Clinical trial NCT03559270
Conditions: Atopic Dermatitis
Keywords: eczema atopic eczema
Sponsor: Eli Lilly and Company
Start date: 2018-06-27; Completion date: 2022-06-13
Enrollment: 374 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This open-label study will evaluate the long-term efficacy and safety of baricitinib in adult participants with moderate to severe atopic dermatitis (AD).

Detailed description:

Arms: arm 1: Open-label 2 mg baricitinib administered orally once daily (QD) to participants who randomized to placebo in the originating study (JAIW). arm 2: Open-label 2 mg baricitinib administered orally QD to participants who randomized to 1 mg baricitinib in the originating study (JAIW). arm 3: Open-label 2 mg baricitinib administered orally QD to participants who randomized to 2 mg baricitinib in the originating study (JAIW). arm 4: Participants were directly enrolled to receive open-label 2 mg baricitinib orally QD.
Interventions: intervention 1: Baricitinib
Intervention descriptions: intervention 1: Administered orally

Protocol documents:
SAP_002.pdf: 
I4V-MC-JAIX Statistical Analysis Plan Version 5 
 
 
A Multicenter, Open-Label, Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib in 
Adult Patients with Moderate to Severe Atopic Dermatitis 
 
NCT03559270 
 
Approval Date: 24-Jun-2022 
 
 
 


I4V-MC-JAIX Statistical Analysis Plan Version 5 
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1. 
Statistical Analysis Plan: 
A Multicenter, Open-Label, Phase 3 Study to Evaluate the 
Efficacy and Safety of Baricitinib in Adult Patients with 
Moderate to Severe Atopic Dermatitis 
BREEZE – AD6 
Confidential Information 
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.   
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries. 
Baricitinib (LY3009104) Atopic Dermatitis 
Study I4V-MC-JAIX is a Phase 3, multicenter, open-label, outpatient, 204-week study 
designed to evaluate the efficacy and safety of baricitinib 2-mg in patients with moderate to 
severe atopic dermatitis.   
Eli Lilly and Company 
Indianapolis, Indiana USA 46285 
Protocol I4V-MC-JAIX 
Phase 3 
Statistical Analysis Plan V1 electronically signed and approved by Lilly on 21 June 2018 
Statistical Analysis Plan V2 electronically signed and approved by Lilly on 24 January 2020 
Statistical Analysis Plan V3 electronically signed and approved by Lilly on 22 May 2020 
Statistical Analysis Plan V4 electronically signed and approved by Lilly on11 Feb 2021 
Statistical Analysis Plan V5 electronically signed and approved by Lilly on date provided 
below: 


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2. Table of Contents 
Section 
Page 
1. 
Statistical Analysis Plan: A Multicenter, Open-Label, Phase 3 Study 
to Evaluate the Efficacy and Safety of Baricitinib in Adult Patients 
with Moderate to Severe Atopic Dermatitis ............................................................................1 
2. 
Table of Contents ....................................................................................................................2 
3. 
Revision History ......................................................................................................................5 
4. 
Study Objectives ......................................................................................................................7 
4.1. 
Primary Objective ...............................................................................................................7 
4.2. 
Secondary Objectives .........................................................................................................7 
4.3. 
Exploratory Objectives .......................................................................................................8 
5. 
Study Design .........................................................................................................................10 
5.1. 
Summary of Study Design................................................................................................10 
5.2. 
Determination of Sample Size ..........................................................................................10 
5.3. 
Method of Assignment to Treatment ................................................................................10 
6. 
A Priori Statistical Methods ..................................................................................................11 
6.1. 
General Considerations ....................................................................................................11 
6.1.1. 
Analysis Populations ................................................................................................12 
6.1.2. 
Definition of Baseline and Post-Baseline Measures ................................................13 
6.1.3. 
Derived Data ............................................................................................................15 
6.2. 
Adjustments for Covariates ..............................................................................................16 
6.3. 
Handling of Dropouts or Missing Data ............................................................................16 
6.3.1. 
Missingness Due to COVID-19 ...............................................................................16 
6.4. 
Multicenter Studies ...........................................................................................................17 
6.5. 
Multiple Comparisons/Multiplicity ..................................................................................17 
6.6. 
Patient Disposition............................................................................................................17 
6.7. 
Patient Characteristics ......................................................................................................17 
6.7.1. 
Patient Demographics ..............................................................................................18 
6.7.2. 
Baseline Disease Characteristics ..............................................................................18 
6.7.3. 
Historical Illnesses and Pre-existing Conditions .....................................................19 
6.8. 
Treatment Compliance .....................................................................................................19 
6.9. 
Previous and Concomitant Therapy .................................................................................20 
6.10. Efficacy Analyses .............................................................................................................20 
6.10.1. 
Primary Outcome and Methodology ........................................................................24 
6.10.2. 
Secondary and Exploratory Efficacy Analyses ........................................................24 
6.11. Health Outcomes/Quality-of-Life Analyses .....................................................................24 
6.12. Safety Analyses ................................................................................................................30 


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6.12.1. 
Extent of Exposure ...................................................................................................30 
6.12.2. 
Adverse Events ........................................................................................................31 
6.12.3. 
Common Adverse Events .........................................................................................31 
6.12.4. 
Serious Adverse Events ...........................................................................................32 
6.12.5. 
Other Significant Adverse Events ............................................................................32 
6.13. Protocol Violations ...........................................................................................................32 
6.14. Planned Exploratory Analyses .........................................................................................32 
6.15. Interim Analyses ...............................................................................................................32 
6.16. Annual Report Analyses ...................................................................................................33 
6.17. Clinical Trial Registry Analyses ......................................................................................33 
7. 
References .............................................................................................................................34 
 


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Table of Contents 
Table 
Page 
Table JAIX.6.1. Efficacy and Safety Analyses Cohort ................................................................12 
Table JAIX.6.2. Description and Derivation of Primary, Secondary, and Exploratory 
Efficacy Outcomes ............................................................................................21 
Table JAIX.6.3. Description and Derivation of Health Outcomes and Quality-of-Life 
Measures ............................................................................................................25 
 


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3. Revision History 
Statistical Analysis Plan (SAP) Version 1 was approved prior to first visit.   
Statistical Analysis Plan Version 2 was approved based on Protocol I4V-MC-JAIX(c) (JAIX) 
and Program Safety Statistical Analysis Plan (PSAP) Version 6.  The overall changes 
incorporated in Version 2 are as follows:   
 updated primary and key secondary efficacy endpoints per JAIX Protocol Amendment 
(c)  
 updated with the extension of the study 
 updated with rolling over of responder from Study I4V-MC-JAIW (JAIW) to Study JAIX 
at Study JAIW Week 104 
 updated baseline definition for the daily diary assessments (Itch Numeric Rating Score 
[NRS], Atopic Dermatitis Sleep Scale [ADSS], Skin Pain NRS, Patient Global 
Impression of Severity– Atopic Dermatitis [PGI-S-AD])  
 updated daily diaries to use an interval mean weekly score 
 updated derived data and baseline variables 
 updated exploratory analyses 
 updated safety analyses to only include duration of exposure, treatment-emergent adverse 
events (TEAEs), serious adverse events (SAEs), and adverse events (AEs) leading to 
permanent study drug discontinuation 
 updated safety analysis period to be the treatment period plus up to 30 days off-drug 
follow-up time 
 updated TEAE definition by using the Study JAIX baseline to derive TEAEs 
 removed previous medication summary 
 updated with interim analyses for the clinical study report (CSR) 
Statistical Analysis Plan Version 3 was approved before the 4 month safety update database lock.  
The overall changes incorporated in Version 2 are as follows:   
 updated safety analyses cohorts 
 updated treatment compliance timeframe 
 detailed efficacy summary analyses for 4 month safety update 
 Section 4.3 – updated to include exploratory analyses accounting for duration of 
treatment exposure in Study JAIW 
 Section 6.3.1 - added a section to include missing data imputation method for 
missingness due to COVID-19 
Statistical Analysis Plan Version 4 was approved before Study JAIX (2) open-label addendum 
first patient visit: 
 Section 4.3, Section 5.1, Section 5.2, and Section 6.1 - added Study JAIX (2) open-label 
addendum information 
 Updated a treatment group for Study JAIX (2) open-label addendum in Table JAIX.6.1. 
 Section 6.1.2 - updated baseline information for Study JAIX (2) open-label addendum 


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Statistical Analysis Plan Version 5 was approved before final data base lock. The overall 
changes incorporated in version 5 are summarized below: 
 Section 4.1, Section 4.2, Section 4.3, Section 5.3, and Section 6.1 - added Study JAIX (2) 
open-label addendum information 
 Section 6.1.1 – added population for Study JAIX (2) open-label addendum 
 Section 6.1.2 - updated baseline information for Study JAIX (2) open-label addendum 
 Section 6.6, Section 6.7, Section 6.7.1, Section 6.8, Section 6.10, and Section 6.10.2 - 
added Study JAIX (2) open-label addendum information 


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4. Study Objectives 
4.1. Primary Objective 
To describe the clinical response to baricitinib 2-mg once daily (QD) in patients with moderate 
to severe atopic dermatitis (AD) by prior treatment received (ie, baricitinib 2-mg, 1-mg, or 
placebo) and responder status achieved in Study JAIW as measured by proportion of patients 
achieving a 75% or greater improvement in the Eczema Area and Severity Index (EASI75) from 
baseline of originating study assessed at Week 16. 
Study JAIX (2) open-label addendum 
To describe the clinical response to baricitinib 2-mg QD in patients with moderate to severe AD 
as measured by proportion of patients achieving a 75% or greater improvement in the Eczema 
Area and Severity Index (EASI75) from baseline, assessed at Week 16. 
4.2. Secondary Objectives 
 To describe the clinical response to baricitinib 2-mg QD in AD as measured by 
improvement in signs and symptoms of AD by prior treatment received (ie, baricitinib 
2-mg, 1-mg, or placebo) and responder status achieved in Study JAIW as measured by the 
following: 
o Proportion of patients achieving Validated Investigator’s Global Assessment for 
Atopic Dermatitis (vIGA-AD) of 0 or 1 assessed at Week 16 
o Proportion of patients achieving IGA of 0 or 1 assessed at or before Week 16 
o Proportion of patients achieving EASI75 from baseline of originating study JAIW 
assessed at or before Week 16 
o Mean percent change from baseline in Eczema Area and Severity Index (EASI) 
score from baseline of originating Study JAIW assessed at Week 16  
o Proportion of patients achieving a body surface area (BSA) of ≤3% assessed at or 
before Week 16 
 To describe the clinical response to baricitinib 2-mg QD in AD as assessed by 
patient-reported outcome measures by prior treatment received (ie, baricitinib 2-mg, 1-mg, 
or placebo) and responder status achieved in Study JAIW as measured by the following: 
o Proportions of patients achieving a ≥4-point improvement in Itch NRS from 
baseline of originating Study JAIW, assessed at Week 16 
o Proportions of patients achieving a ≥4-point improvement in Itch NRS from 
baseline of originating Study JAIW assessed at or before Week 16 
o Mean percent change from baseline of originating Study JAIW in Itch NRS 
assessed at Week 16 
Study JAIX (2) open-label addendum 
 To describe the clinical response to baricitinib 2-mg QD in AD as measured by 
improvement in signs and symptoms of AD as measured by the following: 
o Proportion of patients achieving Validated Investigator’s Global Assessment for 
Atopic Dermatitis (vIGA-AD) of 0 or 1 assessed at Week 16 


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o Proportion of patients achieving IGA of 0 or 1 assessed at or before Week 16 
o Proportion of patients achieving EASI75 from baseline, assessed at or before 
Week 16 
o Mean percent change from baseline in Eczema Area and Severity Index (EASI) 
score from baseline, assessed at Week 16  
o Proportion of patients achieving a body surface area (BSA) of ≤3% assessed at or 
before Week 16 
 To describe the clinical response to baricitinib 2-mg QD in AD as assessed by 
patient-reported outcome measures as measured by the following: 
o Proportions of patients achieving a ≥4-point improvement in Itch NRS from 
baseline, assessed at Week 16 
o Proportions of patients achieving a ≥4-point improvement in Itch NRS from 
baseline, assessed at or before Week 16 
o Mean percent change from baseline in Itch NRS, assessed at Week 16 
4.3. Exploratory Objectives 
 Exploratory objectives may include evaluating the response to baricitinib treatment 
regimens on clinical measures and patient-reported outcomes.  These endpoints may 
include dichotomous endpoints or change from baseline for the following measures:  BSA, 
EASI, SCORing Atopic Dermatitis (SCORAD), Patient-Oriented Eczema Measure 
(POEM), Dermatology Life Quality Index (DLQI), Itch NRS, ADSS Item scores, and 
Skin Pain NRS.   
o Mean change from baseline of the originating study JAIW in Skin Pain NRS  
o Mean change from baseline of the originating study JAIW in 
ADSS1/ADSS2/ADSS3  
o Mean change from baseline of the originating study JAIW in BSA  
o Mean change and percentage from baseline of the originating study JAIW in 
SCORAD 
o Mean change and percentage change from baseline of the originating study JAIW 
in Itch NRS 
o Mean change from baseline of the originating study JAIW in total POEM 
o Mean change from baseline of the originating study JAIW in DLQI 
o Mean change from baseline of the originating study JAIW in EASI 
o Proportion of patients achieving a 90% or greater improvement in the Eczema 
Area and Severity Index (EASI90) or a 50% or greater improvement in the 
Eczema Area and Severity Index (EASI50) from baseline of the originating study  
o Proportions of patients achieving a Skin pain 4-point improvement for those with 
baseline skin pain ≥4 of the originating study JAIW 
o Proportions of patients achieving a DLQI score of 5 or less for those with a 
baseline DLQI score >5 of the originating study JAIW 
o Proportions of patients achieving a DLQI score of 0 or 1  
Summaries of response rates defined based on IGA of 0 or 1, EASI75, or Itch >=4 point 
improvement will also be provided for previous responders at Week 16 of Study JAIW (IGA 0 or 


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1 ) with loss of response (defined as IGA ≥3 or requiring more than low-potency TCS) after 
Week 16, by duration of previous treatment (16-28, 28-36, >36 weeks).  
Summaries or listings of efficacy and patient-reported outcome endpoints from Study JAIX (2) 
open-label addendum will be provided separately from the main protocol population, as 
applicable. 


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5. Study Design 
5.1. Summary of Study Design 
Study JAIX is a Phase 3, multicenter, open-label, outpatient study evaluating the efficacy and 
safety of baricitinib 2-mg QD in adult patients with moderate to severe AD.  The study is divided 
into 2 periods:  a 200-week Open-Label Treatment period and a 4-week Post-Treatment 
Follow-Up period.  In addition, this study includes an open-label addendum, for Study JAIX (2) 
open-label addendum (I4V-MC-JAIX(2) Clinical Protocol Addendum).  The following patients 
will be eligible to participate in this study: 
 Partial Responders (IGA 2 at Week 16 of Study JAIW) 
 Previous Responders at Week 16 of Study JAIW (IGA 0 or 1):  Patients who were 
responders at Week 16 of Study JAIW, and thus remain in Study JAIW but later 
experience loss of response resulting in an IGA ≥3 (or requiring more than low-potency 
topical corticosteroids [TCS] after Week 16 to manage symptoms) 
 Nonresponders (IGA 3 or 4 at Week 16 of Study JAIW or rescued with topical [eg, TCS, 
topical calcineurin inhibitor (TCNI)] or systemic therapies prior to Week 16)  
 Responders who completed Study JAIW through Week 104 (Visit 15) 
 Up to approximately 30 patients are planned to be enrolled in Study JAIX (2) open-label 
addendum 
5.2. Determination of Sample Size 
The study is descriptive in nature and the sample size is not based on any statistical power 
calculations.  All of the approximate 450 patients participating in the originating study can be 
assessed for eligibility to participate in Study JAIX. In addition, there are approximately 30 
patients planned to be enrolled in Study JAIX (2) open-label addendum. 
5.3. Method of Assignment to Treatment 
This is an open-label trial where all patients will receive baricitinib 2-mg QD in the study JAIX 
and in Study JAIX (2) open-label addendum. 


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6. A Priori Statistical Methods 
Statistical analyses of this study will be the responsibility of Eli Lilly and Company (Lilly) or its 
designee.   
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol and the justification for making the change will be described 
in the CSR.  Additional exploratory analyses of the data will be conducted as deemed appropriate 
for the Study JAIX and JAIX (2) open-label addendum. 
6.1. General Considerations 
As this study is open-label and all patients are receiving baricitinib 2-mg, no hypothesis tests for 
differences in treatment will be performed.  Unless otherwise stated, data will be summarized 
both overall and by previous therapy received in the originating Study JAIW.   
Analyses for Study JAIX (2) open-label addendum will be separate and will be analyzed 
descriptively, as deemed appropriate.  
In general, summaries of efficacy and safety data will follow the following reporting rules: 
 Cumulative summaries incorporating data from the originating Study JAIW baseline 
values to evaluate long-term results within Study JAIX. 
 Summaries of Study JAIX alone to evaluate responses for those patients who are either 
up-titrating or receiving baricitinib for the first time.   
All discrete efficacy and health outcome variables in the study JAIX and the study JAIX (2) 
open-label addendum, will be summarized using frequencies and percentages.  Normal 
approximation to the binomial distribution will be used to construct a confidence interval for the 
proportion.  
Continuous efficacy and health outcome variables will be summarized displaying number of 
patients (n), mean, standard deviation (SD), median, minimum, and maximum.  Within-group 
least-squares (LS) mean changes and percent changes will be analyzed within the framework of 
mixed models repeated measures (MMRM) analysis models with baseline disease severity (IGA) 
in Study JAIW, effects for therapy in the originating Study JAIW, visit and therapy (in 
originating study)-by-visit interaction as fixed effects and baseline and baseline-by-visit as fixed 
continuous effects.  An unstructured (co)variance structure will be used to model the between- 
and within-patient errors.  If this analysis fails to converge, the heterogeneous autoregressive 
[ARH(1)], followed by the heterogeneous compound symmetry (CSH), followed by the 
heterogeneous Toeplitz (TOEPH), followed by autoregressive [AR(1)], followed by compound 
symmetry (CS) will be used.  The p-values associated with the null hypothesis tests of LS 
mean=0 will be produced.   
Frequencies and percentages will be computed for TEAE, SAEs, and discontinuations due to 
AEs or death.   


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All the efficacy endpoints will be summarized for Week 0 through Week 16 and can go to 
Week 104 for the study JAIX and to Week 52 for study JAIX (2) open-label addendum. 
6.1.1. Analysis Populations 
Modified Intent-to-Treat (mITT) population:  The mITT population is defined as all patients 
who received at least 1 dose of investigational product in Study JAIX.   
For the US submission safety lock in January 2020, efficacy analyses will not be performed since 
it is expected only part of the subjects would have reached Week 16.  
For the 4-month safety update, efficacy summary will include following using observed values: 
 Proportion of patients achieving EASI75 from baseline of originating Study JAIW, 
assessed at Weeks 0 to 16 
 Proportion of patients achieving vIGA-AD of 0 or 1 assessed at Weeks 0 to 16 
 Proportions of patients achieving a ≥4-point improvement in Itch NRS from baseline of 
originating Study JAIW, assessed at Weeks 0 to 16 
 
Open-label Addendum Modified Intent-to-Treat (mITT) Population: The open-label 
addendum mITT population is defined as all patients who received at least 1 dose of 
investigational product in Study JAIX (2) open-label addendum. 
Safety population:  The safety population is defined as all patients who received at least 1 dose 
of investigational product in Study JAIX  or in the study JAIX (2) open-label addendum, and 
who did not discontinue from the study for the reason ‘Lost to Follow-up’ at the first 
postbaseline visit in Study JAIX or in the study JAIX (2) open-label addendum.  This definition 
excludes patients with no safety assessments postbaseline so that incidence rates are not 
underestimated. 
Unless otherwise specified, the efficacy and health outcome summaries will be conducted on the 
mITT population.  Safety analyses will be performed on the safety population.  
Table JAIX.6.1. 
Efficacy and Safety Analyses Cohort 
Cohort 
Definition  
Placebo/BARI 2-mg 
PBO in Study JAIW switching to BARI 2-mg at entry to Study JAIX up to end of 
the study 
BARI 1-mg/BARI 2-mg  
BARI 1-mg in Study JAIW switching to BARI 2-mg at entry to Study JAIX up to 
end of the study 
BARI 2-mg/BARI 2-mg 
BARI 2-mg in Study JAIW staying at the same dose in Study JAIX up to end of 
the study 
BARI 2-mg 
BARI 2-mg in Study JAIX up to end of the study, all groups including BARI 2-
mg in study JAIX (2) Open-label addendum 
BARI 2-mg open-label 
addendum 
BARI 2-mg for Study JAIX (2) open-label addendum 
Abbreviations:  BARI = baricitinib; PBO = placebo. 


