A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Evaluate the Safety and Efficacy of Baricitinib in Patients With Moderate-to-Severe Atopic Dermatitis
Phase: PHASE2
Conditions: Atopic Dermatitis
Sponsor: Eli Lilly and Company

I4V-MC-JAHG Protocol Amendment (a)   
 
 
Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Evaluate the Safety 
and Efficacy of Baricitinib in Patients with Moderate-to-Severe Atopic Dermatitis. 
 
 
NCT ID: NCT02576938 
Approval Date: 23-October-2015 
 

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Protocol I4V-MC-JAHG(a) 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 
Study to Evaluate the Safety and Efficacy of Baricitinib in 
Patients with Moderate-to-Severe Atopic  Dermatitis 
 
 
 
 
 
 
 
Baricitinib 
 
 
 
 
Chorus, Eli Lilly and Company 
Indianapolis, Indiana USA 46285 
 
 
 
Protocol Approval Date: 30-September-2015 
Amendment (a) Approval Date:  23-October-2015 
 
 
 
 
 
 
 
LY3009104 
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, 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. 
Parallel, double-blinded, randomized placebo-controlled multiple dose study in patients with 
moderate-to-severe atopic dermatitis 

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Table of Contents 
Section 
Page 
1. 
Protocol Synopsis ........................................................................................... 8 
2. 
Introduction .................................................................................................. 10 
2.1. 
Background ............................................................................................. 10 
2.2. 
Study Rationale ....................................................................................... 11 
3. 
Objectives and Endpoints ............................................................................. 12 
4. 
Study Design ................................................................................................ 14 
4.1. 
Overview of Study Design ...................................................................... 14 
4.2. 
Scientific Rationale for Study Design ..................................................... 14 
4.3. 
Justification for Dose .............................................................................. 15 
4.4. 
Benefit/Risk Assessment ......................................................................... 15 
5. 
Study Population .......................................................................................... 17 
5.1. 
Inclusion Criteria ..................................................................................... 17 
5.2. 
Exclusion Criteria ................................................................................... 17 
5.3. 
Screen Failures ........................................................................................ 21 
6. 
Treatment ..................................................................................................... 22 
6.1. 
Treatments Administered ........................................................................ 22 
6.2. 
Method of Treatment Assignment ........................................................... 22 
6.2.1. 
Selection and Timing of Doses ....................................................... 22 
6.3. 
Blinding .................................................................................................. 23 
6.4. 
Packaging and Labeling .......................................................................... 23 
6.5. 
Investigational Products Storage and Handling ...................................... 24 
6.6. 
Dose Modification ................................................................................... 24 
6.7. 
Treatment Compliance ............................................................................ 24 
6.8. 
Concomitant Therapy .............................................................................. 24 
6.9. 
Treatment after Study Completion .......................................................... 25 
6.9.1. 
Continued Access ........................................................................... 25 
7. 
Discontinuation Criteria ............................................................................... 26 
7.1. 
Discontinuation of Investigational Product ............................................. 26 
7.1.1. 
Temporary Interruption of Investigational Product ........................ 26 
7.1.2. 
Permanent Discontinuation of Investigational Product ............................................. 26 
7.1.3. 
Discontinuation of Inadvertently Enrolled Patients ........................ 27 
7.1.4. 
Permanent Discontinuation from the Study .................................... 27 
7.1.5. 
Patients Lost to Follow-Up ............................................................. 28 
8. 
Study Assessments and Procedures .............................................................. 29 
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8.1. 
Efficacy Assessments .............................................................................. 29 
8.1.1. 
Primary Efficacy Assessments ........................................................ 29 
8.1.2. 
Secondary Efficacy Assessments .................................................... 29 
8.1.3. 
Appropriateness of Primary Efficacy Measure ............................... 30 
8.2. 
Adverse Events ....................................................................................... 31 
8.2.1. 
Adverse Events/Laboratory Results of Special Interest ............................................ 32 
8.2.2. 
Serious Adverse Events .................................................................. 32 
8.2.2.1. 
Suspected Unexpected Serious Adverse Reactions ............................................. 33 
8.2.3. 
Complaint Handling ....................................................................... 33 
8.3. 
Treatment of Overdose ............................................................................ 33 
8.4. 
Safety Assessments ................................................................................. 33 
8.4.1. 
Physical Examination ..................................................................... 34 
8.4.2. 
Electrocardiograms ......................................................................... 34 
8.4.3. 
Vital Signs ...................................................................................... 34 
8.4.4. 
Laboratory Tests ............................................................................. 34 
8.4.5. 
Hepatitis B virus (HBV) DNA monitoring ..................................... 34 
8.4.6. 
Quick Inventory of Depressive Symptomatology-Self  Report 
16 (QIDS-SR16) ....................................................................................................... 35 
8.4.7. 
Safety Monitoring ........................................................................... 35 
8.5. 
Pharmacokinetics .................................................................................... 35 
8.5.1. 
PK Sample Collection..................................................................... 35 
8.5.2. 
PK Sample Assay ........................................................................... 36 
8.5.3. 
PK Sample Storage and Retention .................................................. 37 
8.6. 
Pharmacodynamics ................................................................................. 37 
8.7. 
Genetics .................................................................................................. 37 
8.8. 
Biomarkers .............................................................................................. 37 
8.8.1. 
Skin Biopsies .................................................................................. 38 
8.8.2. 
Nonpharmacogenetic Biomarkers ................................................... 38 
8.9. 
Health Economics ................................................................................... 38 
9. 
Statistical Considerations and Data Analysis ............................................... 39 
9.1. 
Determination of Sample Size................................................................. 39 
9.2. 
General Statistical Considerations ........................................................... 39 
9.3. 
Treatment Group Comparability ............................................................. 39 
9.3.1. 
Patient Disposition .......................................................................... 39 
9.3.2. 
Patient Characteristics .................................................................... 40 
9.3.3. 
Concomitant Therapy ..................................................................... 40 
9.4. 
Primary and Secondary Analyses ............................................................ 40 
9.4.1. 
Primary Analyses ............................................................................ 40 
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9.4.2. 
Secondary Analyses ........................................................................ 40 
9.4.3. 
Tertiary/Exploratory Analyses ........................................................ 40 
9.5. 
Safety Analyses ....................................................................................... 41 
9.6. 
Pharmacokinetic/Pharmacodynamic Analyses ........................................ 41 
9.7. 
Other Analyses ........................................................................................ 41 
9.7.1. 
Health Economics ........................................................................... 41 
9.7.2. 
Biomarkers ..................................................................................... 41 
9.8. 
Interim Analyses ..................................................................................... 41 
10. Study Governance Considerations ............................................................... 42 
10.1. Regulatory and Ethical Considerations, Including the  Informed 
Consent Process ................................................................................................................ 42 
10.1.1. 
Informed Consent ........................................................................... 42 
10.1.2. 
Ethical Review ................................................................................ 42 
10.1.3. 
Regulatory Considerations .............................................................. 42 
10.1.4. 
Investigator Information ................................................................. 43 
10.1.5. 
Protocol Signatures ......................................................................... 43 
10.1.6. 
Final Report Signature .................................................................... 43 
10.2. Data Quality Assurance ........................................................................... 43 
10.2.1. 
Data Capture System ...................................................................... 44 
10.3. Study and Site Closure ............................................................................ 45 
10.3.1. 
Discontinuation of Study Sites ....................................................... 45 
10.3.2. 
Discontinuation of the Study .......................................................... 45 
11. References .................................................................................................... 46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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List of Tables 
Table 
Page 
Table JAHG.1.    Objectives and Endpoints ................................................................................... 12 
Table JAHG.2.    Treatment Regimens........................................................................................... 22 
Table JAHG.3.    Criteria for Temporary Interruption from Study Treatment ............................... 26 
Table JAHG.4 
Criteria for Permanent Discontinuation of Investigational Product ................... 27 
Table  JAHG.5.     Timing  of  Dosing  and  Fasting  Requirements  for  PK  Sample  Collection 
Visits .................................................................................................................. 36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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List of Figures 
Figure 
Page 
Figure JAHG.1.   Illustration of study design for Clinical Protocol I4V-MC-JAHG. .................... 14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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List of Appendices 
Appendix 
Page 
Appendix 1. 
Abbreviations and Definitions ........................................................................... 49 
Appendix 2. 
Schedule of Activities ........................................................................................ 54 
Appendix 3. 
Clinical Laboratory Tests ................................................................................... 59 
Appendix 4. 
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ...................... 62 
Appendix 5. 
Protocol I4V-MC-JAHG Signature Page ........................................................... 63 
Appendix 6. 
Protocol Amendment I4V-MC-JAHG(a) Summary  [A Randomized, 
Double-Blind, Placebo-Controlled, Phase 2 Study to Evaluate the 
Safety and Efficacy of Baricitinib in Patients with  Moderate-to-Severe 
Atopic Dermatitis] ............................................................................................. 64 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1. Protocol Synopsis 
 
Title of Study: 
A randomized, double-blind, placebo-controlled, Phase 2 study to evaluate the safety and efficacy of baricitinib in 
patients with moderate-to-severe atopic dermatitis. 
Rationale: 
Baricitinib is a JAK1/JAK2 selective inhibitor that is currently in development for treatment of inflammatory   
diseases such as rheumatoid arthritis and psoriasis. Baricitinib has been administered to healthy subjects and patients 
with rheumatoid arthritis (RA), moderate-to-severe plaque stage psoriasis, and diabetic nephropathy  (DN). 
In addition, baricitinib is also being developed for the treatment of atopic dermatitis (AD). This study will evaluate 
the safety and efficacy of baricitinib in patients with moderate-to-severe atopic  dermatitis. 
Objective(s)/Endpoints: 
 
Objectives 
Endpoints 
Primary 
To compare the proportion of moderate-to-severe atopic dermatitis patients 
achieving a 50% or greater reduction in the Eczema Area and Severity Index 
(EASI-50) between each baricitinib dose group (2 mg and 4 mg) and placebo 
when treated daily for 16 weeks 
Secondary 
To evaluate the absolute and percent change from baseline of the EASI with 
baricitinib compared to placebo at weeks 1 and 4 and monthly intervals  thereafter 
To evaluate the mean change from baseline of the SCORing Atopic Dermatitis 
(SCORAD) with baricitinib compared to placebo at weeks 1 and 4 and monthly 
intervals thereafter 
To evaluate the mean change from baseline of the Investigator’s Global 
Assessment (IGA) with baricitinib compared to placebo at weeks 1 and 4 and 
monthly intervals thereafter 
To assess quality of life based on the Dermatologic Life Quality Index (DLQI) at 
baseline, weeks 1 and 4 and monthly intervals  thereafter 
To assess itch using the itch numerical rating scale (NRS) at baseline, weeks 1 
and 4 and monthly intervals thereafter 
To evaluate the pharmacokinetics of baricitinib in patients with moderate-to- 
severe atopic dermatitis 
 
 
Summary of Study Design: 
 
Study I4V-MC-JAHG is a multicenter, randomized, double-blind, parallel, placebo-controlled study designed to 
compare the efficacy and safety of baricitinib to placebo in patients with moderate-to-severe atopic dermatitis. 
Enrollment will be targeted at 120 patients to enable approximately 96 patients to complete the study. Patients who 
meet all eligibility criteria will be randomized to receive either placebo or baricitinib, administered as once daily   
oral doses of 2 mg or 4 mg.  Randomization will occur at the country  level. 
 
 
 
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Treatment Arms and Duration: 
 
Three arms will be randomized 4:3:3 to placebo, 2 mg baricitinib, or 4 mg baricitinib, respectively. Study drug will 
be administered as oral tablets to be taken once-daily (QD) for 16 weeks. A background therapy of a mid-potency 
topical corticosteroid (triamcinolone 0.1%) will be utilized during the 28-day standardization phase prior to 
randomization and continued throughout the study. This background therapy should be used according to the  
labeling provided by the manufacturer or as directed by the  investigator. 
Number of Patients:  120 
 
Statistical Analysis: 
 
