory, hepatic, 
gastrointestinal, endocrine, hematological, neurological, or neuropsychiatric 
disorders or any other serious and/or unstable illness that, in the opinion of the 
investigator, could constitute an unacceptable risk when taking investigational 
product or interfere with the interpretation of data.
[25] have a history of lymphoproliferative disease; or have signs or symptoms 
suggestive of possible lymphoproliferative disease, including 
lymphadenopathy or splenomegaly; or have active primary or recurrent 
malignant disease; or have been in remission from clinically significant 
malignancy for 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.
[26] have a current or recent clinically serious viral, bacterial, fungal, or parasitic 
infection, including but not limited to the following:
Note:  A recent viral upper respiratory tract infection or uncomplicated urinary tract 
infection should not be considered clinically serious.
a.
symptomatic herpes zoster infection within 12 weeks prior to screening.
b. a history of disseminated/complicated herpes zoster (e.g., 
multidermatomal involvement, ophthalmic zoster, CNS involvement, or 
post-herpetic neuralgia).
c.
symptomatic herpes simplex at the time of randomization.
d. active or chronic viral infection from hepatitis B virus (HBV), hepatitis C 
virus (HCV), or human immunodeficiency virus (HIV).
e.
household contact with a person with active tuberculosis (TB) and 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.


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[27] 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 must occur >4 weeks prior to randomization and start of investigational 
product.  Patients will be excluded if they were exposed to herpes zoster vaccination 
within 4 weeks of planned randomization.  Investigators should review the 
vaccination status of their patients and follow the local guidelines for vaccination of 
those ≥18 years of age with nonlive vaccines intended to prevent infectious disease 
prior to entering patients into the study.
[28] have a history of chronic alcohol abuse, IV drug abuse, or other illicit drug 
abuse within the 2 years prior to screening.
[29] presence of significant uncontrolled neuropsychiatric disorder, are clinically 
judged by the investigator to be at risk for suicide, or have a “yes” answer to 
any of the following:
a.
Question 4 (Active Suicidal Ideation with Some Intent to Act, Without 
Specific Plan) on the “Suicidal Ideation” portion of the Columbia Suicide 
Severity Rating Scale (C-SSRS) or
b. Question 5 (Active Suicidal Ideation with Specific Plan and Intent) on the 
“Suicidal Ideation” portion of the C-SSRS or
c.
Any of the suicide-related behaviors (actual attempt, interrupted attempt, 
aborted attempt, preparatory act or behavior) on the “Suicidal Behavior” 
portion of the C-SSRS;
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.
[30] 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
[31] are unable or unwilling to make themselves available for the duration of the 
study and/or are unwilling to follow study restrictions/procedures.
[32] are currently enrolled in any other clinical trial involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study.


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[33] 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.
[34] have previously been randomized in this study or any other study 
investigating baricitinib.
[35] are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.
[36] are Lilly or Incyte employees or their designee.
Diagnostic Assessments
[37] have screening electrocardiogram (ECG) abnormalities that, in the opinion of 
the investigator, are clinically significant and indicate an unacceptable risk for 
the patient’s participation in the study.
[38] have evidence of active TB or latent TB
a.
have evidence of active TB, defined in this study as the following:
o
documented by a positive PPD test (≥5 mm induration between 
approximately 48 and 72 hours after application, regardless of vaccination 
history), medical history, clinical features, and abnormal chest x-ray at 
screening.
o
The QuantiFERON®-TB Gold test or T-SPOT®.TB test (as available and if 
compliant with local TB guidelines) may be used instead of the PPD test.  
Patients are excluded from the study if the test is not negative and there is 
clinical evidence of active TB.
Exception:  Patients with a history of active TB who have documented evidence of 
appropriate treatment, have no history of re-exposure since their treatment was 
completed, and have a screening chest x-ray with no evidence of active TB may be 
enrolled if other entry criteria are met.  Such patients would not be required to 
undergo the protocol-specific TB testing for PPD, QuantiFERON®-TB Gold test, or 
T-SPOT® TB test but must have a chest x-ray at screening.
b. have evidence of untreated/inadequately or inappropriately treated latent 
TB, defined in this study as the following:
o
documented to have a positive PPD test (≥5 mm induration between 
approximately 48 and 72 hours after application, regardless of vaccination 
history), no clinical features consistent with active TB, and a chest x-ray 
with no evidence of active TB at screening; or 
o
PPD test is positive and the patient has no medical history or chest x-ray 
findings consistent with active TB, the patient may have a 


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QuantiFERON®-TB Gold test or T-SPOT® TB test (as available and if 
compliant with local TB guidelines).  If the test results are not negative, the 
patient will be considered to have latent TB (for purposes of this study); or
o
QuantiFERON®-TB Gold test or T-SPOT® TB test (as available and if 
compliant with local TB guidelines) may be used instead of the PPD test.  
If the test results are positive, the patient will be considered to have latent 
TB.  If the test is not negative, the test may be repeated once within 
approximately 2 weeks of the initial value.  If the repeat test results are 
again not negative, the patient will be considered to have latent TB (for 
purposes of this study).
Exception:  Patients who have evidence of latent TB may be enrolled if he or she 
completes at least 4 weeks of appropriate treatment prior to randomization and agrees 
to complete the remainder of treatment while in the trial.
Exception:  Patients with a history of latent TB who have documented evidence of 
appropriate treatment, have no history of re-exposure since their treatment was 
completed, and have a screening chest x-ray with no evidence of active TB may be 
enrolled if other entry criteria are met.  Such patients would not be required to 
undergo the protocol-specific TB testing for PPD, QuantiFERON®-TB Gold test, or 
T-SPOT® TB test but must have a chest x-ray at screening.
[39] have a positive test 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.
[40] 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.
[41] have evidence of HIV infection and/or positive HIV antibodies.
[42] have screening laboratory test values, including thyroid-stimulating hormone 
(TSH), outside the reference range for the population or investigative site that, 
in the opinion of the investigator, pose an unacceptable risk for the patient’s 
participation in the study.
Note:  Patients who are receiving thyroxine as replacement therapy may participate in 
the study, provided stable therapy has been administered for ≥12 weeks and TSH is 
within the laboratory’s reference range.  Patients who are receiving stable thyroxine 


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replacement therapy who have TSH marginally outside the laboratory’s normal 
reference range may participate if the treating physician has documented that the 
thyroxine replacement therapy is adequate for the patient.
[43] have any of the following specific abnormalities on screening laboratory tests:
a.
AST or ALT ≥2x 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/L (<2.50x103/L or <2.50 GI/L)
f.
neutropenia (absolute neutrophil count [ANC] <1200 cells/L) 
(<1.20x103/L or <1.20 GI/L)
g. lymphopenia (lymphocyte count <750 cells/L) (<0.75x103/L or 
<0.75 GI/L)
h. thrombocytopenia (platelets <100,000/L) (<100x103/L 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 [42] and [43]), the tests may be repeated during screening, and values 
resulting from repeat testing may be accepted for enrollment eligibility if they meet 
the eligibility criterion.
6.3.
Lifestyle Restrictions
Not applicable.
6.4.
Screen Failures
Patients who are entered into the study but do not meet the eligibility criteria for participation in 
this study (screen failure) may be rescreened a maximum of 2 times.  If patients are rescreened, 
rescreening cannot occur until at least 4 weeks after the date of their previous screen failure.  
When rescreening is performed, the individual must sign a new ICF and will be assigned a new 
identification number.  Additionally, all necessary screening procedures must be conducted at 
rescreen to ensure all eligibility criteria are met.


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7. Treatments
7.1.
Treatments Administered
This study involves a comparison of placebo, baricitinib 1-mg, baricitinib 2-mg, and baricitinib 
4-mg administered orally once a day.  Table JAHM.3 shows the treatment regimens.
Table JAHM.3.
Treatment Regimens
Regimen
Investigational Product Supplied
Dose
Baricitinib 4-mg QDa
Baricitinib 4-mg tablets
3 tablets per day
Placebo to match 2-mg tablets
Placebo to match 1-mg tablets
Baricitinib 2-mg QD
Baricitinib 2-mg tablets
3 tablets per day
Placebo to match 4-mg tablets
Placebo to match 1-mg tablets
Baricitinib 1–mg QD
Baricitinib 1-mg tablets
3 tablets per day
Placebo to match 4-mg tablets
Placebo to match 2-mg tablets
Placebo QD
Placebo to match 4-mg tablets
3 tablets per day
Placebo to match 2-mg tablets
Placebo to match 1-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

tablets containing 1-mg of baricitinib

placebo tablets to match baricitinib 4-mg tablets, 2-mg tablets, and 1-mg tablets.
Packaging for each dose will include 3 tablets per day.  Each tablet has a distinctive shape and 
color, 4-mg vs. 2-mg vs. 1-mg, and each strength tablet has a matching placebo.  Each active 


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dose package will contain the appropriate active strength tablet, and corresponding placebo 
tablets for the other strengths, as noted in Table JAHM.3.
Investigational product tablets will be provided in blister packs.
Clinical trial materials will be labeled according to the country’s regulatory requirements.
7.1.2. Medical Devices
An actigraphy device, a hypoallergenic device worn on the wrist, will be used to collect 
sleep/wake patterns and quantify nocturnal scratching events.  Each patient will be dispensed 
2 actigraphy devices.  One should be worn on the wrist during waking hours and the other should
be worn only during hours of sleep.  Patients will be provided instructions on use and when to 
bring the devices back to study site based on Schedule of Activities (Section 2).  If devices are 
not worn as instructed, it will not be considered a protocol violation.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized in a 2:1:1:1 ratio (placebo, 
baricitinib 1-mg; 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 blister packs, each containing double-blind investigational product 
tablets to each patient, starting at Visit 2 (Week 0), and at each visit up to and including Visit 7 
(Week 12).  Site personnel will confirm that they have located the correct blister packs by 
entering a confirmation number found on the blister packs into the IWRS.
7.2.1. Selection and Timing of Doses
The investigational product (3 tablets from blister pack) 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.  Refer to Section 9.5, Pharmacokinetics, for specific 
instructions on dose timing at certain visits where a PK sample is drawn.
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 or 1–mg dose, there will 
be no dose adjustment based on renal function.


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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, 2–mg, or 1 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 (see 
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 
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.  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.


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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).
7.7.
Concomitant Therapy
All concomitant medication, whether prescription or over the counter, used at baseline and/or 
during the course of the study, must be recorded on the Concomitant Medication electronic case 
report form (eCRF).  Patients will be instructed to consult the investigator or other appropriate 
study personnel at the site before taking any new medications or supplements during the study.  
For AD therapies permitted as part of rescue therapy, see Section 7.7.3.
7.7.1. Prohibited Medications and Procedures
Prohibited Medications and Procedures Not Requiring Interruption of Investigational 
Product
The following therapies will not be allowed during the course of the study and, if taken by or 
administered to the patient, the prohibited therapy must be discontinued.  

TCS, TCNIs (e.g., tacrolimus and pimecrolimus), or topical PDE 4 inhibitor (i.e., 
crisaborole) except when given as rescue therapy as described in Section 7.7.3.

topical antihistamines or sedating, systemic antihistamines including, but not 
limited to, alimemazine, chlorphenamine, clemastine, cyproheptadine, 
diphenhydramine, hydroxyzine, ketotifen, and promethazine

leukotriene inhibitors (e.g., montelukast [Singulair], zafirlukast [Accolate], and 
zileuton [Zyflo]) 

allergen immunotherapy


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
phototherapy including PUVA (psoralen and ultraviolet A), 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 [27])
o
For BCG vaccination, investigational product should be temporarily 
interrupted for 12 weeks.
o
For herpes zoster vaccination, investigational product should be 
temporarily interrupted for 4 weeks.  

probenecid:  if a patient is inadvertently started on probenecid, IP should be 
temporarily interrupted, and can be resumed after patient has discontinued 
probenecid.  If a patient is not able to discontinue probenecid, then IP 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.
7.7.2. Permitted Medications and Procedures
Treatment with concomitant AD therapies during the study is permitted only as described below.

Daily use of emollients is required as background treatment.  Moisturizers with 
additives such as antipruritics or antiseptics are not permitted.  If daily 
applications are missed, it will not be considered a protocol violation.

Patients should not apply emollients on the day of their study visit prior to the 
procedures to allow adequate assessment of skin dryness.


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
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.

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 seasonal vaccinations and/or emergency vaccination, such as rabies or 
tetanus vaccinations, are allowed.
Any changes of these concomitant medications must be recorded in the Concomitant Therapy of 
Special Interest eCRF.
Treatment with concomitant therapies for other medical conditions such as diabetes and 
hypertension is permitted during the study.
7.7.3. Rescue Therapy
Criteria for rescue therapy initiation:
Investigators should attempt to manage patients with emollients, however, investigators are 
allowed to rescue patients who are experiencing unacceptable or worsening symptoms of AD at 
any time.  Prior to rescue, it is recommended that increased frequency of emollient use is 
attempted to at least twice a day or more in an effort to control symptoms.  The rationale for 
rescue will be documented.
Choice of rescue therapy treatment

Triamcinolone 0.1% cream and/or hydrocortisone 2.5% ointment.  Where possible both 
these treatments will be supplied by the sponsor.  In the event where providing 1 or both 
of these topical formulations is not possible, an alternate, equivalent potency TCS cream 
and/or ointment may be provided by the sponsor.  TCS use, supplied by the sponsor, 
should be recorded via weight of returned tubes as indicated in the Schedule of Activities
(Section 2).  
o
In the event that the sponsor is unable to supply TCS, commercially available 
triamcinolone 0.1% cream and/or hydrocortisone 2.5% ointment may be supplied 
by the sites.  Where providing triamcinolone 0.1% cream and/or hydrocortisone 
2.5% ointment is not possible, an equivalent-potency TCS cream and/or ointment 
that is in line with local practices can be supplied. Refer to Appendix 7 for 
guidance on potency equivalence.  