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6.1.2. Definition of Baseline and Post-Baseline Measures 
Baseline 
The baseline value for the efficacy and health outcomes for the treatment period is defined as the 
last non-missing measurement on or prior to the date of first study drug administration in 
Study JAIW.   
For the purpose of Study JAIX alone, the safety analyses or relevant analyses for the Study JAIX 
(2) open-label addendum will be conducted using the Study JAIX baseline, which is defined as 
the last non-missing measurement on or prior to the date of first study drug administration in 
Study JAIX.   
The baseline value for the daily diary assessments (Itch NRS, ADSS, Skin Pain NRS, PGI-S-
AD) is defined as the mean assessment of the non-missing assessments in the 7 days prior to the 
date of first study drug administration of the originating Study JAIW.  If there are less than 4 
non-missing assessments in the baseline diary window, the interval lower bound can be extended 
up to 7 additional days, 1 day at a time, to obtain the most recent 4 non-missing values.  If there 
are not at least 4 non-missing assessments in the baseline period, the baseline mean is missing. 
Post-Baseline 
Post-baseline measurements are collected after study drug administration for electronic patient-
reported outcome (ePRO), Itch NRS, Skin Pain NRS, ADSS, and PGI-S-AD up to Week 16 
(Visit 4).   
Non-missing efficacy data collected at scheduled visits (eg, electronic version of Clinical 
Outcome Assessment [eCOA], clinician-reported outcome [ClinRO]) will be used for analyses.  
If an assessment is missing at a scheduled visit, an unscheduled post-baseline assessment can be 
used, provided it falls within a ±4 day window of the scheduled visit date Visit 2 (Week 4) and 
Visit 3 (Week 8) and a ±7 day window to Visit 4 (Week 16) and all other subsequent visits.  If 
there is more than 1 unscheduled visit within the defined visit window and no scheduled visit 
assessment is available, the unscheduled visit closest to the scheduled visit date will be used.  If 
2 unscheduled visits of equal distance are available, then the latter of the 2 will be used.  If there 
is no non-missing measure collected at the scheduled visit, or an unscheduled visit falling within 
the visit window, the assessment is missing for that scheduled visit. 
Postbaseline daily diary endpoints will be the mean of weekly visit windows (diary windows) 
anchored on day of first dose (Day 1) and day of Week 16 scheduled visit.  These are defined as 
follows: 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Day 
1-7 
8-14 
15-
21 
22-
28 
29-
35 
36-
42 
43-
49 
50-
56 
57-
63 
64-
70 
71-
77 
78-
84 
85-
91 
92-
98 
 


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Week 16 Daily Diary Window Construction 
The following sequential steps will be used to determine the Week 16 diary window.  The 
general goal is to anchor on the scheduled Week 16 visit (or a proximal unscheduled visit) if 
such a visit exists, or to use an interval based on days in study for cases where a scheduled 
Week 16 or a proximal surrogate does not exist.  
Step 1:  If the Week 16 scheduled visit exists, the Week 16 diary interval is the 7 days prior to 
the Week 16 date provided that window has at least 4 non-missing observations.  If there are less 
than 4 non-missing observations, the diary window’s lower bound will be extended 1 day at a 
time (up to day 99) to a maximum of 14 days prior to the Week 16 date until 4 non-missing 
observations are obtained.  If, after extending this diary window’s lower bound to 14 days, there 
are less than 4 non-missing observations, then go to Step 3. 
Step 2:  If the Week 16 scheduled visit does not exist, the 7 days prior to the last visit (scheduled 
or unscheduled) occurring after Day 105 and before Visit 8 will constitute the Week 16 diary 
window provided that window contains at least 4 non-missing observations.  If there are less than 
4 non-missing observations, the diary window’s lower bound will be extended 1 day at a time 
(up to Day 99) to a maximum of 14 days prior to the unscheduled visit date until 4 non-missing 
observations are obtained.  If, after extending this diary window’s lower bound to 14 days, there 
are less than 4 non-missing observations, then go to Step 3. 
Step 3:  If neither a Week 16 scheduled visit is available or an unscheduled visit to act as a 
surrogate for the Week 16 diary window, then the Week 16 window will be Day 106 to Day 112.  
If there are less than 4 non-missing observations, the diary window’s lower bound will be 
extended 1 day at a time to Day 99 until 4 non-missing observations are obtained.  If the steps 
above do not detect a window with at least 4 non-missing observations, then the Week 16 
window is 7 days from either the Week 16 visit, the surrogate visit, or Day 106 to Day 112 and 
the mean is missing and subject to imputation rules. 
Week 15 Daily Diary Window Construction 
The lower boundary of the Week 15 diary window is defined as Day 99.  The upper bound of the 
Week 15 diary window is the minimum of either Day 105 or the lower bound of the Week 16 
diary window -1.  Consequently, Week 15 may be less than 4 days if the Week 16 scheduled 
visit is before Day 112.  Moreover, as the Week 15 diary window cannot exceed 7 days, there 
could be daily assessments between Weeks 15 and 16 diary windows that do not fall into a diary 
window.  If, after constructing the diary windows, there are fewer than 4 non-missing values, the 
mean for Week 15 is missing and subject to imputation rules. 
Handling of Duplicate Diary Records 
If there is more than 1 diary record on a particular date, the first record on that particular date 
will be used in the analysis. 


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6.1.3. Derived Data 
 Age (year), derived using first dose date as the reference start date and July 1 of birth 
year, and truncated to a whole-year (integer) age.  Patients whose derived age is less than 
18 will have the required minimum age of 18 at informed consent confirmed.  Reporting 
for age, age groups, and laboratory ranges, however will be based on their derived age. 
 Age group (<65, ≥65 years old) 
 Age group (<65, ≥65 to <75, ≥75 to <85, ≥85 years old) 
 Body mass index (BMI) (kg/m2) = Weight (kg)/((Height (cm)/100)2) 
 BMI category (<25 kg/m2, ≥25 to <30 kg/m2, ≥30 kg/m2) 
 The duration of AD from diagnosis (year) = [(Date of informed consent – Date of AD 
diagnosis )+1]/365.25. 
If year of onset is missing, duration of AD will be set as missing.  Otherwise, unknown 
month will be taken as January, and unknown day will be taken as 01.  The duration of 
AD will be rounded to 1 decimal place. 
 Duration of AD (years) category (0 to <2 years, ≥2 to <5 years, ≥5 to <10 years, ≥10 to 
<20 years, ≥20 years) 
 Diagnosis age (number of months between date of AD diagnosis and July 1 of birth year) 
/12, and truncated to a whole-integer age 
 Diagnosis age group (<18, ≥18 and <50, ≥50 years old) 
 Change from baseline = post-baseline measurement at Visit x – baseline measurement. 
If a baseline value is missing, it will not be imputed and the change from baseline will not 
be calculated.  
 Percent change from baseline at Visit x: 
 
((Post-baseline measurement at Visit x - Baseline measurement)/Baseline 
measurement)*100. 
 
If a baseline value is missing, it will not be imputed and percent change from baseline 
will not be calculated. 
 
 Weight (kg) = weight (lbs)*0.454. 
 Weight category (<60 kg, ≥60 to <100 kg, ≥100 kg) 
 Height (cm) = height (in)*2.54. 
 Cyclosporine inadequate efficacy response(yes, no) 
o Set yes if the reason for discontinuation is inadequate response 
 Cyclosporine intolerance (yes, no) 
o Set yes if the reasons for discontinuation are intolerance to medication or 
contraindication (physician-indicated cyclosporine was used and a 
contraindication was noted) 
 Cyclosporine contraindication [ineligible] (yes, no) 
o Set to yes if cyclosporine never used because of a contraindication 
 Cyclosporine inadvisable (yes, no) 
o Set to yes if the following reasons were selected for either not using the 
medication or discontinuing the medication: 


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▪ Reason for not using medication:  contraindication, unfavorable 
benefit/risk, or physician decision 
▪ Reason for discontinuation:  inadequate response, intolerance to 
medication, or contraindication. 
 TCNI Topical calcineurin inhibitor inadequate efficacy response (yes, no) 
o Set yes if the reason for discontinuation is inadequate response 
 TCNI Topical calcineurin inhibitor intolerance (yes, no) 
o Set yes if the reasons for discontinuation are intolerance to medication or 
contraindication (physician-indicated TCNI was used and a contraindication was 
noted) 
 TCNI Topical calcineurin inhibitor contraindication / [ineligible](yes, no) 
o Set to yes if TCNI never used because of a contraindication 
 TCNI Topical calcineurin inhibitor inadvisable (yes, no) 
o Set to yes if the following reasons were selected for either not using the 
medication or discontinuing the medication: 
▪ Reason for not using medication:  Physician decision, concern about side 
effects, unfavorable benefit risk, contraindication  
▪ Reasons for discontinuation:  inadequate response, intolerance to 
medication, or contraindication 
6.2. Adjustments for Covariates 
Disease severity (IGA), baseline value, and baseline-by-visit interactions will be included as 
covariates when MMRM analysis is performed. 
6.3. Handling of Dropouts or Missing Data 
Patients who discontinue the study or the study treatment at any time for any reason will be 
defined as nonresponders for the nonresponder imputation (NRI) summary of categorical 
efficacy variables such as IGA 0/1 or EASI50/75/90 after discontinuation and onward.  No 
imputation methods will be applied to continuous data.  Missing value will be imputed by 
MMRM for continues efficacy variables. 
6.3.1. Missingness Due to COVID-19 
For missingness that COVID-19 is identified as the cause by the study team, the following 
imputation methods would be applied.  
 For continuous measures, if missing due to COVID-19,  
o When they are analyzed using analysis of covariance (ANCOVA) for a single 
timepoint, modified last observation carried forward (mLOCF) method will be 
used.  
 For categorical variables, if missing due to COVID-19,  
o mLOCF method will be used.  This applies to categorical variables that are 
collected categorically, as well as categorical variables that are derived from 
measures that are collected as continuous, such as EASI50, EASI75 and EASI90. 


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o In addition, for primary and key efficacy measures including IGA 0 or 1 and 
EASI75, multiple imputation (MI) method will be used.  Seed = 123456 will be 
used for MI.  Results from MIs will be aggregated to generate the final estimates 
for statistical inferences.  This will be the main imputation method for these 
primary and key efficacy measures for visits with missing data due to COVID-19.  
All measures collected through ePRO diary device should not be impacted by COVID-19. 
For a specific database lock, if COVID-19 is still ongoing at the time of the database lock, the 
list of visits with missing data due to COVID-19 identified by the study for that lock may not be 
complete and may be updated in future locks.  The imputation for missingness due to COVID-19 
for each database lock is based on the list we receive for that specific lock.  
For the lock to occur on 02 June 2020, as there are very limited missing data due to COVID-19, 
the imputation method specified in this section (Section 6.3.1) will not be applied to this lock.  
6.4. Multicenter Studies 
This study will be conducted by multiple investigators at multiple sites in North America.  As the 
summaries of these data are descriptive in nature, no adjustments for site differences will be 
made. 
6.5. Multiple Comparisons/Multiplicity 
No multiplicity control measures will be used. 
6.6. Patient Disposition 
Patient disposition will be summarized for the mITT population for JAIX study.  Frequency 
counts and percentages of patients who complete the study treatment visits or discontinue early 
from the study will be summarized by prior treatment group and overall.   
Patient disposition will be summarized for the mITT population for JAIX (2) open-label 
addendum study. 
A listing of patient disposition will be provided for all patients, with the extent of their 
participation in the study JAIX and the study JAIX (2) open-label addendum and the reason for 
discontinuation.   
6.7. Patient Characteristics 
Patient characteristics including demographics and baseline characteristics will be summarized 
descriptively by previous treatment group and overall for the mITT population for JAIX study.  
Additionally, historical illnesses and pre-existing conditions will be summarized.  Descriptive 
statistics including n, mean, SD, minimum, 1st quartile, median, 3rd quartile, and maximum will 
be provided for continuous measures, and frequency counts and percentages will be tabulated for 
categorical measures.   
Patient characteristics will also be summarized for the mITT population for JAIX (2) open-label 
addendum study. 


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6.7.1. Patient Demographics 
Patient demographics will be summarized as described above for both in the study JAIX and the 
study JAIX (2) open-label addendum.  The following demographic information will be included: 
 Age 
 Age group (<65 vs. ≥65) 
 Age group (<65, ≥65 to <75, ≥75 to <85, ≥85) 
 Sex (male, female) 
 Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Multiple) 
 Weight (kg) 
 Weight category (<60 kg, ≥60 to <100 kg, ≥100 kg) 
 Height (cm) 
 BMI (kg/m2)  
 BMI category (<25 kg/m2, ≥25 to <30 kg/m2, ≥30 kg/m2) 
A listing of patient demographics will also be provided for the enrolled population.  
6.7.2. Baseline Disease Characteristics 
The following baseline disease information (but not limited to only these) will be categorized 
and presented for baseline AD clinical characteristics, baseline health outcome measures, and 
other baseline demographic and disease characteristics as described above:   
 Duration since AD diagnosis (years)  
 Duration since AD diagnosis category (0 to <2 years, 2 to <5 years, 5 to <10 years, 10 to 
<20 years, ≥20 years) 
 Age at diagnosis (years)  
 Age group at diagnosis (<18 years, ≥18 to <50 years, ≥50 years) 
 Habits (Alcohol:  Never, Current, Former; Tobacco:  Never, Current, Former) 
 Skin infections treated with a pharmacological agent within past year (yes, no, unknown; 
number if yes) 
 Atopic Dermatitis flares within past year (yes, no, unknown; number if yes) 
 Validated Investigator’s Global Assessment for AD score 
 Eczema Area and Severity Index (EASI) score 
 SCORing Atopic Dermatitis (SCORAD) 
 Body Surface Area (BSA) affected by AD 
 Hospital Anxiety Depression Scale (HADS) subscales 
 Patient-Oriented Eczema Measure (POEM) 
 Itch Numerical Rating Scale (NRS) 
 Atopic Dermatitis Sleep Scale (ADSS) Item 2  
 Dermatology Life Quality Index (DLQI) 
 Skin Pain NRS 


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 Patient Global Impression of Severity (PGI-S-AD) 
 prior therapy (topical therapy only, systemic therapy)  
 prior use of Cyclosporine (yes, no) 
 Cyclosporine inadequate response (yes, no) 
 Cyclosporine intolerance (yes, no) 
 Cyclosporine contraindication [ineligible] (yes, no) 
 Cyclosporine inadvisable (yes, no) 
 Prior use of TCNI  (yes, no) 
 TCNI inadequate response (yes, no) 
 TCNI intolerance (yes, no) 
 TCNI contraindication [ineligible] (yes, no) 
 TCNI inadvisable (yes, no) 
 Vaccine: 
o Zoster vaccine ( Yes, No) 
o Tuberculosis vaccine (Yes, No) 
 Baseline renal function status:  impaired (estimated glomerular filtration rate [eGFR] 
<60 mL/min/1.73 m2) or not impaired (eGFR ≥60 mL/min/1.73 m2) 
 Immunoglobulin E:  intrinsic (<200 kU/I) or extrinsic (≥200 kU/I) 
6.7.3. Historical Illnesses and Pre-existing Conditions 
Historical illnesses are recorded in the originating Study JAIW and not in the Study JAIX 
electronic case report form (eCRF).  
Pre-existing conditions are defined as those conditions recorded in the Pre-existing Conditions 
and Medical History eCRF, the Prespecified Medical History:  Comorbidities eCRF, or the 
Adverse Events eCRF with a start date prior to the date of the Study JAIX informed consent and 
an end date after informed consent or missing.  For events occurring on the day of the first dose 
of previous study, the date and time of the onset of the event will both be used to determine if the 
event was pre-existing.  Conditions with a partial or missing start date (or time if needed) will be 
assumed to be ‘not pre-existing’ unless there is evidence, through comparison of partial dates, to 
suggest otherwise.  Pre-existing conditions will be categorized using the Medical Dictionary for 
Regulatory Activities (MedDRA) Standardized MedDRA Queries (SMQs) or similar predefined 
lists of Preferred Terms (PTs) of interest.  Frequency counts and percentages of patients with 
selected pre-existing conditions will be summarized for the mITT population. 
6.8. Treatment Compliance 
Patient compliance with study medication will be assessed using the mITT population. 
A patient is considered noncompliant if he or she misses >20% of the prescribed doses during the 
study, unless the patient’s study drug is withheld by the investigator.  For patients who had their 
treatment temporarily interrupted by the investigator, the period of time that dose was withheld 
will be taken into account in the compliance calculation.  
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Compliance = total number of tablets dispensed –  total number of tablets returned
expected number of total tablets
 
where  
 Total number of tablets dispensed:  sum of tablets dispensed in the period of interest prior 
to Visit x;  
 Total number of tablets returned:  sum of the tablets returned in the period of interest 
prior to and including Visit x; 
 Expected number of tablets:  number of days in the period of interest*number of tablets 
taken per day = [(date of visit – date of first dose + 1) – number of days of temporary 
drug interruption]*number of tablets taken per day  
Descriptive statistics for percent compliance and non-compliance rate will be summarized for the 
mITT population for Week 0 through Week 16 and can go to Week 200, as deemed appropriate.  
Sub-intervals of interest, such as compliance between visits, may also be presented.  The number 
of expected doses, tablets dispensed, tablets returned, and percent compliance will be listed by 
patient for both in the study JAIX and the study JAIX (2) open-label addendum.  
6.9. Previous and Concomitant Therapy 
Previous medications are described in the originating Study JAIW. 
Summaries of concomitant medications will be based on the mITT population.  
Concomitant therapy for the treatment period is defined as therapy that starts before or during the 
treatment period of the previous study and ends during the Study JAIX treatment period or is 
ongoing (has no end date or ends after the treatment period).  Should there be insufficient data to 
make this comparison (eg, the concomitant therapy stop year is the same as the treatment start 
year, but the concomitant therapy stop month and day are missing), the medication will be 
considered as concomitant for the treatment period.  Medications started during Study JAIX are 
also considered as concomitant medications. 
Summaries of concomitant medications will be provided for the following category:   
 Summary of concomitant medications excluding background therapy 
 Summary of background therapy 
6.10. Efficacy Analyses 
The general methods used to summarize efficacy variables is given in Section 6.1.  
Table JAIX.6.2 includes the descriptions and derivations of the primary, secondary, and 
exploratory efficacy outcomes in the study JAIX and the study JAIX (2) open-label addendum. 
 
 


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Table JAIX.6.2. 
Description and Derivation of Primary, Secondary, and Exploratory Efficacy Outcomes 
Measure 
Description 
Variable 
Derivation/Comment 
Imputation Approach if 
Missing Components 
Eczema Area 
and Severity 
Index (EASI) 
The EASI assesses objective physician 
estimates of 2 dimensions of AD, disease 
extent and clinical signs (Hanifin et al. 
2001), by scoring the extent of disease 
(percentage of skin affected:  0 = 0%; 1 = 
1-9%; 2 = 10-29%; 3 = 30-49%; 4 = 50-
69%; 5 = 70-89%; 6 = 90-100%) and the 
severity of 4 clinical signs (erythema, 
edema/papulation, excoriation, and 
lichenification), each on a scale of 0-3 (0 
= none, absent; 1 = mild; 2 = moderate; 
3 = severe) at 4 body sites (head and neck, 
trunk, upper limbs, and lower limbs).  
Half scores are allowed between severities 
1, 2 and 3.  Each body site will have a 
score that ranges from 0-72, and the final 
EASI score will be obtained by weight 
averaging these 4 scores.  Hence, the final 
EASI score will range from 0-72 for each 
time point. 
▪ EASI score 
Derive EASI region score for each of 
head and neck, trunk, upper limbs, and 
lower limbs as follows: 
EASIregion = (Erythema + 
edema/papulation +  Excoriation + 
Lichenification)*(value from percentage 
involvement), where erythema, 
edema/papulation, excoriation, and 
lichenification are evaluated on a scale of 
0-3 and value from percentage 
involvement is on a scale of 0-6.  
Then total EASI score is as follows: 
EASI = 0.1*EASIhead and neck + 
0.3*EASItrunk + 0.2*EASIupper limbs + 
0.4*EASIlower limbs 
N/A – partial assessments 
cannot be saved. 
▪ EASI50 
% improvement in EASI score from 
baseline ≥50%: 
% change from baseline ≤-50 
Missing if baseline or 
observed value is missing 
▪ EASI75 
% improvement in EASI score from 
baseline ≥75%: 
% change from baseline ≤-75 
Missing if baseline or 
observed value is missing 
▪ EASI90 
% improvement in EASI score from 
baseline ≥90%: 
% change from baseline ≤-90 
Missing if baseline or 
observed value is missing 
▪ Change from 
baseline in 
EASI score 
▪ Percent change 
from baseline 
EASI score 
Change from baseline:  observed EASI 
score – baseline EASI score 
% change from baseline: 
100 × 𝑂𝑏𝑠𝑒𝑟𝑣𝑒𝑑 𝑠𝑐𝑜𝑟𝑒−𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒
𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒
 
Missing if baseline or 
observed value is missing 
 


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Description and Derivation of Primary, Secondary, and Exploratory Efficacy Outcomes 
Measure 
Description 
Variable 
Derivation/Comment 
Imputation Approach if 
Missing Components 
Body Surface 
Area (BSA) 
Affected by 
AD 
BSA affected by AD will be assessed for 
4 separate body regions and is collected as 
part of the EASI assessment:  head and 
neck, trunk (including genital region), 
upper extremities, and lower extremities 
(including the buttocks).  Each body 
region will be assessed for disease extent 
ranging from 0% to 100% involvement.  
The overall total percentage will be 
reported based off of all 4 body regions 
combined, after applying specific 
multipliers to the different body regions to 
account for the percent of the total BSA 
represented by each of the 4 regions. 
▪ BSA score 
Use the percentage of skin affected for 
each region (0 to 100%) in EASI as 
follows: 
BSA Total = 0.1*BSAhead and neck + 
0.3*BSAtrunk + 0.2* BSAupper limbs + 
0.4*BSAlower limbs  
 
N/A – partial assessments 
cannot be saved.   
Change from 
baseline in BSA 
score 
Change from baseline:  observed BSA 
score – baseline BSA score 
Missing if baseline or 
observed value is missing. 
▪ Proportion of 
patients 
achieving a 
BSA of ≤3% 
Observed score of ≤3% for patients with 
BSA >3% or missing at baseline  
 
Missing if observed value is 
missing. 
 