Sample Size 
The study will plan to enroll 120 patients that will be randomized 4:3:3 to 
placebo, 2 mg baricitinib, or 4 mg baricitinib,  respectively. 
Primary Outcome & Methodology 
The primary outcome parameter is the proportion of patients achieving 
EASI-50 in each treatment arm. The placebo arm will be compared to each 
of the baricitinib arms using a two-sided chi-square test with alpha=0.05 to 
control the study-wise type 1 error rate; the comparison of the baricitinib 
arms with the placebo arm will be performed in a stepwise fashion.  The 
4-mg baricitinib arm will be compared with the placebo arm; if this test is 
statistically significant, then the 2-mg baricitinib arm will be compared with 
the placebo arm. Enrollment of 120 patients in a 4:3:3 ratio provides 
approximately 90% power for detecting a 35% difference in response rate 
between placebo and 4-mg baricitinib treatment. 
Interim Analysis 
An interim analysis is not planned for this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.1. Background 
2. Introduction 
Atopic dermatitis (AD) is a common skin disorder characterized clinically by chronic 
inflammation and altered skin barrier function, and histologically by skin infiltration of 
inflammatory cells. AD is characterized by excessive T-cell activation, with significant skin 
infiltration by T-cells and dendritic cells. Both Th2 and Th22 activation are hallmarks of AD, 
with some Th17 and Th1 components. Patients with moderate-to-severe AD are afflicted with a 
heavy disease burden including medical as well as psycho-social abnormalities. Patients often 
have bacterial- or viral-mediated cutaneous complications. AD is the most common chronic 
inflammatory skin disease (Schmitt, 2013) with a prevalence of 2%–10% among adults in 
western geographies (Bieber, 2010) and a prevalence of about 3% in Japan (Muto et al,   2003). 
Studies using genomic and histologic profiling of AD skin have defined sets of biomarkers for  
AD that include markers of epidermal hyperplasia (epidermal thickness, K16 and Ki67 staining), 
epidermal barrier components (filaggrin), specific cellular infiltrates, including T-cells (CD3+  
and CD8+) and several dendritic cell subsets (CD11c+, CD1a+, inflammatory dendritic   
epidermal cells). Serum biomarkers that correlate with disease activity include IgE, eosinophils, 
eosinophilic cationic protein, as well as the Th2 chemokines CCL17, CCL18, CCL22, CCL11, 
and CCL26, and the cytokines IL-13, IL-31, and IL-22 (Mansouri,  2015). 
Members of the Janus kinase (JAK) family of protein tyrosine kinases (JAK1, JAK2, JAK3, and 
TYK2), along with the signal transduction and activator of transcription (STAT) pathway, play   
an important role in signal transduction following cytokine and growth factor binding to their 
receptors (Pesu, 2008). Emerging data support the role of JAK and STAT in Th2 immunity, 
activating eosinophils, and suppressing regulatory T cells. The JAK-STAT pathway, activated by 
IL-4, plays a critical role in the pathogenesis of AD by upregulating epidermal chemokines, pro- 
inflammatory cytokines, and proangiogenic factors as well as by down-regulating antimicrobial 
peptides and factors responsible for skin barrier function (Bao, 2013). Consistent with the  
proposed role of IL-4 activation of the JAK-STAT pathway in AD, administration of a  
monoclonal antibody against the alpha subunit of the IL-4 receptor improved clinical endpoints 
associated with AD (Beck, 2014). 
Baricitinib (also previously known as LY3009104 and INCB028050) is a potent and selective 
small molecule inhibitor of JAK1 and JAK 2 enzymes that is currently under development for 
the treatment of inflammatory conditions such as rheumatoid arthritis, diabetic kidney disease, 
psoriasis, and AD. 
Through 04 June 2015, approximately 4300 subjects have received baricitinib. This group of 
subjects was comprised of healthy subjects and patients with rheumatoid arthritis, psoriasis, 
diabetic kidney disease, rare auto-inflammatory syndromes, various degrees of renal impairment, 
and hepatic dysfunction. Baricitinib has been administered as single doses ranging from 1 to 40 
mg, multiple doses of up to 20 mg QD for 10 days, 10 mg QD for 28 days or 5 mg twice daily    
for 28 days in healthy subjects; and as a single 10-mg or 5-mg dose to subjects with mild to 
moderate or severe renal impairment respectively, as well as a single 5-mg dose to patients   with 
 
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end stage renal disease. Treatment duration has ranged from single doses in healthy volunteers  
to approximately 3.5 years in rheumatoid arthritis  patients. 
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). 
 
2.2. Study Rationale 
Inhibition of JAK-STAT signaling by targeting multiple AD-associated cytokine pathways has 
the potential to simultaneously reduce inflammation, cellular activation, and proliferation of key 
immune cells. Treatment of six patients with AD with a JAK1 and JAK3 inhibitor, tofacitinib,  
led to marked improvement in both objective measures of dermatitis and pruritus and patient- 
reported pruritus (Levy, 2015). 
Baricitinib is a potent and selective small molecule inhibitor of JAK1/2 enzymes. In vitro, 
baricitinib inhibits JAK1 and JAK2 with IC50 values in the single-digit nM range, yet it does not 
significantly inhibit a diverse panel of 28 kinases when tested at 100-fold of the IC50 against  
JAK1 and JAK2. In healthy volunteers, baricitinib demonstrated dose and time-dependent 
inhibition of cytokine-induced pSTAT3 (Shi,  2014). 
Study I4V-MC-JAHG will evaluate the safety and efficacy of baricitinib in patients with 
moderate-to-severe atopic dermatitis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3. Objectives and Endpoints 
Table JAHG.1 shows the objectives and endpoints of the  study. 
 
Table JAHG.1. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 To compare the proportion of moderate- 
to-severe atopic dermatitis patients 
achieving a 50% or greater reduction in 
the Eczema Area and Severity Index 
(EASI-50) between each baricitinib dose 
group (2 mg and 4 mg) and placebo when 
treated daily for 16 weeks 
 EASI-50 at 16 weeks 
Secondary 
 To evaluate the absolute and percent 
change from baseline of the EASI with 
baricitinib compared to placebo 
 EASI at Weeks 1, 4, 8, 12, and 16 
 To evaluate the mean change from 
baseline compared to placebo for the 
SCORing Atopic Dermatitis  (SCORAD) 
 SCORAD at  Weeks 1, 4, 8, 12, and  16 
 To evaluate the mean change from 
baseline compared to placebo for the 
Investigator’s Global Assessment  (IGA) 
 IGA at Weeks 1, 4, 8, 12, and 16 
 To assess quality of life based on the 
Dermatologic Life Quality Index (DLQI) 
 DLQI at Weeks 1, 4, 8, 12, and 16 
 
To assess itch based on the Itch 
Numerical Rating Scale (NRS) 
 Itch Numerical Rating Scale at Weeks 1, 
4, 8, 12, and 16 
 To characterize the pharmacokinetics of 
baricitinib in patients with moderate-to- 
severe atopic dermatitis 
 Plasma pharmacokinetic data 
Exploratory 
 To evaluate EASI response in patients 
based on their baseline total serum  IgE 
 EASI at Weeks 1, 4, 8, 12 and 16; baseline 
total serum IgE 
 To evaluate total serum IgE over the 
course of treatment 
 Total serum IgE at baseline, Weeks 4, and 
16 
 
 
 
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Exploratory (continued) 
 To evaluate changes in disease activity 
over the course of treatment 
 Patient-Oriented Eczema Measure (POEM) 
at  Weeks 1, 4, 8, 12, and 16 
 To evaluate changes in sleep quality over 
the course of treatment 
 Change from baseline with data from a 
wearable actigraphy device 
 To evaluate changes in nocturnal itch 
patterns over the course of treatment 
 Change from baseline with data from a 
wearable actigraphy device 
 To evaluate EASI response relative to 
filaggrin genotype 
 EASI-50 and filaggrin genotype data from 
peripheral baseline blood sample 
 To assess tissue biomarkers from  biopsies 
 K16, Ki-67, and IL-4 will be assessed from 
each tissue biopsy (collected at baseline 
(lesion and non-lesion), at Week 4 (lesion), 
and at Week 16 (lesion and  non-lesion) 
 To assess peripheral biomarkers 
mechanistically related to inhibition of 
JAK 1/2 mechanism 
 Peripheral biomarkers collected at baseline, 
Weeks 4 and 16 
 To perform subgroup assessments of 
response based on patient and disease 
characteristics 
 Ad hoc evaluation of potential prognostic 
and predictive disease characteristics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4 mg baricitinib 
2 mg baricitinib 
 
 
 
 
 
 
 
 
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4. Study Design 
4.1. Overview of Study Design 
I4V-MC-JAHG is a randomized, double-blind, placebo-controlled, Phase 2 study to evaluate the 
safety and efficacy of baricitinib in patients with moderate-to-severe atopic dermatitis. The study 
design is illustrated in Figure JAHG.1. 
Standardization 
Treatment 
Follow-up 
 
 
 
 
120 AD 
Patients 
Placebo 
4 Weeks 
16 Weeks 
4 Weeks 
Visit: 
1 
2 
3 
4 
5 
6 
7 
8 
Week: 
-4 
0 
1 
4 
8 
12 
16 
20 
Day: 
-28 
0 
7 
28 
56 
84 
112 
140 
 
 
 
Screening Randomization 
(4:3:3) 
Placebo : 2 mg baricitinib : 4 mg baricitinib 
 
Figure JAHG.1. 
Illustration of study design for Clinical Protocol I4V-MC-JAHG. 
 
 
 
4.2. Scientific Rationale for Study Design 
This study will enroll moderate-to-severe atopic dermatitis patients for whom a systemic 
treatment such as baricitinib may be appropriate. A 16-week course of treatment is expected to 
enable an optimal assessment of efficacy based on previous baricitinib studies in an 
inflammatory skin condition. 
Relatively high (20% to 50%) placebo responses have been observed in previously published 
atopic dermatitis studies (Bissonnette, 2012; Beck, 2014; Epstein and Pinski, 1964). Therefore, a 
4:3:3 randomization scheme of placebo, 2 mg baricitinib, and 4 mg baricitinib will be 
implemented.   Increased placebo enrollment across treatment groups has been reported to  
decrease placebo response and to also increase statistical power (Mallinckrodt,   2011). 
 
 
 
 
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A standardization phase will be incorporated prior to randomization to minimize effects due to 
background treatment. Beginning at standardization and continuing throughout the study, 
patients will be provided a topical corticosteroid to be used as prescribed and may continue use 
of other allowed study-specified palliative care measures as specified in Section   6.8. 
The EASI and SCORAD are the best instruments available to measure clinical severity of AD 
(Schmitt, 2013). Several quality of life assessments are being utilized to evaluate the effect of 
baricitinib on patients’ quality of life. 
 
4.3. Justification for Dose 
This study will evaluate the safety and efficacy of 2-mg and 4-mg doses of baricitinib in patients 
with moderate-to-severe atopic dermatitis. The dose justification for AD is based on a Phase 2 
rheumatoid arthritis (RA) study (Study JADA), reported Phase 3 RA studies (Study JADW and 
Study JADX) and a Phase 2 psoriasis study (Study  JADP). 
In these studies, all doses were generally well tolerated based on the observed adverse event 
profile and infrequent discontinuations of baricitinib dosing. The anticipated on-target, dose- 
limiting effect is a small decline in hemoglobin and hematocrit values. As described in Section 
4.4, this likely results from inhibition of erythropoietin signals via the JAK2/STAT5 signal 
transduction pathway (Klingmüller, 1997; Vera, 2008). These hematologic effects occur in 
higher-dose groups (8 mg daily) upon initiation of treatment and then   stabilize. 
The 2-mg and 4-mg doses have shown efficacy in RA with an acceptable safety profile. There  
was no additional efficacy associated with an 8-mg dose in the Phase 2 RA study, thus only 4 mg 
and 2 mg have been studied in the RA Phase 3 program. Doses less than 2 mg were not clearly 
effective in RA. 
In patients with moderate-to-severe plaque stage psoriasis, doses of 4 mg to 10 mg were found to 
be associated with statistically significant reductions in Psoriasis Area and Severity Index (PASI) 
score, with greater efficacy at the higher doses; however, the 8-mg and 10-mg doses were 
associated with a higher rate of AEs related to laboratory abnormalities (decreases in    
hemoglobin, neutrophils, and lymphocytes). The 2-mg and 4-mg dose groups had a pattern of   
AEs similar to placebo. The 2-mg dose did show numeric reductions in PASI score compared   
with placebo and statistically significant reductions in itch. Thus, in AD, the highest dose to be 
tested will be 4 mg, which would be anticipated to show efficacy together with an acceptable  
safety profile, and also provide the opportunity to cross reference to the large safety database   
from the RA Phase 3 program. The lower dose of 2 mg also has the opportunity to show efficacy  
in AD, where itch is a major component of the disease and may provide data that may be useful    
in the future for patients less than 18 years of  age. 
 
4.4. Benefit/Risk Assessment 
Baricitinib is a specific inhibitor of JAK1/2 and may offer potential benefit to patients with 
moderate-to-severe AD. Increases in serum creatinine and in both LDL and HDL cholesterol 
have been observed in Phase 1 and 2 studies with baricitinib (see Investigator’s   Brochure). 
 
 
 
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Baricitinib is a specific inhibitor of JAK1/2 that has shown to be well-tolerated and effective in 
chronic inflammatory conditions such as rheumatoid arthritis (Keystone, 2015) and psoriasis 
(Menter, 2014). Baricitinib may offer potential benefit in a chronic inflammatory dermatologic 
condition such as AD. 
Phase 1 and 2 studies with baricitinib showed increased levels of serum creatinine and LDL and 
HDL cholesterol (see Investigator’s Brochure). Similar increased levels of creatinine and 
cholesterol were also seen in tofacitinib, a JAK1/3 inhibitor (Fleischmann, 2012; Kremer, 2012). 
In addition, reductions in absolute neutrophil counts have been reported with both baricitinib and 
tofacitinib. Other pathways that signal through JAK include granulocyte macrophage colony 
stimulating factor and granulocyte colony stimulating factor signal and erythropoietin (JAK2) 
(Parganas, 1998). The assessment of safety of baricitinib in this study will therefore also include, 
but will not be limited to, monitoring of creatinine, cholesterol, neutrophil and granulocyte  
counts, hemoglobin levels, and rates of  infection. 
More information about the known and expected benefits, risks, and reasonably anticipated  
adverse events may be found in the Investigator’s Brochure. Information on adverse events 
expected to be related to the investigational product may be found in Section 7 (Development  
Core Safety Information) of the Investigator’s Brochure. Information on serious adverse events 
expected in the study population independent of drug exposure will be assessed by the sponsor in 
aggregate periodically during the course of the study and may be found in Section 6 (Effects in 
Humans) of the Investigator’s  Brochure. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5. Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, will not be  permitted. 
 