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o
If the TSC 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 7 for guidance on 
potency equivalence.

Investigators may also select to use TCNIs and/or crisaborole where approved, 
although use of either during the study is neither encouraged nor provided.  If 
TCNIs are prescribed, use should be limited to problem areas only (e.g., face, 
neck, folds, genital areas, etc.).

On the days of study visits, topical therapy should not be applied before the 
patient has undergone all study procedures and clinical evaluations in order to 
allow adequate assessment of skin dryness

Patients rescued by topical therapy will continue to take investigational product
and use of rescue therapy will be documented in the eCRF.
In patients who do not improve sufficiently with the provided rescue topical therapy after 7 days, 
a higher potency TCS may be used (see Appendix 7) and investigational product may continue.  
Higher potency TCS will not be supplied centrally by the sponsor.  It is recommended that if a 
patient reaches “clear” to “almost clear” skin after topical rescue, then medium- and/or 
high-potency TCS and TCNI should be stopped, and low–potency TCS (e.g., hydrocortisone 
2.5% ointment) should be used once daily for an additional 7 days, then stopped.  If lesions 
return, patients can be retreated with TCS with or without TCNIs and/or crisaborole as before at 
the discretion of the investigator.
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.  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.


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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 Study Treatment
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 adverse event considered to be related to 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 JAHM.4.  
For the abnormal laboratory findings and clinical events (regardless of relatedness) listed in 
Table JAHM.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 JAHM.4 may be restarted at the discretion of the investigator.
Table JAHM.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/L
(<2.00x103/L or <2.00 GI/L)
WBC count 2500 cells/L
(≥2.50x103/L or ≥2.50 GI/L)
ANC <1000 cells/L
(<1.00x103/L or <1.00 GI/L)
ANC ≥1200 cells/L
(≥1.20x103/L or ≥1.20 GI/L)
Lymphocyte count <500 cells/L
(<0.50x103/L or <0.50 GI/L)
Lymphocyte count 750 cells/L
(≥0.75x103/L or ≥0.75 GI/L)
Platelet count <75,000/L
(<75x103/L or <75 GI/L)
Platelet count 100,000/L
(≥100x103/L 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.  If upon evaluation VTE is ruled out and no other 
temporary or permanent discontinuation criteria are met, then IP may be resumed.  
b
If after evaluation and institution of treatment 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 IP after use of a prohibited medication, please 
refer to Section 7.7.1 (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 non-suicidal self-injurious 
behavior.  
8.1.2. Permanent Discontinuation from Study Treatment
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, 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, rash, and/or eosinophilia (>5%)
NOTE:  Patients who are discontinued from investigational product due to a hepatic 
event or liver test abnormality should have additional hepatic safety data collected via 
the hepatic safety eCRF.
Investigational product should be permanently discontinued if any of the following laboratory 
abnormalities are observed:

white blood cell count <1000 cells/L (1.00x103/L or 1.00 GI/L)

ANC <500 cells/L (0.50x103/L or 0.50 GI/L)

lymphocyte count <200 cells/L (0.20x103/L or 0.20 GI/L)

hemoglobin <6.5 g/dL (<65.0 g/L).
NOTE:  Temporary interruption rules (see Section 8.1.1) must be followed where 
applicable.  For laboratory values that meet permanent discontinuation thresholds, 
investigational product should be discontinued.  However, if in the opinion of the 
investigator the laboratory abnormality is due to intercurrent illness such as 
cholelithiasis or another identified factor, laboratory tests may be repeated.  Only 
when the laboratory value meets resumption thresholds (Table JAHM.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 (see 
Section 9.4.8).

develop a second VTE 

certain prohibited medications are taken per Section 7.7.1 (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 


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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.
8.1.3. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identify 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 7.7.3]) 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.


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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
Eczema Area and Severity Index Scores
9.1.2.1.
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.
SCORing Atopic Dermatitis
9.1.2.2.
The SCORing Atopic Dermatitis (SCORAD) index uses the rule of nines to assess disease extent 
and evaluates 6 clinical characteristics to determine disease severity:  (1) erythema, 
(2) edema/papulation, (3) oozing/crusts, (4) excoriation, (5) lichenification, and (6) dryness.  The 
SCORAD index also assesses subjective symptoms of pruritus and sleep loss.  These 3 aspects:  
extent of disease, disease severity, and subjective symptoms combine to give a maximum 
possible score of 103 (Stalder et al. 1993; Kunz et al. 1997; Schram et al. 2012).
Hospital Anxiety Depression Scale
9.1.2.3.
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 


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(anxiety and depression) can range from 0 to 21, with higher scores indicating greater anxiety or 
depression (Zigmond and Snaith 1983; Snaith 2003).
9.1.3. Health Outcomes and Quality-of-Life Measures
The patient self-reported questionnaires will be administered via either an electronic patient diary 
or via an electronic tablet and in countries where the questionnaires have been translated into the 
native language of the region and linguistically validated.
Patient-Oriented Eczema Measure
9.1.3.1.
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).
Itch Numeric Rating Scale
9.1.3.2.
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).
Nocturnal Sleep–Wake and Itch Patterns
9.1.3.3.
An actigraphy device, a hypoallergenic device worn on the wrist, will be used to collect sleep–
wake patterns and quantify nocturnal scratching events.  Each patient will be dispensed 
2 actigraphy devices.  One will be worn on the wrist at all times and the other will be worn only 
during hours of sleep (one on each wrist).  Further details on use of the device will be provided 
in other instructional materials.
Atopic Dermatitis Sleep Scale
9.1.3.4.
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.  
Skin Pain Numeric Rating Scale
9.1.3.5.
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.


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Patient Global Impression of Severity
9.1.3.6.
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.”
Dermatology Life Quality Index
9.1.3.7.
The Dermatology Life Quality Index (DLQI) is a simple, patient-administered, 10-item, 
validated, quality-of-life questionnaire that covers 6 domains including symptoms and feelings, 
daily activities, leisure, work and school, personal relationships, and treatment.  The recall period 
of this scale is over the “last week.”  Response categories include “not at all,” “a lot,” and “very 
much,” with corresponding scores of 1, 2, and 3, respectively, and unanswered (“not relevant”) 
responses scored as 0.  Scores range from 0-30 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).
European Quality of Life–5 Dimensions–5 Levels
9.1.3.8.
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 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]).
Work Productivity and Activity Impairment Questionnaire–Atopic 
9.1.3.9.
Dermatitis
The Work Productivity and Activity Impairment Questionnaire–Atopic Dermatitis (WPAI-AD) 
records impairment due to AD during the past 7 days.  The WPAI-AD consists of 6 items 
grouped into 4 domains:  absenteeism (work time missed), presenteeism (impairment at 
work/reduced on-the-job effectiveness), work productivity loss (overall work 
impairment/absenteeism plus presenteeism), and activity impairment.  Scores are calculated as 
impairment percentages (Reilly et al. 1993), with higher scores indicating greater impairment 
and less productivity.


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9.1.4. Appropriateness of Assessments
All assessments utilized in this study are standard, widely used, and generally recognized as 
reliable, accurate, and relevant 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, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed, study site personnel will record via eCRF the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs. Investigators should record their assessment of the 
potential relatedness of each AE to investigational product, via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.  A “reasonable possibility” means that there is a 
cause-and-effect relationship between the investigational product, study device, and/or study 
procedure and the AE.  The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF, clarifying if possible the circumstances leading 
to any dosage modifications, or discontinuations of treatment.


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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.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.  Patients with a serious hepatic AE should have additional data collected using the 
hepatic safety eCRF.
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements, any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he or she considers the event reasonably possibly related to 
the study treatment or study participation, the investigator must promptly notify Lilly.
Suspected Unexpected Serious Adverse Reactions
9.2.1.1.
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 


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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

Hepatic events (see Section 9.4.9)

major adverse cardiovascular events (MACE) (see 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.
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.


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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 Exam
For each patient, a complete physical examination (excluding pelvic and rectal examinations) 
will be performed at Visit 1 (Screening).  A symptom-directed physical examination will be 
performed at other visits as specified in the Schedule of Activities (Section 2).  A complete
physical examination may be repeated at the investigator’s discretion at any time a patient 
presents with physical complaints.
9.4.4. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).  With the exception of laboratory test results that may unblind 
the study, Lilly or its designee will provide the investigator with the results of laboratory tests 
analyzed by a central vendor, if a central vendor is used for the clinical trial.
9.4.5. Columbia Suicide Severity Rating Scale
The C-SSRS captures the occurrence, severity, and frequency of suicidal ideation and/or 
behavior during the assessment period.  The scale includes suggested questions to solicit the type 
of information needed to determine if suicidal ideation and/or behavior occurred.  The C-SSRS is 
administered by an appropriately trained health care professional with at least 1 year of patient 
care/clinical experience.  The tool was developed by the National Institute of Mental Health trial 
group for the purpose of being a counterpart to the Columbia Classification Algorithm of Suicide 
Assessment categorization of suicidal events.  For this study, the scale has been adapted (with 
permission from the scale authors) to include only the portion of the scale that captures the 
occurrence of the 11 preferred ideation and behavior categories.
The nonleading AE collection should occur 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 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.


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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 (see Section 8.1.2) and should be 
referred to a hepatology specialist.
9.4.9. Hepatic Safety Monitoring and Data Collection
If a study patient experiences elevated ALT ≥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


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
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 
preserve the integrity of the data collected during this trial and minimize any potential for bias 
while providing for appropriate safety monitoring.
Investigators will monitor vital signs and carefully review findings that may be associated with 
cardiovascular and venous thrombotic events.  Adverse event reports and vital signs will be 
collected at each study visit.  The cardiovascular monitoring plan includes the following:

regular monitoring of lipid levels

potential MACE (cardiovascular death, MI, stroke), other cardiovascular events 
(such as hospitalization for unstable angina, hospitalization for heart failure, 
serious arrhythmia, resuscitated sudden death, cardiogenic shock, coronary 
revascularization such as coronary artery bypass graft or percutaneous coronary 
intervention), venous thrombotic events 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.


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9.5.
Pharmacokinetics
A venous blood sample will be drawn at the times indicated in the Schedule of Activities 
(Section 2) (Weeks 0 [first dose, 2 samples], 4, 8, 12, and 16).  These blood samples will be used 
to determine the plasma concentrations of baricitinib using a validated liquid chromatography 
tandem mass spectrometry method.  Blood samples that will be used for other laboratory 
assessments (chemistry, hematology, etc.) should be drawn at approximately the same time as 
the samples drawn to determine plasma concentrations of baricitinib.  The timing will be as 
follows:

At Visit 2 (Week 0), baseline laboratory samples should be taken before 
administration of investigational product.  Patients will take their investigational 
product in the clinic, and PK samples will be drawn 15 minutes and 1 hour 
postdose.

At Visit 5 (Week 4), patients will be asked to take their investigational product at 
home prior to visiting the clinic.  The clinic visit should be scheduled so that the 
blood sample collected during this visit is drawn 2 to 4 hours after the dose is 
taken at home.

For Visit 6 (Week 8) and Visit 7 (Week 12) patients will be asked to not take their 
investigational product before visiting the clinic, and a blood sample will be 
collected at any time predose on the day of the clinic visits.  If the patient has 
taken the oral dose prior to the visit, the sample may be drawn anytime postdose, 
and the inability to collect a predose sample will not be considered a protocol 
violation.

At Visit 8 (Week 16), patients will be asked to take their investigational product 
at home prior to visiting the clinic.  The clinic visit should be scheduled so that 
the blood sample collected during this visit is drawn 4 to 6 hours after the oral 
dose is taken at home.

For the ETV, a sample may be drawn anytime if the last dose of investigational 
drug was taken within the last 48 hours.
For visits where PK samples will be collected, the actual date and 24-hour clock time of sample 
collection, and the date and time of the last 2 doses prior to the sample being drawn, should be 
recorded.  At Visit 5 (Week 4) and Visit 8 (Week 16), these 2 doses should be the dose given the 
morning of the day of sample collection and the dose given the previous day.  At Visit 6 
(Week 8) and Visit 7 (Week 12), the 2 previous doses should be the dose taken yesterday and the 
dose taken the day before that.
This sampling schedule should be followed as closely as possible; however, failure to take PK 
samples at these specified times will not be considered a protocol violation.  If the patient fails to 
follow the directions for a particular visit, the sample should still be collected at that visit, and 
the date and 24-hour clock time of sample collection and the date and time of the 2 doses prior to 
the sample being drawn should be recorded.


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Only samples from patients receiving baricitinib will be assayed; samples from patients receiving 
placebo will not be assayed.  Pharmacokinetic samples will be kept in storage at a laboratory 
facility designated by the sponsor.  Pharmacokinetic samples may also be assayed for additional 
exploratory analyses.  Pharmacokinetic results will not be provided to investigative sites until the 
completion of the study or to the blinded study team until the study has been unblinded.
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following last patient visit for the study.
9.6.
Pharmacodynamics
Not applicable
9.7.
Pharmacogenomics 
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.
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 


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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 (see 
Section 9.1.3).  Medical Resource Utilization parameters will not be evaluated in this study.