Validated 
Investigator’s 
Global 
Assessment 
for AD (IGA) 
 
The validated IGA based on a static, 
numeric 5-point scale from 0 (clear) to 
4 (severe).  The score is based on an 
overall assessment of the degree of 
erythema, papulation/induration, 
oozing/crusting, and lichenification. 
▪ IGA score 
Single item.  Range: 0 to 4 
0 represents “clear” 
4 represents “severe” 
Single item, missing if 
missing. 
▪ IGA[0,1] with 
≥2-point 
improvement 
Observed score of 0 or 1 and change from 
baseline ≤-2 
 
Missing if baseline or 
observed value is missing. 
 
 
 
 


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Description and Derivation of Primary, Secondary, and Exploratory Efficacy Outcomes 
Measure 
Description 
Variable 
Derivation/Comment 
Imputation Approach if 
Missing Components 
SCORing 
Atopic 
Dermatitis 
(SCORAD) 
The SCORAD index uses the rule of nines 
to assess disease extent (head and neck 
9%; upper limbs 9% each; lower limbs 
18% each; anterior trunk 18%; back 18%; 
and genitals 1%).  It evaluates 6 clinical 
characteristics to determine disease 
severity:  (1) erythema, 
(2) edema/papulation, (3) oozing/crusts, 
(4) excoriation, (5) lichenification, and (6) 
dryness on a scale of 0 to 3 (0=absence, 
1=mild, 2=moderate, 3=severe).  The 
SCORAD index also assesses subjective 
symptoms of pruritus and sleep loss in the 
last 72 hours on visual analog scales of 0 
to 10, where 0 is no itch or sleep loss and 
10 is worst imaginable itch or sleep loss.  
The 3 aspects of extent of disease, disease 
severity, and subjective symptoms 
combine to give a maximum possible 
score of 103 (Stalder et al. 1993; Kunz et 
al. 1997; Schram et al. 2012). 
▪ SCORAD score 
SCORAD = A/5 + 7B/2 + C, where  
A is extent of disease, range 0-100 
B is disease severity, range 0-18 
C is subjective symptoms, range 0-20 
Missing if components A 
and B are missing or if 
component C is missing.  
Partial assessments 
performed by physician 
cannot be saved and partial 
assessments performed by 
subject cannot be saved.  
▪ Change from 
baseline in 
SCORAD score 
 
Change from baseline: observed 
SCORAD score – baseline SCORAD 
score 
 
Missing if baseline or 
observed value is missing 
Abbreviations:  AD = atopic dermatitis; N/A = not applicable. 
 


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6.10.1. Primary Outcome and Methodology 
The primary analysis of the study is to summarize the baricitinib 2-mg patients in the proportion 
of patients achieving EASI75 from baseline at Week 16 for the mITT population.  Missing data 
will be imputed using the NRI method described in Section 6.3. 
6.10.2. Secondary and Exploratory Efficacy Analyses 
Secondary efficacy analyses are detailed in Table JAIX.6.2.  Secondary and exploratory 
endpoints will be summarized as described in Section 6.1.  Missing EASI50/75/90 and responses 
will be imputed using the NRI method described in Section 6.3. Exploratory, health outcomes 
and quality-of-life measures endpoint may be analyzed, as deemed appropriate. 
6.11. Health Outcomes/Quality-of-Life Analyses 
The general methods used to summarize health outcomes and quality-of-life measures, including 
the definition of baseline value for assessments, are described in Section 6.1. 
Health outcomes and quality-of-life measures will generally be analyzed according to the 
formats discussed in Section 6.10.2.   
Table JAIX.6.3 includes the descriptions and derivations of the health outcomes and quality-of-
life measures.  
 
 


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Table JAIX.6.3. 
Description and Derivation of Health Outcomes and Quality-of-Life Measures 
Measure 
Description 
Variable 
Derivation/Comment 
Imputation Approach 
if with Missing 
Components 
Itch Numeric 
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 selecting the number that best 
describes the worst level of itching in the 
past 24 hours (Naegeli et al. 2015; Kimball 
et al. 2016).  Refer to Section 6.1.2 for 
details on how to calculate the weekly score 
that will be used in the continuous analysis.  
Itch NRS score 
Single item; range 0-10.  Refer 
to Section 6.1.2 for how to 
derive the visit score.   
Refer to Section 6.1.2 
for how to derive the 
visit score.  
▪ Change from baseline in 
Itch NRS 
▪ Percent change from 
baseline in Itch NRS 
Change from baseline:  
observed itch score – baseline 
itch score 
% change from baseline: 
100
× 𝑂𝑏𝑠𝑒𝑟𝑣𝑒𝑑 𝑠𝑐𝑜𝑟𝑒−𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒
𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒
 
Missing if baseline or 
observed value is 
missing 
▪ 4-point itch improvement 
in subgroup of patients 
with baseline Itch NRS ≥4  
Change from baseline ≤-4 and 
baseline ≥4 
Missing if baseline is 
missing or <4 or 
observed value is 
missing 
Skin Pain NRS 
 
 
The Skin Pain NRS is a 
patient-administered, 11-point horizontal 
scale anchored at 0 and 10, with 0 
representing “no pain” and 10 representing 
“worst pain imaginable.”  Overall severity 
of a patient’s skin pain is indicated by 
selecting the number that best describes the 
worst level of skin pain in the past 24 hours  
Refer to Section 6.1.2 for details on how to 
calculate the weekly score that will be used 
in the continuous analysis.   
Skin Pain NRS score 
Single item; range 0-10.  Refer 
to Section 6.1.2 for how to 
derive the visit score.   
Refer to Section 6.1.2 
for how to derive the 
visit score.   
▪ Change from baseline in 
Skin Pain NRS 
Change from baseline:  
observed skin pain score – 
baseline skin pain score 
Missing if baseline or 
observed value is 
missing 
▪ 4-point Skin Pain 
improvement in subgroup 
of patients with baseline 
Skin Pain NRS ≥4  
Change from baseline ≤-4 and 
baseline ≥4 
Missing if baseline is 
missing or <4 or 
observed value is 
missing 
 
 
 


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Description and Derivation of Health Outcomes and Quality-of-Life Measures 
Measure 
Description 
Variable 
Derivation/Comment 
Imputation Approach 
if with Missing 
Components 
Atopic 
Dermatitis Sleep 
Scale (ADSS) 
 
 
The ADSS is a 3-item, patient-administered 
questionnaire developed to assess the 
impact of itch on sleep including difficulty 
falling asleep, frequency of waking, and 
difficulty getting back to sleep last night.  
Patients rate their difficulty falling asleep 
and difficulty getting back to sleep, items 1 
and 3, respectively, using a 5-point 
Likert-type scale with response options 
ranging from 0 “not at all” to 4 “very 
difficult.”  Patients report their frequency of 
waking last night, item 2, by selecting the 
number of times they woke up each night, 
ranging from 0 to 29 times.  The ADSS is 
designed to be completed each day with 
respondents thinking about sleep “last 
night.”  Each item is scored individually.  
Refer to Section 6.1.2 for details on how to 
calculate the weekly score which will be 
used in the continuous analysis.   
▪ Item 1 score of ADSS 
▪ Item 2 score of ADSS 
▪ Item 3 score of ADSS 
Single items: Item 1, range 0 to 
4; Item 2, range 0 to 29; Item 3, 
range 0 to 4.  Refer to Section 
6.1.2 for how to derive the visit 
score.   
Refer to Section 6.1.2 
for how to derive the 
visit score.   
▪ Change from baseline in 
score of Item 1 of ADSS 
▪ Change from baseline in 
score of Item 2 of ADSS 
▪ Change from baseline in 
score of Item 3 of ADSS 
 
Change from baseline: 
observed ADSS item score – 
baseline ADSS item score 
 
Missing if baseline or 
observed value is 
missing. 
 
 
 
 


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


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Description and Derivation of Health Outcomes and Quality-of-Life Measures 
Measure 
Description 
Variable 
Derivation/Comment 
Imputation Approach 
if with Missing 
Components 
Dermatology Life 
Quality Index (DLQI) 
 
The DLQI is a simple, patient-administered, 
10-item, validated, quality-of-life 
questionnaire that covers 6 domains 
including symptoms and feelings, daily 
activities, leisure, work and school, personal 
relationships, and treatment.  The recall 
period of this scale is over the “last week.”  
Response categories include  “a little,” “a 
lot,” and “very much,” with corresponding 
scores of 1, 2, and 3, respectively, and “not at 
all,” or unanswered (“not relevant”) 
responses scored as 0.  Scores range from 
0-30 with higher scores indicating greater 
impairment of quality of life.  A DLQI total 
score of 0 to 1 is considered as having no 
effect on a patient’s health-related QoL 
(Hongbo et al. 2005) and a 4-point change 
from baseline is considered as the minimal 
clinically important difference threshold 
(Khilji et al. 2002; Basra et al. 2015).   
 
Symptoms and 
feelings domain 
Sum of questions 1 and 2, range 
0 to 6. 
N/A – partial 
assessments cannot be 
saved.    
Daily activities 
domain 
Sum of questions 3 and 4, range 
0 to 6. 
N/A – partial 
assessments cannot be 
saved.    
Leisure domain 
Sum of questions 5 and 6, range 
0 to 6. 
N/A – partial 
assessments cannot be 
saved.    
Work and school 
domain 
Sum of questions 7 and 7B (if it 
is answered), range 0 to 3.  
Responses of “yes” and “no” on 
Question 7 are given scores of 
3 and 0 respectively.  If 
Question 7 is answered “no” 
then Question 7b is answered 
with “a lot”, “a little”, “not at 
all” getting scores of 2, 1, 0 
respectively.   
N/A – partial 
assessments cannot be 
saved.    
Personal relationships 
domain 
Sum of questions 8 and 9, range 
0 to 6. 
N/A – partial 
assessments cannot be 
saved.    
Treatment domain  
Question 10, range 0 to 3. 
N/A – partial 
assessments cannot be 
saved.    
DLQI total score 
DLQI total score: sum of all six 
DLQI domain scores, range 0 
to 30. 
N/A – partial 
assessments cannot be 
saved.    
Change from baseline 
in DLQI 
Change from baseline: 
observed DLQI score – 
baseline DLQI score 
Missing if baseline or 
observed value is 
missing. 
 
 


I4V-MC-JAIX Statistical Analysis Plan Version 4 
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LY3009104 
Description and Derivation of Health Outcomes and Quality-of-Life Measures 
Measure 
Description 
Variable 
Derivation/Comment 
Imputation Approach 
if with Missing 
Components 
Dermatology Life 
Quality Index (DLQI) 
(continued) 
 
Proportions of 
patients achieving a 
DLQI score of 5 or 
less for those with 
baseline DLQI >5 of 
originating study 
Post-baseline DLQI total score 
≤5 with baseline total score >5 
Missing if baseline is 
missing or ≤5 or 
observed value is 
missing 
DLQI 0 or 1 
Post-baseline DLQI total score 
in (0,1) 
N/A – partial 
assessments cannot be 
saved.    
Abbreviations:  N/A = not applicable; QoL = quality of life. 
 


I4V-MC-JAIX Statistical Analysis Plan Version 4 
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6.12. Safety Analyses 
Detailed analyses and discussion of Study JAIX safety data are more thoroughly assessed in the 
context of combining the safety data from the originating Study JAIW with the safety data from 
Study JAIX, and will be presented in an integrated submission document and not in the JAIX 
CSR.  Those planned analyses are described in the PSAP.   
For the purpose of Study JAIX and JAIX (2) open-label addendum, the following are planned to 
be analyzed:   
 TEAEs by PT nested within System Organ Class (SOC)  
 SAEs by PT nested within SOC, and listing of SAEs including deaths, if any 
 AEs leading to permanent study drug discontinuation and temporarily interruption to 
study drug by PT nested within SOC, and listing of AEs leading to permanent study drug 
discontinuation 
The general methods used to summarize safety data, including the definition of baseline value, 
are described in Section 6.1. 
For selected safety assessments, descriptive statistics may be presented for the last measure 
observed during post-treatment follow-up (up to 30 days after the last dose of treatment 
including rescue, regardless of study period). 
For all the safety analysis, data from the study JAIX and JAIX (2) open-label addendum study 
will be presented together. 
6.12.1. Extent of Exposure  
Duration of exposure (in days) to study drug will be summarized for the safety population using 
descriptive statistics (n, mean, SD, minimum, 1st quartile, median, 3rd quartile, maximum).  
Cumulative exposure and duration of exposure will be summarized in terms of frequency counts 
and percentages by category and treatment group.  
Duration of exposure will be calculated as follows: 
 Duration of exposure to investigational product:  date of last dose of treatment– date of first 
dose of study drug + 1. 
Last dose of treatment is calculated as last date on study drug. 
Total patient-years (PY) of exposure will be reported using descriptive statistics (n, mean, SD, 
minimum, 1st quartile, median, 3rd quartile, and maximum) will be provided as patient-days of 
exposure and the frequency of patients falling into different exposure ranges will be summarized.  
Exposure ranges will generally be reported in weeks using the following as a general guide:   
 ≥28 days, ≥56 days, ≥112 days, ≥168 days, ≥252 days, ≥364 days, ≥448 days, 532 days, 
≥616 days, ≥728 days, ≥840 days, ≥952 days, ≥1064 days, ≥1176 days, ≥1288 days, and 
≥1400 days 
 >0 to <28 days, ≥28 to <56 days, ≥56 to <112 days, ≥112 to <168 days, ≥168 to <252 
days, ≥252 to <364 days, ≥364 to <448 days, ≥448 to <532 days,  ≥532 to <616 days, 


I4V-MC-JAIX Statistical Analysis Plan Version 4 
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LY3009104 
≥616 to <728 days, ≥728 to <840 days, ≥840 to <952 days, ≥952 to <1064 days,  ≥1064 
to <1176 days, ≥1176 to <1288 days,  ≥1288 to <1400 days, and ≥1400 days 
Overall exposure will be summarized in total PY, which is calculated according to the following 
formula: 
PYE = sum of duration of exposure in days (for all patients in treatment group) / 365.25  
6.12.2. Adverse Events 
Adverse events are recorded in the eCRFs.  Each AE will be coded to SOC and PT using the 
MedDRA version that is current at the time of database lock.  Severity of AEs is recorded as 
mild, moderate, or severe. 
A TEAE is defined as an event that either first occurred or worsened in severity after the first 
dose of study treatment in Study JAIX and JAIX (2) open-label addendum study and on or prior 
to the last visit date during the analysis period.  The analysis period is defined as the treatment 
period plus up to 30 days off-drug follow-up time. 
Adverse events are classified based on the MedDRA PT.  The MedDRA Lowest Level Term 
(LLT) will be used in defining which events are treatment-emergent.  The maximum severity for 
each LLT during the baseline period up to first dose of the study medication in Study JAIX will 
be used as baseline.  If an event with missing severity is preexisting during the baseline period, 
and persists during the treatment period, then the baseline severity will be considered mild for 
determining TEAE (that is, the event is treatment-emergent if the severity is coded moderate or 
severe postbaseline and not treatment-emergent if the severity is coded mild postbaseline).  If an 
event occurring postbaseline has a missing severity rating, then the event is considered 
treatment-emergent unless the baseline is severe, in which case the event is not treatment-
emergent.  The day and time for events where onset is on the day of the first dose of study 
treatment will both be used to distinguish between pretreatment and posttreatment in order to 
derive treatment-emergence.  Should there be insufficient data for AE start date to make this 
comparison (eg, the AE start year is the same as the treatment start year, but the AE start month 
and day are missing), the AE will be considered treatment-emergent. 
In general, summaries will include the number of patients in the safety population (N), frequency 
of patients experiencing the event (n), and percentage n/N*100.  For any events that are gender-
specific based on the displayed PT, the denominator used to compute the percentage will only 
include patients from the given gender.  The number and percentage of patients with TEAEs will 
be summarized by MedDRA PT nested within SOC with decreasing frequency in SOC, and 
events ordered within each SOC by decreasing frequency in the baricitinib 2-mg group.  
6.12.3. Common Adverse Events 
Common TEAEs are defined as TEAEs that occurred in ≥2% (before rounding) of patients.  
Common TEAEs will be analyzed in the context of combining the safety data from the 
originating Study JAIW with the safety data from Study JAIX.  The planned analyses are 
described in the PSAP and will not be analyzed for Study JAIX alone. 


I4V-MC-JAIX Statistical Analysis Plan Version 4 
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6.12.4. Serious Adverse Events 
Consistent with the International Conference on Harmonisation (ICH) E2A guideline (1994) and 
21 Code of Federal Regulations (CFR) 312.32 (a) (2010), a SAE is any AE that results in any 
one of the following outcomes: 
 Death 
 Initial or prolonged inpatient hospitalization 
 A life-threatening experience (that is, immediate risk of dying) 
 Persistent or significant disability/incapacity 
 Congenital anomaly/birth defect 
 
Important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above.   
The number and percentage of patients who experienced any SAE will be summarized using 
MedDRA PT nested within SOC.   
An individual listing of all SAEs will be provided.  A listing of deaths, regardless of when they 
occurred during the study, will also be provided. 
6.12.5. Other Significant Adverse Events 
Other significant AEs to be summarized will provide the number and percentage of patients who 
permanently discontinued study drug because of an AE or death; by treatment using MedDRA 
PT nested within SOC.  Events will be ordered by decreasing frequency in the SOC.   
A listing of all AEs leading to permanent discontinuation from the study drug or from the study 
will be provided.   
6.13. Protocol Violations 
Protocol deviations will be tracked by the clinical team, and their importance will be assessed by 
key team members during protocol deviation review meetings.   
The number and percentage of patients having important protocol deviations (IPDs) will be 
summarized within category and subcategory of deviation using the mITT population.  
Individual patient listings of IPDs will be provided.   
6.14. Planned Exploratory Analyses  
Exploratory objectives are listed in Section 4.3 and their associated analyses are described in 
Sections 6.10 and 6.11.  
6.15. Interim Analyses 
The first interim database lock is a safety lock to support US Food and Drug Administration 
(FDA) submission.  It is anticipated that at the time of data cutoff, only some patients will be 


I4V-MC-JAIX Statistical Analysis Plan Version 4 
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LY3009104 
able to reach the end of the Week 16 (the primary endpoint); thus, efficacy analyses will not be 
included.  The summary on safety analyses will be up to the date cut for all safety population. 
Additional interim analyses may be performed to support global regulatory submissions and 
reviews. 
6.16. Annual Report Analyses 
Annual report analyses, such as the Development Update Safety Report (DSUR), will be 
documented in a separate document.  
6.17. Clinical Trial Registry Analyses 
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.   
Analyses provided for the CTR requirements include a summary of AEs, provided as a dataset 
which will be converted to an XML file.  Both SAEs and ‘Other’ AEs are summarized by 
treatment group, by MedDRA PT. 
 An AE is considered ‘Serious’ whether or not it is a TEAE. 
 An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious.  For 
each SAE and ‘Other’ AE, for each term and treatment group, the following are provided: 
o the number of participants at risk of an event 
o the number of participants who experienced each event term 
o the number of events experienced. 
 Consistent with ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer than 5% 
of patients/subjects in every treatment group may not be included if a 5% threshold is 
chosen (5% is the minimum threshold). 
 AE reporting is consistent with other document disclosures (eg, CSR, manuscripts).  
Similar methods will be used to satisfy the European Clinical Trials Database (EudraCT) 
requirements.  