5.1. Inclusion Criteria 
Patients are eligible to be included in the study only if they meet all of the following   criteria: 
Type of Patient and Disease  Characteristics 
[1] Are at least 18 years of age at the time of Visit  1 
[2] Have moderate-to-severe AD, as determined by all of the  following: 
 EASI ≥12 at Visits 1 and 2 
 ≥10% of body surface area (BSA) involvement at Visits 1 and  2 
 Were diagnosed with AD at least 2 years before Visit  1 
With a history of inadequate clinical response, in the opinion of the 
investigator, to one or more of the three treatment categories listed below 
(used for at least 4 weeks): 
 Category 1: Hydration plus topical steroids and/or antibiotics (e.g., 
tetracycline, trimethoprim and sulfamethoxazole, cephalosporins) and/or 
topical immune modulators (e.g.,  tacrolimus/pimecrolimus) 
 Category 2:   Systemic steroids and/or phototherapy 
 Category 3: Cyclosporine and/or other immunomodulators (e.g., 
methotrexate, mycophenolate mofetal, and  azathioprine) 
[3] Agree to discontinue use of the following excluded medications for at least 4 
weeks prior to randomization (Visit 2) and throughout the  study 
 oral cyclosporine, steroids, and leukotriene  inhibitors 
 phototherapy 
 potent topical steroids (e.g., clobetasol) or topical immune modulators 
(e.g., tacrolimus/pimecrolimus). 
 cyclosporine and/or other immunomodulators (e.g., methotrexate, 
mycophenolate mofetal, and  azathioprine) 
 
5.2. Exclusion Criteria 
Patients will be excluded from participating in the study if they meet any of the following 
criteria: 
Medical Conditions 
[4] Are female subjects who are pregnant or  nursing 
 
 
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[5] Are females of childbearing potential who do not agree to use 2 forms of  
highly effective methods of birth control or remain abstinent while enrolled in 
the study and for at least 28 days following the last dose of investigational 
product 
Note: Females of nonchildbearing potential are defined as women ≥60 years 
of age, or women >40 and <60 years of age who have had a cessation of 
menses for at least 12 months, or women who are congenitally or surgically 
sterile (that is, have had a hysterectomy or bilateral oophorectomy or tubal 
ligation). 
The following birth control methods are considered highly effective (the 
patient should choose 2): 
 Oral, injectable, or implanted hormonal  contraceptives 
 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 
 Intrauterine device 
 Intrauterine system (for example, progestin-releasing  coil) 
 Vasectomized male (with appropriate post-vasectomy documentation 
of the absence of sperm in the  ejaculate). 
[6] 
Are males who do not agree to use 2 forms of highly effective birth control 
(see above) with female partners of childbearing potential while enrolled in 
the study, and for at least 28 days following the last dose of investigational 
product 
Are currently experiencing or have a history of any of the  following: 
[7] Other concomitant skin conditions (e.g., psoriasis, or lupus erythematosus) 
that would interfere with evaluations of the effect of study medication on 
atopic dermatitis 
[8] Erythrodermic, refractory or unstable skin disease that requires frequent 
hospitalizations and/or intravenous treatment for skin  infections 
[9] Immunocompromised and, in the opinion of the investigator, at an 
unacceptable risk for participating in the  study 
[10] Serious concomitant illness that could require the use of systemic 
corticosteroids or otherwise interfere with study participation or require active 
frequent monitoring (e.g., unstable chronic  asthma) 
[11] Organ transplant(s) (corneal transplant performed >3 months prior to 
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[12] Clinically important deviation, in the opinion of the investigator, from normal 
limits in physical examination, vital sign measurements, and/or 
electrocardiograms, that is not associated with a chronic, well-controlled 
medical condition 
[13] Electrocardiogram (ECG) abnormalities at Visit 1 that, in the opinion of the 
investigator or the sponsor, are clinically significant and indicate an 
unacceptable risk for the patient’s participation in the study (Bazett’s 
corrected QT interval >470 msec for men and  women) 
[14] Have evidence of active or latent TB as documented by a positive PPD test   
(≥5 mm in duration between approximately 2 and 3 days after application, 
regardless of vaccination history), medical history, or chest x-ray at screening. 
Exceptions are patients with a history of latent TB who have documented 
evidence of completing a course of appropriate  treatment. 
 If the PPD test is positive or not conducted and the patient has no medical 
history or chest x-ray findings consistent with active or latent TB, the 
patient should have a QuantiFERON®-TB Gold test or the T-SPOT.TB® 
test. If either of these tests is positive or indeterminate (a single re-test is 
allowed), the patient is excluded from the  study. 
[15] Active or latent granulomatous disorders or a non-tuberculous mycobacterial 
infection or opportunistic systemic infection (e.g., Pneumocystis carinii, and 
aspergillosis) within 6 months prior to  screening 
[16] Uncompensated heart failure, fluid overload, myocardial infarction, or 
evidence of ischemic heart disease or other serious cardiac disease within 12 
weeks of Visit 1 
[17] Uncontrolled arterial hypertension characterized by a repeated systolic blood 
pressure >160mm Hg or diastolic blood pressure >100mm Hg at the time of 
Visit 1 
[18] Malignancy (except for basal or squamous cell carcinoma completely excised 
without evidence of recurrence) or lymphoproliferative diseases or have signs 
or symptoms suggestive of possible lymphoproliferative disease, including 
lymphadenopathy or splenomegaly including  lymphoma 
Note: Patients with cervical carcinoma in situ that has been resected with no 
evidence of recurrence or metastatic disease, or with basal cell or squamous 
epithelial skin cancers that have been completely resected with no evidence of 
recurrence for at least 3 years may participate in the  study. 
[19] Evidence of HIV infection or are positive for HIV antibodies (based on 
history or point-of-care testing (POCT)) at Visit  1 
[20] Positive test for hepatitis B defined as: 
a) positive for hepatitis B surface antigen (HBsAg),  or 
 
 
 
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b) positive for anti-hepatitis B core antibody (HBcAb) and positive for hepatitis B 
deoxyribonucleic acid (HBV DNA), or 
c) for sites in Japan only, positive for HBcAb and/or positive for anti-hepatitis B 
surface antibody (HBsAb), and positive for HBV  DNA. 
 
If any of the hepatitis B tests have an indeterminate result, confirmatory testing will 
be performed by an alternate method. 
 
[21] Positive for anti-hepatitis C antibody with confirmed presence of hepatitis C 
virus, or chronic liver disease with the most recent available AST or ALT >2X 
the ULN 
[22] Serious and/or unstable mental and/or physical illness that, in the opinion of 
the investigator, poses an unacceptable risk for the patient’s participation in 
the study 
Prior/Concomitant Therapy 
[23] Received any oral JAK inhibitor (e.g., Xeljanz) within the past 6  months 
[24] Currently receiving any immunosuppressive therapy (e.g.,  cyclosporine) 
[25] Received any monoclonal antibody intended for AD (e.g., ustekinumab or 
dupilumab) within the past 6  months. 
[26] Currently using or expected to use concomitant medications or treatments for 
AD other than those allowed for use in the  protocol 
[27] Exposed to a live vaccine, including the nasal flu vaccine, within 12 weeks 
prior to planned enrollment (with the exception of herpes zoster vaccination; 
patients will be excluded if they were exposed to herpes zoster vaccination 
within 30 days of planned enrollment) or are expected to need/receive a live 
vaccine during the course of the  study. 
Prior/Concurrent Clinical Trial  Experience 
[28] Currently enrolled in any other clinical study involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this  study 
[29] Participated, within the last 30 days (for Japan, 4 months) 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. 
[30] Previously completed or withdrawn from this  study 
Diagnostics Assessments 
Have any of the following specific abnormalities on screening laboratory   tests: 
[31] AST or ALT >2X the ULN 
 
 
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[32] Total bilirubin ≥1.5X the ULN 
[33] Hemoglobin <11.0 g/dL (100.0 g/L) 
[34] Total white blood cell count <2500  cells/µL 
[35] Neutropenia (absolute neutrophil count <1200  cells/µL) 
[36] Lymphopenia (lymphocyte count <750  cells/µL) 
[37] Thrombocytopenia  (platelets <100,000/µL) 
[38] eGFR <50 mL/min/1.73 m2 (based on CKD  EPI) 
Note: In the case of any of the aforementioned laboratory abnormalities, they may 
be repeated once within 1 week of the initial values, and values resulting from  
repeat testing may be used to assess enrollment  eligibility. 
Other Exclusions 
[39] Donated blood of more than 500 mL or blood products within 4 weeks prior to 
entry. 
[40] Unwilling to commit to refrain from donating blood or blood products during 
the study. 
[41] History of substance abuse (drug or alcohol) within the two years before 
screening. 
[42] Unable or unwilling to be available for the duration of the study and/or are 
unwilling to follow study  restrictions/procedures. 
[43] Unable or unwilling to have skin biopsies performed, unless exempted by the 
investigator. 
[44] 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. 
[45] Employees of the sponsor. 
[46] Unwilling or unable to comply with the use of all potential data collection 
devices. 
 
5.3. Screen Failures 
Individuals who do not meet the criteria for participation in this study (screen failure) may be re- 
screened. Individuals may be re-screened once (time period from screen fail to re-screen to be 
determined by the investigator). If re-screening is performed, the individual must sign a new 
informed consent form (ICF) and will be assigned a new identification number. Additionally, all 
screening procedures must be conducted at re-screen to ensure all eligibility criteria are   met. 
 
 
 
 
 
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6. Treatment 
6.1. Treatments Administered 
This study includes the treatment regimens outlined in Table JAHG.2 below. Doses of baricitinib 
or placebo will be administered orally. 
 
 
Table JAHG.2. 
Treatment Regimens 
 
    Treatment Group 
Dose (QD) 
Day 1 through Day 112 
2 mg LY 
(1  2-mg LY tab; 1  4-mg placebo tab) 
4 mg LY 
(1  2-mg placebo tab; 1  4-mg LY tab) 
Placebo 
(1  2-mg placebo tab; 1  4-mg placebo tab) 
Abbreviations:  tab = tablet; LY = baricitinib 
 
 
The investigator or his/her designee is responsible for the  following: 
 explaining and verifying the correct use of the investigational agent(s) to the 
patient and site personnel 
 maintaining accurate records of investigational product dispensing and   collection 
 returning, at the end of the study, all unused investigational product to the 
sponsor, 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 
 
6.2. Method of Treatment Assignment 
Patients who meet all criteria for enrollment will be randomized to double-blind treatment at   
Visit 2. Assignment to treatment groups will be determined by a computer-generated random 
sequence using an interactive response technology (IRT) system. The IRT system will be used to 
assign blister packs containing double-blind investigational product to each patient. The IRT 
system will dispense a number of blister packs adequate for each visit   interval. 
The randomization will be stratified by  country. 
 
6.2.1. Selection and Timing of Doses 
Patient treatment assignments will be based on the randomization scheme as described   above. 
On PK sample collection days (Appendix 2), specific fasting and dose timing requirements are 
outlined in Table JAHG.5 (Section  8.5.1). 
 
 
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6.3. Blinding 
This is a double-blind study in which the patients, investigator, and study site personnel will be 
blinded to treatment allocation. 
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. 
Emergency unblinding for AEs may be performed through an IRT system, which may  
supplement or take the place of emergency codes generated by a computer drug-labeling system. 
This option may be used ONLY if the patient’s well-being requires knowledge of the patient’s 
treatment assignment. All calls resulting in an unblinding event are recorded and reported by the 
IRT system. 
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted. Patient safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the sponsor CRP prior to  
unblinding a patient’s treatment  assignment. 
If an investigator, site personnel performing assessments, or patient is unblinded to the treatment 
code assignment, the sponsor must be contacted  immediately. 
 
6.4. Packaging and Labeling 
The sponsor (or its designee) will provide the following investigational   products: 
 tablets containing 2 mg of baricitinib 
 tablets containing 4 mg of baricitinib 
 placebo to match baricitinib 2 mg tablets 
 placebo to match baricitinib 4 mg tablets 
Additionally, the sponsor (or its designee) will also provide the following concomitant therapy 
product: 
 triamcinolone 0.1% cream which should be used according to the labeling provided 
by the manufacturer or as directed by the  investigator 
Investigational products and triamcinolone 0.1% cream will be dispensed to the patient at the 
investigator’s study site. 
Investigational product will be packaged in blister packs. Investigational product packaging will 
be labeled with a unique identifier for drug dispensing by the IRT system. Blister packs will 
contain additional tablets to allow for sufficient administration of investigational product within 
the allowed visit internal window. 
Investigational product will be labeled according to the country’s regulatory requirements. All 
investigational products will be stored, inventoried, reconciled, and destroyed according to 
applicable regulations. Investigational products will be manufactured and tested by the sponsor 
or its representative in accordance with current Good Manufacturing Practices   (cGMP) 
 
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requirements for clinical studies, and will be supplied with lot numbers, expiry dates, and 
certificates of analysis (as applicable). 
 
6.5. Investigational Products Storage and  Handling 
Investigational products should be stored between 15°C and 30°C. All investigational products 
should be stored in a secure and locked area with strictly limited access and monitored for 
temperature and will be allocated and dispensed by appropriately trained   personnel. 
 
6.6. Dose Modification 
No dose modifications will be  allowed. 
 
6.7. Treatment Compliance 
Patient compliance with study medication will be assessed at each visit. Compliance will be 
assessed by counting returned tablets. Deviation(s) from the prescribed dosage regimen should 
be recorded in the CRF. 
The patient will be considered significantly noncompliant if he or she misses more than 20% of 
the prescribed doses during the study. 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. 
Patients found to be noncompliant with investigational product should be assessed to determine 
the reason for noncompliance, and educated and/or managed as deemed appropriate by the 
investigator to improve compliance. 
 
6.8. Concomitant Therapy 
The use of triamcinolone 0.1% cream will be allowed throughout the trial. Patients will be 
instructed to apply the triamcinolone 0.1% cream according to the labeling provided by the 
manufacturer or as directed by the investigator. The triamcinolone 0.1% cream container will be 
weighed at each visit to assess usage. 
All other concomitant medication taken during the study must be recorded on the Concomitant 
Medication case report form (CRF). Treatment with concomitant atopic dermatitis therapies 
during the study is permitted only as outlined in the inclusion/exclusion criteria (Section 5.1 and 
Section 5.2) and as described in the paragraphs  below. 
Additional systemic drugs are to be avoided during the study, unless required to treat an   AE. 
Non-live seasonal vaccinations and/or emergency vaccination (such as rabies or tetanus 
vaccinations) are allowed. 
The following will be allowed as needed: use of topical antibiotics in the event of secondary 
infections of lesions; nonprescription shampoos; NSAIDs; diphenhydramine (50 mg); and 
topical moisturizers/emollients, bath oils, oatmeal bath preparations, bleach baths if using a  
stable regimen prior to enrollment, and salicylic acid preparations.  Patients will be instructed   to 
 
 
 
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consult the investigator or other appropriate study personnel at the site before taking any new 
medications or supplements. 
 