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10. Statistical Considerations
10.1. Sample Size Determination
Study JAHM will aim to enroll approximately 600 patients ≥18 years of age.  The proposed 
sample size will ensure a >90% 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, 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. 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:

proportion of baricitinib 1-mg patients achieving IGA of 0 or 1 with a ≥2-point 
improvement at Week 16.
Evaluated for 1-mg, 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 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.


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10.3.2. Treatment Group Comparability
Patient Disposition
10.3.2.1.
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.
Patient Characteristics
10.3.2.2.
Demographic and baseline characteristics will be summarized descriptively by treatment group.  
Descriptive statistics including number of patients, mean, standard deviation, median, minimum, 
and maximum will be provided for continuous measures, and frequency counts and percentages 
will be tabulated for categorical measures.  No formal statistical comparisons will be made 
among treatment groups unless otherwise stated.
Concomitant Therapy
10.3.2.3.
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.
Treatment Compliance
10.3.2.4.
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, 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
Primary Analyses
10.3.3.1.
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.


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Secondary Analyses
10.3.3.2.
The following secondary categorical outcomes will be analyzed in a similar manner as the 
primary, that is, using the same logistic regression model.  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.
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
o
EQ-5D-5L.
The EASI total score and SCORAD total score will also be analyzed as observed, that is, not 
assuming missing values after rescue medication is given.
10.3.4. Safety Analyses
All safety data will be descriptively summarized by treatment groups and analyzed using the 
safety population.
Treatment-emergent adverse events (TEAEs) are defined as AEs that first occurred or worsened 
in severity after the first dose of study treatment.  The number of TEAEs as well as the number 
and percentage of patients who experienced at least 1 TEAE will be summarized using 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 


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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 
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
All plasma baricitinib concentration–time data will be pooled and evaluated using population PK 
methods.  A covariate screen of patient and study-specific factors will be included in the analyses 
based on factors investigated in previous and (if any) ongoing PK analyses, and on their 
relevance to the target population.  Exploratory and/or model-based analyses examining the 
relationships between baricitinib exposure and efficacy and response endpoints will be 
conducted.  Other analyses of efficacy and safety outcome measures may also be assessed as 
scientifically appropriate and warranted by available data.  Details about the analyses to be 
conducted will be contained in the PK/PD analysis plan.
10.3.6. Other Analyses
Health Outcome Measures
10.3.6.1.
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.
Subgroup Analyses
10.3.6.2.
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 


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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.  Because this study is not powered for 
subgroup analyses, all subgroup analyses will be treated as exploratory.
10.3.7. Interim Analyses
Data Monitoring Committee
10.3.7.1.
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.
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 interim or final database 
lock to initiate the final population PK/PD model development processes or for preparation of 
regulatory documents.  Information that may unblind the study during the analyses will not be 
reported to study sites or blinded study team until the study has been unblinded.
Unblinding details will be specified in a separate unblinding plan document.
Adjudication Committee
10.3.7.2.
A blinded Clinical Event Committee will adjudicate potential MACE (cardiovascular death, MI, 
stroke), other cardiovascular events (such as hospitalization for unstable angina, hospitalization 
for heart failure, serious arrhythmia, resuscitated sudden death, cardiogenic shock, coronary 
revascularization such as coronary artery bypass graft or percutaneous coronary intervention), 
venous thrombotic events, 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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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
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received.
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


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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
Food and Drug Administration
GCP
good clinical practice
HADS
Hospital Anxiety Depression Scale
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


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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
NRI
nonresponder imputation
NRS
Numeric Rating Scale
PD
pharmacodynamics(s)
PDE-4 inhibitor
phosphodiesterase type 4 inhibitor
PK
pharmacokinetic(s)
POEM
Patient-Oriented Eczema Measure
PPD
purified protein derivative
PRO/ePRO
patient-reported outcomes/electronic patient-reported outcomes
QD
once daily
QoL
quality of life
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
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.


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


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


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Appendix 3.
Study Governance Considerations


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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.


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The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Electronic patient-reported outcome (ePRO) measures (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, or its designee, 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 
Investigational 
Product
Permanent Discontinuation 
of investigational product 
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
≥3x ULN
≥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 >3x ULN AND 
TBL >2x ULN

ALP >2.5x ULN AND 
TBL >2x ULN
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; IP = investigational product; TBL = total bilirubin level; ULN = upper 
level of normal.
a
Fatigue, nausea, vomiting, right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).


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Appendix 6.
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 et al. Guidelines of care for the management of atopic dermatitis: section 1. 
Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70(2):338-3351.


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Appendix 7.
Classification of Potency for Topical 
Corticosteroids
Potency
Class
Topical Corticosteroid
Formulation
Ultra high
I
Clobetasol propionate
Cream 0.05%
Diflorasone diacetate
Ointment 0.05%
High
II
Amcinonide
Ointment 0.1%
Betamethasone dipropionate
Ointment 0.05%
Desoximetasone
Cream or ointment 0.025%
Fluocinonide
Cream, ointment or gel 0.05%
Halcinonide
Cream 0.1%
III
Betamethasone dipropionate
Cream 0.05%
Betamethasone valerate
Ointment 0.1%
Diflorasone diacetate
Cream 0.05%
Triamcinolone acetonide
Ointment 0.1%
Moderate
IV
Desoximetasone
Cream 0.05%
Fluocinolone acetonide
Ointment 0.025%
Fludroxycortide
Ointment 0.05%
Hydrocortisone valerate
Ointment 0.2%
Triamcinolone acetonide
Cream 0.1%
V
Betamethasone dipropionate
Lotion 0.02%
Betamethasone valerate
Cream 0.1%
Fluocinolone acetonide
Cream 0.025%
Fludroxycortide
Cream 0.05%
Hydrocortisone butyrate
Cream 0.1%
Hydrocortisone valerate
Cream 0.2%
Triamcinolone acetonide
Lotion 0.1%
Low
VI
Betamethasone valerate
Lotion 0.05%
Desonide
Cream 0.05%
Fluocinolone acetonide
Solution 0.01%
VII
Dexamethasone sodium phosphate
Cream 0.1%
Hydrocortisone 
Lotion, cream, or ointment 2.5%
Hydrocortisone acetate
Cream 1%
Methylprednisolone acetate
Cream 0.25%
Source:  WHO (1997) and Tadicherla et al 2009


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Appendix 8.
Protocol Amendment I4V-MC-JAHM(b) 
Summary - A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Phase 3 Study to Evaluate the 
Efficacy and Safety of Baricitinib in Patients with 
Moderate to Severe Atopic Dermatitis
Overview
Protocol I4V-MC-JAHM, A Multicenter, Randomized, Double Blind, Placebo Controlled, 
Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib in Patients with Moderate to 
Severe Atopic Dermatitis, has been amended.  The new protocol is indicated by amendment (b) 
and will be used to conduct the study in place of any preceding version of the protocol.  
The overall changes and rationale for the changes made to this protocol are described in the 
following tables for amendment (a) and amendment (b). Please note that I4V-MC-JAHM has a 
companion protocol, I4V-MC-JAHL, that was designed to be identical.  Thus some of the 
changes below were made to align with the companion protocol.  Other minor typographical 
corrections and minor formatting changes not affecting content have been made in the document, 
and these changes are not identified in the amendment summary table or with 
strikethrough/underscore.
Amendment Summary for Protocol I4V-MC-JAHM Amendment (a)
Section # and Name
Description of Change
Brief Rationale
Protocol cover page
Added “Adult” to describe patients in study 
title
Corrected title to match the title of 
companion protocol JAHL
Protocol  cover page
Added BREEZE-AD2 after title of study
Added to associate the alternative 
study title to the protocol study alias
Protocol cover page
Added EudraCT number
Updated accordingly to align with 
new protocol template instructions
1.  Synopsis
Added IL-4 in discussion section of study 
rationale 
IL-4 also plays a role in the 
pathogenesis of AD 
1.  Synopsis
Moved the 2-mg dose from Key Secondary 
to Primary Objective such that 4 mg and 
2mg will be tested as co-primary objectives
Aligned the Primary Objective to 
support global regulatory feedback 
that require 2 mg and 4 mg to be 
tested on equal footing
1.  Synopsis
Added baricitinib 1-mg QD to the  “Other 
Secondary Objective/Endpoint” evaluating 
the superiority of baricitinib compared to 
placebo, as measured by the proportion of 
patients achieving IGA of 0 or 1 with a ≥2-
point improvement at Week 4
Updated to align with all “Other 
Secondary Objectives”
2.Schedule of Activities 
Removed wording about weighing tube 
with cap when dispensing rescue TCS
Decision made post-approval that 
the sponsor will take a baseline 
weight of full TCS tubes that are 


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Section # and Name
Description of Change
Brief Rationale
centrally supplied by the sponsor, 
instead of requiring the sites to 
weigh each full tube upon 
dispensing
2.  Schedule of Activities
Footnote “n” in the Schedule of Activities:  
corrected Visit 12 to Visit 7 (Week 12)
Corrected error
4.  Objectives and Endpoints
Moved the 2-mg dose from Key Secondary 
to Primary Objective
Aligns with changes in Section 1
4.  Objectives and Endpoints
Added baricitinib 1-mg QD to the  “Other 
Secondary Objective/Endpoint” evaluating 
the superiority of baricitinib compared to 
placebo, as measured by the proportion of 
patients achieving IGA of 0 or 1 with a ≥2-
point improvement at Week 4
Aligns with changes in Section 1
5.1 Overall Design
Amended number of baricitinib 4 mg QD 
patients from 250 patients to 240 patients
Correction of typographical error
5.1.1.Period 1:  Screening
Last sentence reworded to:  “Patients who 
meet all of the inclusion and none of the 
exclusion criteria (Section 6) will continue 
on to Visit 2” 
Changed to reflect current protocol 
classification based on inclusion and 
exclusion criteria rather than entry 
and enrollment
5.1.2.  Period 2:  Double-
Blind Placebo-Controlled 
Treatment
First sentence reworded to:  “At Visit 2 
(Week 0, baseline), study eligibility for 
each patient will be reviewed, based on all 
inclusion and exclusion criteria”
Changed to reflect current protocol 
classification based on inclusion and 
exclusion criteria rather than entry 
and enrollment
5.1.3.  Period 3:  Post-
Treatment Follow-Up
Changed the word “must” to “should” in 
paragraph 4:  “patients should complete an 
unscheduled visit prior to the first dose of 
the new therapy”
Amended to reflect that patients may 
not be able to attend an unscheduled 
visit
6.1 Inclusion Criteria
#[6a] changed to read oral corticosteroids
Corrected alphabetized list:  
[6e] now [6d]
[6f] now [6e]
Clarified to distinguish between 
oral systemic corticosteroids versus 
parenteral corticosteroids 
administration which is covered in 
Exclusion Criterion #[17c]
Corrected to align with the 
corresponding section in companion 
protocol JAHL
6.1.  Inclusion Criteria
#[7c]:  deleted criterion “topical JAK 
inhibitor (e.g. tofacitinib or ruxolitinib) 
and/or any other investigative topical 
treatments”
This Inclusion Criterion was 
redundant since topic is already 
covered in Exclusion Criterion #[33] 
which has a broader time window
6.2.  Exclusion Criteria
#[17b]:  added wording “less than 4 weeks 
prior to randomization” for prior treatment 
with any oral JAK inhibitor 
Since several oral JAK inhibitors are 
under development and 
discontinuation was most likely due 
to study participation completion 
and not adverse effects it was 
determined to allow prior use with a 


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Section # and Name
Description of Change
Brief Rationale
4 week washout restriction
6.2.  Exclusion Criteria
#[17e]:  Added criterion:  "probenecid at 
the time of randomization (Visit 2) that 
cannot be discontinued for the duration of 
the study"
Co-administration of probenecid (an 
OAT3 inhibitor with strong 
inhibition potential) with baricitinib 
resulted in approximately a 2-fold 
increase in AUC(0-∞) with no 
change in tmax or Cmax of 
baricitinib.  Thus, exclusion added to 
prohibit coadministration
6.2 Exclusion Criteria
#[20]:  added “if participating in the trial at 
end of sentence
Added to clarify that the investigator 
is not evaluating the risk to the 
patient of the surgical procedure, 
rather the risk of participating in the 
trial
6.2 Exclusion Criteria
#[25a]:  changed wording for cervical 
carcinoma in situ from “has been resected” 
to “has been appropriately treated”
#[25b]:  changed wording for basal cell or 
squamous epithelial skin cancers from 
“have been completely resected” to “have 
been appropriately treated”
Updated wording to address 
alternative treatment options 
available other than resection (e.g. 
surgical curettage and cautery, 
cryotherapy)
6.2.  Exclusion Criteria
#[31]:  Removed “including use of data 
collection devices” 
Revised in order to allow for some 
needed flexibility with the use of 
daily data collection devices (e.g. 
actigraphy)
7.1.2.  Medical devices
Instructions for use on the wearing of 
actigraphy devices was revised and 
language was added to state that if not worn 
as instructed that  not considered a protocol 
violation 
Revised in order to allow for some 
needed flexibility with the use of 
wearing daily actigraphy devices.  
The patients are allowed to remove 
the device if needed (e.g. 
showering); thus revised protocol 
language that previously stated “One 
will be worn on the wrist at all 
times…” and added the statement 
that if not worn as instructed that it 
won’t be considered a protocol 
violation
7.2.  Method of Treatment 
Assignment
Removed North America from region 
stratification
The US is no longer participating,  
in this study and since they were the 
largest contributor to the NA region, 
this region was removed
7.6.  Treatment Compliance
Visit 7 changed to Visit 8
Correction of typographical error
7.7.1.  Prohibited 
Medications and Procedures
Added 3 new subheader titles and 
reorganized and reordered excising bullets 
beneath each as appropriate
Probenecid was added as a prohibited 
Done to clarify which prohibited 
medications would or would not 
require temporary interruption or 
permanent discontinuation of IP 
Co-administration of probenecid (an 