I4V-MC-JAIX Statistical Analysis Plan Version 4 
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7. References  
Basra MK, Salek MS, Camilleri L, Sturkey R, Finlay AY. Determining the minimal clinically 
important difference and responsiveness of the Dermatology Life Quality Index (DLQI): 
further data. Dermatology. 2015;230(1):27-33. 
[CFR] US National Archives and Records Administration. Code of Federal Regulations (CFR). 
Investigational New Drug Application (IND) safety reporting. 2010;Title 21:Section 312.32. 
Available at: https://www.ecfr.gov/cgi-bin/text-
idx?SID=fd87d5f6fb00b95672dbe924a6d3b2f0&mc=true&node=se21.5.312_132&rgn=div8. 
Accessed July 21, 2017. 
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 [published correction appears in Arch Dermatol. 2005;141(3):381]. Arch 
Dermatol. 2004;140(12):1513-1519. 
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and 
severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. 
Exp Dermatol. 2001;10(1):11-18. 
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;125(4):659-664. 
[ICH] International Conference on Harmonisation. Harmonised Tripartite Guideline: Clinical 
safety data management: definitions and standards for expedited reporting. E2A. 1994;Step 4. 
Available at: http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html. 
Accessed July 21, 2017. 
Khilji FA, Gonzalez M, Finlay AY. Clinical meaning of change in Dermatology Life Quality 
Index scores. Br J Dermatol. 2002;147(suppl 62):25-54. 
Kimball AB, Naegeli AN, Edson-Heredia E, Lin CY, Gaich C, Nikai E, Yosipovitch G. 
Psychometric properties of the Itch Numeric Rating Scale in patients with moderate-to-severe 
plaque psoriasis. Br J Dermatol. 2016;175(1):157-162. 
Kunz B, Oranje A, Labrèze, Stadler JF, Ring J, Taїeb A. Clinical validation and guidelines for 
the SCORAD index: consensus report of the European Task Force Atopic Dermatitis. 
Dermatology. 1997;195(1):10-19.  
Naegeli AN, Flood E, Tucker J, Devlen J, Edson-Heredia E. The Worst Itch Numeric Rating 
Scale for patients with moderate to severe plaque psoriasis or psoriatic arthritis. Int J 
Dermatol. 2015;54(6):715-722. 
Schram ME, Spuls PI, Leeflang MMG, Lindeboom R, Bos JD, Schmitt J. EASI, (objective) 
SCORAD and POEM for atopic eczema: responsiveness and minimal clinically important 
difference. Allergy. 2012;67(1):99-106.  
 
 


I4V-MC-JAIX Statistical Analysis Plan Version 4 
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Stalder J, Taieb A, Atherton D, Bieber P, Bonifazi E, Broberg A, Calza A, Coleman R, De Prost 
Y, Stalder J, Gelmetti C, Cuannetti A, Harper J, Kunz B, Lachapelle J, Langeland T, Lever R, 
Oranje A, Oueille-Roussel C, Revuz J, Ring J, Roujeau J, Saurat J, Song M, Tennstedt D, Van 
Neste D, Vieluf D, Poncet M. Severity scoring of atopic dermatitis: the SCORAD index. 
Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology. 
1993;186(1):23-31. 
 

Prot_001.pdf: 
I4V-MC-JAIX(2) Clinical Protocol Addendum 
 
 
A Multicenter, Open-Label, Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib in 
Adult Patients with Moderate to Severe Atopic Dermatitis 
 
NCT03559270 
 
Approval Date: 19-Nov-2020 
 
 


I4V-MC-JAIX(2) Clinical Protocol Addendum
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1. Protocol Addendum I4V-MC-JAIX(2)
A Multicenter, Open-Label, Phase 3 Study to Evaluate the 
Efficacy and Safety of Baricitinib in Adult Patients with 
Moderate to Severe Atopic Dermatitis
BREEZE-AD6
Confidential Information
The information contained in this protocol addendum is confidential and is 
intended for the use of clinical investigators.  It is the property of Eli Lilly and Company or 
its subsidiaries and should not be copied by or distributed to persons not involved in the 
clinical investigation of baricitinib (LY3009104), unless such persons are bound by a 
confidentiality agreement with Eli Lilly and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries
Baricitinib (LY3009104)
This addendum is to be performed in addition to all procedures required by protocol I4V-
MC-JAIX(c) or any subsequent amendments to that protocol unless otherwise specified 
within this addendum.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Addendum (2) Electronically Signed and Approved by Lilly on date provided 
below.
Approval Date: 19-Nov-2020 GMT


I4V-MC-JAIX(2) Clinical Protocol Addendum
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2. Table of Contents
Protocol Addendum I4V-MC-JAIX (2)
A Multicenter, Open-Label, Phase 3 Study to Evaluate the 
Efficacy and Safety of Baricitinib in Adult Patients with 
Moderate to Severe Atopic Dermatitis
Section
Page
1.
Protocol Addendum I4V-MC-JAIX(2) A Multicenter, Open-Label, 
Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib in 
Adult Patients with Moderate to Severe Atopic Dermatitis..................................................1
2.
Table of Contents................................................................................................................2
3.
Rationale for Addendum .....................................................................................................7
4.
Protocol Additions ..............................................................................................................8
4.1.
Overview of Protocol Additions .....................................................................................8
4.2.
Section 3.3. Benefit/Risk Assessment.............................................................................8
4.3.
Section 4. Objectives and Endpoints...............................................................................8
4.4.
Section 5. Study Design .................................................................................................9
4.4.1.
Section 5.1. Overall Design....................................................................................9
4.4.2.
Screening Period..................................................................................................10
4.4.3.
Section 5.1.1. Open-Label Treatment, Weeks 0 to 200 .........................................11
4.4.4.
Section 5.1.2. Post-treatment Follow-up Period....................................................13
4.4.5.
Section 5.2. Number of Participants .....................................................................13
4.4.6.
Section 5.4. Scientific Rationale for Study Design................................................13
4.5.
Section 6. Study Population..........................................................................................14
4.5.1.
Section 6.1 Inclusion Criteria ...............................................................................14
4.5.2.
Section 6.2 Exclusion Criteria ..............................................................................17
4.5.3.
Section 6.4. Screen Failures .................................................................................23
4.6.
Section 7. Treatments...................................................................................................23
4.6.1.
Section 7.7. Concomitant Therapy........................................................................23
4.6.1.1.
Section 7.7.1. Prohibited Medications and Procedures ....................................23
4.6.1.2.
Section 7.7.2. Permitted Medications and Procedures .....................................24
4.6.1.3.
Section 7.7.3. Rescue Therapy........................................................................25
4.7.
Section 8. Discontinuation Criteria...............................................................................25
4.7.1.
Section 8.1.1 Temporary Interruption from Investigational 
Product ................................................................................................................25
4.7.2.
Section 8.1.2 Permanent Discontinuation from Investigation 
Product ................................................................................................................25
4.7.3.
Section 8.2 Discontinuation from the Study..........................................................26


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4.8.
Section 9. Study Assessments and Procedures..............................................................26
4.8.1.1.
Photography ...................................................................................................26
4.8.1.1.1.
Intended Use of Photographs ....................................................................26
4.8.1.2.
Section 9.1.4. Appropriateness of Assessments...............................................26
4.9.
Section 9.4. Safety .......................................................................................................27
4.9.1.
Section 9.4.2. Physical Exam ...............................................................................27
4.9.2.
Section 9.4.6. Hepatitis B Virus DNA Monitoring................................................27
4.9.3.
Electrocardiograms ..............................................................................................27
4.9.4.
Chest X-ray and Tuberculosis Testing..................................................................27
4.10. Section 10. Statistical Considerations ...........................................................................27
4.10.1.
Section 10.1. Sample Size Determination.............................................................27
4.10.2.
Section 10.2. Populations for Analyses.................................................................28
5.
References ........................................................................................................................29


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List of Tables
Table
Page
Table JAIX.1.
Objectives and Endpoints.................................................................................9


I4V-MC-JAIX(2) Clinical Protocol Addendum
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List of Figures
Figure
Page
Figure JAIX.1.
Illustration of study design for Clinical Protocol I4V-MC-JAIX(2)................10


I4V-MC-JAIX(2) Clinical Protocol Addendum
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List of Attachments
Attachment
Page
Attachment 1.
I4V-MC-JAIX(2) Schedule of Activities........................................................30
Attachment 2.
JAIX(2) Clinical Laboratory Tests.................................................................35
Attachment 3.
American Academy of Dermatology:  Criteria for the Diagnosis and 
Assessment of Atopic Dermatitis ...................................................................37
Attachment 4.
Provisions for Changes in Study Conduct During Exceptional 
Circumstances ...............................................................................................38


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3. Rationale for Addendum
The purpose of addendum JAIX(2) is to collect qualitative visual evidence of clinical response to 
treatment with baricitinib as monotherapy to pair with the clinical assessments and patient self-
assessments collected under the main protocol. Sequential photographs of selected lesions or 
involved areas will be obtained at specific visits before and after treatment with study medication
through Week 16.  
This addendum will apply to select sites in the United States that have participated in JAIX and 
its originating study (I4V-MC-JAIW). Eligible patients will enroll directly into JAIX(2).  
This addendum is to be performed in addition to all other procedures required by the clinical 
protocol for Study JAIX(c) unless otherwise specified within this addendum.  JAIX(2) applies to 
JAIX(c) and all subsequent amendments (referred to throughout as the “main protocol”). 


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4. Protocol Additions
4.1.
Overview of Protocol Additions
With this addendum, up to approximately 30 patients with moderate to severe atopic dermatitis
(AD) will enroll directly into Study JAIX.  This group of patients will be in addition to the 
approximately 450 patients who may enroll after participating in JAIW.  Patients entering this 
addendum cannot have previously enrolled in any other study investigating baricitinib. Patients 
will complete a screening period (up to 5 weeks in duration).  If all inclusion criteria and none of 
the exclusion criteria of this addendum are met, patients may enroll into JAIX(2) where they will 
receive open-label baricitinib 2-mg daily as monotherapy until the Week 16 visit. After Week 16, 
use of background low-potency topical corticosteroids (TCS) is allowed throughout the 
remaining treatment period.  The screening procedures and inclusion/exclusion criteria in this 
addendum are similar to those of study JAIW.
Patients participating in the addendum will have multiple photographs taken during the first 
16 weeks of the treatment period.  Study procedures starting at Visit 1 will be similar to those in 
the main protocol, with the exception of photography and the fact that TCS will not be dispensed 
or weighed during the first 16 weeks of the study. Atopic dermatitis rescue treatments are not 
permitted during this study.  Due to the monotherapy nature of the first 16 weeks of treatment, 
patients requiring more than baricitinib prior to Week 16 will be discontinued from the study. 
Provisions for managing study activities under exceptional circumstances
(such as pandemics or natural disasters) have been added to this addendum (Attachment 4).
4.2.
Section 3.3. Benefit/Risk Assessment
The overall benefit risk assessment is consistent with the main protocol.  All patients will be 
assigned to the baricitinib 2-mg dose, which showed efficacy in improving disease signs and 
symptoms of AD in Phase 2. However, in this addendum, patients will not be allowed to use 
low-potency TCS as concomitant therapy until after Week 16.  
4.3.
Section 4. Objectives and Endpoints
The objectives of this addendum are to estimate the clinical response to baricitinib 2-mg.
Table JAIX.1 shows the objectives and endpoints of this addendum.  Data collected at Visit 1 of 
JAIX(2) will be used as baseline for efficacy assessments.  


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Table JAIX.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To describe the clinical response to baricitinib 2-mg 
QD in patients with moderate to severe AD.

Proportion of patients achieving EASI75 from 
baseline, assessed at Week 16
Secondary
To describe the clinical response to baricitinib 2-mg 
QD in AD as measured by improvement in signs and 
symptoms of AD.

Proportion of patients achieving IGA of 0 or 1 
assessed at Week 16

Proportion of patients achieving IGA of 0 or 1 
assessed at or before Week 16

Proportion of patients achieving EASI75 from 
baseline, assessed at or before Week 16

Mean percent change from baseline in EASI score,
assessed at Week 16 

Proportion of patients achieving a BSA of ≤3%,
assessed at or before Week 16
To describe the clinical response to baricitinib 2-mg 
QD in AD as assessed by patient-reported outcome 
measures.

Proportions of patients achieving a ≥4-point 
improvement in Itch NRS from baseline, assessed 
at Week 16

Proportions of patients achieving a ≥4-point 
improvement in Itch NRS from baseline, assessed 
at or before Week 16

Mean percent change from baseline in Itch NRS,
assessed at Week 16
Exploratory Objectives/Endpoints

Exploratory objectives may include evaluating the response to baricitinib treatment regimens on clinical 
measures and patient reported outcomes.  These endpoints may include dichotomous endpoints or change 
from baseline for the following measures:  IGA, EASI, SCORAD, POEM, HADS, DLQI, WPAI-AD, EQ-
5D-5L, Itch NRS, ADSS Item 2 score, Skin Pain NRS, PGI-S-AD.
Abbreviations:  AD = atopic dermatitis; ADSS = Atopic Dermatitis Sleep Scale; BSA = body surface area; 
DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; EASI75 = 75% 
improvement from baseline in EASI; EQ-5D-5L = the European Quality of Life–5 Dimensions–5 Levels; 
HADS = Hospital Anxiety Depression Scale; IGA = Investigator’s Global Assessment; NRS = numeric rating 
scale; PGI-S-AD = Patient Global Impression of Severity–Atopic Dermatitis; POEM = Patient-Oriented Eczema 
Measure; QD = once daily; SCORAD = SCORing Atopic Dermatitis; WPAI-AD = Work Productivity and 
Activity Impairment – Atopic Dermatitis.
4.4.
Section 5. Study Design
4.4.1. Section 5.1. Overall Design
Addendum JAIX(2) allows patients to enter directly into Study JAIX without first completing at 
least 16 weeks of treatment in an originating study.  Patients entering this addendum cannot have 
previously enrolled in any other study investigating baricitinib. Up to approximately 30 patients 
are planned to be enrolled in this addendum.  


I4V-MC-JAIX(2) Clinical Protocol Addendum
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All patients enrolled in JAIX(2) will receive open-label baricitinib 2-mg daily beginning at 
Visit 1.  Patients will use emollient daily throughout the study.  Moisturizers with additives such 
as TCS, antipruritics, or antiseptics are not permitted.  Use of other AD treatments including
TCS, other topical treatments such as topical calcineurin inhibitors (TCNIs) and 
phosphodiesterase type 4 (PDE-4) inhibitors, and systemic treatments are either not permitted or 
are limited to use only after treatment Week 16 (see Section 4.6 of this addendum).  
Figure JAIX.1 illustrates the design of this addendum which includes 3 study periods; a 5-week 
screening period, a 200-week open-label treatment period, and a 4-week posttreatment follow-up 
(PTFU) period.  The full visit schedule for patients enrolled in the addendum is outlined in the 
Study Schedule of Activities for this addendum (Attachment 1).
Abbreviations:  AD = atopic dermatitis; QD = once daily; TCS = topical 
corticosteroids; V = visit.
a
The first 16 weeks of the treatment period are monotherapy.  Refer Section 4.4.3 and Section 4.6.1
of this addendum for full details.
b
After completion of the Week 16 visit (V4), the patient may begin using low potency TCS as 
background therapy in addition to daily use of emollients.  Other AD treatments are not allowed.  Refer to 
Section 4.4.3 and Section 4.6.1 of this addendum for full details.
c
Occurs approximately 28 days after the last dose of investigational product.
Figure JAIX.1.
Illustration of study design for Clinical Protocol I4V-MC-JAIX(2).
Throughout the trial, investigators should continue to assess benefit-risk for patients to remain in
the trial and should consider discontinuing patients if AD symptoms are unacceptable.
4.4.2. Screening Period
The duration of the screening period for patients enrolled in JAIX(2) is between 8 and 35 days 
prior to Visit 1 (Week 0).  Eligibility of each patient will be reviewed based on all addendum
entry criteria described in Section 4.5. At Visit 0, the patient will sign the addendum informed 
consent form (ICF) prior to any study assessments, examinations, or procedures being 


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performed.  All screening procedures will be performed according to the Schedule of Activities 
(Attachment 1).  
Patients who receive a purified protein derivative (PPD) skin test at Visit 0 will need to return 
within 48 to 72 hours later to read the skin test.  Prior to enrollment, treatments for AD will be 
washed-out:  2 weeks for systemic treatments and 1 week for topical treatments (not including 
emollients).  Patients will be required to use emollients daily during the 7 days preceding 
enrollment and throughout the study.  Emollients must not contain additives, such as TCS, 
antiseptics, and antipruritics.  If patients have been using emollients daily at the time of 
screening, then those cumulative days can be utilized to meet inclusion criterion [8].  Site staff 
should review all washout requirements and prohibited medications with the patient prior to the 
conclusion of Visit 0 to minimize the risk of patients using these medications inappropriately.
All patients who have not previously received the herpes zoster vaccine by screening will be 
encouraged (per local guidelines) to do so prior to enrollment.  Investigators should review the 
vaccination status of their patients and follow the local guidelines for vaccination of those aged 
≥18 years with nonlive vaccines intended to prevent infectious disease before entering patients 
into the study. Refer to Exclusion Criterion [27] in Section 4.5.2 for additional information 
regarding herpes zoster vaccinations. 
Patients who meet all of the inclusion and none of the exclusion criteria for this addendum 
(Section 4.5) will continue to Visit 1 and follow all study procedures described in the Schedule 
of Activities (Attachment 1).  
4.4.3. Section 5.1.1. Open-Label Treatment, Weeks 0 to 200
Study activities will be conducted according to the Schedule of Activities (Attachment 1) and as 
described in Section 4.8 and Section 4.9 of this addendum and Section 9 of the main protocol.  
Treatment Weeks 0 to 16
At Visit 1 (Week 0, baseline), study eligibility for each patient will be reviewed, based on all 
inclusion and exclusion criteria (Section 4.5), and Visit 0 (Screening) laboratory test results.  
Patients who meet all criteria for inclusion and none of the exclusion criteria will proceed to 
enrollment and begin the open-label treatment period.  
During the first 16 weeks of the study, patients will be treated with baricitinib 2-mg as 
monotherapy (i.e. no TCS, TCNIs, or topical PDE-4 inhibitors or systemic AD treatments are 
allowed).  However, emollients are required to be used daily throughout the treatment period and 
must not contain additives, such as TCS, antiseptics or antipruritics.  There are no rescue 
therapies available during this open-label study. Additional prohibited therapies are listed in 
Section 4.6.1.1 of this addendum.  
At Visit 1, open-label investigational product (IP) will be allocated by interactive web-response 
system (IWRS), and the patient will begin treatment with baricitinib 2-mg once daily (QD).  The 
IP will be administered daily.  Daily diaries will be utilized during the screening period and 
through Week 16. 


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Study procedures and assessments of disease severity will be performed as described in the 
Schedule of Activities (Attachment 1).  At Week 16, all patients should be formally assessed to 
determine if sufficient clinical benefit has been observed to justify continuing in this study.  
Clinical benefit is defined as meeting at least 1 of the criteria defined in the main JAIX protocol
(Section 5.1.1) during the first 16 weeks of this addendum.
All patients who permanently discontinue IP prior to the primary endpoint will follow the study 
discontinuation requirements as outlined in the main protocol.
Photographs Weeks 0 to 16
Serial photographs will be taken of select lesions or body regions following guidelines provided 
by the sponsor.  At baseline (Visit 1), the investigator should identify approximately 4 to 6 areas 
to photograph that are representative of the patient’s overall baseline disease severity 
(Investigator’s Global Assessment [IGA] scores 3 or 4).  The areas selected should demonstrate 
the diversity of the body areas impacted and include areas such as the trunk and limbs, hands, 
feet, neck, and/or face if these areas are affected.  The PI should consider the size and visibility 
of the lesion to determine the most appropriate visual field to be included in the photograph(s).  
To provide visual context of areas of involvement and perspective of body surface area involved, 
consideration should be given to collecting both anatomical and target images of lesions/areas.  
For example, photographing a specific lesion on the abdomen from a distance of a few inches 
(referred to as targeted) vs a photo of the entire abdominal region (or even entire trunk) taken 
from a distance of a few feet (referred to as anatomical) or obtaining both targeted and 
anatomical images of the involved area. No full-body images should be collected.
One to three photos should be taken of each selected area at baseline (Visit 1); no more than 
12 total photos.  At Visits 2, 3, and 4, the areas photographed at baseline will be photographed 
again to document changes in disease severity over the first 16 weeks of study treatment.  A 
maximum of 12 photos will be collected at each timepoint.  
To enable comparison of the serial photographs for a single patient, the photographs taken at 
each visit should be obtained under similar lighting conditions, magnification, distance from 
target, subject preparation and positioning, and per instructions provided by the sponsor or 
designee. Because masking (deidentification) is required, sites should avoid photographing 
regions with tattoos that will affect visualization of disease severity after masking is completed.
Standardized photography equipment may be provided by the sponsor. If sites have their own 
equipment on site, use of this equipment may be permitted instead of sponsor-provided 
equipment, after agreement with the sponsor.  If possible, the same equipment should be used to 
capture all images collected for a single patient.  All images collected under this addendum will 
be uploaded to a central repository managed by an imaging vendor selected by the sponsor.  The 
imaging vendor will ensure that appropriate masking has been applied to deidentify the image 
prior to transferring these images to the sponsor.
Treatment Weeks 16 to 200
Patients will continue treatment with 2-mg baricitinib QD.