6.9. Treatment after Study Completion 
6.9.1.   Continued Access 
The Investigational Product will not be made available to patients after the conclusion of the 
study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7. Discontinuation Criteria 
7.1. Discontinuation of Investigational  Product 
7.1.1. Temporary Interruption of Investigational  Product 
In some circumstances, it may be necessary to temporarily interrupt treatment as a result of AEs   
or abnormal laboratory values as described in Table JAHG.3 that may have an unclear  
relationship to investigational product. Except in cases of emergency, it is recommended that the 
investigator consult with the sponsor (or its designee) before temporarily interrupting   therapy. 
The investigator must obtain approval from the sponsor (or its designee) before restarting 
investigational product that was temporarily discontinued because of an AE or abnormal 
laboratory value. Investigational product must be held in the following situations involving 
laboratory abnormalities and may be resumed as noted in Table  JAHG.3. 
Table JAHG.3. 
Criteria for Temporary Interruption from Study Treatment 
 
 
Hold Investigational Product if the Following 
Laboratory Test Results Occur: 
Investigational Product May Be Resumed after 
Approval from Lilly (or its Designee) and When: 
WBC count <2000 cells/µL 
WBC count 2500 cells/µL 
ANC <1000 cells/L 
ANC >1200 cells/µL 
Lymphocyte count <500 cells/µL 
Lymphocyte count 750 cells/µL 
Platelet count <75,000/µL 
Platelet count 100,000/µL 
eGFR <40 mL/min/1.73 m2 (from serum 
 creatinine) 
eGFR 50 mL/min/1.73 m2 
ALT or AST >5 times the ULN 
ALT and AST return to <2 times the ULN, and 
investigational product is not considered to be the cause 
of enzyme elevation 
Hemoglobin <9 g/dL 
Hemoglobin 10 g/dL 
Symptomatic herpes zoster 
All skin lesions have crusted and are resolving 
Severe infection that, in the opinion of the 
investigator, merits the investigational product 
 being discontinued 
Resolution of infection 
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; eGFR = estimated glomerular filtration rate; min = minute; ULN = upper limit of normal; 
WBC = white blood cell. 
 
 
7.1.2. Permanent Discontinuation of Investigational  Product 
Any patient who is permanently discontinued from investigational product for an AE or  
abnormal laboratory result should have the reason for investigational product discontinuation 
reported as the AE or abnormal laboratory value. If any of the criteria listed in Section 7.1.1. 
above recur after investigational product is restarted, the investigator must obtain approval from 
the sponsor (or its designee) before restarting investigational product.  In addition, patients   will 
 
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be permanently discontinued from investigational product if they experience any of the criteria 
listed in Table JAHG.4. 
Table JAHG.4 
Criteria for Permanent Discontinuation of Investigational Product 
 
Permanently Discontinue Investigational Product if any of the Following are  Observed: 
ALT or AST >8 times the ULN 
ALT or AST >5 times the ULN persisting for more than 2 weeks after temporary interruption of investigational 
product 
ALT or AST >3 times the ULN and total bilirubin level >2 times the  ULN 
ALT or AST >3 times the ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%) 
WBC count <1000 cells/L 
ANC <500 cells/L 
Lymphocyte count <200 cells/L 
Hemoglobin <8 g/dL 
Pregnancy 
Malignancy (except for successfully treated basal cell or squamous epithelial skin  cancers) 
HBV DNA ≥29 IU/mLa 
 
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; HBV DNA = hepatitis B virus deoxyribonucleic acid; ULN = upper limit of normal; 
WBC = white blood cell. 
a If a HBV DNA result of ‘target detected’ 29 IU/mL or greater, then the patient should be referred to a hepatology 
specialist immediately. In selected cases, investigators may temporarily continue study drug in accordance with 
current immunomodulator management in the setting of HBV DNA positivity. This option may be considered in 
consultation with the sponsor (or its designee) and evaluation of individual patient risks and benefits. Refer to 
Section 8.4.5 for additional instruction on HBV DNA  monitoring. 
 
7.1.3. Discontinuation of Inadvertently Enrolled  Patients 
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the sponsor CRP and the investigator to 
determine if the patient may continue in the study. If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the sponsor CRP to allow the 
inadvertently enrolled patient to continue in the study with or without treatment with 
investigational product. 
 
7.1.4. Permanent Discontinuation from the  Study 
Some possible reasons that may lead to permanent discontinuation   include: 
 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 
 
 
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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 
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 
Patients who discontinue the study early will have early termination (ET) procedures performed 
as shown in the Schedule of Activities (Appendix  2). 
 
7.1.5. Patients 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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8. Study Assessments and  Procedures 
Appendix 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing). 
Appendix 3 lists the laboratory tests that will be performed for this  study. 
Appendix 4 provides the hepatic monitoring tests for treatment-emergent   abnormalities. 
Additionally, a study addendum will be compiled to detail the capture of photographs from 
selected lesions for patients enrolled at up to three selected study sites. These photographs will 
permit documentation of the clinical response through sequential photography of a selected 
lesion or involved area before and following study drug  treatment. 
 
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. 
 
8.1. Efficacy Assessments 
Study procedures and their timing are summarized in the Schedule of Activities (Appendix   2). 
 
8.1.1. Primary Efficacy Assessments 
The clinical outcome measure that will be used in this study is the EASI score (specifically, the 
proportion of patients achieving a 50% reduction in EASI or  EASI-50). 
 Eczema Area and Severity Index (EASI) scores: The EASI assesses extent of disease 
at four body sites and measures four clinical signs: (1) erythema, (2) 
induration/papulation, (3) excoriation, and (4) lichenification each on a scale of 0 to 3. 
EASI confers a maximum score of 72. EASI evaluates two dimensions of atopic 
dermatitis: disease extent and clinical signs.
 
8.1.2. Secondary Efficacy Assessments 
 Mean and Percentage change in Eczema Area and Severity Index (EASI) scores: See 
above.
 
 SCORing Atopic Dermatitis (SCORAD): The SCORAD index uses the rule of nines to 
assess disease extent and evaluates five clinical characteristics to determine disease 
severity: (1) erythema, (2) edema/papulation, (3) oozing/crusts, (4) excoriation and (5) 
lichenification. SCORAD also assesses subjective symptoms of pruritus and sleep loss 
with Visual Analogue Scales (VAS). These three aspects: extent of disease, disease 
severity and subjective symptoms combine to give a maximum possible score of 103.
 
 
Investigator’s Global Assessment (IGA): The IGA consists of a 6-point severity scale 
from clear to very severe disease (0 = clear, 1 = almost clear, 2 = mild disease, 3 = moderate 
disease, 4 = severe disease and 5 = very severe disease). IGA uses clinical characteristics
 
 
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of erythema, infiltration, papulation, oozing and crusting as guidelines for the overall 
severity assessment. 
 
 
Dermatology Life Quality Index (DLQI): The DLQI is a simple, patient-administered, 
10-question, 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. A DLQI total score 
of 0 to 1 is considered as having no effect on a patient’s health-related quality of life, and 
a 5-point change from baseline is considered as the minimal clinically important 
difference threshold (Finlay, 1994; Khilji, 2002; Hongbo, 2005).
 
 
Itch Numerical Rating Scale (NRS): The Itch 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 circling the number that best describes the worst level of itching in the 
past 24 hours. Analyses were performed to support a responder definition that was 
defined as proportion of patients achieving an Itch NRS ≥4-point reduction from 
baseline for patients who had baseline Itch NRS  ≥4.
8.1.2.2 Exploratory Efficacy Assessments 
Data on the following exploratory efficacy measures will be collected at the times shown in the 
Schedule of Activities (Appendix 2): 
 Patient-Oriented Eczema Measure (POEM): The Patient-Oriented Eczema Measure 
(POEM) was originally developed to help address the imbalance between physician and 
patient-based outcome measures in eczema research. Patients answer simple questions 
about the frequency of seven symptoms: itch, sleep disturbance, skin bleeding, skin 
weeping/oozing, skin cracking, skin flaking, and skin dryness/roughness over the last 
week. The total score from this assessment reflects overall disease activity. The POEM 
utilizes a 5-point Likert scale for each question and is intended for ages 1-60 years. 
POEM scores can range from 0 to 28 where lower total scores reflect lower disease 
activity and higher scores reflect higher disease activity (Charman, 2004).
 
 Actigraphy Device: A hypoallergenic wrist watch-like device that is used to collect 
sleep/wake patterns and quantify nocturnal scratching events (Ferguson, 2015).
 
8.1.3. Appropriateness of Primary Efficacy  Measure 
 Eczema Area and Severity Index (EASI): The EASI is one of the best instruments 
available to measure clinical signs of AD. EASI utilizes objective physician estimates of 
disease extent and severity. The EASI is valid and internally consistent and has adequate 
intraobserver reliability, intermediate interobserver reliability, and adequate 
responsiveness. One advantage of the EASI is its unidimensionality; that is, it only 
measures clinical signs of AD and does not include symptoms. Another advantage of the
 
 
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EASI is that it measures the intensity of the lesions at multiple body parts (rather than 
relying on a representative lesion) (Schmitt, 2013). 
 
8.2. Adverse Events 
The investigator remains responsible for following, through an appropriate health care option,  
AEs that are (1) serious or otherwise medically important, (2) considered related to the 
investigational product or the study, or that (3) 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. 
The sponsor has standards for reporting AEs that are to be followed regardless of applicable 
regulatory requirements that may be less stringent. Study site personnel will record the 
occurrence and nature of each patient’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study. All AEs collected in the study 
CRF will be validated and reported in the final study  report. 
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 the CRF/electronic data entry, the 
occurrence and nature of each patient’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study. In addition, site personnel will 
record any change in the condition(s) and any new conditions as AEs. Investigators should  
record their assessment of the potential relatedness of each AE to protocol procedure or 
investigational product. 
Investigators must document their review of each laboratory safety  report. 
Any clinically significant findings from ECGs, laboratory tests, vital sign measurements, and 
other procedures that result in a diagnosis should be reported to the sponsor or its designee. In 
addition, all AEs occurring after the patient receives the first dose of the investigational product 
must be reported to the sponsor or its  designee. 
Investigators will be instructed to report to the sponsor or its designee their assessment of the 
potential relatedness of each AE to protocol procedure or investigational product via the case 
report form. 
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the  study. 
Cases of pregnancy that occur during maternal or paternal exposures to the investigational   
product should be reported. Data on fetal outcome and breast-feeding are collected for regulatory 
reporting and drug safety evaluation. 
Study site personnel must alert the sponsor or its designee immediately of the investigator 
unblinding a patient’s treatment group assignment for any  reason. 
 
 
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If a patient’s treatment is discontinued as a result of an AE, study site personnel must clearly 
report to the sponsor or its designee the circumstances and data leading to any such 
discontinuation of treatment. 
 
8.2.1. Adverse Events/Laboratory Results of Special Interest  
Adverse events or laboratory results of special interest include infections; myelosuppressive 
events of anemia, leukopenia, neutropenia, lymphopenia, thrombocytopenia; thrombocytosis; 
hyperlipidemia; hypercholesterolemia; and elevations in ALT/AST (≥3X ULN) and total 
bilirubin (≥2X ULN). 
8.2.2. Serious Adverse Events 
Study site personnel must alert the sponsor or its designee of any SAE within 24 hours of 
investigator awareness of the event via a sponsor-approved method. Alerts issued via telephone 
are to be immediately followed with official notification on study-specific SAE   forms. 
All SAEs will be reported in the study CRF and on the approved study-specific SAE form by the 
study site personnel. In addition, the study-specific SAE forms will be collected by 
sponsor/designee and subsequently entered into the clinical study database and the study safety 
database. Investigators will be required to update the study-specific SAE forms when new 
information becomes available, and address questions from the sponsor/designee until the SAE  
has been fully resolved or explained to the satisfaction of the sponsor. The SAE data from both 
CRF and study-specific SAE forms will be validated and included in the final CSR. If the SAE 
cases are closed after the completion of database lock, such information may not be included in  
the final study report. Such additional information will continue to be collected in the study- 
specific SAE form, and be reported either in an amendment to study report if such information 
leads to clinically significant change(s) in the conclusion of the study; or in the annual 
Development Safety Update Report (DSUR) or IB update if the information from the SAE does 
not alter the overall conclusion of the  study. 
An SAE is any AE from this study that results in one of the following   outcomes: 
 death 
 initial or prolonged inpatient  hospitalization 
 a life-threatening experience (that is, immediate risk of  dying) 
 persistent or significant  disability/incapacity 
 congenital anomaly/birth defect 
 considered significant by the investigator for any other  reason 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Previously planned (prior to signing of ICF) surgeries should  
not be reported as SAEs unless the underlying medical condition has worsened during the course 
of the study. 
 