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Section # and Name
Description of Change
Brief Rationale
medication requiring temporary 
discontinuation of IP
OAT3 inhibitor with strong 
inhibition potential) with baricitinib 
resulted in approximately a 2-fold 
increase in AUC(0-∞) with no 
change in tmax or Cmax of 
baricitinib  
7.7.2.  Permitted Medications 
and Procedures
Removed “prescription” with regards to use 
of emollients
Reimbursement for some non-
additive emollients may require a 
prescription in some countries thus 
to avoid these country specific 
differences, the term prescription 
was removed
7.7.3.  Rescue Therapy
Section revised to incorporate language 
regarding additional options to supply 
equivalent potency TCS options (in 
addition to triamcinolone and 
hydrocortisone) 
Due to potential supply issues, 
revisions were made to allow for 
other potential supply options for 
low-to-mid potency TCS options 
7.7.3.  Rescue Therapy
Added bullet point stating that topical 
therapy is not to be applied before study 
procedures
Application of topical therapies 
could impact adequate assessment of 
skin dryness thus clarification added 
in regards to application of topical 
rescue therapy on day of study visits
8.1.1.  Temporary 
Interruption from 
Investigational Product
Deleted duplicated wording in first 
paragraph
Corrected error
8.1.1.  Temporary 
Interruption from 
Investigational Product
Table JAHM.4:  
Table Headings:  

Capitalized “Investigational Product”

Added “or Clinical Events”

Deleted “after Approval from Lilly 
(or Its Designee)”
All corrections to the table were 
made to align with the same table in  
companion protocol JAHL
- Formatting corrected
- Corrected title to reflect that 
clinical events are also listed in table
- Table JAHM.4 outlines 
prespecified resumption criteria for 
IP defined by the sponsor thus no 
additional requirement needed to 
obtain approval if this criteria has 
been met 
8.1.1.  Temporary 
Interruption from 
Investigational Product
Table JAHM.4:  last row wording modified 
to state “After evaluation and institution of 
appropriate treatment of VTEb.”  Removed 
“and resolution”
Criteria of “resolution of VTE” is 
not routinely assessed in clinical 
practice, thus language changed to a 
more objective measure
8.1.1.  Temporary 
Interruption from 
Investigational Product
Table JAHM.4:  related footnote b to VTE, 
revised the wording to align with changes 
listed above
Updated to match corresponding 
wording in table
8.1.1.  Temporary 
Added text to refer reader to prohibited 
Added for clarification


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Section # and Name
Description of Change
Brief Rationale
Interruption from 
Investigational Product
medications section (7.7.1) for details 
regarding temporary interruption of IP if a 
prohibited medication is taken
8.1.2.  Permanent 
Discontinuation from 
Investigational Product
Deleted “or the patient’s designee”
Removed since we are not allowing 
patients less than 18 year of age and 
we require patients to provide their 
own consent therefore not allowing 
consent from a patient’s designee
8.1.2.  Permanent 
Discontinuation from
Investigational Product
Deleted “event” after VTE
Corrected error – use of “event” is 
redundant after VTE
8.1.2.  Permanent 
Discontinuation from 
Investigational Product
Added the following wording to bullet 3; 
“or 2 sequential tests return a value of 
below the limit of quantitation” as part of 
the permanent DC of IP criteria for HBV 
DNA results
Wording was added to bullet 3 to 
align with companion protocol 
JAHL
8.1.2.  Permanent 
Discontinuation from 
Investigational Product
Added a final bullet to refer reader to 
prohibited medications section (7.7.1) for 
details regarding permanent discontinuation 
of IP if a prohibited medication is taken
Added for clarification
8.1.3.  Discontinuation of 
Inadvertently Enrolled 
Patients
Added “Patients” to section heading
Amended to align with companion 
protocol JAHL
8.2.  Discontinuation from the 
Study
Deleted wording regarding a “patient's 
designee”
Removed since we are not allowing 
patients less than 18 year of age and 
we require patients to provide their 
own consent therefore not allowing 
consent from a patient’s designee
9.1.2.1.  Eczema Area and 
Severity Index Scores
Added references
Updated based on feedback from a 
regulatory agency
9.1.2.2.  SCORing Atopic 
Dermatitis
Added references
Updated based on feedback from a 
regulatory agency
9.4.8.  Hepatitis B virus DNA 
Monitoring
Amended the frequency of HBV DNA 
monitoring  
Corrected to align with existing 
SOA in JAHM and to align with 
companion protocol JAHL 
9.5.  Pharmacokinetics
Added wording that baseline laboratory 
samples are to be taken before 
administration of IP
Added for clarification
10.1.  Sample Size 
Determination
Updated to reflect the change to co-primary 
objectives with no further implications on 
sample size
Aligns with changes to the primary 
objective 
10.2.  Populations for 
Analyses
Removed definition for safety follow-up 
population and added text to refer to SAP
The majority of patients are 
expected to enroll into extension 
study so safety follow-up population 
may not be useful for analysis 
Further populations will be defined 
in the SAP 
10.3.1.  General Statistical 
Removed text that the Fisher exact test is 
Both logistic regression and the 


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Section # and Name
Description of Change
Brief Rationale
Considerations
only produced when logistic regression 
sample size requirements are not met
Fisher exact test will be performed, 
regardless of logistic regression 
sample size requirements
10.3.1.  General Statistical 
Considerations
Moved the 2-mg dose from Key Secondary 
Endpoint to Primary Endpoint
Aligns with changes to the primary 
objective
10.3.4.  Safety Analyses
Removed C-SSRS score from change from 
baseline analyses 
Correction of an error.  C-SSRS will 
only be presented at the patient level 
as a listing.  Further details will be in 
the SAP  
11.  References
References added to text updated in 
Reference list
Updated to align with Sections 
9.1.2.1 and 9.1.2.2
Appendix 1.  Abbreviations 
and Definitions
Deleted US (United States) from list of 
abbreviations
Abbreviation not used in document
Appendix 1.  Abbreviations 
and Definitions
Added “(deep vein thrombosis or 
pulmonary embolism)” to definition of 
“VTE”
Added for clarification
Appendix 3.  Study 
Governance Considerations
Appendix 3.1.1 Informed Consent
Removed “or legal representative” from 
second bullet point
Removed text “A legal representative must 
give informed consent for a child to 
participate in this study”
Removed since we are not allowing 
patients less than 18 year of age and 
we require patients to provide their 
own consent therefore not allowing 
consent from a legal representative
Amendment Summary for Protocol I4V-MC-JAHM Amendment (b)
Section # and Name
Description of Change
Brief Rationale
Protocol cover page
Removed “Adult” from study title
The word “Adult” was added to the 
title in amendment (a) to match 
companion protocol JAHL and to 
make it immediately clear to the 
reader that the study would include 
only adult patients. Due to 
implications of this change on other 
study documents the decision was 
made to revert to the original 
approved title.  Thus, the word 
“adult” has now been removed with 
amendmet (b).  However, there has 
not been a change in the population 
being studied; JAHM is and 
continues to be an adult only study 
population.


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Revised Protocol Sections:  Amendment (a)
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Protocol Cover Page:
Protocol I4V-MC-JAHM(a)
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy 
and Safety of Baricitinib in Adult Patients with Moderate to 
Severe Atopic Dermatitis
BREEZE-AD2
EudraCT Number: 2017-000871-10
1.
Synopsis
Rationale:
…
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)
…
Objectives
Endpoints
Primary
To test the hypothesis that baricitinib 4-mg QD or 
baricitinib 2-mg QD is superior to placebo in the 
treatment of patients with moderate to severe AD.

Proportion of patients achieving IGA of 0 or 1 with 
a ≥2-point improvement at Week 16.
Key Secondary
These are prespecified objectives that will be adjusted for multiplicity
To test the hypothesis that baricitinib 2 mg QD or
baricitinib 1-mg QD is superior to placebo in the 
treatment of patients with moderate to severe AD.

Proportion of patients achieving IGA of 0 or 1 with 
a ≥2-point improvement at Week 16.
…
Other Secondary Objectives
These are prespecified objectives that will not be adjusted for multiplicity.
To test the hypothesis that baricitinib 1-mg QD, 2-mg 
QD, or baricitinib 4-mg QD is superior to placebo in 
the treatment of patients with moderate to severe AD

Proportion of patients achieving IGA of 0 or 1 with 
a ≥2-point improvement at Week 4.




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4. 
Objectives and Endpoints
Table JAHM.2
Objectives and Endpoints
Objectives
Endpoints
Primary
To test the hypothesis that baricitinib 4-mg QD or 
baricitinib 2-mg QD is superior to placebo in the 
treatment of patients with moderate to severe AD.

Proportion of patients achieving IGA of 0 or 1 
with a ≥2-point improvement at Week 16.
Key Secondary 
These are prespecified objectives that will be adjusted for multiplicity
To test the hypothesis that baricitinib 2 mg QD or
baricitinib 1-mg QD is superior to placebo in the 
treatment of patients with moderate to severe AD.

Proportion of patients achieving IGA of 0 or 1 
with a ≥2-point improvement at Week 16.
Other Secondary Objectives
These are prespecified objectives that will not adjusted for multiplicity.
To test the hypothesis that baricitinib 1-mg QD,
2-mg QD, or baricitinib 4-mg QD is superior to 
placebo in the treatment of patients with moderate to 
severe AD.

Proportion of patients achieving IGA of 0 or 1 with 
a ≥2-point improvement at Week 4
5.1. 
Overall Design
Approximately 600 patients ≥18 years of age who have responded inadequately to or who are 
intolerant to topical therapy will be randomized at a 2:1:1:1 ratio to receive placebo QD, 
baricitinib 1-mg QD, baricitinib 2-mg QD, or baricitinib 4-mg QD (250 240 patients in the 
placebo group; 120 patients in each baricitinib treatment group).  
5.1.1. 
Period 1:  Screening
… 
Patients who continue to meet all of the inclusion entry criteria and none of the exclusion 
enrollment 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 
entry inclusion and enrollment exclusion criteria (Section 6), and laboratory test results.  
5.1.3. 
Period 3:  Post-Treatment Follow-Up
… However, if patients or investigators must initiate treatment, patients must should complete an 
unscheduled visit prior to the first dose of the new therapy.


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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.
sedating antihistamines, including, but not limited to, alimemazine, 
chlorphenamine, clemastine, cyproheptadine, diphenhydramine, hydroxyzine, 
ketotifen, and promethazine
d Note:  Patients may use newer, less sedating antihistamines (e.g., fexofenadine, 
loratadine, cetirizine)
ed. any other systemic therapy used to treat AD or symptoms of AD (approved or 
off label use)
fe.
phototherapy, includes therapeutic phototherapy (psoralen plus 
ultraviolet A, ultraviolet B), excimer laser as well as self–treatment with 
tanning beds.  
…
[7] agree to discontinue use of the following excluded medications for at least 
2 weeks prior to randomization (Visit 2) and throughout the study:
c
Topical JAK inhibitor (e.g., tofacitinib or ruxolitinib) and/or any other 
investigative topical treatments.
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
…
[17] have been treated with the following therapies: …
b
received prior treatment with any oral JAK inhibitor (e.g., tofacitinib, 
ruxolitinib) less than 4 weeks prior to randomization
e.
probenecid at the time of randomization (Visit 2) that cannot be 
discontinued for the duration of the study


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Medical Conditions in General
…
[20] 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.
[25] have a history of lymphoproliferative disease; or have signs or symptoms 
suggestive of possible lymphoproliferative disease, including 
lymphadenopathy or splenomegaly; or have active primary or recurrent 
malignant disease; or have been in remission from clinically significant 
malignancy for less than 5 years.
a.
Patients with cervical carcinoma in situ that has been appropriately treated
resected 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 completely resected with no evidence of recurrence 
for at least 3 years may participate in the study.
Other Exclusions
[31] are unable or unwilling to make themselves available for the duration of the 
study and/or are unwilling to follow study restrictions/procedures, including 
use of data collection devices.
7.1.2.
Medical Devices
An actigraphy device, a hypoallergenic device worn on the wrist, will be used to collect 
sleep/wake patterns and quantify nocturnal scratching events.  Each patient will be dispensed 
2 actigraphy devices.  One shouldwill be worn on the wrist during wakinge hoursat all times and 
the other shouldwill be worn only during hours of sleep.  Patients will be provided instructions 
on use and when to bring the devices back to study site based on Schedule of Activities 
(Section 2).  If devices are not worn as instructed, it will not be considered a protocol violation.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized in a 2:1:1:1 ratio (placebo, 
baricitinib 1 mg; baricitinib 2 mg; baricitinib 4 mg) to double blind treatment at Visit 2 (Week 0).  
Randomization will be stratified by geographic region (North America [NA], Europe [EU], 
Japan [JPN], rest of world [ROW]) and disease severity at baseline (IGA 3 vs. 4).  
7.6. 
Treatment Compliance
Patient compliance with study medication will be assessed at each visit during the treatment 
period (Visit 3 through Visit 87) by counting returned tablets.