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After Week 16, addendum patients may begin receiving low potency TCS (e.g. 
Hydrocortisone 2.5% ointment) as background therapy for comfort, if needed.  
Study procedures and assessments of disease severity will continue to be performed as described 
in the Schedule of Activities (Attachment 1).  As per the main protocol (Section 5.1.1), a formal 
assessment of clinical benefit is required at Week 16, and only those patients meeting the 
protocol-defined Clinical Benefit criteria should continue in the study beyond Week 16.
4.4.4. Section 5.1.2. Post-treatment Follow-up Period
Patients enrolled in the addendum will follow the requirements for early termination visit (ETV)
and PTFU as described in the main protocol.
4.4.5. Section 5.2. Number of Participants
Up to approximately 30 participants may be enrolled into Study JAIX via this addendum. This 
group of patients will be in addition to the approximately 450 patients who may enroll after 
participating in JAIW.
4.4.6. Section 5.4. Scientific Rationale for Study Design
This open-label addendum will enroll moderate to severe AD patients with a history of 
inadequate response or intolerance to existing topical therapies for which a systemic treatment 
such as baricitinib may therefore be appropriate. This addendum study will generate long-term 
efficacy and safety data in AD and allow for collection of high-quality photographs to highlight 
the observed efficacy in this study.
During the screening period, a washout of systemic and topical treatments for AD is incorporated 
to minimize confounding effects of background treatment when establishing baseline disease 
severity. 
During the open-label treatment period, patients will be treated with baricitinib 2-mg, which has 
been shown to be efficacious as monotherapy in completed Phase 3 AD studies JAHL, JAHM, 
and JAIW. To ensure that the primary and secondary outcome results represent the effectiveness 
of baricitinib alone, patients will not be permitted to use background therapies, including TCS, 
prior to Visit 4 (Week 16).  For patient comfort, daily treatment with emollient is required for 
7 days prior to treatment initiation and will continue throughout the study.  At Week 16, all 
patients should be formally assessed to determine if sufficient clinical benefit has been observed
to justify continuing in the study. The criteria for determining sufficient clinical benefit are 
discussed in Section 5.1.1. of the main protocol.  
Photographs will be obtained at each scheduled visit from baseline through Week 16 to collect 
visual evidence of time to onset and extent of clinical response. 
The PTFU period is for safety monitoring after the patient has been off IP for approximately 
28 days.  The length of the PTFU period is consistent with other baricitinib AD protocols. 


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4.5.
Section 6. Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
At participating centers, patients may be eligible to enroll in this addendum if they meet all of the 
addendum inclusion criteria and none of the addendum exclusion criteria. All screening 
activities must be completed and reviewed before the patient is enrolled.  The 
inclusion/exclusion criteria of this addendum are similar to those of the originating study 
(JAIW), except for:  inclusion of an upper limit for body surface area (BSA) extent during 
screening, reduction of duration of washout from topical and systemic therapies for AD, and 
exclusion of sedating antihistaminic therapies from prohibited medications.
4.5.1. Section 6.1 Inclusion Criteria
Informed Consent
[1]
are aged ≥18 years at the time of informed consent.
Note:  Use local requirements to provide consent if the age of adulthood is 
defined as >18 years.
[2]
are able to read, understand, and give documented (electronic or paper 
signature) informed consent.
Type of Patient and Disease Characteristics
[3]
have a diagnosis of AD at least 12 months before screening, as defined by the 
American Academy of Dermatology:  Criteria for the Diagnosis and 
Assessment of Atopic Dermatitis (see Attachment 3).
[4]
have moderate to severe AD, including all of the following:
a.
Eczema Area and Severity Index (EASI) score ≥16 at screening (Visit 0)
and enrollment (Visit 1)
b. IGA score of ≥3 at screening (Visit 0) and enrollment (Visit 1)
c.
10% to 50% BSA involvement at screening (Visit 0) and enrollment 
(Visit 1).
[5]
have a documented history by a physician and/or investigator of inadequate 
response to existing topical medications within 6 months of screening
(Visit 0), or history of intolerance to topical therapy as defined by at least 1 of 
the following:
a.
inability to achieve good disease control defined as mild disease or better 
(for example, IGA ≤2) after use of at least a medium-potency TCS for at 
least 4 weeks or for the maximum duration recommended by the product
prescribing information (for example, 14 days for super-potent TCS), 
whichever is shorter.  Topical corticosteroids may be used with or 
without TCNIs.


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b. documented history of clinically significant adverse reactions with the use 
of TCS such as skin atrophy, allergic reactions, or systemic effects that in 
the opinion of the investigator outweigh the benefits of retreatment.
c.
patients who failed systemic therapies intended to treat AD (such as 
cyclosporine, methotrexate, azathioprine, or mycophenolate mofetil) 
within 6 months of screening (Visit 0) will also be considered as
surrogates for having inadequate response to topical therapy.
[6]
agree to discontinue use of the following excluded medications/treatments for
at least 2 weeks before enrollment (Visit 1):
a.
oral systemic corticosteroids and leukotriene inhibitors
b. systemic immunomodulators, including but not limited to cyclosporine, 
methotrexate, mycophenolate mofetil, and azathioprine
c.
any other systemic therapy used to treat AD or symptoms of AD 
(approved or off-label use)
d. phototherapy, includes therapeutic phototherapy (psoralen plus 
ultraviolet-A, ultraviolet-B), excimer laser, as well as self-treatment with 
tanning beds.
[7]
agree to discontinue use of the following excluded medications for at least 
1 week before enrollment (Visit 1):
a.
TCS or topical immune modulators (for example, tacrolimus or 
pimecrolimus)
b. Topical PDE-4 inhibitor (crisaborole).
[8]
have applied emollients daily for at least 7 days before enrollment and agree 
to use emollient daily throughout the treatment period.
[9]
Patients who are receiving chronic treatments to improve sleep should be on a 
stable dose for at least 2 weeks before screening as determined by the 
investigator.  
Patient Characteristics
[10] are male or nonpregnant, nonbreastfeeding female patients, and
a.
Male patients will either remain abstinent (if this is their preferred and 
usual lifestyle) or agree to use 2 forms of birth control (1 must be highly 
effective, see below) while engaging in sexual intercourse with female 
partners of childbearing potential while enrolled in the study and for at 
least 4 weeks following the last dose of IP.
Men who are in exclusively same-sex relationships (when it is their 
preferred and usual lifestyle) are not required to use contraception.


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


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4.5.2. Section 6.2 Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria:
Medical Conditions Related to Atopic Dermatitis
[11] are currently experiencing or have a history of other concomitant skin 
conditions (for example, psoriasis or lupus erythematosus) that would 
interfere with evaluations of the effect of study medication on AD.
[12] patients who are currently experiencing or have a history of erythrodermic, 
refractory, or unstable skin disease that requires frequent hospitalizations 
and/or intravenous (IV) treatment for skin infections that, in the opinion of the 
investigator, may interfere with participation in the study.
[13] a history of eczema herpeticum within 12 months of screening.
[14] a history of 2 or more episodes of eczema herpeticum.
[15] patients who are currently experiencing a skin infection that requires treatment 
or is currently being treated with topical or systemic antibiotics.
Note:  Patients may not be rescreened until at least 4 weeks after the date of 
their screen failure and at least 2 weeks after resolution of the infection.
[16] have any serious concomitant illness that is anticipated to require the use of
systemic corticosteroids or otherwise interfere with study participation or
require frequent monitoring (for example, unstable chronic asthma).
[17] have been treated with the following therapies:
a.
monoclonal antibody (for example, ustekinumab, omalizumab, 
dupilumab) for less than 5 half-lives before enrollment.
b. received prior treatment with any oral Janus kinase (JAK) inhibitor (for 
example, tofacitinib, ruxolitinib) less than 2 weeks before enrollment.
c.
received any parenteral corticosteroid administered by intramuscular or 
IV injection within 6 weeks of planned enrollment (Visit 1) or are 
anticipated to require parenteral injection of corticosteroids during the 
study.
d. have had an intra-articular corticosteroid injection within 6 weeks of
planned enrollment (Visit 1).
Note:  Intranasal or inhaled steroid use is allowed during the trial.
e.
probenecid at the time of enrollment (Visit 1) that cannot be discontinued 
for the duration of the study.
Medical Conditions in General
[18] are largely or wholly incapacitated permitting little or no self-care, such as 
being bedridden.


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


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b. a history of disseminated/complicated herpes zoster (for example,
multidermatomal involvement, ophthalmic zoster, central nervous system
involvement, or post-herpetic neuralgia).
c.
symptomatic herpes simplex at the time of enrollment.
d. active or chronic viral infection from hepatitis B virus (HBV), hepatitis C 
virus (HCV), or human immunodeficiency virus (HIV).
e.
household contact with a person with active tuberculosis (TB) and have
not received appropriate and documented prophylaxis for TB.
f.
evidence of active TB or have previously had evidence of active TB and 
have not received appropriate and documented treatment.
g. clinically serious infection or received IV antibiotics for an infection, 
within 4 weeks of enrollment.
h. any other active or recent infection within 4 weeks of enrollment that, in 
the opinion of the investigator, would pose an unacceptable risk to the 
patient if participating in the study.
[27] have been exposed to a live vaccine within 12 weeks of planned enrollment or 
are expected to need/receive a live vaccine during the course of the study 
(with the exception of herpes zoster vaccination).
Note:  All patients who are eligible to receive the herpes zoster vaccine (per 
local guidelines) and who have not received it by screening will be 
encouraged to do so before enrollment; vaccination must occur >4 weeks 
before enrollment and first dose of IP.  Patients will be excluded if they were 
exposed to herpes zoster vaccination within 4 weeks of planned enrollment.  
[28] have a history of chronic alcohol abuse, IV drug abuse, or other illicit drug 
abuse within 2 years of screening.
[29] presence of significant uncontrolled neuropsychiatric disorder, are clinically 
judged by the investigator to be at risk for suicide, or have a “yes” answer to 
any of the following within the 2 months before Visit 0:
a.
Question 4 (Active Suicidal Ideation with Some Intent to Act, Without 
Specific Plan) on the “Suicidal Ideation” portion of the Columbia Suicide 
Severity Rating Scale (C-SSRS) or
b. Question 5 (Active Suicidal Ideation with Specific Plan and Intent) on the 
“Suicidal Ideation” portion of the C-SSRS or
c.
Any of the suicide-related behaviors (actual attempt, interrupted attempt, 
aborted attempt, preparatory act or behavior) on the “Suicidal Behavior” 
portion of the C-SSRS.


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


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


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


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4.5.3. Section 6.4. Screen Failures
Patients who are entered into the addendum but do not meet the eligibility criteria for 
participation in the addendum (screen failure) may be rescreened a maximum of 2 times.  If 
patients are rescreened, rescreening cannot occur until at least 4 weeks after the date of their 
previous screen failure.  When rescreening is performed, the individual must sign a new ICF and 
will be assigned a new identification number. Additionally, all necessary screening procedures 
must be conducted at rescreen to ensure all eligibility criteria are met.
4.6.
Section 7. Treatments
Sections 7.1 through 7.6 will follow the main protocol; there are no modifications to these 
sections with this addendum.
4.6.1. Section 7.7. Concomitant Therapy
All concomitant medication, whether prescription or over-the-counter, used at baseline and/or 
during the course of the study must be recorded on the Concomitant Medication electronic case 
report form (eCRF).  Patients will be instructed to consult the investigator or other appropriate 
study personnel at the site before taking any new medications or supplements during the study.
Rescue therapy is not permitted, see Section 4.6.1.3 of this addendum.
Concomitant therapies permitted/not permitted during the addendum study are described below.
4.6.1.1.
Section 7.7.1. Prohibited Medications and Procedures
Prohibited Medications and Procedures Not Requiring Interruption of Investigational 
Product
The following therapies will not be allowed during the study:

Medium-potency TCS or higher potency TCS, TCNIs (for example, tacrolimus and 
pimecrolimus), or topical PDE-4 inhibitor (that is, crisaborole) are not allowed.  
Low-potency TCS is not allowed prior to Week 16 (Visit 4).

Allergen immunotherapy.

Phototherapy including psoralen and ultraviolet A (PUVA), ultraviolet B, tanning booth,
and excimer laser.

Bleach baths.
Prohibited Medications Requiring Temporary Interruption of Investigational Product
The following therapies will not be allowed during the course of the study and, if taken by or 
administered to the patient, temporary interruption of IP is required:

Live vaccines (including Bacillus Calmette-Guérin [BCG] or herpes zoster)
o
For BCG vaccination, IP should be temporarily interrupted for 12 weeks.
o
For herpes zoster vaccination, IP should be temporarily interrupted for 4 weeks.  


I4V-MC-JAIX(2) Clinical Protocol Addendum
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
Probenecid:  if a patient is inadvertently started on probenecid, IP should be temporarily 
interrupted and can be resumed after patient has discontinued probenecid.  If a patient is 
not able to discontinue probenecid, then IP should be permanently discontinued.

Systemic corticosteroids may be used for the treatment of an adverse event (AE) (for 
example, worsening of existing condition, such as asthma flare).  Investigational product 
may be restarted if systemic corticosteroids were used for a short duration (<30 days).  If 
used for >30 days, sponsor approval to restart IP is required.  Systemic corticosteroids 
may not be used to treat AD.
Prohibited Medications Requiring Permanent Discontinuation of Investigational Product

Any systemic therapy, investigational or commercial (approved or off-label use), used for 
the treatment of AD or symptoms of AD (except for antihistamines, as specified below).

Other JAK inhibitors (for example, tofacitinib and ruxolitinib).

Systemic immunosuppressive/immunomodulatory substances, including, but not limited 
to cyclosporine, methotrexate, mycophenolate mofetil, interferon γ, azathioprine, or 
biologic agents.
4.6.1.2.
Section 7.7.2. Permitted Medications and Procedures
Treatment with concomitant AD therapies during the study is permitted only as described below:

Daily use of emollients is required as background treatment.  Moisturizers with 
additives such as TCS, antipruritics, or antiseptics are not permitted.  If daily 
applications are missed, it will not be considered a protocol violation.
o
Patients should not apply emollients on the day of their study visit before study 
procedures to allow adequate assessment of skin dryness.

Antihistamines are allowed.

Intra-articular or soft tissue (bursa, tendons, and ligaments) corticosteroid 
injection:  No more than 1 intra-articular or soft tissue (bursa, tendons, and 
ligaments) corticosteroid injection is allowed up until Week 16 (Visit 4).  After 
Week 16, such injections are permitted.  

Intranasal or inhaled steroid use is allowed.

Topical anesthetics and topical and systemic anti-infective medications are 
allowed.

Nonlive seasonal vaccinations and/or emergency vaccination, such as rabies or 
tetanus vaccinations, are allowed.

Low-potency TCS (for example, Hydrocortisone 2.5% ointment) is permitted after 
Week 16 (Visit 4).
o
Patients should not apply TCS on the day of their study visit before study procedures 
to allow adequate assessment of skin dryness.
Any changes of these concomitant medications must be recorded on the Concomitant Therapy
pages of the eCRF.


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Treatment with concomitant therapies for other medical conditions such as diabetes and 
hypertension is permitted during the study.
4.6.1.3.
Section 7.7.3. Rescue Therapy
No rescue therapy options are available during the study. Background TCS is not permitted prior 
to Week 16 (Visit 4).  After Week 16, patients are allowed to use low-potency TCS as 
background therapy for comfort if needed. Patients who experience worsening and unacceptable 
symptoms of AD should consider discontinuing from the study.  Patients requiring more than 
low-potency TCS to manage their symptoms after Week 16 should also be discontinued.
After completing the monotherapy portion of the open-label treatment period, 
Hydrocortisone 2.5% ointment will be supplied by the sponsor for use for the remainder of the 
first 2 years of the treatment period (dispensed at Visits 4 to 10 only).  In the event that providing 
this topical formulation during this period is not possible, an alternate, equivalent potency TCS 
cream and/or ointment may be provided by the sponsor.  Use of sponsor-supplied TCS should be 
recorded via weight of returned tubes as indicated in the Schedule of Activities (Attachment 1).  
Sponsor will not provide or reimburse the cost of TCS at Visit 11 or after.
In the event that the sponsor is unable to supply TCS as described above, commercially available 
Hydrocortisone 2.5% ointment or an equivalent-potency TCS cream and/or ointment that is in 
line with local practices can be supplied by the sponsor or the sites.  Refer to Appendix 7 of the 
main protocol for guidance on potency equivalence.  
On the days of study visits, topical therapy should not be applied before the patient has 
undergone all study procedures and clinical evaluations to allow adequate assessment of skin 
dryness.
4.7.
Section 8. Discontinuation Criteria
4.7.1. Section 8.1.1 Temporary Interruption from Investigational 
Product
Refer to Section 4.6.1 of this addendum for interruption requirements related to concomitant 
medications.  Otherwise, criteria for temporary interruption of IP due to abnormal laboratory 
findings and clinical events and C-SSRS findings are the same as those in the main protocol as 
are the expectations for retesting and resumption of IP.  
4.7.2. Section 8.1.2 Permanent Discontinuation from Investigation 
Product
Refer to Section 4.6.1.1 above for a list of prohibited treatments that require permanent 
discontinuation of investigation product.  Otherwise, the permanent discontinuation requirements 
of the main protocol (Section 8.1.2) apply to patients enrolled in this addendum.  


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4.7.3. Section 8.2 Discontinuation from the Study
No rescue therapies are available during this study (Section 4.6.1.3 of this addendum) and 
patients are not permitted to use low potency TCS prior to Week 16.  An investigator may 
choose to discontinue the patient from the study to allow patient to receive other therapies.  
Otherwise, the requirements of the main protocol apply.  
4.8.
Section 9. Study Assessments and Procedures
Attachment 1 lists the Schedule of Activities, with the study procedures and their timing 
(including tolerance limits for timing).
During the screening period, tests will be conducted to support eligibility assessments.  From 
Visit 1 onward, patients included in the addendum will undergo laboratory testing procedures as 
defined in the main protocol.  Attachment 2 lists the laboratory tests that will be performed for 
this addendum as part of scheduled study visits.  Hepatic monitoring will be completed as 
defined in Appendix 4 of the main protocol.
Unless otherwise stated in the main protocol, 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.
4.8.1.1. Photography
4.8.1.1.1. Intended Use of Photographs
No formal analyses of the photographs are planned.  The photographs may be included in the 
clinical study report, a regulatory submission package, scientific publications, or other public 
dissemination of clinical data to demonstrate disease presentation at baseline and clinical 
response following treatment with baricitinib.  
These photographs may also be used in advertising and promotional activities including, but not 
limited to, communication with health care professionals and payers, patient education, speaker 
programs, and digital and print media messaging.  
These potential uses will be included in the consent form signed by patients participating in this
addendum. Patients must agree with the terms for use of their photographs to participate in this 
study. 
4.8.1.2. Section 9.1.4. Appropriateness of Assessments
All assessments utilized in this study are standard, widely used, and generally recognized as 
reliable, accurate, and relevant except Atopic Dermatitis Sleep Scale (ADSS) and Skin Pain 
Numeric Rating Scale (NRS), which are currently being developed and validated according to 
regulatory guidances.
Photographs are commonly obtained in research investigations of atopic dermatitis to document 
disease presentation at baseline and clinical response following treatment with baricitinib.  This 
study is being conducted with the objective of acquiring images of patients treated with 


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baricitinib as monotherapy, and therefore patients must agree to have their photos taken to 
participate in this study.
4.9.
Section 9.4. Safety
All safety evaluations and AE reporting requirements described in Section 9.4 of the main 
protocol are required by this addendum.  In addition, the following screening measures will be 
completed for patients entering addendum JAIX(2).
4.9.1. Section 9.4.2. Physical Exam
For each patient entered in addendum JAIX(2), a complete physical examination (excluding 
pelvic and rectal examinations) will be performed at screening (Visit 0).  Thereafter, symptom-
directed physical exams should be performed as described in Section 9.4.2 of the main protocol.
4.9.2. Section 9.4.6. Hepatitis B Virus DNA Monitoring
Hepatitis B virus DNA testing will be performed in enrolled patients who tested positive for 
anti-HBcAb during screening of this addendum.  Hepatitis B virus DNA monitoring for these 
patients will occur as described in Section 9.4.6 of the main protocol.
4.9.3. Electrocardiograms
For patients entered in addendum JAIX(2), a single 12-lead standard ECG will be obtained 
locally at screening (Visit 0) and read by a qualified physician (the investigator or qualified 
designee) at the site to determine whether the patient meets entry criteria.
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.
4.9.4. Chest X-ray and Tuberculosis Testing
For patients entered in addendum JAIX(2), a posterior-anterior view chest x-ray will be obtained 
locally at screening (Visit 0), unless results from a chest x-ray obtained within 6 months prior to 
the study are available.  The chest x-ray will be reviewed by the investigator or his or her 
designee to exclude patients with active TB infection.  In addition, patients will be tested at 
screening (Visit 0) for evidence of active or latent TB as described in the Exclusion Criterion 
[38], Section 4.5.2 of this addendum.
Investigators should follow local guidelines for monitoring patients for TB if a patient is at high 
risk for acquiring TB or reactivation of latent TB.
4.10. Section 10. Statistical Considerations
4.10.1. Section 10.1. Sample Size Determination
This addendum will aim to enroll up to approximately 30 additional patients ≥18 years of age 
into the JAIX Study.  This addendum is descriptive in nature and the sample size is not based on 
any statistical power calculations. 