 
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SAEs occurring after a patient has taken the last dose of the investigational product will be 
collected in the pharmacovigilance system and clinical data collection database for 30 days after 
the last dose of the investigational product, regardless of the investigator’s opinion of causation. 
Thereafter, SAEs are not required to be reported unless the investigator feels the events were 
related to either investigational product, drug delivery system, or a protocol   procedure. 
Sponsor/designee has the option to request follow up information or clarification of existing 
information from the investigators up to closure of the case. SAEs should be followed by the 
investigator until resolution of all queries, clinical recovery is complete or until a stable clinical 
endpoint has been reached. Follow up may therefore continue after the patient has been  
discharged from the study. The type and extent of follow up undertaken will be determined for 
each individual case and depends upon the nature, severity, and medical significance of the  
report. The follow up may include supplemental investigations, additional laboratory tests, 
histopathological examinations, or consultations with other health care professionals. If a patient 
dies during participation in the study, the follow up may include a copy of any post-mortem 
findings, if available. 
The investigator site will be required to contact the patient in accordance with their procedures to 
obtain necessary information to provide updates to the study-specific SAE forms. Requests for 
outstanding information from the investigational site to patients should be maintained as part of  
the clinical study documents. 
8.2.2.1. 
Suspected Unexpected Serious Adverse  Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed   
in the IB and that the investigator identifies as related to investigational product or procedure. 
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries  
require the reporting of SUSARs. The sponsor 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. 
 
8.2.3.   Complaint Handling 
The Sponsor collects product complaints on investigational products and drug delivery systems 
used in clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product  improvements. 
Patients 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. 
 
8.3. Treatment of Overdose 
Refer to the baricitinib Investigator’s  Brochure. 
 
8.4. Safety Assessments 
Safety assessments include vital signs, physical examination, electrocardiograms, AEs, patient- 
reported scale data, and safety laboratory  testing. 
 
 
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8.4.1. Physical Examination 
A complete physical examination will be performed during Visit 1 (screening). Directed physical 
examinations will be performed according to the Schedule of Activities (Appendix 2) and may    
be repeated at the investigator’s discretion any time a patient presents with physical   complaints. 
 
8.4.2. Electrocardiograms 
For each patient, an electrocardiogram (ECG) should be performed according to the Schedule of 
Activities (Appendix 2) and as deemed necessary by the  investigator. 
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
patient receives the first dose of the investigational treatment should be reported to Lilly or its 
designee as an AE via the CRF. 
 
8.4.3. Vital Signs 
For each patient, vital signs measurements should be conducted according to the Schedule of 
Activities (Appendix 2) and following study specific recommendations provided by the sponsor 
for the study. 
Any clinically significant findings from vital signs measurement that result in a diagnosis and 
that occur after the patient receives the first dose of study treatment should be reported to the 
sponsor or its designee as an AE via designated data transmission   methods. 
 
8.4.4. Laboratory Tests 
For each patient, laboratory tests detailed in (Appendix 3) should be conducted according to the 
Schedule of Activities (Appendix 2). 
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of investigational product should be reported to the 
sponsor or its designee as an AE via designated data transmission   methods. 
 
8.4.5. Hepatitis B virus (HBV) DNA  monitoring 
Patients enrolled in the US who are HBsAg negative, HBcAb positive, and HBV DNA negative 
(undetectable) at Visit 1, will require HBV DNA monitoring at Visits 5 and 8 or ET, regardless  
of their HBsAb status. 
Patients enrolled in Japan who are HBsAg negative, HBcAb and/or HBsAb positive, and HBV 
DNA negative (undetectable) at Visit 1, will require HBV DNA monitoring at Visits 5 and 8 or 
ET. 
If the HBV DNA result is ‘target detected’ ≥29 IU/mL at any point in the study, then the patient 
should be referred to a hepatology specialist immediately and discontinuation considered (refer   
to Table JAHG.4). In selected cases, investigators may temporarily continue study drug in 
accordance with current immunomodulator management in the setting of HBV DNA   positivity. 
 
 
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This option may be considered in consultation with the sponsor (or its designee) and evaluation 
of individual patient risks and  benefits. 
 
8.4.6. Quick Inventory of Depressive Symptomatology-Self Report 16 
(QIDS-SR16) 
For each patient, the QIDS-SR16 should be administered according to the Schedule of Activities 
(Appendix 2). 
The QIDS-SR16 is a self-administered 16-item instrument intended to assess the existence and 
severity of symptoms of depression as listed in the American Psychiatric Association’s 
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) (American 
Psychiatry Association [APA] 1994). The QIDS-SR16 scale is used to assess the potential  
impact of treatment on new onset or changes in depression, thoughts of death, and /or suicidal 
ideation severity. A patient is asked to consider each statement as it relates to the way they   have 
felt for the past 7 days. There is a 4-point scale for each item ranging from 0 to 3. The 16 items 
corresponding to 9 depression domains are summed to give a single score ranging from 0 to 27, 
with higher scores denoting greater symptom severity. The domains assessed by the instrument 
include: (1) sad mood, (2) concentration, (3) self-criticism, (4) suicidal ideation, (5) interest, (6) 
energy/fatigue, (7) sleep disturbance (initial, middle, and late insomnia or   hypersomnia), 
(8) decrease/increase in appetite/weight, and (9) psychomotor agitation/retardation (Rush,   2003). 
 
8.4.7. Safety Monitoring 
The sponsor will periodically review evolving aggregate safety data within the study by 
appropriate methods. 
If a patient experiences elevated ALT ≥3X ULN, ALP ≥3X ULN, or elevated TBL ≥2X ULN, 
clinical and laboratory monitoring should be initiated by the investigator. Details for hepatic 
monitoring depend upon the severity and persistence of observed laboratory test abnormalities.  
To ensure patient safety and comply with regulatory guidance, the investigator is to consult with 
the sponsor CRP regarding collection of specific recommended clinical information and follow- 
up laboratory tests (Appendix 4). 
 
8.5. Pharmacokinetics 
8.5.1. PK Sample Collection 
A total of 6 venous blood samples (approximately 5 mL per sample) for the measurement of 
baricitinib concentrations will be drawn at visits scheduled within the time windows specified in 
the Schedule of Activities (Appendix 2). Specific dosing and fasting requirements for each PK 
visit are described in Table JAHG.5  below. 
 
 
 
 
 
 
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Table JAHG.5. 
Timing of Dosing and Fasting Requirements for PK Sample 
Collection Visits 
 
Events 
Visit 
2 
4 
5 
6 
7 
ET 
Overnight 
(8-hr) fast 
Yes 
No 
No 
No 
Yes 
No 
Take study 
drug 
At clinic 
At home 
At home 
At clinic 
At clinic 
N/A 
Morning Fast 
Until PK 
samples are 
taken 
N/A 
N/A 
N/A 
Until PK 
sample is 
taken 
N/A 
Sample time 
windows 
relative to dose 
 
Pre-dose 
 
15-30min 
post-dose 
1.5 – 4 hr 
post-dose 
4 – 8 hr 
post-dose 
Pre-dose 
30-90 min 
post-dose 
N/A 
 
On all PK sample collection days, patients should take all study medication within 5   minutes. 
At Visits 2 and 7, patients will be asked to arrive at the study site after an overnight fast. Patients 
will receive an oral dose of placebo or baricitinib at the study site and will remain fasted until PK 
blood samples have been collected. A light snack will be provided after PK samples have been 
collected. 
At Visits 4 and 5, patients will be advised to take the study drug at home. Patients will then go  
to the study site in the scheduled time window for study  assessments. 
At Visit 6, patients will be advised to NOT take study drug prior to visiting the study site. A 
single blood sample will be collected prior to the patient taking their drug at the study   site. 
A single PK sample will be obtained, whenever possible, at the early termination visit. In the 
event of an SAE, up to 2 additional blood samples may be taken at the investigator’s discretion, 
up to 6 hours after the reported event and within 24 hours of the patient’s last   dose. 
For any PK sample taken, the actual date and time (24-hour clock) of PK sample collection as 
well as the date and time of the last 2 dose administrations prior to the PK sample should be 
recorded. 
The sponsor, or its designee, will provide instructions for the collection and handling of blood 
samples. 
 
8.5.2. PK Sample Assay 
Plasma samples will be assayed for baricitinib using a validated liquid chromatography with 
tandem mass spectrometry (LC/MS/MS) method at a laboratory approved by the   sponsor. 
 
 
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Samples from patients receiving baricitinib will be assayed. PK samples from patients on 
placebo are not planned to be assayed. 
 
8.5.3. PK Sample Storage and  Retention 
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following last patient visit for the study. Pharmacokinetic samples will  
be kept in storage at a laboratory facility designated by the sponsor and may also be assayed for 
additional exploratory analyses. Pharmacokinetic results will not be provided to investigative   
sites or blinded personnel until the study has been  unblinded. 
 
8.6. Pharmacodynamics 
Further pharmacodynamic data, beyond efficacy and biomarker data, will not be   collected. 
 
8.7. Genetics 
A blood sample (approximately 10 mL) will be collected for pharmacogenetic analysis as 
specified in the Schedule of Activities (Appendix 2) where local regulations and ethical review 
boards (ERBs) allow. 
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 atopic dermatitis or other inflammatory skin 
disorders. Assessment of variable response may include evaluation of AEs or differences in 
efficacy.  These studies may include but are not limited to evaluate their association with  
observed response to baricitinib. 
All pharmacogenetic samples will be coded with the patient number. Only investigator site 
personnel can link these samples, and any data generated, back to the patient. Samples will be 
destroyed according to a process consistent with local  regulations. 
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 ERBs impose shorter time limits, at a facility 
selected by the sponsor. 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 drug development or when the drug is commercially  available. 
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named. However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, candidate gene studies, and epigenetic analyses. 
Regardless of technology utilized genotyping data generated will be used only for the specific 
research scope described here. 
 
8.8. Biomarkers 
Skin biopsies, serum, plasma, and whole blood ribonucleic acid (RNA) samples for non-genetic 
biomarker research will be collected at the times specified in the Schedule of Activities 
(Appendix 2) where local regulations and ERBs  allow. 
 
 
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Samples may be used for research on the drug target, disease process, pathways associated with 
atopic dermatitis, mechanism of action of baricitinib, and/or research method or in validating 
diagnostic tools or assay(s) related to atopic  dermatitis. 
All biomarker samples will be coded with the patient number. Only investigator site personnel 
can link these samples, and any data generated, back to the patient. Samples will be destroyed 
according to a process consistent with local  regulations. 
Samples will be retained for a maximum 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   
the sponsor. 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 drug 
development or when the drug is commercially  available. 
 
8.8.1. Skin Biopsies 
Patients will be required to provide skin punch biopsy samples collected per the Schedule of 
Activities (Appendix 2), unless exempted by the  investigator. 
Skin biopsy samples from atopic dermatitis lesions and adjacent normal tissue will be collected 
and used to study biomarkers related to atopic dermatitis and/or related to the mechanism of  
action of baricitinib. Techniques used may include but are not limited to immunohistochemistry 
and microarray expression profiling. Samples will be de-identified as described in International 
Conference on Harmonisation (ICH) guideline E15, and may be used for exploratory microarray 
expression profiling or transcriptome sequencing. Detailed instructions for sample collection and 
handling will be provided by the sponsor. Samples will be sent to a sponsor-designated lab for 
immunohistochemistry. 
 
8.8.2. Nonpharmacogenetic  Biomarkers 
Peripheral serum samples (approximately 10 mL) will be collected at pre- and post-treatment 
time points for the assessment of biomarkers expected to be mechanistically related to JAK 1/2 
inhibition and/or the atopic dermatitis disease state. A blood sample for genotyping of filaggrin 
will also be collected. Sample processing and handling instructions will be provided by the 
sponsor. Samples will be sent to a sponsor-designated lab for  evaluation. 
Exploratory biomarker serum, plasma, and blood for mRNA samples will also be collected and 
stored at a sponsor-designated vendor. 
 
8.9.    Health Economics 
The self-reported questionnaires will be administered according to the Schedule of Activities 
(Appendix 2). The questionnaires will be administered in countries where they have been 
translated into the native language of the region and linguistically  validated. 
 
 
 
 
 
 
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9. Statistical Considerations and Data  Analysis 
9.1. Determination of Sample Size 
Approximately 120 patients will be enrolled using a 4:3:3 randomization scheme of placebo,  
2 mg baricitinib, or 4 mg baricitinib, respectively. Assuming a drop-out rate no greater than 
20%, approximately 96 patients will complete the  study. 
This sample size provides 90% power to detect a 35% difference in EASI-50 between placebo 
and the 4-mg baricitinib treatment group using a 2-sided chi-square test with alpha =   0.05. 
 
9.2. General Statistical Considerations 
Statistical analysis of this study will be the responsibility of the sponsor or its designee. A 
detailed statistical analysis plan (SAP) will be provided by the sponsor or its designee, and will 
be finalized prior to database lock and  unblinding. 
Investigator site data will be pooled for statistical analysis  purposes. 
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated. 
Data analyses will be provided by treatment groups and for all study patients combined wherever 
appropriate. For continuous variables, summary statistics will include number of patients, mean, 
median, standard deviation, minimum, and maximum.  Categorical endpoints will be    
summarized using number of patients, frequency, and  percentages. 
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report. Additional exploratory analyses of the data will be conducted as 
deemed appropriate. 
 
9.3. Treatment Group Comparability 
9.3.1. Patient Disposition 
All patients who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported. If known, a reason for their discontinuation will be 
given.  Data tabulations will summarize the following patient numbers, per treatment   group: 
 Enrolled 
 Received treatment 
 Violated the protocol 
 Completed the protocol 
 Withdrew because of: 
o Adverse event 
o Lack of efficacy 
o Consent withdrawal 
 
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o Other reasons, as applicable 
A detailed description of patient disposition will be provided at the end of the   study. 
 
9.3.2. Patient Characteristics 
Baseline and demographic characteristics will be summarized descriptively by treatment group 
and overall. 
 