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7.7.1. 
Prohibited Medications and Procedures
Prohibited Medications and Procedures Not Requiring Interruption of Investigational 
Product
The following therapies will not be allowed during the course of the study and, if taken by or 
administered to the patient, the prohibited therapy must be discontinued.  

TCS, TCNIs (e.g., tacrolimus and pimecrolimus), or topical PDE 4 inhibitor (i.e., 
crisaborole) except when given as rescue therapy as described in Section 7.7.3.

topical antihistamines or sedating, systemic antihistamines including, but not limited to, 
alimemazine, chlorphenamine, clemastine, cyproheptadine, diphenhydramine, 
hydroxyzine, ketotifen, and promethazine

leukotriene inhibitors (e.g., montelukast [Singulair], zafirlukast [Accolate], and zileuton 
[Zyflo]) 

allergen immunotherapy

phototherapy including PUVA (psoralen and ultraviolet A), 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 [27])
o
For BCG vaccination, investigational product should be temporarily interrupted 
for 12 weeks.
o
For herpes zoster vaccination, investigational product should be temporarily 
interrupted for 4 weeks. 

probenecid:  if a patient is inadvertently started on probenecid, IP should be temporarily 
interrupted, and can be resumed after patient has discontinued probenecid.  If a patient is 
not able to discontinue probenecid, then IP 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

other JAK inhibitors (e.g., tofacitinib and ruxolitinib)


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
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.
7.7.2. 
Permitted Medications and Procedures
Treatment with concomitant AD therapies during the study is permitted only as described below.

Daily use of emollients is required as background treatment.  Prescription 
moisturizers or Mmoisturizers with additives such as antipruritics or antiseptics 
are not permitted.  If daily applications are missed, it will not be considered a 
protocol violation.
7.7.3. 
Rescue Therapy
Choice of rescue therapy treatment

Triamcinolone 0.1% cream and/or hydrocortisone 2.5% ointment.  Where possible bBoth 
of these treatments will be centrally supplied by the sponsor.  In the event countries 
where providing 1 or both of these topical formulations is not possible, an alternate, 
equivalent potency TCS cream and/or ointment that is in line with local practices can be 
considered; however, it will not may be provided centrally by the sponsor.  TCS use, 
supplied by the sponsor, should be recorded via weight of returned tubes as indicated in 
the Schedule of Activities (Section 2).  
o
In the event that the sponsor is unable to supply TCS, commercially available 
triamcinolone 0.1% cream and/or hydrocortisone 2.5% ointment may be supplied 
by the sites.  Where providing triamcinolone 0.1% cream and/or hydrocortisone 
2.5% ointment is not possible, an equivalent-potency TCS cream and/or ointment 
that is in line with local practices can be supplied. Refer to Appendix 7 for 
guidance on potency equivalence. 
o
If the TSC 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 7 for guidance on 
potency equivalence.

Investigators may also select to use TCNIs and/or crisaborole where approved, 
although use of either during the study is neither encouraged nor provided.  If 
TCNIs are prescribed, use should be limited to problem areas only (e.g., face, 
neck, skin folds, genital areas, etc.).

On the days of study visits, topical therapy should not be applied before the patient has   
undergone all study procedures and clinical evaluations in order to allow adequate 
assessment of skin dryness


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8.1.1. 
Temporary Interruption from Study Treatment
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 adverse event considered to be related to 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 JAHM.4.  For the abnormal 
laboratory findings and clinical events (regardless of relatedness) listed in  Table JAHM.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 
JAHM.4 may be restarted at the discretion of the investigator.
Table JAHM.4.  
For the abnormal laboratory findings and clinical events (regardless of relatedness) listed in 
Table JAHM.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 JAHM.4 may be restarted at the discretion of the investigator.
Table JAHM.4.
Criteria for Temporary Interruption of Investigational Product
Hold Iinvestigational Pproduct if the Following 
Laboratory Test Results or Clinical Events Occur:
Investigational Pproduct May Be Resumed after 
Approval from Lilly (or Its Designee) When:  
WBC count <2000 cells/L
(<2.00x103/L or <2.00 GI/L)
WBC count 2500 cells/L
(≥2.50x103/L or ≥2.50 GI/L)
ANC <1000 cells/L
(<1.00x103/L or <1.00 GI/L)
ANC ≥1200 cells/L
(≥1.20x103/L or ≥1.20 GI/L)
…
Clinical features of VTE (such as deep vein thrombosis 
or pulmonary embolism) are presenta
After evaluation and institution of appropriate 
treatment and resolution of VTEb
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.  If upon evaluation VTE is ruled out and no other 
temporary or permanent discontinuation criteria are met, then IP may be resumed.  
b
If uponafter evaluation and institution of treatment resolution 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


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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 IP after use of a prohibited medication, please 
refer to Section 7.7.1 (Prohibited Medications and Procedures)
8.1.2. 
Permanent Discontinuation from Study Treatment 
Investigational product should be permanently discontinued if the patient or the patient’s 
designee requests to discontinue investigational product.
…
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 (see 
Section 9.4.8).

develop a second VTE event

certain prohibited medications are taken per Section 7.7.4, Prohibited Medications 
and Procedures
8.1.3. 
Discontinuation of Inadvertently Enrolled Patients
8.2. 
Discontinuation from the Study
…
Some possible reasons that may lead to permanent discontinuation include the following:

…

patient decision
o
The patient or the patient’s designee, for example, parents or legal 
guardian, requests to be withdrawn from the study.
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).  


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9.1.2.2. 
SCORing Atopic Dermatitis
The SCORing Atopic Dermatitis (SCORAD) index uses the rule of nines to assess disease extent 
and evaluates 6 clinical characteristics to determine disease severity:  (1) erythema, 
(2) edema/papulation, (3) oozing/crusts, (4) excoriation, (5) lichenification, and (6) dryness.  The 
SCORAD index also assesses subjective symptoms of pruritus and sleep loss.  These 3 aspects:  
extent of disease, disease severity, and subjective symptoms combine to give a maximum 
possible score of 103 (Stalder et al. 1993; Kunz et al. 1997; Schram et al. 2012).
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 monitoring every 3 months and at Week 16 (Visit 8) or early 
termination the patient’s last visit, regardless of their hepatitis B surface antibody (HBsAb) 
status.
9.5. Pharmacokinetics
A venous blood sample will be drawn at the times indicated in the Schedule of Activities 
(Section 2) (Weeks 0 [first dose, 2 samples], 4, 8, 12, and 16).  These blood samples will be used 
to determine the plasma concentrations of baricitinib using a validated liquid chromatography 
tandem mass spectrometry method.  Blood samples that will be used for other laboratory 
assessments (chemistry, hematology, etc.) should be drawn at approximately the same time as 
the samples drawn to determine plasma concentrations of baricitinib.  The timing will be as 
follows:

At Visit 2 (Week 0), baseline laboratory samples should be taken before 
administration of investigational product.  Ppatients will take their investigational 
product in the clinic, and PK samples will be drawn 15 minutes and 1 hour 
postdose.
10.1. 
Sample Size Determination
Study JAHM will aim to enroll approximately 600 patients ≥18 years of age.  The proposed 
sample size will ensure a >90% 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 
group, each using a 2-sided alpha of 0.025, assuming a 10% placebo response rate for the 
primary endpoint using a 2 sided alpha of 0.05.  
10.2. 
Populations for Analyses
…
Safety analyses for the post treatment Follow up Period will be conducted on the follow up 
population, defined as all randomized patients who received at least 1 dose of investigational 
product and have entered the post treatment Follow Up Period.  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.


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10.3.1. 
General Statistical Considerations
…
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 
(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). 
When logistic regression sample size requirements are not met (<5 responders in any category 
for any factor), Tthe p-value from the Fisher exact test will also beis produced instead of the 
odds ratio and CI.
Adjustment for Multiple Comparisons:
…
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:

proportion of baricitinib 2-mg or 1-mg patients achieving IGA of 0 or 1 with a 
≥2-point improvement at Week 16.
10.3.4.
Safety Analyses
…
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, C SSRS score, and body weight will be 
analyzed using ANCOVA with treatment and baseline value in the model.
11.
References
…
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and 
severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. 
Exp Dermatol. 2001;10(1):11-18.


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…
Kunz B, Oranje A, Labrèze, Stadler JF, Ring J, Taїeb A, Clinical Validation and Guidelines for 
the SCORAD Index: Consensus Report of the European Task Force on Atopic Dermatitis. 
Dermatology. 1997;195:10-19.
…
Schram ME, Spuls PI, Leeflang MM, Lindeboom R, Bos J, Schmitt J. EASI, (objective) 
SCORAD and POEM for atopic eczema:responsiveness and minimal clinically important 
difference. Allergy. 2012;67:99-106.
…
Stalder JF, Taïeb A, Atherton DJ, et al. for the European Task Force on Atopic Dermatitis. 
Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report of the European 
Task Force on Atopic Dermatitis. Dermatology. 1993;186(1):23-31.
Appendix 1.  Abbreviations and Definitions
Term
Definition
…
US
United States
…
VTE
venous thromboembolic event (deep vein thrombosis or pulmonary embolism)
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 or legal representative.  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.
A legal representative must give informed consent for a child to participate in this study.  In 
addition to informed consent given by the legal representative, the child may be required to give 
documented assent, if capable.


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Revised Protocol Sections:  Amendment (b)
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Protocol Cover Page:
Protocol I4V-MC-JAHM(a)(b)
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy 
and Safety of Baricitinib in Adult Patients with Moderate to 
Severe Atopic Dermatitis


Leo Document ID = 685cf5fd-ebf1-4bc4-8eea-b817da71da39
Approver: 
Approval Date & Time: 22-Jan-2018 18:17:55 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 22-Jan-2018 19:32:27 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
 
I4V-MC-JAHM Statistical Analysis Plan Version 2 
 
 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the 
Efficacy and Safety of Baricitinib in Adult Patients with Moderate to Severe Atopic Dermatitis. 
 
NCT03334422 
 
Approval Date: 22-Jan-2019 
 
 


I4V-MC-JAHM Statistical Analysis Plan Version 2
Page 1
LY3009104
1.
Statistical Analysis Plan:
I4V-MC-JAHM:  A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Phase 3 Study to Evaluate the 
Efficacy and Safety of Baricitinib in Adult Patients with 
Moderate to Severe Atopic Dermatitis
BREEZE-AD2
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-JAHM (NCT03334422) is a Phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group, outpatient, 25-week study designed to evaluate the 
efficacy and safety of baricitin b 1-mg, 2-mg, and 4-mg in adult patients with moderate to 
severe atopic dermatitis.  
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I4V-MC-JAHM
Phase 3
Statistical Analysis Plan Version 1 electronically signed and approved by Lilly:  26-
March-2018
Statistical Analysis Plan Version 2 electronically signed and approved by Lilly on date 
provided below.
Approval Date: 22-Jan-2019 GMT


I4V-MC-JAHM Statistical Analysis Plan Version 2
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:  I4V-MC-JAHM:  A Multicenter, 
Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to 
Evaluate the Efficacy and Safety of Baricitinib in Adult Patients with 
Moderate to Severe Atopic Dermatitis.................................................................................1
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 ...................................................................................9
4.3.
Exploratory Objectives.................................................................................................10
5.
Study Design.....................................................................................................................11
5.1.
Summary of Study Design............................................................................................11
5.2.
Method of Assignment to Treatment ............................................................................12
6.
A Priori Statistical Methods ..............................................................................................14
6.1.
Determination of Sample Size ......................................................................................14
6.2.
General Considerations ................................................................................................14
6.2.1.
Analysis Populations............................................................................................14
6.2.2.
Definition of Baseline and Postbaseline Measures................................................15
6.2.3.
Analysis Methods.................................................................................................17
6.2.4.
Derived Data........................................................................................................19
6.3.
Covariate Adjustment...................................................................................................20
6.4.
Handling of Dropouts or Missing Data.........................................................................20
6.4.1.
Nonresponder Imputation.....................................................................................22
6.4.2.
Mixed Model for Repeated Measures...................................................................22
6.4.3.
Modified Last Observation Carried Forward ........................................................22
6.4.4.
Placebo Multiple Imputation ................................................................................23
6.4.5.
Tipping Point Analyses ........................................................................................24
6.5.
Multicenter Studies ......................................................................................................26
6.6.
Multiple Comparisons/Multiplicity...............................................................................26
6.7.
Patient Disposition .......................................................................................................31
6.8.
Patient Characteristics ..................................................................................................31
6.8.1.
Demographics......................................................................................................32
6.8.2.
Baseline Disease Characteristics ..........................................................................32