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4.10.2. Section 10.2. Populations for Analyses
The populations for analyses for this addendum are the same as the main protocol.


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5. References
Eichenfield LF, Tom WL, Chamlin SL, Feldman SR, Hanifin JM, Simpson EL, Berger TG, 
Bergman JN, Cohen DE, Cooper KD, Cordoro KM, Davis DM, Krol A, Margolis DJ, 
Paller AS, Schwarzenberger K, Silverman RA, Williams HC, Elmets CA, Block J, Harrod CG, 
Smith Begolka W, Sidbury R. Guidelines of care for the management of atopic dermatitis: 
section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 
2014;70(2):338-351.


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Attachment 1.
I4V-MC-JAIX(2) Schedule of Activities








I4V-MC-JAIX(2) Clinical Protocol Addendum
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screening.)
f
If PPD testing was chosen to test for TB, then the patient must return and have her or his PPD test read 48 to 72 hours after Visit 0 (post-PPD).
g
Applies to ET Visit if conducted prior to Week 16 only.
h
TCS is not allowed prior to Visit 4 (study Week 16).  Low-potency TCS can be used as background therapy from study Week 16 onward.  Note, however, that 
at Visit 11 and after, low potency TCS is allowed but will not be provided by the sponsor or reimbursed by the sponsor.  
i
Returned TCS weight is collected, documented in the source notes and captured in INFORM for sponsor-provided TCS.  If non-sponsor provided low potency 
TCS is dispensed, it is not necessary to collect weight details and if collected, these details should not be reported in INFORM.
j
Refer to JAIX(2) addendum Section 4.4.3 for photography requirement details.
k
The following measures (POEM, DLQI, HADS, EQ-5D-5L, WPAI-AD) should be completed prior to any clinical assessments being performed on days when
study visits occur. 
l
Suicidal ideation and behavior subscales excerpt-adapted for the assessment of 11 preferred ideation and behavior categories.
m The Self-Harm Follow-Up Form is required only if triggered by the Self-Harm Supplement Form.
n
Fasting lipid profile.  Patients should not eat or drink anything except water for 12 hours prior to sample collection.  If a patient attends these visits in a 
nonfasting state, this will not be considered a protocol violation.  Unscheduled lipid testing can be performed at the discretion of the investigator.
o
For ET visits, collect fasting lipids when possible. 
p
Clinical chemistry will include the following value calculated from serum creatinine:  estimated glomerular filtration rate (eGFR; calculated using the Chronic 
Kidney Disease Epidemiology Collaboration [CKD-EPI] Creatinine 2009 equation).
q
For all women of childbearing potential, a serum pregnancy test (central laboratory) will be performed at Visit 0.  Urine pregnancy tests (local laboratory)
will be performed at Visit 1 and at all subsequent scheduled study visits.  If required per local regulations and/or institutional guidelines, pregnancy testing 
can occur at other times during the study treatment period.
r
For female patients aged ≥40 and <60 years who have had a cessation of menses for ≥12 months, an FSH test will be performed to confirm nonchildbearing 
potential (FSH ≥40 mIU/mL).
s
For patients who are positive for HCV antibody, a follow-up test for HCV RNA will be performed automatically.  Patients who are positive for HCV antibody 
and negative for HCV RNA may be enrolled.
t
Patients who are positive for HBcAb and negative for HBV DNA may be enrolled.  Any enrolled patient who is HBcAb positive, regardless of HBsAb status 
or level, must undergo HBV DNA testing per the schedule.
u
Urinalysis, serum IgE, exploratory storage samples, and RNA and biomarker samples are only collected for ET visits occurring at or before Week 104.  These 
samples are not collected as a component of Visit 17.


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


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e
eGFR for serum creatinine calculated by the central laboratory using the Chronic Kidney Disease Epidemiology 
Collaboration Creatinine 2009 equation.
f
Test required at Visit 0 only to determine eligibility of patient for the study.
g
A positive hepatitis C antibody result will be confirmed with an alternate hepatitis C method.
h
For all women of childbearing potential, a serum pregnancy test will be performed at Visit 0 and a local urine 
pregnancy test will be performed at Visit 1 and at all subsequent scheduled study visits.  If required per local 
regulations and/or institutional guidelines, pregnancy testing can occur at other times during the study treatment 
period.
i
To confirm postmenopausal status for women ≥40 and <60 years of age who have had a cessation of menses, an 
FSH test will be performed.  Nonchildbearing potential is defined as an FSH ≥40 mIU/mL and a cessation of 
menses for at least 12 months.
j
The QuantiFERON®-TB Gold test is the preferred alternative to the PPD test for the evaluation of TB infection, 
and it may be used instead of the PPD test or T-SPOT® TB test and may be read locally.  If the 
QuantiFERON-TB Gold test is indeterminate, 1 retest is allowed.  If the retest is indeterminate, then the patient 
is excluded from the study.
k
HBV DNA testing will be done in those patients who are HBcAb+ at screening.


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


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Attachment 4.
Provisions for Changes in Study Conduct 
During Exceptional Circumstances
CCI


I4V-MC-JAIX(2) Clinical Protocol Addendum
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CCI


I4V-MC-JAIX(2) Clinical Protocol Addendum
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CCI


I4V-MC-JAIX(2) Clinical Protocol Addendum
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CCI


Leo Document ID = 64b232bd-097a-4dd5-a210-da7631039438
Approver: 
Approval Date & Time: 19-Nov-2020 01:58:45 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 19-Nov-2020 10:28:54 GMT
Signature meaning: Approved
PPD
PPD

Prot_000.pdf: 
Protocol I4V-MC-JAIX(c) 
 
 
A Multicenter, Open-Label, Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib in 
Adult Patients with Moderate to Severe Atopic Dermatitis 
 
NCT03559270 
 
Approval Date: 28-Oct-2019 
 
 


I4V-MC-JAIX(c) Clinical Protocol
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Protocol I4V-MC-JAIX(c)
A Multicenter, Open-Label, Phase 3 Study to Evaluate the 
Efficacy and Safety of Baricitinib in Adult Patients with 
Moderate to Severe Atopic Dermatitis 
BREEZE-AD6
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
baricitin b (LY3009104), unless such persons are bound by a confidentiality agreement with 
Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Baricitinib (LY3009104)
Study I4V-MC-JAIX is a Phase 3, multicenter, open-label, outpatient, 204-week study 
designed to evaluate the efficacy and safety of baricitinib 2-mg in patients with moderate to 
severe atopic dermatitis.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on 08 February 2018.
Amendment (a) Electronically Signed and Approved by Lilly on 9 July 2018.
Amendment (b) Electronically Signed and Approved by Lilly on 1 April 2019.
Amendment (c) Electronically Signed and Approved by Lilly on approval date provided 
below
Approval Date: 28-Oct-2019 GMT


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Table of Contents
Section
Page
Protocol I4V-MC-JAIX(c) A Multicenter, Open-Label, Phase 3 Study to 
Evaluate the Efficacy and Safety of Baricitinib in Adult Patients with 
Moderate to Severe Atopic Dermatitis.................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................14
3.1.
Background..................................................................................................................14
3.2.
Study Rationale............................................................................................................15
3.3.
Benefit/Risk Assessment..............................................................................................16
4.
Objectives and Endpoints..................................................................................................18
5.
Study Design.....................................................................................................................19
5.1.
Overall Design .............................................................................................................19
5.1.1.
Period 1:  Open-Label Treatment, Weeks 0 to 200 ...............................................20
5.1.2.
Period 2:  Post-Treatment Follow-Up...................................................................21
5.2.
Number of Participants.................................................................................................21
5.3.
End of Study Definition ...............................................................................................22
5.4.
Scientific Rationale for Study Design...........................................................................22
5.5.
Justification for Dose ...................................................................................................22
6.
Study Population...............................................................................................................23
6.1.
Inclusion Criteria..........................................................................................................23
6.2.
Exclusion Criteria ........................................................................................................24
6.3.
Lifestyle Restrictions....................................................................................................25
6.4.
Screen Failures.............................................................................................................25
7.
Treatments........................................................................................................................26
7.1.
Treatments Administered .............................................................................................26
7.1.1.
Packaging and Labeling .......................................................................................26
7.2.
Method of Treatment Assignment ................................................................................26
7.2.1.
Selection and Timing of Doses.............................................................................26
7.3.
Blinding .......................................................................................................................26
7.4.
Dosage Modification....................................................................................................27
7.5.
Preparation/Handling/Storage/Accountability...............................................................27
7.6.
Treatment Compliance .................................................................................................27
7.7.
Concomitant Therapy...................................................................................................27


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7.7.1.
Prohibited Medications and Procedures................................................................28
7.7.2.
Permitted Medications and Procedures.................................................................29
7.7.3.
Rescue Therapy....................................................................................................29
7.8.
Treatment after the End of the Study............................................................................30
7.8.1.
Continued Access.................................................................................................30
8.
Discontinuation Criteria ....................................................................................................31
8.1.
Discontinuation from Study Treatment.........................................................................31
8.1.1.
Temporary Interruption from Investigational Product...........................................31
8.1.2.
Permanent Discontinuation from Investigational Product .....................................33
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................34
8.2.
Discontinuation from the Study....................................................................................34
8.3.
Lost to Follow-Up........................................................................................................35
9.
Study Assessments and Procedures ...................................................................................36
9.1.
Efficacy Assessments...................................................................................................36
9.1.1.
Primary Efficacy Assessments .............................................................................36
9.1.2.
Secondary Efficacy Assessments..........................................................................36
9.1.2.1.
Validated Investigator’s Global Assessment for Atopic 
Dermatitis (vIGA-AD)....................................................................................36
9.1.2.2.
Eczema Area and Severity Index scores..........................................................36
9.1.2.3.
SCORing Atopic Dermatitis ...........................................................................36
9.1.2.4.
Hospital Anxiety Depression Scale.................................................................37
9.1.3.
Health Outcomes and Quality-of-Life Measures...................................................37
9.1.3.1.
Patient-Oriented Eczema Measure ..................................................................37
9.1.3.2.
Itch Numeric Rating Scale..............................................................................37
9.1.3.3.
Atopic Dermatitis Sleep Scale ........................................................................37
9.1.3.4.
Skin Pain Numeric Rating Scale .....................................................................37
9.1.3.5.
Patient Global Impression of Severity.............................................................38
9.1.3.6.
Dermatology Life Quality Index.....................................................................38
9.1.3.7.
European Quality of Life–5 Dimensions–5 Levels..........................................38
9.1.3.8.
Work Productivity and Activity Impairment 
Questionnaire–Atopic Dermatitis....................................................................38
9.1.4.
Appropriateness of Assessments ..........................................................................39
9.2.
Adverse Events ............................................................................................................39
9.2.1.
Serious Adverse Events........................................................................................39
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................40
9.2.2.
Adverse Events of Special Interest .......................................................................41
9.2.3.
Complaint Handling.............................................................................................41
9.3.
Treatment of Overdose.................................................................................................41


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9.4.
Safety...........................................................................................................................41
9.4.1.
Vital Signs ...........................................................................................................41
9.4.2.
Physical Exam .....................................................................................................41
9.4.3.
Laboratory Tests ..................................................................................................41
9.4.4.
Columbia Suicide Severity Rating Scale...............................................................42
9.4.5.
Self-Harm and Follow-Up Supplement Forms......................................................42
9.4.6.
Hepatitis B Virus DNA Monitoring......................................................................42
9.4.7.
Hepatic Safety Monitoring and Data Collection....................................................43
9.4.8.
VTE Assessment..................................................................................................43
9.4.9.
Safety Monitoring ................................................................................................43
9.5.
Pharmacokinetics .........................................................................................................44
9.6.
Pharmacodynamics ......................................................................................................44
9.7.
Pharmacogenetics.........................................................................................................44
9.8.
Biomarkers...................................................................................................................44
9.9.
Medical Resource Utilization and Health Economics ...................................................45
10.
Statistical Considerations ..................................................................................................46
10.1. Sample Size Determination ..........................................................................................46
10.2. Populations for Analyses..............................................................................................46
10.3. Statistical Analyses ......................................................................................................46
10.3.1.
General Statistical Considerations ........................................................................46
10.3.2.
Descriptive Population Analyses ..........................................................................47
10.3.2.1.
Patient Disposition..........................................................................................47
10.3.2.2.
Patient Characteristics ....................................................................................47
10.3.2.3.
Concomitant Therapy .....................................................................................47
10.3.2.4.
Treatment Compliance....................................................................................47
10.3.3.
Efficacy Analyses ................................................................................................47
10.3.4.
Safety Analyses....................................................................................................48
10.3.5.
Other Analyses.....................................................................................................48
10.3.5.1.
Health Outcome Measures..............................................................................48
10.3.6.
Interim Analyses..................................................................................................48
10.3.6.1.
Adjudication Committee.................................................................................48
11.
References ........................................................................................................................49
12.
Appendices .......................................................................................................................52


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List of Tables
Table
Page
Table JAIX.1.
Schedule of Activities....................................................................................11
Table JAIX.2.
Objectives and Endpoints...............................................................................18
Table JAIX.3.
Treatment Regimen .......................................................................................26
Table JAIX.4.
Criteria for Temporary Interruption of Investigational Product.......................32


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List of Figures
Figure
Page
Figure JAIX.1.
Illustration of study design for Clinical Protocol I4V-MC-JAIX. ...................20


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................53
Appendix 2.
Clinical Laboratory Tests...............................................................................56
Appendix 3.
Study Governance Considerations..................................................................57
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................60
Appendix 5.
Liver Function Testing and Hepatic Safety Monitoring..................................61
Appendix 6.
Monitoring Tests for Confirmed VTE............................................................62
Appendix 7.
Classification of Potency for Topical Corticosteroids.....................................63
Appendix 8.
Investigator Global Assessment .....................................................................64
Appendix 9.
Protocol   I4V MC JAIX(c) Summary - A Multicenter, Open-Label, 
Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib in 
Adult Patients with Moderate to Severe Atopic Dermatitis.............................66


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


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Objectives/Endpoints:
Objectives
Endpoints
Primary
To describe the clinical response to baricitinib 2-mg 
QD in patients with moderate to severe AD by prior 
treatment received (ie., baricitinib 2-mg, 1-mg, or 
placebo) and responder status achieved in Study I4V-
MC-JAIW (JAIW).

Proportion of patients achieving EASI75 from 
baseline of originating study, assessed at Week 16
Secondary
To describe the clinical response to baricitinib 2-mg 
QD in AD as measured by improvement in signs and 
symptoms of AD by prior treatment received (ie., 
baricitinib 2-mg, 1-mg, or placebo) and responder 
status achieved in Study JAIW.

Proportion of patients achieving IGA of 0 or 1 
assessed at Week 16 

Proportion of patients achieving IGA of 0 or 1 
assessed at or before Week 16

Proportion of patients achieving EASI75 from 
baseline of originating study, assessed at or before 
Week 16

Mean percent change from baseline in EASI score 
from baseline of originating study, assessed at 
Week 16 

Proportion of patients achieving a BSA of ≤3% 
assessed at or before Week 16
To describe the clinical response to baricitinib 2-mg 
QD in AD as assessed by patient-reported outcome 
measures by prior treatment received (ie., baricitinib 
2-mg, 1-mg, or placebo) and responder status 
achieved in Study JAIW.

Proportions of patients achieving a ≥4-point 
improvement in Itch NRS from baseline of 
originating study, assessed at Week 16

Proportions of patients achieving a ≥4-point 
improvement in Itch NRS from baseline of 
originating study, assessed at or before Week 16

Mean percent change from baseline of originating 
study, in Itch NRS assessed at Week 16
Abbreviations:  AD = atopic dermatitis; BSA = body surface area EASI = Eczema Area and Severity Index; 
EASI75 = 75% improvement from baseline in EASI; IGA = Investigator’s Global Assessment; NRS = numeric 
rating scale; QD = once daily.
Summary of Study Design:
Study I4V-MC-JAIX (JAIX) is a Phase 3, multicenter, open-label outpatient study evaluating the efficacy and safety 
of baricitinib 2-mg once daily (QD) in adult patients with moderate to severe AD.  The study population will include 
patients 18 years or older with a history of inadequate response or intolerance to existing topical therapies, and who 
have completed protocol-defined minimal participation in Study JAIW based on responder status.
The study duration will be up to 204 weeks over 2 study periods:

Period 1:  Open-Label Treatment Period, lasting from Week 0 (baseline, Visit 1) through Week 200
(Visit 17).

Period 2:  Post-Treatment Follow-Up Period (Visit 801), spanning the period from the last treatment visit at 
Week 200 (Visit 17) or Early Termination Visit (ETV) to approximately 4 weeks following the last dose of 
investigational product.


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Treatment Arms and Duration:
Patients will be assigned at baseline to open-label treatment with baricitinib 2-mg QD.  The study duration will be 
up to 204 weeks (Open-Label Treatment Period:  200 weeks; Post-Treatment Follow-Up Period:  approximately 
4 weeks after the last dose of investigational product).
Number of Patients:
This study will include up to 450 patients with AD who will be treated with baricitinib 2-mg QD.
Statistical Analysis:
Unless otherwise specified, the efficacy and health outcomes summaries will be conducted on all enrolled patients
who receive at least 1 dose of investigational product in Study JAIX, even if the patient does not follow the protocol, 
and safety analyses will be conducted on all enrolled patients who receive at least 1 dose of investigational product
and who do not discontinue from the study for the reason “Lost to Follow-up” at the first postbaseline visit.  
Treatment comparisons of discrete efficacy variables between prior-treatment-received groups may be performed 
using group percentages.    All patients who discontinue the study or study treatment at any time for any reason will 
be defined as nonresponders for the nonresponder imputation (NRI) analysis for categorical variables after 
discontinuation onward.  
Continuous efficacy variables will be descriptively summarized in terms of number of patients, mean, standard 
deviation, median, minimum, and maximum.   
Frequencies and percentages will be computed for adverse event (AE), discontinuation, and other categorical safety 
data.    






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a
Any assessments/procedures conducted during the final visit of the patient’s originating study (Study JAIW) should not be repeated during their first visit 
for Study JAIX.
b An ET visit should be conducted if a patient discontinues from the study before Week 200.  Early termination visit activities do not need to be duplicated 
if occurring at the time of a scheduled visit. Weighing of TCS and collection of HADS, EQ-5D-5L, and WPAI-AD are not to be performed at Study Visit 17; 
these activities should only be performed at the ET visit if it occurs at or before Week 104. 
c
Visit 801 is the PTFU visit, which occurs after the patient has been off baricitinib/IP for approximately 4 weeks.  Patients who have permanently discontinued 
IP but remain in the study for more than 28 days without IP will only complete Visit 17/ET; Visit 801 (follow-up visit) is not required. 
d Screening should occur during the LPV of the originating study.   It may be permissible for screening to occur after the last visit of the originating study 
if needed, upon approval from the sponsor.
e Applies to ET visit if conducted prior to Week 16 only.
f
Only required at investigator discretion. Sponsor provided low potency TCS will be available to dispense to patients at anytime prior to study visit 11.  
At visit 11 and after, low potency TCS is allowed as background therapy but will not be provided by the sponsor or reimbursed by the sponsor.  
g The following measures (POEM, DLQI, HADS, EQ-5D-5L, WPAI-AD) should be completed prior to any clinical assessments being performed on days when 
study visits occur.
h Suicidal ideation and behavior subscales excerptadapted for the assessment of 11 preferred ideation and behavior categories.
i
The Self-Harm Follow-Up Form is required only if triggered by the Self-Harm Supplement Form.
j
Fasting lipid profile.  Patients should not eat or drink anything except water for 12 hours prior to sample collection.  If a patient attends these visits in a 
nonfasting state, this will not be considered a protocol violation.  Unscheduled lipid testing can be performed at the discretion of the investigator.
k If laboratory examinations have been performed ≤4 weeks from previous study visit, then they do not need to be repeated.
l
For ET visits, collect fasting lipids when possible. 
m Clinical chemistry will include the following value calculated from serum creatinine:  estimated glomerular filtration rate (eGFR; calculated using the Chronic 
Kidney Disease Epidemiology Collaboration [CKD-EPI] Creatinine 2009 equation).
n Patients who are positive for HBcAb and negative for HBV DNA may be enrolled.  Any enrolled patient who is HBcAb positive as determined at screening 
of originating study, Study JAIW, regardless of HBsAb status or level, must undergo HBV DNA testing per the schedule.
o Urinalysis, serum IgE, exploratory storage samples, and RNA and biomarker samples are only collected for ET visits occurring at or before Week 104.  These 
samples are not collected as a component of Visit 17.
p   For all women of childbearing potential, urine pregnancy tests (local laboratory) will be performed at all specified visits. If required per local regulations 
and/or institutional guidelines, pregnancy testing can occur at other times during the study treatment period.