9.3.3. Concomitant Therapy 
Concomitant use of topical corticosteroids will be summarized by treatment   group. 
 
9.4. Primary and Secondary Analyses 
9.4.1. Primary Analyses 
The primary outcome will be the proportion of patients achieving EASI-50 in each treatment   
arm. The primary analysis will be performed using all randomized patients utilizing a Non- 
Responder Imputation (NRI) analysis. The proportion of patients achieving EASI-50 in the 
placebo arm will be compared to proportion of patients in each of the baricitinib arms using a two-
sided chi-square test with alpha=0.05. To control the study-wise type 1 error rate, the comparison 
of the baricitinib arms with the placebo arm will be performed in a stepwise fashion. The 4-mg 
baricitinib arm will be compared with the placebo arm; if this test is statistically significant, then 
the 2-mg baricitinib arm will be compared with the placebo arm. Enrollment of 120 patients in a 
4:3:3 ratio will provide approximately 90% power for detecting a 35%  difference in the EASI-50 
response rate between placebo and the 4-mg baricitinib treatment   arm. 
For EASI-50 endpoint, all Non-Responders, as well as all patients who discontinue study 
treatment at any time prior to the time point of interest or discontinue from the study for any 
reason, will be defined as Non-Responders for the NRI analysis. Randomized patients without at 
least 1 post-baseline observation will also be defined as Non-Responders for the NRI   analysis. 
 
9.4.2. Secondary Analyses 
Continuous secondary endpoints will be summarized and analyzed using treatment groups by use 
of a mixed effects model with treatment as the main factor and baseline values as covariates. The 
treatment (intercept) effects and their standard errors from the mixed effects model will be used   
to produce p-values and 90% confidence intervals for the treatment   comparison. 
For continuous endpoints collected longitudinally, missing data will assumed to be missing at 
random and a mixed model repeated measures (MMRM) approach will be used. Other 
imputation techniques, such as multiple imputation, may be utilized in sensitivity   analyses. 
Categorical secondary endpoints will be summarized and analyzed using a chi-square test or 
Fisher’s exact test, if needed. 
 
9.4.3. Tertiary/Exploratory Analyses 
Continuous secondary endpoints will be summarized and may be analyzed by use of a mixed 
effects model with treatment as the main factor and baseline values as covariates. The   treatment 
 
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(intercept) effects and their standard errors from the mixed effects model will be used to produce 
p-values and 90% confidence intervals for the treatment  comparison. 
Categorical secondary endpoints will be summarized and may be analyzed using a chi-square 
test or Fisher’s exact test, if needed. 
 
9.5. Safety Analyses 
Safety analyses will be conducted on all patients who received at least one dose of study drug. 
No statistical comparisons of treatment groups will be completed for safety   endpoints. 
All adverse events will be summarized and listed. The incidence of symptoms for each treatment 
will be presented by severity and by association with study drug as perceived by the investigator. 
Symptoms reported to occur prior to enrollment will be distinguished from those reported as new 
or increased in severity during the  study. 
Additional safety parameters that will be assessed include safety lab parameters and vital signs. 
The parameters will be listed, and summarized using standard descriptive statistics. Additional 
analysis will be performed if warranted upon review of the  data. 
 
9.6. Pharmacokinetic/Pharmacodynamic  Analyses 
The pharmacokinetics of baricitinib will be assessed using population PK analysis techniques. 
The relationship between the primary and secondary efficacy endpoints and plasma exposure, 
race, and age of onset may be explored. PK and PD data may be combined with prior data for an 
integrated analysis. 
 
9.7. Other Analyses 
9.7.1. Health Economics 
Patient reported outcome endpoints will be summarized and analyzed using treatment groups by 
use of a mixed effects model with treatment as the main factor and baseline values as covariates. 
The treatment (intercept) effects and their standard errors from the mixed effects model will be 
used to produce p-values and 90% confidence intervals for the treatment   comparison. 
 
9.7.2. Biomarkers 
Biomarker data from all patients undergoing biomarker assessments will be analyzed. Biomarker 
data will be summarized and listed, and may be displayed  graphically. 
 
9.8.    Interim Analyses 
An interim analysis is not planned for this  study. 
 
 
 
 
 
 
 
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10. Study Governance Considerations 
10.1. Regulatory and Ethical Considerations, Including the Informed 
Consent Process 
10.1.1. Informed Consent 
The investigator is responsible for ensuring  that: 
 the patient understands the potential risks and benefits of participating in the 
study 
 informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of 
investigational product. 
 any questions the patient may have throughout the study are answered and 
shares, in a timely manner, any new information that may be relevant to the 
patient’s willingness to continue his or her participation in the  study. 
 
10.1.2. Ethical Review 
The investigator or designee must give assurance that the ethical review board (ERB) was 
properly constituted and convened as required by International Conference on Harmonisation 
(ICH) guidelines and other applicable laws and  regulations. 
Documentation of ERB approval of the protocol and the ICF must be provided to the sponsor 
before the study may begin at the investigative site(s). The sponsor 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  GCP. 
The study site’s ERB(s) should be provided with the  following: 
 current IB and updates during the course of the  study 
 ICF 
 relevant curricula vitae 
10.1.3. 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 
 
 
 
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The investigator or designee will promptly submit the protocol to applicable   ERB(s). 
All or some of the obligations of the Sponsor may be assigned to a Contract Research 
Organization (CRO). 
An identification code assigned by the investigator to each patient will be used in lieu of the 
patient’s name to protect the patient’s identity when reporting AEs and/or other study-related 
data. 
 
10.1.4. Investigator Information 
Physicians with a specialty in dermatology will participate as investigators in this clinical   study. 
 
10.1.5. 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 sponsor  representative. 
 
10.1.6. Final Report Signature 
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 investigator with the most enrolled patients will be requested to serve as the CSR 
coordinating investigator. If this investigator is unable to fulfill this function, another 
investigator will be chosen by the sponsor to serve as the CSR coordinating   investigator. 
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study. 
 
10.2. Data Quality Assurance 
To ensure accurate, complete, and reliable data, the sponsor/designee will perform the   following: 
 provide instructional material to the study sites, as  appropriate 
 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 
 
 
 
 
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 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, the sponsor/designee will periodically check a sample of the patient data recorded 
against source documents at the study site. The sponsor/designee and/or regulatory agencies 
may audit the study at any time.  Investigators will be given notice before an audit   occurs. 
The investigator will keep records of all original source data.  This might include laboratory  
tests, medical records, and clinical notes. If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents. 
 
10.2.1. Data Capture System 
An electronic data capture (EDC) system will be used in this study. The site maintains a source 
for the data entered into the sponsor-designated EDC system, if collected external to the EDC 
system. 
Electronic patient-reported outcome (ePRO) measures (for example, a rating scale) or other data 
reported directly by the patient (for example, daily dosing schedule, event diary) may be entered 
into an ePRO instrument (for example, personal digital assistant [PDA]), or by means of an 
interactive response technology system (IRT) at the time the information is obtained. In these 
instances where there is no prior written or electronic source data at the site, the ePRO  
instrument record will serve as the  source. 
If ePRO 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 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 a clinical study  database. 
Case report form data collected by a third-party will be encoded by the third-party and stored 
electronically in the third-party’s database system. Validated data will subsequently be 
transferred to the sponsor designated  database. 
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 sponsor designated  database. 
Any data for which paper documentation provided by the patient will serve as the source  
document will be identified and documented by each site in that site’s study file. Paper 
documentation provided by the patient may include, for example, a paper diary to collect patient- 
reported outcome (PRO) measures (for example, a rating scale), a daily dosing schedule, or an 
event diary. 
 
 
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Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management  system. 
 
10.3. Study and Site Closure 
10.3.1. Discontinuation of Study Sites 
Study site participation may be discontinued if the sponsor or its designee, the investigator, or 
the ERB of the study site judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and  GCP. 
 
10.3.2. Discontinuation of the Study 
The study will be discontinued if the sponsor or its designee judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and   GCP. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11. References 
[APA] American Psychiatry Association. 1994. Diagnostic and Statistical Manual of Mental 
Disorders. 4th ed. Washington DC. 
Bao L, Zhang H, Chan LS. The involvement of the JAK-STAT signaling pathway in chronic 
inflammatory skin disease atopic dermatitis. JAKSTAT. 2013 Jul   1;2(3):e24137. 
Beck, LA, Thaçi, D, Hamilton, JD, Graham, NM, Bieber, T, Rocklin, R, Ming, JE, Ren, H, Kao, 
R, Simpson, E, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. 
New Engl. J. Med. 2014, 371,  130–139. 
Bieber, T. Atopic Dermatitis. Ann Derm. 2010,  125-137. 
Bissonnette R, Poulin Y, Zhou Y, Tan J, Hong HC, Webster J, Ip W, Tang L, Lyle M. Efficacy 
and safety of topical WBI-1001 in patients with mild to severe atopic dermatitis: results from a 
12-week, multicentre, randomized, placebo-controlled double-blind trial. Br J Dermatol. 2012 
Apr;166(4):853-60. 
Charman CR, Venn AJ, Williams HC. The patient-oriented eczema measure: development and 
initial validation of a new tool for measuring atopic eczema severity from the patients' 
perspective. Arch Dermatol. 2004  Dec;140(12):1513-9. 
Epstein E, Pinski JB. A blind study. Arch Dermatol 1964; 89:  548–549. 
Ferguson T, Rowlands AV, Olds T, Maher C. Validity of consumer-level, activity monitors in 
healthy adults worn in free-living conditions: a cross-sectional study. International Journal of 
Behavioral Nutrition and Physical Activity (2015)  12:42. 
 
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure for 
routine clinical use. Clin Exp Dermatol. 1994  May;19(3):210-6. 
Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, Gruben D, 
Wallenstein GV, Zwillich SH, Kanik KS; ORAL Solo Investigators. Placebo-controlled trial of 
tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012 Aug   9;367(6):495-507. 
Hongbo Y, Thomas CL, Harrison MA, Salek MS, Finlay AY. Translating the science of quality 
of life into practice: What do dermatology life quality index scores mean? J Invest   Dermatol. 
2005 Oct;125(4):659-64. 
Keystone EC, Taylor PC, Drescher E, Schlichting DE, Beattie SD, Berclaz PY, Lee CH, Fidelus- 
Gort RK, Luchi ME, Rooney TP, Macias WL, Genovese MC. Safety and efficacy of baricitinib    
at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to 
methotrexate. Ann Rheum Dis. 2015  Feb;74(2):333-40. 
Khilji FA, Gonzalez M, Finlay AY. Clinical meaning of change in Dermatology Life Quality 
Index scores. Br J Dermatol 2002; 147 (Suppl 62):  50. 
 
 
 
 
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Klingmüller U, Wu H, Hsiao JG, Toker A, Duckworth BC, Cantley LC, Lodish HF. 
Identification of a novel pathway important for proliferation and differentiation of primary 
erythroid progenitors. Proc Natl Acad Sci U S A. 1997 Apr  1;94(7):3016-21. 
Kremer JM, Cohen S, Wilkinson BE, Connell CA, French JL, Gomez-Reino J, Gruben D, Kanik 
KS, Krishnaswami S, Pascual-Ramos V, Wallenstein G, Zwillich SH. A phase IIb dose-ranging 
study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with 
background methotrexate in patients with active rheumatoid arthritis and an inadequate response 
to methotrexate alone. Arthritis Rheum. 2012  Apr;64(4):970-81. 
Levy LL, Urban J, King BA. Treatment of recalcitrant atopic dermatitis with the oral Janus 
kinase inhibitor tofacitinib citrate. J Am Acad Dermatol. 2015   Sep;73(3):395-9. 
Mallinckrodt C, Tamura RN, Tanaka Y. Recent developments in improving signal detection and 
reducing placebo response in psychiatric clinical trials. J Psychiatric Research 45 (2011) 1202- 
1207. 
Mansouri Y, Guttman-Yassky E. Immune Pathways in Atopic Dermatitis, and Definition of 
Biomarkers through Broad and Targeted Therapeutics. J Clin Med. 2015 Apr   29;4(5):858-73. 
Menter A, Disch D, Clemens J, Janes J, Papp K, Macias W. A phase 2b trial of baricitinib, an 
oral JAK inhibitor, in patients with moderate to severe psoriasis. J Am Acad Dermatol. 2014 
May;70(5, Suppl 1): AB162. 
Muto T, Hsieh SD, Sakurai Y, Yoshinaga H, Suto H, Okumura K, Ogawa H. Brit J Derm. 2003; 
148: 117–121. 
Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, Vanin EF, Bodner S, 
Colamonici OR, van Deursen JM, Grosveld G, Ihle JN. Jak2 is essential for signaling through a 
variety of cytokine receptors. Cell. 1998 May  1;93(3):385-95. 
Pesu M, Laurence A, Kishore N, Zwillich SH, Chan G, O'Shea JJ. Therapeutic targeting of Janus 
kinases. Immunol Rev. 2008  Jun;223:132-42. 
Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, Markowitz JC, Ninan  
PT, Kornstein S, Manber R, Thase ME, Kocsis JH, Keller MB. The 16-Item Quick Inventory of 
Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a 
psychometric evaluation in patients with chronic major depression. Biol Psychiatry. 2003 Sep 
1;54(5):573-83. 
Schmitt J, Langan S, Deckert S, Svensson A, von Kobyletzki L, Thomas K, Spuls P; 
Harmonising Outcome Measures for Atopic Dermatitis (HOME) Initiative. Assessment of 
clinical signs of atopic dermatitis: a systematic review and recommendation. J Allergy Clin 
Immunol.  2013 Dec;132(6):1337-47. 
Shi JG, Chen X, Lee F, Emm T, Scherle PA, Lo Y, Punwani N, Williams WV, Yeleswaram S.  
The pharmacokinetics, pharmacodynamics, and safety of baricitinib, an oral JAK 1/2 inhibitor, in 
healthy volunteers. J Clin Pharmacol. 2014  Dec;54(12):1354-61. 
 