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6.8.3.
Historical Illness and Pre-existing Conditions ......................................................33
6.9.
Treatment Compliance .................................................................................................33
6.9.1.
Rescue Treatment.................................................................................................34
6.10. Previous and Concomitant Therapy..............................................................................35
6.11. Efficacy Analyses ........................................................................................................35
6.11.1.
Primary Outcome and Methodology.....................................................................43
6.11.2.
Secondary and Exploratory Efficacy Analyses .....................................................43
6.11.3.
Sensitivity Analyses.............................................................................................44
6.12. Health Outcomes/Quality-of-Life Analyses..................................................................44
6.13. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................56
6.14. Safety Analyses............................................................................................................56
6.14.1.
Extent of Exposure...............................................................................................56
6.14.2.
Adverse Events ....................................................................................................57
6.14.2.1.
Common Adverse Events ...............................................................................58
6.14.2.2.
Serious Adverse Event Analyses.....................................................................59
6.14.2.3.
Other Significant Adverse Events...................................................................59
6.14.2.4.
Criteria for Notable Patients ...........................................................................59
6.14.3.
Clinical Laboratory Evaluation.............................................................................59
6.14.4.
Vital Signs and Other Physical Findings...............................................................61
6.14.5.
Special Safety Topics, including Adverse Events of Special 
Interest.................................................................................................................62
6.14.5.1.
Abnormal Hepatic Tests .................................................................................62
6.14.5.2.
Hematologic Changes.....................................................................................63
6.14.5.3.
Lipids Effects .................................................................................................64
6.14.5.4.
Renal Function Effects ...................................................................................65
6.14.5.5.
Elevations in Creatine Phosphokinase (CPK)..................................................65
6.14.5.6.
Infections........................................................................................................66
6.14.5.7.
Major Adverse Cardiovascular Events (MACE) and 
Other Cardiovascular Events...........................................................................68
6.14.5.8.
Venous and Pulmonary Artery Thromboembolic (VTE)
Events ............................................................................................................69
6.14.5.9.
Arterial Thromboembolic (ATE) Events.........................................................70
6.14.5.10. Malignancies ..................................................................................................70
6.14.5.11. Allergic Reactions/Hypersensitivities .............................................................71
6.14.5.12. Gastrointestinal Perforations...........................................................................72
6.14.5.13. Columbia Suicide Severity Rating Scale.........................................................72
6.14.5.14. Self-Harm Supplement Form and Self-Harm Follow-up 
Form...............................................................................................................72
6.15. Subgroup Analyses.......................................................................................................72


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6.16. Protocol Deviations......................................................................................................73
6.17. Interim Analyses and Data Monitoring.........................................................................74
6.17.1.
Interim Analysis Plan...........................................................................................74
6.18. Planned Exploratory Analyses......................................................................................75
6.19. Annual Report Analyses...............................................................................................75
6.20. Clinical Trial Registry Analyses...................................................................................75
7.
Unblinding Plan................................................................................................................77
8.
References ........................................................................................................................78


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Table of Contents
Table
Page
Table JAHM.5.1.Geographic Regions for Stratification............................................................13
Table JAHM.6.1. Imputation Techniques for Various Variables ................................................21
Table JAHM.6.2. Seed Values for Multiple Imputation .............................................................24
Table JAHM.6.3.Seed Values for Imputation............................................................................26
Table JAHM.6.4.Description and Derivation of Primary, Secondary and Exploratory 
Efficacy Outcomes ........................................................................................37
Table JAHM.6.5.Description of Primary, Secondary and Exploratory Efficacy Analyses .........41
Table JAHM.6.6. Description and Derivation of Health Outcomes and Quality-of-Life 
Measures .......................................................................................................45
Table JAHM.6.7. Description of Health Outcomes and Quality-of-Life Measures 
Analyses........................................................................................................52
Table JAHM.6.8.Categorical Criteria for Abnormal Treatment-Emergent Blood Pressure 
and Pulse Measurement, and Categorical Criteria for Weight Changes 
for Adults ......................................................................................................61


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Table of Contents
Figure
Page
Figure JAHM.5.1.
Illustration of study design for Clinical Protocol I4V-MC-JAHM. ............12
Figure JAHM.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-JAHM(a) and was 
approved prior to the production transfer for the first DMC meeting.  SAP Version 2 was 
approved prior to the final database lock and includes the following changes:  

added additional exploratory objective for TCS use

added follow-up population definition

removed details included in the standards

updated daily diaries to use an interval mean weekly score

updated baseline and post-baseline algorithm for actigraphy to use time

updated frequency of itch and skin pain to use 28-day visit intervals

added estimand language

added additional details for MMRM and ANCOVA

added time to event analysis

added baseline value to logistic regression model

added seed values for tipping point

updated diagnosis age group categories

updated definition for deriving age and diagnosis age

added BMI category, weight category and PGI-S-AD to baseline summaries

added 2 cyclosporine subset definitions and revised existing subset definition; added to 
baseline summaries

updated seed values for pMI

added overall summary of rescue therapies

clarified sensitivity analyses for PPS, pMI and tipping point in Tables JAHM.6.4 and 
JAHM.6.6

removed comparisons in Table JAHM.6.6 when not needed

updated mapping of ET visits to closest, not next visit 

added definition for safety baseline for clarity 

added sensitivity analysis for safety to censor on last dose of study drug for rescue to 
systemics

update exposure ranges from weeks to days

removed temporary interruption of study drug to AE or lab from overview of AE table

removed mention of incidence-rates, including exposure adjusted incidence rates

updated to refer to compound level safety standards instead of PSAP

added PT for malignancy

provided clarity that CSSRS summary will be created when positive responses happen 
during treatment

updated subgroup analyses

added a Cox proportional hazard (CPH) model of minimum time (in days) to 4-point itch 
reduction with effects for treatment, region (where applicable), baseline mean itch, and 
disease severity to section 6.2.3   

updated the graphical approach


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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) 
or baricitinib 2-mg QD is superior to placebo 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 discontinued from the study 
or treatment.  See Sections 6.4.1 and 6.11.1 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 test the hypothesis that baricitinib 1-mg QD is 
superior to placebo in the treatment of patients with 
moderate to severe AD.

Proportion of patients achieving IGA of 0 or 1 with 
a ≥2-point improvement at Week 16
To compare the efficacy of baricitinib 1-mg QD,
2-mg QD, or 4-mg QD to placebo in AD during the 
16-week double-blind placebo-controlled treatment 
period as measured by improvement in signs and 
symptoms of AD.

Proportion of patients achieving 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 1-mg QD,
2-mg QD, or 4-mg QD to placebo in AD during the 
16-week double-blind placebo-controlled treatment 
period as assessed by patient-reported outcome 
measures.

Proportions of patients achieving a 4-point 
improvement from baseline in Itch NRS at 1 week, 
2 weeks, 4 weeks, and 16 weeks

Mean change from baseline in the score of Item 2 
of the ADSS at 1 week and 16 weeks

Mean change from baseline in Skin Pain NRS at 
16 weeks 


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4.2.2. Other Secondary Objectives
These are prespecified objectives that will not be adjusted for multiplicity.
Objectives
Endpoints
To test the hypothesis that baricitinib 1-mg QD, 
2-mg QD, or 4-mg QD is superior to placebo in the 
treatment of patients with moderate to severe AD.

Proportion of patients achieving IGA of 0 or 1 with 
a ≥2-point improvement at Week 4
To compare the efficacy of baricitinib 1-mg QD,
2-mg QD, or 4-mg QD to placebo in AD during the 
16-week double-blind placebo-controlled period as 
measured by physician-assessed 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
To compare the efficacy of baricitinib 1-mg QD, 
2-mg QD, or 4-mg QD to placebo 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 
1 week and 16 weeks

Mean change from baseline in Itch NRS at 4 weeks 
and 16 weeks

Mean change from baseline in the total score of the 
POEM at 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


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4.3.
Exploratory Objectives
The exploratory objectives of this study are the following:
Objectives/Endpoints

Mean change from baseline in nocturnal itch assessed by actigraphy device at 1 week and 4 weeks

Frequency of patient-reported “no itch” (Itch NRS score = 0) days from daily diaries from Week 12 to 
Week 16

Frequency of patient-reported “no pain” (Skin Pain NRS score = 0) days from daily diaries from 
Week 12 to Week 16

Mean change from baseline in the score of Item 1 of the ADSS at 1 week and 16 weeks

Mean change from baseline in the score of Item 3 of the ADSS at 1 week and 16 weeks

To evaluate changes from baseline in immunoglobulin E levels during the study

To evaluate changes from baseline in eosinophil levels during the study

To characterize baricitinib pharmacokinetics in the AD population and explore relationships between 
baricitinib exposure and study endpoints

To assess time to 4-pt itch reduction during the first 14 days after initiation of treatment

To assess time to improvement in Skin Pain during the first 14 days after the initiation of treatment

To assess the use of rescue therapy through the weight of sponsor provided topical corticosteroid and 
number of days not using rescue therapy


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5.
Study Design
5.1.
Summary of Study Design
Study I4V-MC-JAHM (JAHM) is a Phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group, outpatient study evaluating the efficacy and safety of 
baricitinib 1-mg once daily (QD), 2-mg QD, and 4-mg QD as compared to placebo in adult 
patients with moderate to severe AD.  The study is divided into 3 periods, a 5-week Screening 
period, a 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 600 patients ≥18 years of age who have responded inadequately to or who are 
intolerant to topical therapy will be randomized at a 2:1:1:1 ratio to receive placebo QD, 
baricitinib 1-mg QD, baricitinib 2-mg QD, or baricitinib 4-mg QD (240 patients in the placebo 
group; 120 patients in each baricitinib treatment group).  Patients will be stratified at 
randomization according to disease severity (IGA 3 vs. 4) and geographic region.
Study JAHM 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 JAHM.5.1 illustrates the study design.  The blinding procedure is described in the 
Protocol.


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Figure JAHM.5.1.
Illustration of study design for Clinical Protocol I4V-MC-JAHM.
Abbreviations:  AD = atopic dermatitis; eGFR = estimated glomerular filtration rate; PPD = purified protein 
derivative; QD = once daily; 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 2:1:1:1 ratio (placebo, 
baricitinib 1-mg; 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 interactive web-
response system (IWRS).  The IWRS will be used to assign blister packs, each containing 
double-blind investigational product tablets to each patient, starting at Visit 2 (Week 0), and at 
each visit up to and including Visit 7 (Week 12).  Site personnel will confirm that they have 
located the correct blister packs by entering a confirmation number found on the blister packs 
into the IWRS.


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This study will be conducted internationally in multiple sites. Table JAHM.5.1 describes how 
regions will be defined for stratification.  Regions may be combined for statistical analyses in the 
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 JAHM.5.1.
Geographic Regions for Stratification
Region
Countries
Europe
Austria, Hungary, Poland, Spain, Switzerland 
Japan
Japan
Rest of World
Argentina, Australia, Israel, Korea


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6.
A Priori Statistical Methods
6.1.
Determination of Sample Size
Study JAHM will aim to enroll approximately 600 patients ≥18 years of age.  The proposed 
sample size will ensure a >90% power to detect any difference 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 0.05, assuming 10% placebo, 25% baricitinib 2-mg, and 30% baricitinib 4-mg
response rates for the primary endpoint.  The assumptions are based on what was observed in the 
Phase 2 Study (I4V-MC-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.
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 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 early termination visits 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 
significant or important protocol violations will be determined while the study remains blinded, 
prior to database lock.


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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 will 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) and for the actigraphy analyses period 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.
The baseline value for actigraphy assessments is the mean of the non-missing assessments in the 
7 days prior to the date and time of first study drug administration.  The baseline mean for 
actigraphy variables require there be at least 4 non-missing measurements occurring in at least 4 
separate 24-hour increments in the 7 days prior to the date and time of first study drug 
administration.  If this condition is not satisfied, an expanded window of up to 14 days (336 
hours) prior to first study drug administration may be utilized in order to obtain the most recent 4 
non-missing measurements, occurring in 4 separate 24-hour increments.  If there are not at least 
4 non-missing assessments collected in the baseline period, the baseline mean will be designated 
as missing.  Other definitions of baseline value, such as the last measurement on or prior to 
rescue, may be used to conduct additional supporting analyses.  


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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 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 
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) and day of Week 16 scheduled visit.  Weeks 1-14 are 
defined as follows:
       Week
Days
1
1-7
2
8-14
3
15-21
4
22-28
5
29-35
6
36-42
7
43-49
8
50-56
9
57-63
10
64-70
11
71-77
12
78-84
13
85-91
14
92-98
The Week 16 diary window is the 7 days prior to the scheduled Week 16 visit.  If there is no 
Week 16 scheduled visit, the 7 days prior to the last visit (whether scheduled or unscheduled) 


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occurring after Day 105 constitutes the Week 16 diary window if one exists.  If there is no visit 
on which to anchor the Week 16 diary window, the Week 16 interval and its associated mean are 
defined as missing.  If there are less than 4 non-missing assessments in the Week 16 diary 
window, the interval can be extended up to 7 additional days, one at a time, to obtain the most 
recent 4 non-missing values.  The assessment of whether 4 non-missing values exist in the Week 
16 diary window, and subsequent extension of that window, does not consider censored data in 
window construction (i.e., they are counted as non-missing unless they are truly unobserved).  If 
the Week 16 diary window has less than 4 non-missing values after extending the Week 16 diary 
window up to a maximum of 14 days, the Week 16 diary window is defined as 7 days and the 
mean of the window is missing.
The lower bound of 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 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 
that particular window is missing and subject to imputation rules.
The postbaseline value of the actigraphy analyses will be analyzed similarly through Week 4 
(Visit 5) or early discontinuation but will include time.  Thus, Week 1 will be the mean of the 7 
days of actigraphy events which has a start date and time occurring within 168 hours of the date 
and time of first study drug administration.  The Week 2, Week 3 and Week 4 scores will be 
similarly defined.  If there are less than 4 non-missing assessments occurring in at least 4 
separate 24-hour increments, the weekly interval will be missing.  Furthermore, 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 and actigraphy analyses.  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.  
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.  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)% confidence interval (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.  