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3.
Introduction
3.1.
Background
Atopic dermatitis (AD), also known as eczema or atopic eczema, is a common, chronic, 
relapsing, highly symptomatic inflammatory skin disease (Bieber 2010).  Patients with AD may 
present with skin lesions that can be acute with oozing, crusted, eroded vesicles or papules on 
erythematous plaques.  Patients may also present with lesions that have a subacute appearance, 
with thick and excoriated plaques, or chronic appearance, with lichenified, slightly pigmented, 
excoriated plaques (Bieber 2010).  AD causes pruritus attacks throughout the day, which is the 
primary source of morbidity in this disorder (Simpson 2012). Pruritus often leads to an “itch–
scratch” cycle, further compromising the epidermal barrier and resulting in dry skin, microbial 
colonization, and secondary infections (Krakowski et al. 2008), with 36% of patients reporting 
that they often or always scratch until their skin bleeds (Langenbruch et al. 2014). Pruritus from 
AD can worsen at night, resulting in sleep disturbances, with approximately 27% of adult 
patients with AD experiencing sleep disturbance as a result of itching (Langenbruch et al. 2014).
In adult patients with moderate to severe AD, poor sleep quality and latency were significantly 
associated with poor quality of life (Yano et al. 2013).
In clinical practice, AD is classified as mild, moderate, or severe based on a variety of clinical 
features, including severity of skin lesions and pruritus and extent of disease (body surface area 
[BSA] involved).
Until recently, there were no US Food and Drug Administration-approved systemic treatments 
for patients with moderate to severe AD, with the exception of systemic corticosteroids.  In 
March 2017, Dupixent® (dupilumab) injection, an IgG4 monoclonal antibody that inhibits IL-4 
and IL-13, was approved by the US Food and Drug Administration for this patient population.  
In the European Union, only cyclosporine has been approved for the treatment of patients with 
severe AD (Bieber and Straeter 2015).  A recently completed Phase 2 study 
(Study I4V-MC-JAHG [JAHG]) evaluated the safety and efficacy of baricitinib (a JAK inhibitor) 
in AD, and results showed significant improvement in disease severity compared to placebo, and 
no new safety concerns were identified.
In addition to AD, baricitinib has also been studied in Phase 3 in patients with rheumatoid 
arthritis (RA) and in Phase 2 in patients with diabetic nephropathy, moderate to severe psoriasis,
and systemic lupus erythematosus.
Through 13 February 2019, baricitinib has been studied in more than 548 healthy volunteers and 
6555 patients have received baricitinib in clinical studies.  As of 13 February 2018, more than 
2700 patients have been treated with baricitinib for more than a year and more than 1800 patients 
have been treated with baricitinib for more than 2 years at doses of 2-mg once daily or 4-mg 
once daily across the RA clinical program. Baricitinib has been administered as single doses 
ranging from 1- to 40-mg and as repeat oral doses ranging from 2- to 20-mg to healthy 
subjects. Baricitinib has also been administered to patients with RA at doses up to 15-mg daily 
for 4 weeks, 10-mg daily for 24 weeks, 8-mg daily for 76 weeks, and lower doses up to 4-mg 
daily for up to approximately 7 years. 


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3.2.
Study Rationale
The underlying cause of AD is not completely understood.  Loss of function mutations in the 
gene for filaggrin (filament aggregating protein), a key protein in terminal differentiation of the
epidermis contributing to barrier function, has been identified as the strongest genetic risk factor
for AD in European populations (Palmer et al. 2006). At a cellular level, AD is characterized by 
excessive T cell activation caused by genetic and environmental factors, leading to significant 
skin infiltration by T cells and dendritic cells. The cytokine TSLP is thought to act as a master 
switch that triggers the initiation and maintenance of AD (Moniaga et al. 2013; Ziegler et al. 
2013). Overexpression of TSLP in keratinocytes, the most prevalent cell type in the skin, 
triggers robust itch-evoked scratching and the development of an AD-like skin phenotype in 
mice (Li et al. 2005). In addition to directly inducing itch by activating sensory neurons in the 
skin, TSLP also enhances maturation and differentiation of dendritic cells and naive CD4+ 
T cells and induces production of Th2-related cytokines involved in AD pathogenesis (Wilson 
et al. 2013; Divekar and Kita 2015). TSLP and other key cytokines involved in AD 
pathogenesis, such as IL-13, IL-5, IL-22, and IL-31, signal through receptors associated with 
intracellular JAK1/JAK2/TYK2 signaling (Ziegler et al. 2013; Nomura and Kabashima 2016).
JAKs are a family of tyrosine kinases that mediate cytokine receptor signalling through 
phosphorylation and activation of signal transducers and activators of transcription proteins.  
There are 4 known JAK family members:  JAK1, JAK2, JAK3, and TYK2 (Clark et al. 2014).
The relative affinity of JAK inhibitors for different members of the JAK kinase family allows for 
differentiation of JAK inhibitors in relation to their enzymatic inhibitory profile. In vitro assays 
indicate that baricitinib is a selective inhibitor of JAKs with potency and selectivity for JAK1/2 
and less potency for JAK3 or TYK2 (Fridman et al. 2010).  The balanced JAK1/JAK2 inhibitory 
profile of baricitinib suggests that baricitinib will have the greatest modulatory effect in 
cytokines signalling through a JAK1/JAK2 heterodimer intracellularly (or a JAK1/JAK2/TYK2), 
such as IL-6, TSLP, IL-13, or IL-31 (Vaddi and Luchi 2012).
The recently completed Phase 2 study of baricitinib in AD, Study JAHG, met its primary 
objective of proportion of patients achieving a 50% improvement from baseline in Eczema Area 
and Severity Index (EASI50) scores compared to placebo. Baricitinib also showed statistically 
significant improvements for other disease severity analyses as well as multiple different 
patient-reported outcome scales compared to placebo, further validating the hypothesis that 
JAK1/JAK2 signaling plays a key role in AD pathogenesis.  Phase 3 placebo-controlled studies 
are ongoing to define baricitinib efficacy in AD.  This open-label, long-term extension study is 
designed to further assess long-term efficacy and safety of baricitinib in patients with moderate 
to severe AD, who did not achieve Investigator’s Global Assessment [IGA] 0 or 1 in the 
originating study, Study I4V-MC-JAIW (JAIW).  This will allow patients originally randomized 
to baricitinib 1-mg or placebo in Study JAIW to have the opportunity for treatment with 
baricitinib 2-mg QD, and also assess the longer-term clinical utility of the 2-mg dose beyond 
achieving an IGA 0,1.  In addition, this study will give patients completing Study JAIW as 
responders the opportunity for ongoing access to baricitinib 2-mg.


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3.3.
Benefit/Risk Assessment
CCI
CCI
CCI


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Additional information about the known and expected benefits, risks, serious AEs (SAEs), and 
reasonably anticipated AEs of baricitinib can be found in the investigator’s brochure (IB).  
CCI


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4.
Objectives and Endpoints
Table JAIX.2 shows the objectives and endpoints of the study.
Table JAIX.2.
Objectives and Endpoints
Objectives
Endpoints
Primary
To describe the clinical response to baricitinib 2-mg 
QD in patients with moderate to severe AD by prior 
treatment received (ie., baricitinib 2-mg, 1-mg, or 
placebo) and responder status achieved in Study I4V-
MC-JAIW (JAIW)

Proportion of patients achieving EASI75 from 
baseline of originating study, assessed at Week 16
Secondary
To describe the clinical response to baricitinib 2-mg 
QD in AD as measured by improvement in signs and 
symptoms of AD by prior treatment received (ie., 
baricitinib 2-mg, 1-mg, or placebo) and responder 
status achieved in Study JAIW.

Proportion of patients achieving IGA of 0 or 1 
assessed at Week 16

Proportion of patients achieving IGA of 0 or 1 
assessed at or before Week 16

Proportion of patients achieving EASI75 from 
baseline of originating study, assessed at or before 
Week 16

Mean percent change from baseline in EASI score 
from baseline of originating study, assessed at 
Week 16 

Proportion of patients achieving a BSA of ≤3% 
assessed at or before Week 16
To describe the clinical response to baricitinib 2-mg 
QD in AD as assessed by patient-reported outcome 
measures by prior treatment received (ie., baricitinib 
2-mg, 1-mg, or placebo) and responder status 
achieved in Study JAIW.

Proportions of patients achieving a ≥4-point 
improvement in Itch NRS from baseline of
originating study, assessed at Week 16

Proportions of patients achieving a ≥4-point 
improvement in Itch NRS from baseline of 
originating study, assessed at or before Week 16

Mean percent change from baseline of originating 
study, in Itch NRS assessed at Week 16
Exploratory Objectives/Endpoints

Exploratory objectives may include evaluating the response to baricitinib treatment regimens on clinical 
measures and patient reported outcomes.  These endpoints may include dichotomous endpoints or change 
from baseline for the following measures:  IGA, EASI, SCORAD, POEM, HADS, DLQI, WPAI-AD, EQ-
5D-5L, Itch NRS, ADSS Item 2 score, Skin Pain NRS, PGI-S-AD.
Abbreviations:  AD = atopic dermatitis; ADSS = Atopic Dermatitis Sleep Scale; BSA = body surface area; DLQI = 
Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; EASI75 = 75% improvement from 
baseline in EASI; EQ-5D-5L = the European Quality of Life–5 Dimensions–5 Levels; HADS = Hospital Anxiety 
Depression Scale; IGA = Investigator’s Global Assessment; NRS = numeric rating scale; QD = once daily; 
PGI-S-AD = Patient Global Impression of Severity–Atopic Dermatitis; POEM = Patient-Oriented Eczema 
Measure; SCORAD = SCORing Atopic Dermatitis; WPAI-AD = Work Productivity and Activity Impairment –
Atopic Dermatitis.




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Abbreviations:  AD = atopic dermatitis; QD = once daily; V = visit; W = week.
a
Occurs approximately 28 days after the last dose of investigational product.
Figure JAIX.1.
Illustration of study design for Clinical Protocol I4V-MC-JAIX.
5.1.1. Period 1:  Open-Label Treatment, Weeks 0 to 200
Screening should occur during the last visit of the originating study. Study eligibility for each 
patient will be reviewed based on all enrollment criteria (Section 6). Patients who meet all 
criteria will have treatment allocated by interactive web-response system (IWRS) and begin their 
treatment period at Visit 1. Patients who meet all of the inclusion and none of the exclusion 
criteria (Section 6) will be enrolled in the study.  It may be permissible for screening to occur
after the last visit of the originating study if needed, upon approval from the sponsor. For 
example, patients requiring elective procedures may want to have those in between studies, or 
responders who complete Visit 15 of Study JAIW have the option to delay enrollment into open-
label Study JAIX to assess response while off investigational product.
Patients who received oral systemic AD treatment and/or topical rescue therapy during the 
originating study must discontinue use of the prohibited medications listed in Section 7.7.1 prior 
to initiating IP in Study JAIX.  Low-potency TCS (e.g., hydrocortisone 2.5% ointment) is 
permitted (Section 7.7.2).
Patients will receive open-label baricitinib 2–mg QD.  Investigational product will be 
administered daily for a maximum of 200 weeks (treatment period Visits 1 through 17; see 
Section 7).  All patients will be required to use emollients daily.  Daily diaries will continue to be 
utilized through Week 16.  Download of this data will be required at study visits.  Patients are 
allowed to use low potency TCS (e.g., hydrocortisone 2.5% ointment) in combination with 
investigational product.  Rescue with higher potency TCS, topical calcineurin inhibitors
(TCNIs), or systemic therapies is not allowed.  Assessments of disease severity will be 
performed by the investigator as described in the Schedule of Activities (Section 2).


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The primary efficacy endpoint will be at Week 16 (Visit 4). All patients who permanently 
discontinue investigational product prior to the primary endpoint should complete an ETV and 
post-treatment follow-up visit.  
At Week 16, all patients should be formally assessed to determine if sufficient clinical benefit 
has been observed to justify continuing in this study.  Clinical benefit is defined as meeting at 
least 1 of the following criteria during the first 16 weeks:

IGA score of 0 or 1 with a ≥2-point improvement from baseline of originating study, 

≥4-point improvement from baseline of originating study in Itch NRS, 

EASI-75 from baseline of originating study, or

BSA involvement of ≤3%. 
If a patient achieves any of these treatment goals during the first 16 weeks of the treatment 
period, the patient will be allowed to continue in the study. Although formal criteria for 
sufficient clinical benefit should be assessed at Week 16, investigators are strongly encouraged 
to discontinue patients who have not shown signs of clinical benefit by Week 8 of Study JAIX, 
defined as improvement in IGA, itch NRS, EASI, or BSA. Attention should be given to patients 
treated continuously for 16 weeks during Study JAIW (no IP discontinuation for systemic rescue 
therapy) and who then show no benefit in Study JAIX, to avoid exposing patients to a potentially 
ineffective therapy for an additional 16 weeks before discontinuation.  Since no rescue therapies 
are available during this study, patients requiring more than low-potency TCS at any time during 
the study will be discontinued.
5.1.2. Period 2:  Post-Treatment Follow-Up
Patients who complete the study through Visit 17 (Week 200) will have a post-treatment
follow-up visit (Visit 801) approximately 28 days after the last dose of investigational product.
Patients who have received at least 1 dose of investigational product and discontinue early from 
the study should have an ETV, and return for the post-treatment safety follow-up visit (Visit 801) 
approximately 28 days after the last dose of investigational product.
Patients who have discontinued investigational product but remain in the study for more than 
28 days without investigational product will have an ETV if they choose to discontinue early; 
however, a separate follow-up visit (V801) is not required.
Patients should not initiate new systemic AD treatment during this period.  However, if patients 
or investigators must initiate treatment, investigators should make every attempt to conduct 
efficacy and safety assessments immediately before administering any new treatment. 
An unscheduled visit can be used for this purpose if necessary. 
5.2.
Number of Participants
Up to 450 participants may be enrolled.


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5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
This open-label long-term extension study will enroll moderate to severe AD patients who have 
completed Visit 8, Week 16 of Study JAIW but who did not achieve IGA 0,1, or who experience 
loss of response after Week 16, or who complete Study JAIW as responders at Visit 15, Week 
104. This study will further assess long-term efficacy and safety of baricitinib in this population.  
This will allow patients originally randomized to baricitinib 1-mg or placebo in Study JAIW to 
have the opportunity for treatment with baricitinib 2-mg QD, and also assess the longer-term 
clinical utility of the 2-mg dose beyond achieving an IGA 0,1.
During the open-label treatment period, patients will be treated with baricitinib 2-mg, which has 
been shown to be efficacious in the Phase 2 study in AD (JAHG). Patients will also be allowed 
to use low-potency TCS (e.g., hydrocortisone 2.5% ointment) as background therapy for comfort 
if needed. Daily treatment with emollient will continue. To avoid confounding effect of topical 
therapies, higher-potency TCS, as well as TCNIs and topical phosphodiesterase type 4 (PDE-4) 
inhibitors are not allowed at any time during the study. If a patient does not experience sufficient 
clinical benefit during the study, the patient should be discontinued.  The criteria for determining 
sufficient clinical benefit are discussed in Section 5.1.1.  This 4-year-long study will generate 
important long-term efficacy and safety data in AD.
The post-treatment follow-up period (Period 2) is for safety monitoring after the patient has been 
off investigational product for approximately 28 days.
5.5.
Justification for Dose
The dose used in Study JAIX is baricitinib 2-mg QD.  This dose was chosen primarily on the 
basis of the recently completed Phase 2 AD study, Study JAHG, and is additionally supported by 
pharmacokinetic, safety, and efficacy data for baricitinib in Phase 2 and Phase 3 RA studies and 
a Phase 2 psoriasis study.
In the Phase 2 Study JAHG, baricitinib 2-mg showed benefit on the clinically important
endpoints (EASI, IGA, SCORAD, POEM, and DLQI) as compared to placebo, and had an 
acceptable safety profile at Week 16.  To ensure that all patients participating in the originating 
study, Study JAIW, have the opportunity to receive the highest dose proposed in the study, this 
open-label study will treat all patients with the 2-mg dose.   


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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
Study investigator(s) will determine if the patient meets all inclusion criteria and none of the 
exclusion criteria to qualify for enrollment in the study.  All screening activities must be 
completed and reviewed before the patient is enrolled.
6.1.
Inclusion Criteria
Type of Patient and Disease Characteristics
[1]
have completed the minimum number of visits based on responder status in 
Study JAIW

nonresponder/partial responder: have completed at least 16 weeks of 
treatment in Study JAIW (i.e., Visit 8, Week 16)
A nonresponder/partial responder is defined as a patient who met at least 1 
of the following in Study JAIW: 

did not achieve an IGA of 0 or 1 at Week 16, or

achieved an IGA ≥3 after Week 16, or

required rescue therapy at any time.
or

responder: have completed the full treatment period of Study JAIW (i.e., 
Visit 15, Week 104)
A responder is defined as a patient who achieved IGA 0 or 1 and who did
not require rescue therapy at or before Week 16 in Study JAIW.
[2]
are able to read, understand, and give documented (electronic or paper 
signature) informed consent.
[3]
are male or nonpregnant, nonbreastfeeding female patients, and
a.
Male patients will either remain abstinent (if this is their preferred and 
usual lifestyle) or agree to use 2 forms of birth control (1 must be highly 
effective, see below) while engaging in sexual intercourse with female 
partners of childbearing potential while enrolled in the study and for at 
least 4 weeks following the last dose of investigational product.
Men who are in exclusively same sex relationships (when it is their 
preferred and usual lifestyle) are not required to use contraception.


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b. Female patients of childbearing potential who are abstinent (if this is 
complete abstinence, as their preferred and usual lifestyle) or in a 
same-sex relationship (as part of their preferred and usual lifestyle) must 
agree to either remain abstinent or stay in a same-sex relationship without 
sexual relationships with males. Periodic abstinence (for example,
calendar, ovulation, symptothermal, post-ovulation methods), declaration 
of abstinence just for the duration of a trial, and withdrawal are not 
acceptable methods of contraception. 
Otherwise, female patients of childbearing potential must agree to use 
2 forms of birth control when engaging in sexual intercourse with a male 
partner while enrolled in the study and for at least 4 weeks following the 
last dose of investigational product.
The following birth control methods are considered acceptable (the patient 
should choose 2 to be used with their male partner, and 1 must be highly 
effective):
o
Highly effective birth control methods: oral, injectable, or implanted 
hormonal contraceptives (combined estrogen/progesterone or 
progesterone only, associated with inhibition of ovulation); 
intrauterine device or intrauterine system (for example,
progestin-releasing coil); or, vasectomized male (with appropriate 
post-vasectomy documentation of the absence of sperm in the 
ejaculate).
o
Effective birth control methods: condom with a spermicidal foam, gel, 
film, cream, or suppository; occlusive cap (diaphragm or cervical/vault 
caps) with a spermicidal foam, gel, film, cream, or suppository; or, 
oral hormonal contraceptives.
Note:  When local guidelines concerning highly effective or effective 
methods of birth control differ from the above, the local guidelines 
must be followed.
c.
Females of nonchildbearing potential are not required to use birth control.
They are defined as:
o
women aged ≥60 years or women who are congenitally sterile, or
o
women aged ≥40 and <60 years who have had a cessation of menses 
for ≥12 months and a follicle-stimulating hormone test confirming 
nonchildbearing potential (≥40 mIU/mL or ≥40 IU/L), or women who 
are surgically sterile (that is, have had a hysterectomy or bilateral 
oophorectomy or tubal ligation).
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria:


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[4]
are currently enrolled in any other clinical trial involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study.
[5]
have significant uncontrolled cerebro-cardiovascular (e.g., myocardial 
infarction [MI], unstable angina, unstable arterial hypertension, severe heart 
failure, or cerebrovascular accident), respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematologic, neuropsychiatric disorders, or 
abnormal laboratory values that developed during a previous baricitinib study 
that, in the opinion of the investigator, pose an unacceptable risk to the patient 
if investigational product continues to be administered. 
[6]
have a history of VTE, or are considered at high risk of VTE as deemed by the 
investigator.
[7]
Have a known hypersensitivity to baricitinib or any component of this 
investigational product.
[8]
Had investigational product permanently discontinued at any time during a 
previous baricitinib study, except for patients who had investigational product 
discontinued during originating study because of rescue with an oral systemic 
AD therapy (e.g., corticosteroid, cyclosporine, methotrexate).
[9]
Had temporary investigational product interruption continue at the final study 
visit of a previous baricitinib study and, in the opinion of the investigator, this 
poses an unacceptable risk for the patient’s participation in the study.
[10] Have any other condition that, in the opinion of the investigator, renders the 
patient unable to understand the nature, scope, and possible consequences of 
the study or precludes the patient from following and completing the protocol.
[11] Are unwilling or unable to comply with the use of a data collection device to 
directly record data from the subject.
6.3.
Lifestyle Restrictions
Not applicable.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.