 
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Vera J, Bachmann J, Pfeifer AC, Becker V, Hormiga JA, Darias NV, Timmer J, Klingmüller U, 
Wolkenhauer O. A systems biology approach to analyse amplification in the JAK2-STAT5 
signalling pathway. BMC Syst Biol. 2008 Apr  25;2:38. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 1. 
Abbreviations and Definitions 
 
 
 
 
 
Term 
Definition 
AD 
Atopic Dermatitis 
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 
AST 
aspartate aminotransferase 
Audit 
A systematic and independent examination of the study-related activities and    
documents to determine whether the evaluated study-related activities were conducted, 
and the data were recorded, analyzed, and accurately reported according to the protocol, 
applicable standard operating procedures (SOPs), good clinical practice (GCP), and the 
applicable regulatory requirement(s). 
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 patients are 
aware of the treatment received. 
BSA 
body surface area 
Chorus 
A semi-autonomous clinical development organization within Eli Lilly and  Company. 
CIOMS 
Council for International Organizations of Medical  Sciences 
CKD EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
Compliance 
Adherence to all the study-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory  requirements. 
 
 
 
 
 
 
 
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Confirmation 
A process used to confirm that laboratory test results meet the quality requirements 
defined by the laboratory generating the data and that Lilly is confident that results are 
accurate. Confirmation will either occur immediately after initial testing or will require 
that samples be held to be retested at some defined time point, depending on the steps 
required to obtain confirmed results. 
CRF/eCRF 
case report form/electronic case report form (sometimes referred to as clinical report 
form): A printed or electronic form for recording study participants’ data during a 
clinical study, as required by the protocol. 
CRO 
contract research organization 
CRP 
Clinical research physician:  individual responsible for the medical conduct of the 
study. Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical  officer. 
CRU 
clinical research unit 
CS 
Corticosteroid 
CSE 
clinically significant event.  A moderate-to-severe adverse event (AE), abnormal 
clinical sign, or clinical laboratory finding that may pose a risk to the well-being of the 
patient. 
CSR 
clinical study report 
DLQI 
Dermatologic Life Quality Index 
DMC 
data monitoring committee 
DN 
Diabetic Nephropathy 
DNA 
deoxyribonucleic acid 
DSUR 
Development Safety Update Report 
EASI 
Eczema Area and Severity Index 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eGFR 
estimated glomerular filtration  rate 
End of study 
Date of the last visit or last scheduled procedure shown in the Study Schedule for the 
last active patient in the study 
Enroll 
The act of assigning a patient to a treatment. Patients who are enrolled in the study are 
those who have been assigned to a treatment. 
 
 
 
 
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Enter 
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives. 
ePRO 
electronic patient-reported outcome 
ERB/IRB 
ethical review board/institutional review board: a board or committee (institutional, 
regional, or national) composed of medical professionals and nonmedical members 
whose responsibility is to verify that the safety, welfare, and human rights of the 
patients participating in a clinical study are protected. 
e-source 
electronic source documentation 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
GGT 
gamma glutamyltransferase 
H2 receptor 
histamine H2 receptor 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV DNA 
hepatitis B virus DNA 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IFN-γ 
interferon-gamma 
IGA 
Investigator’s Global Assessment 
IgE 
immunoglobulin E 
IL 
Interleukin 
INR 
international normalized ratio 
Informed consent 
A process by which a subject voluntarily confirms his or her willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the subject's decision to participate. Informed consent is documented by 
means of a written, signed and dated informed consent  form. 
 
 
 
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Interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is  created/locked. 
Investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical study, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. 
Investigator 
A person responsible for the conduct of the clinical study at a study site. If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal  investigator. 
ITT 
intention to treat: The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given. It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that treatment group irrespective of their 
compliance to the planned course of treatment. 
IRT 
interactive response technology system 
JAK 
Janus kinase 
JAK1, JAK2, JAK3 
kinases belonging to the Janus kinase family 
Legal Representative 
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective subject, to the subject’s participation in the clinical  study. 
Lilly 
Eli Lilly and Company 
LRL 
Lilly Research Laboratories 
MMRM 
mixed model repeated measures 
MOS 
margin of safety 
NRI 
non-responder imputation 
NRS 
numerical rating scale 
PASI 
Psoriasis Area and Severity Index 
Patient 
A study participant who has the disease or condition for which the investigational 
product is targeted. 
PK/PD 
pharmacokinetics/pharmacodynamics 
PO 
per os; oral administration 
POCT 
point-of-care testing 
POEM 
Patient-Oriented Eczema Measure 
 
 
 
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PPD 
purified protein derivate 
PRO/ePRO 
patient-reported outcomes/electronic patient-reported  outcomes 
QIDS-SR16 
Quick Inventory of Depressive Symptomatology-Self Report  16 
QD 
once daily 
Randomize 
the process of assigning subjects to an experimental treatment group according to the 
randomization schedule for the study. 
RA 
Rheumatoid Arthritis 
RNA 
ribonucleic acid 
SAE 
serious adverse event; any untoward medical occurrence that at any dose results in 
death, is life threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability/incapacity, or is a 
congenital anomaly/birth defect. 
SAP 
statistical analysis plan 
SCORAD 
SCORing of Atopic Dermatitis 
Screening 
The act of determining if an individual meets minimum requirements to become part of  
a pool of potential candidates for participation in a clinical  study. 
SUSARs 
suspected unexpected serious adverse reactions 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event: Any untoward medical occurrence that either occurs 
or worsens at any time after treatment baseline and that does not necessarily have to  
have a causal relationship with this treatment. 
Th1, Th 2 
subsets of T helper cells; T lymphocytes expressing CD4 are also known as helper T 
cells 
TSH 
thyroid stimulating hormone. 
ULN 
upper limit of normal 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 2. 
Schedule of Activities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study Schedule of Activities Protocol  I4V-MC-JAHG 
 
Procedure 
Screening 
Treatment Period 
Washout 
Period 
Early 
Term 
Study Visit 
V1 
V1a a 
V2 
V3 
V4 
V5 
V6 
V7 
V8 (LPV) 
Study Week relative to Start of 
Investigational Product 
0 
1 
4 
8 
12 
16 
20 
ET 
Study Day Relative to Start of Investigational 
Product 
-38 to 
-28 
1 to 3 days 
after V1 
0 
7 
28 
56 
84 
112 
140 
ET 
Visit Tolerance Window (days) 
±2 
±4 
±4 
±4 
±4 
±4 
Study Site/CRU Visit 
X 
X (applicable for 
PPD only) 
X 
X 
X 
X 
X 
X 
X 
X 
ICF 
X 
Clinical Assessments 
Demographics, Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
QuantiFERON®-TB Gold, or 
T-SPOT.TB® test or PPD (read 48-72 hrs  later) 
X 
Read PPD (if applicable) 
X 
ECG (single)-Taken prior to all other 
assessments at V1 
X 
Chest x-ray
b (posterior-anterior view) 
X 
Inclusion/Exclusion Review for Entry 
X 
Inclusion/Exclusion Review for Enrollment 
X 
Randomization 
X 
Medical History and PE 
X 
Symptom Directed PE 
X 
X 
X 
X 
X 
X 
X 
X 
Previous AD Therapy 
X 
Habits 
X 
continued on next page 
 
a If the QuantiFERON-TB Gold test or T-SPOT.TB test is available and, if, in the judgment of the investigator, it is preferred as an alternative to the PPD skin test for the evaluation of tuberculosis    
infection, it may be used instead of the PPD skin 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 will be 
excluded from the study. 
b 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. 
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Procedure 
Screening 
Treatment Period 
Washout 
Period 
Early 
Term 
Study Visit 
V1 
V1a 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
(LPV) 
Study Week relative to Start of 
Investigational Product 
0 
1 
4 
8 
12 
16 
20 
ET 
Study Day Relative to Start of Investigational 
Product 
-38 to 
-28 
1 to 3 days 
after V1 
0 
7 
28 
56 
84 
112 
140 
ET 
Visit Tolerance Window (days) 
±2 
±4 
±4 
±4 
±4 
±4 
Clinical Assessments (continued) 
Vital Signs (BP and pulse) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense topical corticosteroid (as needed) 
X 
X 
X 
X 
X 
X 
X 
Weigh and record topical corticosteroid 
container with cap 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Discontinue all excluded AD medications 
X 
Pre-existing Conditions 
X 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigational Product Package Dispensed 
X 
X 
X 
X 
X 
Investigational Product Package 
Returned/Compliance Assessed 
X 
X 
X 
X 
X 
X 
Dose administration at site 
X 
X 
X 
EASI 
X 
X 
X 
X 
X 
X 
X 
X 
SCORAD 
X 
X 
X 
X 
X 
X 
X 
X 
IGA 
X 
X 
X 
X 
X 
X 
X 
X 
Itch NRS 
X 
X 
X 
X 
X 
X 
X 
DLQI 
X 
X 
X 
X 
X 
X 
X 
POEM 
X 
X 
X 
X 
X 
X 
X 
continued on next page 
 
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Procedure 
Screening 
Treatment Period 
Washout 
Period 
Early 
Term 
Study Visit 
V1 
V1a 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
(LPV) 
Study Week relative to Start of 
Investigational Product 
0 
1 
4 
8 
12 
16 
20 
ET 
Study Day Relative to Start of 
Investigational Product 
-38 to 
-28 
1 to 3 
days 
after V1 
0 
7 
28 
56 
84 
112 
140 
ET 
Visit Tolerance Window (days) 
±2 
±4 
±4 
±4 
±4 
±4 
Clinical Assessments (continued) 
QIDS-SR16 
X 
X 
X 
X 
X 
X 
X 
Actigraphy Device Download 
X 
X 
X 
X 
X 
X 
Biopsy performed (NL: non-lesion and L: lesion to 
be performed following Investigator and Patient rating 
scale assessments) 
X 
(NL, L) 
X 
(L) 
X 
(NL, L) 
Laboratory Assessments-(collect all non- 
PK samples pre-dose, as applicable) 
Hematology 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry 
X 
X 
X 
X 
X 
X 
X 
Lipids (fasting) 
X 
X 
eGFR (CKD EPI) 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
HBsAg, HBcAb, HBsAb (including 
Quantitative HBsAb load assessment) 
X 
HBV DNA 
X 
 
continued on next page 
 
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Procedure 
Screening 
Treatment Period 
Washout 
Period 
Early 
Term 
Study Visit 
V1 
V1a 
V2 
V3 
V4 
V5 
V6 
V7 
V8 (LPV) 
Study Week relative to Start of 
Investigational Product 
0 
1 
4 
8 
12 
16 
20 
ET 
Study Day Relative to Start of Investigational 
Product 
-38 to 
-28 
1 to 3 
days 
after 
V1 
0 
7 
28 
56 
84 
112 
140 
ET 
Visit Tolerance Window (days) 
±2 
±4 
±4 
±4 
±4 
±4 
Laboratory Assessments (cont.-collect all 
non-PK samples pre-dose, as applicable) 
Hep C Antibody 
X 
HIV 
X 
Thyroid Function Tests 
X 
Serum Pregnancy Test 
X 
Urine Pregnancy Test 
X 
X 
X 
X 
X 
X 
X 
FSH 
X 
Stored serum and plasma for /Exploratory 
Biomarkers 
X 
X 
X 
X 
Stored blood for RNA and Exploratory 
Biomarkers 
X 
X 
X 
X 
Blood for DNA (filaggrin genotyping) 
X 
Plasma for baricitinib Concentration (See PK 
Sample Collection Visits Table JAHG.5) 
X 
X 
X 
X 
X 
X 
Stored blood for pharmacogenetics 
X 
Serum for Disease State Biomarkers 
X 
X 
X 
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Appendix 3. 
Clinical Laboratory Tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Laboratory Tests 
Hematologya,b 
Clinical Chemistrya,b 
Hemoglobin 
Serum Concentrations of: 
Hematocrit 
Sodium 
Erythrocyte count (RBC) 
Potassium 
Mean cell volume 
Total bilirubin 
Mean cell hemoglobin concentration 
Direct bilirubin 
Leukocytes (WBC) 
Alkaline phosphatase 
Reticulocyte 
Alanine aminotransferase (ALT/SGPT) 
Absolute counts of: 
Aspartate aminotransferase (AST/SGOT) 
Neutrophils, segmented 
Blood urea nitrogen (BUN) 
Neutrophils, juvenile (bands) 
Creatinine 
Lymphocytes 
Uric acid 
Monocytes 
Calcium 
Eosinophils 
Glucose 
Basophils 
Albumin 
Platelets 
Total protein 
Cell morphology 
Estimated glomerular filtration rate (eGFR)e 
Creatine phosphokinase (CPK) 
Urinalysisa,b,d 
Color 
Other Testsa 
Specific gravity 
Hepatitis B Surface antigenf 
pH 
Anti-Hepatitis B Core antibodyf 
Protein 
Quantitative HBsAb load assessmenta 
Glucose 
Hepatitis B Surface antibodyf 
Ketones 
Human immunodeficiency virusf 
Bilirubin 
Hepatitis C antibodyf,g 
Urobilinogen 
Thyroid-stimulating hormonef 
Blood 
Thyroxinef 
Leukocyte esterase 
Pregnancy Testh 
Nitrite 
FSHf,i 
Serum immunoglobulin (IgA, IgG, and IgM) 
Lipid (Fasting) a,c 
PPD, QuantiFERON®-TB Gold or T-SPOT.TB® j 
Total cholesterol 
Low-density lipoprotein 
Baricitinib plasma levels 
High-density lipoprotein 
HBV DNA 
Triglycerides 
 
Abbreviations: CKD-EPI= Chronic Kidney Disease Epidemiology Collaboration; DNA = deoxyribonucleic   acid; 
FSH = folliclestimulatinghormone; HBV = Hepatitis B virus;; RBC =  red 
blood cells; RNA = ribonucleic acid; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic 
pyruvic transaminase; TB = tuberculosis; WBC = white blood  cells. 
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. 
d Microscopic examination of sediment performed only if abnormalities are noted on the routine urinalysis.  
e eGFR for serum creatinine calculated by the central laboratory using the -CKD EPI   method. 
 