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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) 
will be used.  The 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 BARI 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.  The day on which the first 4-point reduction in itch NRS is achieved will be 
modeled.  If any significant treatment difference is observed then the same analysis will be 
performed 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, 


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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.  
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 1st
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)


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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)
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.  


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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 

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 JAHM.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 JAHM.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


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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 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.  
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 imputation 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 JAHM.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 intercurent 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


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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, 
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, 


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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 JAHM.6.2.
Table JAHM.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
223450
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.
223451
Proportion of patients achieving SCORAD75 at 16 week using the primary censoring rule, 
with data up to rescue
223452
Proportions of patients achieving a 4-point improvement from baseline in Itch NRS at 
Week 16 using the primary censoring rule
223453
Mean change from baseline in Skin Pain NRS at Week 16 using the primary censoring rule
223454
Mean change from baseline in the score of Item 2 of the ADSS at Week 16 using the 
primary censoring rule
223455
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:

IGA (0,1) with ≥2-point improvement at Week 16, baricitinib 1-mg, 2-mg and 4-mg 
compared to placebo

EASI percent change from baseline to Week 16, baricitinib 1-mg, 2-mg and 4-mg compared 
to placebo

Itch NRS 4-point improvement from baseline to Week 16, baricitinib 1-mg, 2-mg and 4-mg 
compared to placebo
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.


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Within each analysis, a most extreme case will be considered, in which all missing data for 
patients randomized to baricitinib 1-mg, 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.  
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 


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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 JAHM.6.3. 
Table JAHM.6.3.
Seed Values for Imputation
Analysis
Seed value
Proportion of patients achieving IGA (0,1) with ≥2-point improvement at Week 16, with 
data up to rescue. 
123470
EASI percent change from baseline to Week 16, with data up to rescue
123471
Proportions of patients achieving a 4-point improvement from baseline in Itch NRS at 
Week 16, with data up to rescue
123472
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.  The subscript for H
denotes dose (4-mg, 2-mg, 1-mg), the numerical identifier of the endpoint within the dose, and 
the type of hypothesis (0 for null, 1 for alternative), respectively. 


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Primary Null Hypotheses: 

H4,1,0:  Proportion of baricitinib 4-mg patients achieving IGA of 0 or 1 with a ≥2-point 
improvement from baseline at Week 16 is less than or equal to the proportion of placebo 
patients achieving IGA of 0 or 1 with a ≥2-point improvement from baseline at Week 16 

H2,1,0:  Proportion of baricitinib 2-mg patients achieving IGA of 0 or 1 with a ≥2-point 
improvement from baseline at Week 16 is less than or equal to the proportion of placebo 
patients achieving IGA of 0 or 1 with a ≥2-point improvement from baseline at Week 16 
Key Secondary Null Hypotheses:

H4,2,0:  Proportion of baricitinib 4-mg patients achieving EASI75 is less than or equal to 
the proportion of placebo patients achieving EASI75 at Week 16 [EASI75]

H4,3,0:  Proportion of baricitinib 4-mg patients achieving a 4-point improvement in Itch 
NRS is less than or equal to the proportion of placebo patients achieving a 4-point 
improvement in Itch NRS at Week 16 [ITCH W16]

H4.4,0:  Percent change from baseline in EASI score for baricitinib 4-mg patients is greater
than or equal to the percent change from baseline in EASI score for placebo patients at 
Week 16 [EASI PCFB]

H4,5,0:  Proportion of baricitinib 4-mg patients achieving a 4-point improvement in Itch 
NRS is less than or equal to the proportion of placebo patients achieving a 4-point 
improvement in Itch NRS at Week 4 [ITCH W4]

H4,6,0:  Proportion of baricitinib 4-mg patients achieving SCORAD75 is less than or equal 
to the proportion of placebo patients achieving SCORAD75 at Week 16 [SCORAD75]

H4,7,0:  Proportion of baricitinib 4-mg patients achieving EASI90 is less than or equal to 
the proportion of placebo patients achieving EASI90 at Week 16 [EASI 90]

H4,8,0:  Mean change from baseline in Skin Pain NRS for baricitinib 4-mg patients is 
greater than or equal to the mean change from baseline in Skin Pain NRS for placebo 
patients at Week 16 [PAIN W16]

H4,9,0:  Mean change from baseline in the score of Item 2 of the ADSS for baricitinib 
4-mg patients is greater than or equal to the mean change from baseline in the score of 
Item 2 of the ADSS for placebo patients at Week 16 [ADSS2 W16]

H4,10,0:  Proportion of baricitinib 4-mg patients achieving a 4-point improvement in Itch 
NRS is less than or equal to the proportion of placebo patients achieving a 4-point 
improvement in Itch NRS at Week 2 [ITCH W2]

H4,11,0:  Mean change from baseline in the score of Item 2 of the ADSS for baricitinib 
4-mg patients is greater than or equal to the mean change from baseline in the score of 
Item 2 of the ADSS for placebo patients at Week 1 [ADSS2 W1]

H4,12,0:  Proportion of baricitinib 4-mg patients achieving a 4-point improvement in Itch 
NRS is less than or equal to the proportion of placebo patients achieving a 4-point 
improvement in Itch NRS at Week 1[ITCH W1]

H2,2,0:  Proportion of baricitinib 2-mg patients achieving EASI75 is less than or equal to 
the proportion of placebo patients achieving EASI75 at Week 16 [EASI75]

H2,3,0:  Proportion of baricitinib 2-mg patients achieving a 4-point improvement in Itch 
NRS is less than or equal to the proportion of placebo patients achieving a 4-point 
improvement in Itch NRS at Week 16 [ITCH W16]


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
H2.4,0:  Percent change from baseline in EASI score for baricitinib 2-mg patients is greater
than or equal to the percent change from baseline in EASI score for placebo patients at 
Week 16 [EASI PCFB]

H2,5,0:  Proportion of baricitinib 2-mg patients achieving a 4-point improvement in Itch 
NRS is less than or equal to the proportion of placebo patients achieving a 4-point 
improvement in Itch NRS at Week 4 [ITCH W4]

H2,6,0:  Proportion of baricitinib 2-mg patients achieving SCORAD75 is less than or equal 
to the proportion of placebo patients achieving SCORAD75 at Week 16 [SCORAD75]

H2,7,0:  Proportion of baricitinib 2-mg patients achieving EASI90 is less than or equal to 
the proportion of placebo patients achieving EASI90 at Week 16 [EASI90]

H2,8,0:  Mean change from baseline in Skin Pain NRS for baricitinib 2-mg patients is 
greater than or equal to the mean change from baseline in Skin Pain NRS for placebo 
patients at Week 16 [PAIN W16]

H2,9,0:  Mean change from baseline in the score of Item 2 of the ADSS for baricitinib 
2-mg patients is greater than or equal to the mean change from baseline in the score of 
Item 2 of the ADSS for placebo patients at Week 16 [ADSS2 W16]

H2,10,0:  Proportion of baricitinib 2-mg patients achieving a 4-point improvement in Itch 
NRS is less than or equal to the proportion of placebo patients achieving a 4-point 
improvement in Itch NRS at Week 2 [ITCH W2]

H2,11,0:  Mean change from baseline in the score of Item 2 of the ADSS for baricitinib 
2-mg patients is greater than or equal to the mean change from baseline in the score of 
Item 2 of the ADSS for placebo patients at Week 1 [ADSS2 W1]

H2,12,0:  Proportion of baricitinib 2-mg patients achieving a 4-point improvement in Itch 
NRS is less than or equal to the proportion of placebo patients achieving a 4-point 
improvement in Itch NRS at Week 1 [ITCH W1]

H1,1,0:  Proportion of baricitinib 1-mg patients achieving IGA of 0 or 1 with a ≥2-point 
improvement from baseline at Week 16 is less than or equal to the proportion of placebo 
patients achieving IGA of 0 or 1 with a ≥2-point improvement from baseline at Week 16
[IGA0-1]

H1,2,0:  Proportion of baricitinib 1-mg patients achieving EASI75 is less than or equal to 
the proportion of placebo patients achieving EASI75 at Week 16 [EASI75]

H1,3,0:  Proportion of baricitinib 1-mg patients achieving a 4-point improvement in Itch 
NRS is less than or equal to the proportion of placebo patients achieving a 4-point 
improvement in Itch NRS at Week 16 [ITCH W16]

H1.4,0:  Percent change from baseline in EASI score for baricitinib 1-mg patients is greater
than or equal to the percent change from baseline in EASI score for placebo patients at 
Week 16 [EASI PCFB]

H1,5,0:  Proportion of baricitinib 1-mg patients achieving a 4-point improvement in Itch 
NRS is less than or equal to the proportion of placebo patients achieving a 4-point 
improvement in Itch NRS at Week 4 [ITCH W4]

H1,6,0:  Proportion of baricitinib 1-mg patients achieving SCORAD75 is less than or equal 
to the proportion of placebo patients achieving SCORAD75 at Week 16 [SCORAD75]

H1,7,0: Proportion of baricitinib 1-mg patients achieving EASI90 is less than or equal to 
the proportion of placebo patients achieving EASI90 at Week 16 [EASI90]


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
H1,8,0:  Mean change from baseline in Skin Pain NRS for baricitinib 1-mg patients is 
greater than or equal to the mean change from baseline in Skin Pain NRS for placebo 
patients at Week 16 [PAIN W16]

H1,9,0:  Mean change from baseline in the score of Item 2 of the ADSS for baricitinib 
1-mg patients is greater than or equal to the mean change from baseline in the score of 
Item 2 of the ADSS for placebo patients at Week 16 [ADSS2 W16]

H1,10,0:  Proportion of baricitinib 1-mg patients achieving a 4-point improvement in Itch 
NRS is less than or equal to the proportion of placebo patients achieving a 4-point 
improvement in Itch NRS at Week 2 [ITCH W2]

H1,11,0:  Mean change from baseline in the score of Item 2 of the ADSS for baricitinib 
1-mg patients is greater than or equal to the mean change from baseline in the score of 
Item 2 of the ADSS for placebo patients at Week 1 [ADSS2 W1]

H1,12,0:  Proportion of baricitinib 1-mg patients achieving a 4-point improvement in Itch 
NRS is less than or equal to the proportion of placebo patients achieving a 4-point 
improvement in Itch NRS at Week 1 [ITCH W1]
The multiple testing procedure is specified by Figure JAHM.6.1.


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Figure JAHM.6.1.
Illustration of graphical multiple testing procedure with initial α 
allocation and weights.
The primary null hypotheses includes testing whether each of the baricitinib 4-mg and the 
baricitinib 2-mg dose is less than or equal to placebo at the primary endpoint defined as the 
proportion of placebo patients achieving IGA of 0 or 1 and ≥2 point improvement from baseline 
at Week 16. The initial alpha allocation is split so that H4,1,0 has 0.04 and H2,1,0 and 0.01. 
Together with these primary hypotheses, multiplicity adjusted analyses will be performed on key 
secondary null hypotheses to control the overall family wise Type I error rate at a 2-sided alpha
level of 0.05.  The graphical multiple testing procedure described in Bretz et al. (2011), which is 
a closed testing procedure will be used; hence it strongly controls the family-wise error rate 
across all endpoints (Alosh et al. 2014).  


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If H4,1,0 and H2,1,0 are not rejected, no further testing is conducted as the α for that test is 
considered “spent” and cannot be passed to other endpoints.  If H4,1,0 or H2,1,0 is rejected, the 
testing process continues in either branches (starting with H4,1,0 and H2,2,0 respectively), with α 
propagated according to the weights on the corresponding edges displayed in Figure JAHM.6.1, 
as long as each hypothesis in the sequence can be rejected at its allocated α level.  Each time a 
hypothesis is rejected, the graph is updated to reflect the reallocation of α, which is considered 
“recycled” by Alosh et al. (2014).  This iterative process of updating the graph and reallocating α 
is repeated until all hypotheses have been tested or when no remaining hypotheses can be 
rejected at their corresponding α levels.
For Japan, the same testing strategy described in the Figure JAHM.6.1 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 with a 
specific α level based on the graphical multiple testing procedure in order to demonstrate a 
superiority of a given baricitinib dose (baricitinib 4-mg and/or baricitinib 2-mg) compared with 
placebo.  That is, H4,1,0 and H4,2,0 have to be rejected in order to demonstrate the superiority of 
baricitinib 4-mg compared with placebo and H2,1,0 and H2,2,0 have to be rejected in order to 
demonstrate the superiority of 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 
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.


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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 JAHM.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)

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)


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
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 
(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 3 tablets daily from a blister pack as described in the protocol.  
Each blister pack contains 27 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. 