 
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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 all visits thereafter. 
i To confirm postmenopausal status for women ≥40 and <60 years of age who have had a cessation of menses, an 
FSH test will be performed. Non-childbearing 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 sponsor, its designee, or 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 
Anti-smooth muscle antibodya 
Abbreviations: ALT = alanine aminotransferase; AST = aspirate aminotransferase; GGT = gamma-glutamyl 
transferase; Ig = immunoglobulin; INR = international normalised ratio; RBC = red blood cells; WBC = white 
blood cells. 
a Assayed by sponsor-designated or local laboratory. 
b Reflex/confirmation dependent on regulatory requirements and/or testing  availability. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14V -MC.J AHG( a ) C lini ca l Pro toco l 
P ag e 6 3 
 
Appendix 5. 
Protocol 14V-MC-JAHG Signature Page 
 
 
 
I confinn that I have read this protocol; I understandit and I will work according to this protocol. 
I will also work consistently with the ethical p1inciples that have their origin in the Declaration 
of Helsinki and that are consistent with good clinical practices and applicable laws and 
regulations. I will accept the monitor's overseeingof the study. I will abide bythe publication 
plan set forth in my Agreement with the sponsor (Choms, Eli Lilly and Company) or designee. I 
will promptly submit the protocol to applicable ethical review board(s). I confirm that ifl or any 
of mystaff are members of the ethical review board, we will abstain from voting on this 
protocol. 
 
 
Signature of Investigator 
Date 
 
 
Investigator Name (Title) 
 
 
Name of Facility 
 
 
Location of Facility 
(City, State(if applicable), Country) 
 
 
 
Signature of sponsor 
Date (dd-m1mn-yyyy) 
PD 
(Chief Medical Officer, Choms-Eli 
  Lilly and Company) 
 
Sponsor name (Title) 
 
   Eli Lilly and Company 
 
Name 
Lilly Coroorate Center. Indianapolis, Indiana. USA 
Location (City, State (if applicable), Country) 
 
 
LY3009104 
Instructionsto the Investigator: Please SIGNand DATEthis signaturepage. PRINT your 
name, tiUe andthe name of thefacility in which thestudy will beconductedon bothcopies. 
Return 1 of the·s   nedco iesto the 
nsor Chorus, Eli Lil  andCorn  n  or desi  nee. 

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Appendix 6. 
Protocol  Amendment I4V-MC-JAHG(a) 
Summary [A Randomized, Double-Blind, Placebo- 
Controlled, Phase 2 Study to Evaluate the Safety and 
Efficacy of Baricitinib in Patients with Moderate-to- 
Severe Atopic Dermatitis] 
 
 
 
Overview 
Protocol I4V-MC-JAHG [A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to 
Evaluate the Safety and Efficacy of Baricitinib in Patients with Moderate-to-Severe Atopic 
Dermatitis] has been amended. The new protocol is indicated by amendment (a) and will be  
used to conduct the study in place of any preceding version of the  protocol. 
The overall changes and rationale for the changes made to this protocol are as   follows: 
 The number of patients to be enrolled in this study has been increased from 90 to 120. 
The statistical analysis and power statements in the protocol have been revised to reflect 
this patient increase. The study diagram and all text related to the number of enrolled 
patients have been revised accordingly. 
 The original statistical analysis included two 1-sided tests for comparing the two 
baricitinib dose levels with placebo. The protocol has been revised to reflect a plan to 
control the type 1 error for the primary efficacy analysis at 5%, by including 2, 5% level, 
2-sided tests for testing the two baricitinib dose levels with placebo and a sequential 
testing strategy that first examines the highest dose relative to placebo and only tests the 
lower dose relative to placebo if there is statistical significance for the highest   dose. 
 
 The planned interim analysis has been removed based on the aforementioned statistical 
analysis strategy. 
 
 The definition of a positive Hepatitis B test was clarified as were the HBV DNA 
monitoring criteria. 
 
 The BSA inclusion criteria was changed from >10% BSA to ≥10%  BSA. 
 
 Minor textual edits were made for the purpose of clarification or  correction. 
 
 
 
 
 
 
 
 
 
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Revised Protocol Sections 
 
Note: 
Deletions have been identified by strikethroughs or grayed out for  figures. 
Additions have been identified by the use of  underscore. 
1 
Protocol Synopsis 
Summary of Study Design: 
 
Study I4V-MC-JAHG is a multicenter, randomized, double-blind, parallel, placebo-controlled study designed to 
compare the efficacy and safety of baricitinib to placebo in patients with moderate-to-severe atopic dermatitis. 
Enrollment will be targeted at 90120 patients to enable approximately 7296 patients to complete the study. An 
interim analysis may be implemented and could result in up to an additional 30 patients being enrolled. Patients 
who meet all eligibility criteria will be randomized to receive either placebo or baricitinib, administered as once 
daily oral doses of 2 mg or 4 mg.  Randomization will occur at the country  level. 
Number of Patients:  90120 
 
Statistical Analysis: 
 
Sample Size 
The study will begin with a plan to enroll 90120 patients that will be 
randomized 4:3:3 to placebo, 2 mg baricitinib, or 4 mg baricitinib, 
respectively. A maximum of 30 additional patients may be enrolled 
depending on the results of the interim analysis. 
Primary Outcome & Methodology 
The primary outcome parameter is the proportion of patients achieving 
EASI-50 in each treatment arm. The placebo arm will be compared to each  
of the baricitinib arms using a one two-sided chi-square test with  
alpha=0.05. To control the study-wise type 1 error rate, the comparison of  
the baricitinib arms with the placebo arm will be performed in a stepwise 
fashion. The 4-mg baricitinib arm will be compared with the placebo arm;    
if this test is statistically significant, then the 2-mg baricitinib arm will be 
compared with the placebo arm. As this is a proof of concept study, there  
will not be any adjustment of alpha for multiple comparisons. Enrollment of 
120 90 patients in a 4:3:3 ratio provides approximately 90% power for 
detecting and a 35% difference in the EASI-50 response rate between 
placebo and either the 4-mg baricitinib treatment arm , statistical power is 
estimated to be apprxoimately 80%. 
Interim Analysis 
An interim analysis is not planned for this study. 
An interim analysis may be conducted to assess variability, effect size, and 
placebo effect during the course of the study in order to evaluate the 
potential need for an increase in the number of patients randomized (up to a 
total of 120) and/or a possible change in randomization ratio.  Details  
around this potential interim analysis will be described in the statistical 
analysis plan (SAP) or in interim analysis planning documentation,  as 
 
 
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appropriate. 
 
 
4.1 
Overview of Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4 mg baricitinib 
2 mg baricitinib 
 
 
 
 
 
 
 
 
I4V-MC-JAHG(a) Clinical Protocol 
Page 67 
 
Standardization 
Treatment 
Follow-up 
 
 
 
 
120 AD 
Patients 
Placebo 
4 Weeks 
16 Weeks 
4 Weeks 
Visit: 
1 
2 
3 
4 
5 
6 
7 
8 
Week: 
-4 
0 
1 
4 
8 
12 
16 
20 
Day: 
-28 
0 
7 
28 
56 
84 
112 
140 
 
 
 
Screening Randomization 
(4:3:3) 
Placebo : 2 mg baricitinib : 4 mg baricitinib 
Figure JAHG.1. 
Illustration of study design for Clinical Protocol  I4V-MC-JAHG. 
 
 
5.1 
Inclusion Criteria 
[2] Have moderate-to-severe AD, as determined by all of the  following: 
 EASI ≥12 at Visits 1 and 2 
 >≥10% of body surface area (BSA) involvement at Visits 1 and  2 
 Were diagnosed with AD at least 2 years before Visit  1 
5.2 
Exclusion Criteria 
[20] Positive test for hepatitis B defined as: 
a) positive for hepatitis B surface antigen (HBsAg),  or 
b) positive for anti-hepatitis B core antibody (HBcAb), but negative for hepatitis B 
surface antibody (HBsAb) or 
c)b) positive for anti-hepatitis B core antibody (HBcAb) positive and positive for 
hepatitis B deoxyribonucleic acid (HBV DNA) positive,  or 
d)c)for sites in Japan only, positive for HBcAb and/or anti-hepatitis B surface 
antibody (HBsAb) and positive for hepatitis B deoxyribonucleic acid (HBV 
DNA). 
 
If any of the hepatitis B tests have an indeterminate result, confirmatory testing will 
be performed by an alternate method. 
 
 
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8.4.5. 
Hepatitis B virus (HBV) DNA  monitoring 
Patients enrolled in the US who are HBsAg negative, HBcAb positive, and HBV DNA negative 
(undetectable) at Visit 1 will require HBV DNA monitoring at Visits 5 and 8 or ET, every 3 
months and at the patient’s last visit (V8 or ET), regardless of their HBsAb   status. 
For patients enrolled at study sites in Japan onlyPatients enrolled in Japan who are HBsAg 
negative, HbBsAb and/or HBcAb positive, and negative for HBV DNA negative (undetectable) 
at Visit 1 will require HBV DNA needs to be monitoring atVisits 5 and 8 or ETchecked at least 
monthly and at the patient’s last visit (V8or  ET). 
In all geographies, if the HBV DNA result is ‘target detected’ ≥29 IU/mL, then the patient  
should be referred to a hepatology specialist immediately and discontinuation considered (refer  
to Table JAHG.4). In selected cases, investigators may temporarily continue study drug in 
accordance with current immunomodulator management in the setting of HBV DNA positivity. 
This option may be considered in consultation with the sponsor (or its designee) and evaluation 
of individual patient risks and benefits. The following actions should be taken in response to 
HBV DNA test results: 
* If a result of “target detected” is obtained at any time during the study with a value of ≥29 
IU/mL, refer to Table JAHG.4. 
 
9.1 
Determination of Sample Size 
Approximately 90120 patients will be enrolled using a 4:3:3 randomization scheme of placebo,  
2 mg baricitinib, or 4 mg baricitinib, respectively. Assuming a drop-out rate no greater than 
20%, approximately 7296 patients will complete the  study. 
This sample size provides 8090% power to see detect a 35% difference in EASI-50 between 
placebo and either the 4-mg baricitinib treatment group of 35%, assuming a placebo response 
rate of 40%, using a 12-sided chi-square test with alpha =  0.05. 
An interim analysis may be conducted to assess variability, effect size, and placebo effect to 
evaluate the need for an increase in the number of patients randomized up to a total of 120 and/or  
a possible change in randomization ratio. Details around this potential interim analysis will be 
described in the statistical analysis plan (SAP) or in interim analysis planning documentation, as 
appropriate. 
9.2 
General Statistical Considerations 
All tests of treatment effects will be conducted at a 12-sided alpha level of 0.05, unless otherwise 
stated. 
9.4.1  Primary Analyses 
The primary outcome will be the proportion of patients achieving EASI-50 in each treatment 
arm. The primary analysis will be performed using all randomized patients utilizing a Non- 
Responder Imputation (NRI) analysis. The proportion of patients achieving EASI-50 in the 
placebo arm will be compared to proportion of patients in each of the baricitinib arms using   a 
 
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onetwo-sided chi-square test with alpha=0.05. To control the study-wise type 1 error rate, the 
comparison of the baricitinib arms with the placebo arm will be performed in a stepwise fashion. 
The 4-mg baricitinib arm will be compared with the placebo arm; if this test is statistically 
significant, then the 2-mg baricitinib arm will be compared with the placebo arm. Enrollment of 
120 patients in a 4:3:3 ratio will provide approximately 90% power for detecting a 35%  
difference in the EASI-50 response rate between placebo and 4-mg baricitinib treatment arm.As 
this is a proof of concept study, there will not be any adjustment of alpha for multiple 
comparisons. 
9.8 
Interim Analyses 
An interim analysis is not planned for this  study. 
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, in order to initiate the 
final  population pharmacokinetics/pharmacodynamics  (PK/PD) model  development  processes 
for interim or final analyses. 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. 
An interim analysis may be conducted to assess variability of response, effect size, and placebo 
effect during the course of the study in order to evaluate the potential need for an increase in the 
number of patients randomized up to a total of 120 and/or a possible change in randomization 
ratio. Details around this potential interim analysis will be described in the statistical analysis 
plan (SAP) or in interim analysis planning documentation, as  appropriate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14V-MC-JAHG(a) Clinical Protocol 
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Appendix 5. 
Protocol 14V-MC-JAHG Signature Page 
 
 
I confirm that I have read this protocol; I understand it and I will workaccording to this protocol. 
I will also work consistently with the ethical principles that have their origin in the Declaration 
of Helsinki and that are consistent with good clinical practices and applicable laws and 
regulations.I will accept the monitor's overseeingof the study. I will abide by the publication· 
plan set forth in my Agreement with the sponsor (Chorus, Eli Lilly and Company) or designee. I 
will promptly submit the protocol to applicable ethical review board(s). I confirm that ifI or any 
of my staff are members of the ethical review board, we will abstain from voting on this 
protocol. 
 
 
 
 
Signature ofl nvestigator 
Date 
 
 
Investigator Name (Title) 
 
 
Name of Facility 
 
 
Location ofF acility 
(City, Stale (if applicable), Country) 
 
PPD  
  
 
rt,c,1, a tneo- -pongo- p  p  o 
Date (dd-mmm-yyyy) 
PPD 
Medical Officer, Chorus-Eli 
:cmy ancfi 
pany) 
Sponsor name (Title) 
 
   Eli Lilly and Company 
Name 
Lilly Corporate Center, Indianapolis. Indiana, USA 
Location (City, State (if applicable), Country) 
 
 
LY3009104 
Instructions to the Investigator: Please SIGN and DATE thissignature page. PRINT your 
name, title and the name of the facility in which the study willbe conducted onboth copies. 
Return 1 of the s·.  ned co  ies to the s  onsor   Chorus, Eli Lill   and Com  an    or desi nee.