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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. 
6.9.1. Rescue Treatment
Descriptive statistics for drug accountability of topical low and moderate potency rescue 
medication provided by the sponsor will also be supplied, including the amount utilized 
throughout the treatment period.  The total amount in grams for low and moderate potency will 
be summarized between scheduled visits as well as throughout the entire 16 week treatment 
period.  
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. 
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, Hungary, Israel, Poland, Spain, and 
Switzerland), the dispensed weight of low potency TCS is 21g.  The remaining countries, 
supplied by US distributors (Argentina, Australia, and Republic of Korea), 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.


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Tubes not returned by the end of the study will be marked as one of three options based on 
patient information:  unused, partially used, or fully used.  Unused tubes will be considered as 
weighing the original dispensed amount.  Fully used tubes will be considered as weighing the 
equivalent of an empty tube.  Partially used tubes will be considered to be 50% used.  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 number of days rescue therapy is used for each patient is also collected on the diary device.  
The proportion of time that the patients did not use rescue therapy will be summarized for the 
aforementioned visit intervals by potency (low or moderate) and both potencies combined.  For 
this analysis, the date of the first entry on the diary device will be used to signify the first day of 
rescue therapy use.
Additionally, 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 rescued at each study visit.  
A summary of all rescue medications will be provided.
6.10. 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 will be as follows:

Concomitant medications excluding rescue medicine
6.11. 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 JAHM.6.4 includes the descriptions and derivations of the primary, secondary, and 
exploratory efficacy outcomes.


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














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6.11.1. 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.
6.11.2. 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 JAHM.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 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 method described in Table JAHM.6.1.


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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 
endpoints are detailed in Table JAHM.6.4 and analyses are provided in Table JAHM.6.5.  Health 
outcomes analyses are described in Section 6.12.
6.11.3. 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). 
6.12. 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 6.11.
Table JAHM.6.6 includes the descriptions and derivations of the health outcomes and quality-of-
life measures. 
Table JAHM.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.
Additional psychometric analyses will be performed by Global Patient Outcomes Real World 
Evidence at Lilly and documented in a separate analysis plan.






















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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.


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6.13. 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.
6.14. Safety Analyses
The general methods used to summarize safety data, including the definition of baseline value 
are described in Section 6.2.
Safety analyses will include data before and 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 take place using the safety population 
defined in Section 6.2.1.
Safety topics that will be addressed include the following:  AEs, 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 6.14.5), 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.  Listings will include all safety data.
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).
6.14.1. 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.  For patients 
discontinuing study drug or study due to the reason ‘Lost to Follow-up’, the duration of exposure 
is calculated as date of to second last visit - date of first dose of study drug +1.  


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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 PYE = sum of duration of exposure in days  / 365.25
6.14.2. Adverse Events
Adverse events are recorded in the eCRFs.  Each AE will be coded to system organ class (SOC) 
and 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 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 moderate or 
severe postbaseline and not treatment-emergent if the severity is mild postbaseline).  If an event 
occurring postbaseline has a missing severity, then the event is considered treatment-emergent
unless the baseline 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 experiencing 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.
For events of special interest, a more robust incidence rate, IR per 100 patient-years of 
observation (PYO) may be provided.  Patient-years of observation will be calculated as the sum 


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of all patient observation time in the treatment group.  For a patient with an event, the 
observation time will be censored at the event date; for a patient without the event, the 
observation time will be counted until the end of the analysis period. 
PYO will be calculated as follows: 
ܻܱܲൌ
෍
݁ݒ݁݊ݐ ݏݐܽݎݐ ݀ܽݐ݁െ݂݅ݎݏݐ ݐݎݐ ݀݋ݏ݁ ݀ܽݐ݁൅1 
365.25 
௣௧ ௪ ௘௩௘௡௧
൅
෍
݈ܽݏݐ ݋ܾݏ݁ݎݒܽݐ݅݋݊ ݀ܽݐ݁െ݂݅ݎݏݐ ݐݎݐ ݀݋ݏ݁ ݀ܽݐ݁൅1 
365.25 
௣௧ ௪/௢ ௘௩௘௡௧
 
 
IR will be calculated as follows:  
ܫܴൌ݊ݑܾ݉݁ݎ ݋݂ ݌ܽݐ݅݁݊ݐݏ ݓ݅ݐ݄ ݁ݒ݁݊ݐ 
ܻܱܲ
x100 
For each IR provided, a Poisson Distribution 95% CI will be calculated.  Treatment group 
comparisons will be provided based on the incidence rate difference (IRD) together with its 95% 
CI.   
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; 
 by MedDRA PT with events ordered by decreasing frequency in the baricitinib 4-mg 
group. 
6.14.2.1. 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.   
 


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6.14.2.2. 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, regardless of when they 
occurred during the study, will also be provided.
6.14.2.3. 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;
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.
6.14.2.4. 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.
6.14.3. Clinical Laboratory Evaluation
For the categorical laboratory analyses (shift and treatment emergent), the analysis period is 
defined as the treatment period plus 30 days off-drug follow-up time.  The analysis period for the 
continuous laboratory analyses (e.g., change from baseline) is defined as the treatment period 
excluding off-drug follow-up time.


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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.  Key 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 6.14.5.1).
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 at 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 will be used to aid in 
viewing the measures of central tendency and dispersion.  Unplanned measurements will 
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.
For laboratory analyte measurements collected qualitatively, a listing of abnormal findings will 
be provided.  The listing will include but not be limited to patient ID, treatment group, laboratory 
collection date, analyte name, and analyte finding.  If needed by the safety physician/scientist, 
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.


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The listing of specific reference ranges used in analysis of laboratory data will be provided.
Note that additional analyses of certain laboratory analytes will be discussed within sub-sections 
of Section 6.14.5 pertaining to Special Safety topics (Section 6.14.5.1 for hepatic analytes, 
Section 6.14.5.2 for analytes related to hematological changes, Section 6.14.5.3 for analytes 
related to lipids, Section 6.14.5.4 for analytes related to renal function, and Section 6.14.5.5 for 
CPK).
6.14.4. 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 30 days off-drug follow-up time.  The analysis 
period for the continuous analyses (e.g., change from baseline) 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 
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 6.14.3 will be used to 
analyze the vital signs and physical characteristics.
Table JAHM.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 29 April 29 2015 as 
recommended by the Lilly Cardiovascular Safety Advisory Committee (CVSAC).
Table JAHM.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


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6.14.5. 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.
6.14.5.1. 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 6.14.3, 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 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.  


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
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.
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 will be created for all patients whether treated with baricitinib 
and/or other treatment using the whole study period(s).  Each patient with at least 1 postbaseline 
ALT and total bilirubin will be included in the eDISH; therefore, a patient could contribute 1 or 
more points to the plot.  The points correspond to maximum total bilirubin and maximum ALT, 
even if not obtained from the same blood draw.  Scheduled and unscheduled measures will be 
used.  Another eDISH plot will be provided where maximum AST is used in place of maximum 
ALT.  A listing of patients potentially meeting Hy’s rule will be provided (defined as ≥3× ULN 
for ALT or AST, and ≥2× ULN for total bilirubin, not necessarily at the same time).
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).
6.14.5.2. 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):


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
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,

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.
6.14.5.3. Lipids Effects
Lipids effects will be assessed through analysis of elevated total cholesterol, elevated LDL 
cholesterol, decreased HDL cholesterol, and elevated triglycerides as described in Section 6.14.3
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 


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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’ 

increase to categories ‘High’ or ‘Very high’ 

increase to ‘Very high.’
Treatment-emergent abnormal HDL cholesterol will be characterized as

decreased
o
decrease to categories ‘Normal’ or ‘Low’
o
decrease to category ‘Low’

increased
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].  
6.14.5.4. Renal Function Effects
Effects on renal function will be assessed through analysis of elevated creatinine.
Common Terminology Criteria for Adverse Events 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 treatment 
period will be tabulated.  Refer to the Compound level safety standards for details.
6.14.5.5. Elevations in Creatine Phosphokinase (CPK)
Elevations in creatine phosphokinase (CPK) will be addressed using CTCAE criteria 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.  Analyses will be the same as the 


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CTCAE analyses specified for laboratory tests related to renal function events in Section 
6.14.5.2.
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.  
6.14.5.6. 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. 
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 is identified through these search approaches and may be 
combined in one list for medical assessment and final classification of whether the case met the 
modified Winthrop definitions for OI.
A final listing for OIs will be provided for the CSR and to assist the composition of patient 
narratives.


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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 that are not complicated

disseminated-systemic infection, widespread, often bilateral with or without internal 
organ involvement (i.e., visceral involvement) and other systemic signs/symptoms.

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 6.14.2).  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 ATC codes).  
For specific data lock, medical representatives will review the concomitant medication list 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 preferred term 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 GPS/medical prior 
to data locks (final and interim).  The summary table will also include event maximum severity, 
seriousness, whether resulting in temporary study drug interruption, whether resulting in study 


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drug discontinuation, and whether treated with antiviral medication.  The exposure-adjusted 
incidence rate (EAIR) will also be provided.
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 will be provided.  Skin infections will be defined based on 
MedDRA preferred term as listed in 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., LLOD], 
quantifiable [i.e., LLOD]) will be summarized by treatment group stratified by baseline HBV 
serology status, specifically:
HBsAb+ / HBcAb+
HBsAb- / HBcAb+
Association between infection and neutropenia/lymphopenia
To evaluate the association between infection and neutropenia, for the controlled analysis sets, 
the frequency of infections will be provided by patient subgroups defined by the worst CTCAE 
grades of neutropenia during the analysis period, respectively.  Infection outcomes considered 
for this analysis are any treatment-emergent infection, serious infection and herpes zoster.  For 
this analysis, no statistical comparison will be provided. 
In addition, and 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 
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. 
6.14.5.7. 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 


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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 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 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.
6.14.5.8. Venous and Pulmonary Artery Thromboembolic (VTE) Events
Events identified as representative of 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 
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
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 thrombi in calf (i.e., below the knee), 
portal vein, subclavian vein, or mesenteric vein.  Superficial thrombophlebitis alone is 
not considered a VTE event.

Other peripheral venous thromboses of the lower limbs:  DVT (above knee) and non-
superficial below knee thromboses will also be summarized.
In general, events requiring adjudication are documented by investigative sites using an endpoint 
reporting CRF.  Refer to Section 6.14.5.7 for more details as the process is the same as that of 
MACE. 
The number and percentage of patients with a VTE according to the 4 classifications defined 
above, as positively adjudicated, will be summarized by treatment group.  
A listing of the VTE 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.
6.14.5.9. Arterial Thromboembolic (ATE) Events
Refer to the Compound level safety standards.
6.14.5.10.
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 by GPS/medical team 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 following MedDRA version 21.1 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)


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
Skin cancer (10040808)

Carcinoma in situ of skin (10007390)

Keratoacanthoma (10023347).

Cutaneous lymphoma (10079945)

Vulvar squamous cell hyperplasia (10079905).
This internal review is to be done 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 by Global Product Safety (GPS)/medical team 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.  
6.14.5.11.
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.  An algorithmic 
case comprises one or more events associated with an individual administration of study drug, 
where the events include:

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)
o
Category C - (Angioedema/Urticaria/Pruritus/Flush)
o
Category D - (Cardiovascular/Hypotension).
In the present studies, where study drug is administered daily, events will be considered as 
associated with an individual administration of study drug when the events are reported on the 
same study day.
Events that satisfy the queries will be listed, by temporal order within patient ID, and will 
include SOC, PT, SMQ event categorization including detail on the scope (narrow, algorithmic
or broad), reported AE term, AE onset and end dates, severity, seriousness, outcome, etc.
In addition, a summary table will be provided. Refer to the Compound safety level standards for 
details.


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6.14.5.12.
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 by the medical safety team.  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.
6.14.5.13.
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 may be provided.
6.14.5.14.
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.  
6.15. 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 
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)


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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 JAHM.5.1)
o
Specific regions (Europe, 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.
6.16. 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.


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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.
6.17. Interim Analyses and Data Monitoring 
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 
Dermatitis DMC charter and further details are given in the Interim Analysis Plan in 
Section 6.17.1.
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.
6.17.1. Interim Analysis Plan
Analyses for the DMC will include listings and/or summaries of the following information:

patient disposition, demographics, and baseline characteristics

concomitant medications 

exposure


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
AEs, to include the following:
o
TEAEs
o
SAEs, including deaths
o
selected special safety topics

clinical laboratory results

vital signs

Columbia-Suicide Severity Rating Scale
Summaries will include TEAEs, SAEs, special topics AEs, and treatment-emergent high and low 
laboratory and vital signs in terms of counts and percentages where applicable.  For continuous 
analyses, box plots of laboratory analytes will be provided by time point and summaries will 
include descriptive statistics.
The DMC may request efficacy data if they feel there is value and to confirm a reasonable 
benefit/risk profile for ongoing patients in the studies.  If efficacy data is requested, it will be 
mean change from baseline of EASI score.  Further details are given in the DMC charter.
6.18. Planned Exploratory Analyses 
The planned exploratory analyses are described in Sections 6.11 and 6.12.  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. 
6.19. Annual Report Analyses
Annual report analyses, such as the Development Update Safety Report (DSUR), will be 
documented in a separate document. 
6.20. 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).


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
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 
Refer to a separate blinding and unblinding plan document for details. 


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8.
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Leo Document ID = 2695a5ce-ce3e-4dde-8dee-dffb1e6df6e0
Approver: 
Approval Date & Time: 22-Jan-2019 17:35:21 GMT
Signature meaning: Approved
PPD