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7. Treatments
7.1.
Treatments Administered
This study involves baricitinib 2-mg administered orally QD.  Table JAIX.3 shows the treatment 
regimen.
Table JAIX.3.
Treatment Regimen
Regimen
Investigational Product Supplied
Dose
Baricitinib 2–mg QD
Baricitinib 2-mg tablet
1 tablet per day
Abbreviation:  QD = once daily.
The investigator or his or her designee is responsible for the following:

explaining the correct use of the investigational agent(s) to the patient

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

returning all unused medication to Lilly or its designee at the end of the study,
unless the sponsor and sites have agreed all unused medication is to be destroyed 
by the site, as allowed by local law
7.1.1. Packaging and Labeling
The sponsor (or its designee) will provide the following investigational product:

tablets containing 2-mg of baricitinib
Investigational product tablets will be provided in bottles. Clinical trial materials will be labeled 
according to the country’s regulatory requirements. Patients will be instructed to take 1 tablet 
each day.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will receive baricitinib 2-mg at Visit 1 (Week 0).  
Site personnel will confirm that they have located the correct bottles by entering the confirmation 
number found on the bottle into an interactive web-response system (IWRS).
7.2.1. Selection and Timing of Doses
The investigational product (1 tablet) should be taken once daily without regard to food and, if 
possible, at approximately the same time every day, usually at the start of the patient’s day, to aid 
patient compliance.  
7.3.
Blinding
This is an open-label study.


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7.4.
Dosage Modification
Not applicable.
7.5.
Preparation/Handling/Storage/Accountability
All investigational product (used and partially used) will be returned to the sponsor or destroyed 
at site level with the sponsor’s written approval.  In some cases, sites may destroy the material if, 
during the investigative site selection, the evaluator has verified and documented that the site has 
appropriate facilities and written procedures to dispose of clinical trial materials.
Follow storage and handling instructions on the investigational product packaging.
7.6.
Treatment Compliance
Patient compliance with study medication will be assessed at each visit during the treatment 
period (Visit 2 through Visit 17) by counting returned tablets.  
A patient will be considered significantly noncompliant if he or she misses more than 20% of the 
prescribed doses of investigational product during the study, unless the patient’s investigational 
product is withheld by the investigator for safety reasons.  Similarly, a patient will be considered 
significantly noncompliant if he or she is judged by the investigator to have intentionally or 
repeatedly taken 20% more than the prescribed amount of medication during the study.
Patients will be counseled by study staff on the importance of taking the investigational product 
as prescribed, as appropriate.
Patients’ compliance will be further defined in the statistical analysis plan (SAP).
7.7.
Concomitant Therapy
All concomitant medication, whether prescription or over the counter, used at baseline and/or
during the course of the study, must be recorded on the Concomitant Medication electronic case 
report form (eCRF).  Patients will be instructed to consult the investigator or other appropriate 
study personnel at the site before taking any new medications or supplements during the study. 
For AD therapies permitted as part of rescue therapy, see Section 7.7.3.


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7.7.1. Prohibited Medications and Procedures
Prohibited Medications and Procedures Not Requiring Interruption of Investigational 
Product
The following therapies will not be allowed during the study. 

Medium-potency TCS or higher potency TCS, TCNIs (for example, tacrolimus and 
pimecrolimus), or topical PDE-4 inhibitor (that is, crisaborole) are not allowed.  
Low-potency TCS is allowed (see Section 7.7.2).

Allergen immunotherapy.

Phototherapy including PUVA (psoralen and ultraviolet A), ultraviolet B, tanning booth 
and excimer laser.

Bleach baths
Prohibited Medications Requiring Temporary Interruption of Investigational Product
The following therapies will not be allowed during the course of the study and, if taken by or 
administered to the patient, temporary interruption of investigational product is required.

Live vaccines (including Bacillus Calmette-Guérin [BCG] or herpes zoster)
o
For BCG vaccination, investigational product should be temporarily interrupted for 
12 weeks.
o
For herpes zoster vaccination, investigational product should be temporarily 
interrupted for 4 weeks. 

Probenecid:  if a patient is inadvertently started on probenecid, investigational product
should be temporarily interrupted and can be resumed after patient has discontinued 
probenecid. If a patient is not able to discontinue probenecid, then investigational 
product should be permanently discontinued.

Systemic corticosteroids may be used for the treatment of an AE (for example, worsening 
of existing condition, such as asthma flare). Investigational product may be restarted if 
systemic corticosteroids were used for a short duration (<30 days).  If used for >30 days, 
sponsor approval to restart investigational product is required.  Systemic corticosteroids 
may not be used to treat AD.


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Prohibited Medications Requiring Permanent Discontinuation of Investigational Product

Any systemic therapy, investigational or commercial (approved or off-label use), used for 
the treatment of AD or symptoms of AD (except for antihistamines, as specified below).

Other JAK inhibitors (for example, tofacitinib and ruxolitinib).

Systemic immunosuppressive/immunomodulatory substances, including, but not limited 
to cyclosporine, methotrexate, mycophenolate mofetil, interferon γ, azathioprine, or 
biologic agents.
7.7.2. Permitted Medications and Procedures
Treatment with concomitant AD therapies during the study is permitted only as described below.

Daily use of emollients is required as background treatment.  Moisturizers with 
additives such as antipruritics or antiseptics are not permitted.  If daily 
applications are missed, it will not be considered a protocol violation.
o
Patients should not apply emollients on the day of their study visit before study 
procedures to allow adequate assessment of skin dryness.

Antihistamines are allowed.

Intra-articular or soft tissue (bursa, tendons, and ligaments) corticosteroid 
injection:  No more than 1 intra-articular or soft tissue (bursa, tendons, and 
ligaments) corticosteroid injection is allowed up until Week 16 (Visit 4).  After 
Week 16, such injections are permitted.  

Intranasal or inhaled steroid use is allowed.

Topical anesthetics and topical and systemic anti-infective medications are 
allowed.

Nonlive seasonal vaccinations and/or emergency vaccination, such as rabies or 
tetanus vaccinations, are allowed.

Low-potency TCS (for example, hydrocortisone 2.5% ointment) is permitted.
o
Patients should not apply TCS on the day of their study visit before study procedures 
to allow adequate assessment of skin dryness.
Any changes of these concomitant medications must be recorded in the Concomitant Therapy of 
Special Interest eCRF.
Treatment with concomitant therapies for other medical conditions such as diabetes and 
hypertension is permitted during the study.
7.7.3. Rescue Therapy
No rescue therapy options are available during the study.  Patients are allowed to use low-
potency TCS as background therapy for comfort if needed. Patients who experience worsening 
and unacceptable symptoms of AD should consider discontinuing from the study.  Patients 
requiring more than low-potency TCS to manage their symptoms should also be discontinued.


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Hydrocortisone 2.5% ointment will be supplied by the sponsor for use during the first 2 years of 
the treatment period (dispensed at Visits 1-10 only).  In the event that providing this topical 
formulation during the first 2 years is not possible, an alternate, equivalent potency TCS cream 
and/or ointment may be provided by the sponsor.  Use of sponsor-supplied TCS should be 
recorded via weight of returned tubes as indicated in the Schedule of Activities (Section 2).  
Sponsor will not provide or reimburse the cost of TCS at Visit 11 or after.
In the event that the sponsor is unable to supply TCS during the first 2 years of the treatment 
period, commercially available hydrocortisone 2.5% ointment or an equivalent-potency TCS 
cream and/or ointment that is in line with local practices can be supplied by the sponsor or the 
sites. Refer to Appendix 7 for guidance on potency equivalence.  
On the days of study visits, topical therapy should not be applied before the patient has 
undergone all study procedures and clinical evaluations to allow adequate assessment of skin 
dryness.
7.8.
Treatment after the End of the Study
7.8.1. Continued Access
After the conclusion of the study, continued access to baricitinib will not be provided to patients.  
Patients will be referred to their local treatment centers for AD therapy as clinically indicated.


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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Temporary Interruption from Investigational Product
In some circumstances, it may be necessary to temporarily interrupt treatment as a result of AEs 
or abnormal laboratory values that may have an unclear relationship to investigational product.  
For example, investigational product should be temporarily interrupted if the patient experiences
a cardiovascular AE considered to be related to study treatment, is graded as moderate (Grade 2
according to Common Terminology Criteria for Adverse Events [CTCAE] Version 3.0), and that 
does not resolve promptly with supportive care.  Except in cases of emergency, it is 
recommended that the investigator consult with Lilly (or its designee) before temporarily 
interrupting therapy for reasons other than those defined in Table JAIX.4.  
Patients who met criteria for temporary interruption of investigational product during the 
originating study or during screening may be enrolled in Study JAIX, but will remain on 
temporary interruption until the criteria for resuming investigational product has been met.
For the abnormal laboratory findings and clinical events (regardless of relatedness) listed in 
Table JAIX.4, specific guidance is provided for temporarily interrupting treatment and 
determining when treatment may be restarted. Retest frequency and timing of follow-up 
laboratory tests to monitor the abnormal finding is at the discretion of the investigator.  
Investigational product that was temporarily interrupted because of an AE or abnormal 
laboratory value not specifically covered in Table JAIX.4 may be restarted at the discretion of 
the investigator.




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8.1.2. Permanent Discontinuation from Investigational Product
Investigational product should be permanently discontinued if the patient requests to discontinue 
investigational product.
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a patient meets 1 of the following conditions after consultation with the 
Lilly-designated medical monitor:

ALT or AST >8 x upper limit of normal (ULN)

ALT or AST >5 x ULN for >2 weeks

ALT or AST >3 x ULN and total bilirubin level (TBL) >2 x ULN or 
international normalized ratio >1.5

ALT or AST >3 x ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, and/or rash

alkaline phosphatase (ALP) >3 x ULN

ALP >2.5 x ULN and TBL >2 x ULN

ALP >2.5 x ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, and/or rash
Note:  Patients who are discontinued from investigational product because of a 
hepatic event or liver test abnormality should have additional hepatic safety data 
collected via the hepatic safety eCRF.
Investigational product should be permanently discontinued if any of the following laboratory 
abnormalities are observed:

white blood cell count <1000 cells/µL (1.00 × 103/µL or 1.00 GI/L)

absolute neutrophil count <500 cells/µL (0.50 × 103/µL or 0.50 GI/L)

lymphocyte count <200 cells/µL (0.20 × 103/µL or 0.20 GI/L)

hemoglobin <6.5 g/dL (<65.0 g/L)
Note:  Temporary interruption rules (see Section 8.1.1) must be followed where 
applicable.  For laboratory values that meet permanent discontinuation thresholds, 
investigational product should be discontinued.  However, if in the opinion of the 
investigator the laboratory abnormality is due to intercurrent illness such as 
cholelithiasis or another identified factor, laboratory tests may be repeated.  Only 
when the laboratory value meets resumption thresholds (Table JAIX.4) following the 
resolution of the intercurrent illness or other identified factor, may the investigator 
restart investigational product, after consultation with the Lilly-designated medical 
monitor.


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In addition, patients will be discontinued from investigational product in the following 
circumstances:

pregnancy

malignancy (except for successfully treated basal or squamous cell skin 
carcinoma)

HBV DNA is detected with a value above limit of quantitation or 2 sequential 
tests return a value below the limit of quantitation (see Section 9.4.6)

certain prohibited medications are taken per Section 7.7.1

develop a VTE 
Note:  Patients who develop a VTE may have additional follow up and testing 
recommended (see Section 9.4.8. and Appendix 6).
If a patient develops multiple risk factors for a VTE during the conduct of the study, the 
investigator may consider study discontinuation if he/she believes the risk outweighs the benefits 
of continuing therapy.  It is recommended that the investigator consult with Lilly (or its 
designee) before discontinuing therapy for this reason.  
Patients discontinuing from the investigational product prematurely for any reason should 
complete AE and other follow-up procedures per Section 2 (Schedule of Activities), Section 9.2
(Adverse Events), and Section 9.4 (Safety) of this protocol.
8.1.3. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the patient to continue on 
study treatment.  If the investigator and the sponsor clinical research physician agree it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
sponsor clinical research physician to allow the inadvertently enrolled patient to continue in the 
study with or without treatment with investigational product. Safety follow up is as outlined in 
Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety) of this 
protocol.
8.2.
Discontinuation from the Study
Patients may choose to withdraw from the study for any reason at any time, and the reason for 
early withdrawal will be documented.
Some possible reasons that may lead to permanent discontinuation include the following:

enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study


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
participation in the study needs to be stopped for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and good clinical 
practice

study termination may occur in a specific country or region when baricitinib is approved 
for the treatment of AD and becomes reimbursed or commercially available in that 
country or region, or a negative regulatory opinion is received in that country or region

investigator decision
o
The investigator decides that the patient should be discontinued from the 
study.
o
If the patient, for any reason, requires treatment with another therapeutic 
agent (not allowed as part of rescue therapy [Section 7.7.3]) that has been 
demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new 
agent.

patient decision
o
The patient requests to be withdrawn from the study.
Patients discontinuing from the study prematurely for any reason should complete AE and other 
safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety) of this protocol.
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 and Appendix 4 list the laboratory tests that will be performed for this study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1. Primary Efficacy Assessments
Eczema Area and Severity Index Scores (EASI): The EASI assesses extent of disease at 4 
body regions and measures 4 clinical signs: (1) erythema, (2) induration/papulation, (3) 
excoriation, and (4) lichenification, each on a scale of 0 to 3. The EASI confers a maximum 
score of 72. The EASI evaluates 2 dimensions of AD: disease extent and clinical signs (Hanifin
et al. 2001).  
9.1.2. Secondary Efficacy Assessments
9.1.2.1.
Validated Investigator’s Global Assessment for Atopic Dermatitis (vIGA-
AD)
The IGA used in this study, the vIGA-AD (referred to as the IGA throughout the protocol) 
measures the IGA of the patient’s overall severity of their AD, based on a static, numeric 5-point 
scale from 0 (clear skin) to 4 (severe disease).  The score is based on an overall assessment of the 
degree of erythema, papulation/induration, oozing/crusting, and lichenification.
9.1.2.2.
Eczema Area and Severity Index scores
The EASI assesses extent of disease at 4 body regions and measures 4 clinical signs: 
(1) erythema, (2) induration/papulation, (3) excoriation, and (4) lichenification, each on a scale 
of 0 to 3. The EASI confers a maximum score of 72. The EASI evaluates 2 dimensions of AD: 
disease extent and clinical signs (Hanifin et al. 2001).  
BSA affected by AD will be derived from data collected as part of the EASI assessment.
9.1.2.3.
SCORing Atopic Dermatitis
The SCORAD index uses the rule of nines to assess disease extent and evaluates 6 clinical 
characteristics to determine disease severity: (1) erythema, (2) edema/papulation, 
(3) oozing/crusts, (4) excoriation, (5) lichenification, and (6) dryness. The SCORAD index also 
assesses subjective symptoms of pruritus and sleep loss. These 3 aspects (extent of disease, 
disease severity, and subjective symptoms) combine to give a maximum possible score of 103
(Stalder et al. 1993; Kunz et al. 1997; Schram et al. 2012).


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


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


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


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
initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention 
to prevent 1 of the other outcomes listed in the definition above.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug 
abuse.
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  The SAE reporting to the sponsor begins after the patient has signed the ICF and has 
received investigational product.  However, if an SAE occurs after signing the ICF, but prior to 
receiving investigational product, the SAE should be reported to the sponsor as per SAE 
reporting requirements and timelines if it is considered reasonably possibly related to study 
procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.  Patients with a serious hepatic AE should have additional data collected using the 
hepatic safety eCRF.
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements, any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he or she considers the event reasonably possibly related to 
the study treatment or study participation, the investigator must promptly notify Lilly.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs. Lilly has procedures that will be followed for the recording 
and expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidances.


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9.2.2. Adverse Events of Special Interest
AEs of special interest will include the following:

infections (including tuberculosis, herpes zoster, or opportunistic infections)

malignancies

hepatic events (see Section 9.4.7)

major adverse cardiovascular events (MACE) (see Section 9.4.9)

thrombotic events (such as deep vein thrombosis and pulmonary embolism) (see 
Section 9.4.8).
Sites will provide details on these AEs as instructed on the eCRF and may be asked for 
additional description by Lilly.
9.2.3. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
Refer to the IB.
9.4.
Safety
Any clinically significant findings from physical examination, vital signs measurements, or 
laboratory measurements that result in a diagnosis and that occur after the patient receives the 
first dose of study treatment should be reported to Lilly or its designee as an AE via eCRF.
9.4.1. Vital Signs
For each patient, vital signs should be measured according to the Schedule of Activities 
(Section 2).
9.4.2. Physical Exam
For each patient, a symptom-directed physical examination will be performed at all visits.  
A complete physical examination may be performed at the investigator’s discretion at any time a 
patient presents with physical complaints.
9.4.3. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). Lilly or its designee will provide the investigator with the 


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results of laboratory tests analyzed by a central vendor, if a central vendor is used for the clinical 
trial.
9.4.4. Columbia Suicide Severity Rating Scale
The C-SSRS captures the occurrence, severity, and frequency of suicidal ideation and/or 
behavior during the assessment period.  The scale includes suggested questions to solicit the type 
of information needed to determine if suicidal ideation and/or behavior occurred.  The C-SSRS is 
administered by an appropriately trained health care professional with at least 1 year of patient 
care/clinical experience.  The tool was developed by the National Institute of Mental Health trial 
group for the purpose of being a counterpart to the Columbia Classification Algorithm of Suicide 
Assessment categorization of suicidal events.  For this study, the scale has been adapted (with 
permission from the scale authors) to include only the portion of the scale that captures the 
occurrence of the 11 preferred ideation and behavior categories.
The nonleading AE collection should occur prior to the collection of the C-SSRS. If a 
suicide-related event is discovered during the C-SSRS but was not captured during the 
nonleading AE collection, sites should not change the AE form. If an event is serious or leads to 
discontinuation, this is an exception and the SAE and/or AE leading to discontinuation should be 
included on the AE form, and the process for reporting SAEs should be followed.
9.4.5. Self-Harm and Follow-Up Supplement Forms
Suicide-related events (behavior and/or ideations) will be assessed and evaluated at every visit 
with the administration of the C-SSRS and the Self-Harm Supplement Form.  The Self-Harm 
Supplement Form is a single question to enter the number of suicidal behavior events, possible 
suicide behaviors, or nonsuicidal self-injurious behaviors.  If the number of behavioral events is 
greater than zero, it will lead to the completion of the self-harm follow-up form.  The self-harm 
follow-up form is a series of questions that provides a more detailed description of the behavior 
cases.
9.4.6. Hepatitis B Virus DNA Monitoring
Hepatitis B virus DNA testing will be performed in enrolled patients who tested positive for anti-
hepatitis B core antibody (HBcAb) at screening in the originating study (Study JAIW).
Patients who are HBcAb positive and HBV DNA negative (undetectable) at screening (Visit 1) 
in the originating study (Study JAIW) will require measurement of HBV DNA per Schedule of 
Activities (Section 2), regardless of their hepatitis B surface antibody (HBsAb) status.
The following actions should be taken in response to HBV DNA test results:

If a single result is obtained with a value “below limit of quantitation,” the test 
should be repeated within approximately 2 weeks.  If the repeat test result is 
“target not detected,” monitoring will resume as specified in the Schedule of 
Activities (Section 2).


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
If the patient has 2 or more test results with a value “below limit of quantitation”
or a test result above the limit of quantitation, the patient will be permanently 
discontinued from investigational product (see Section 8.1.2) and should be 
referred to a hepatology specialist.  
9.4.7. Hepatic Safety Monitoring and Data Collection
If a study patient experiences elevated ALT ≥3 x ULN, ALP ≥2 x ULN, or elevated TBL 
≥2 x ULN, liver testing (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, 
ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator in consultation 
with the study medical monitor.  Monitoring of ALT, AST, TBL, and ALP should continue until 
levels normalize or return to approximate baseline levels.
Criteria for discontinuation of investigational products (either temporary interruption or 
permanent discontinuation) due to abnormal ALT, AST, TBL, or ALP are detailed in 
Section 8.1.
Additional safety data should be collected via the hepatic eCRF if 1 or more of the following 
conditions occur:

elevation of serum ALT to ≥5 x ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2 x ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2 x ULN on 2 or more consecutive blood tests

patient discontinued from treatment because of a hepatic event or abnormality of 
liver tests

hepatic event considered to be an SAE
See Appendix 4 and Appendix 5 for a description of hepatic laboratory values that warrant 
exclusion from the study, temporary or permanent discontinuation of investigational product, or 
additional safety collection via the hepatic eCRF.
9.4.8. VTE Assessment
If a patient develops the signs and symptoms of a deep vein thrombosis or pulmonary embolism, 
appropriate local laboratory tests and imaging should be performed, as necessary, for diagnosis 
of the event.  For confirmed cases, additional laboratory testing should be performed as outlined 
in Appendix 6.  All suspected VTE events will be independently adjudicated by a Clinical Event
Committee (see Section 10.3.6.1).
9.4.9. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.


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The Lilly clinical research physician will monitor safety data throughout the course of the study. 
Lilly will review SAEs within time frames mandated by company procedures. The Lilly clinical 
research physician will, as is appropriate, consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical scientist and periodically review trends in 
safety data and laboratory analytes. Any concerning trends in frequency or severity noted by an 
investigator and/or Lilly (or designee) may require further evaluation.
All deaths and SAE reports will be reviewed by Lilly during the clinical trial. 
Investigators will monitor vital signs and carefully review findings that may be associated with 
cardiovascular and VTEs. AE reports and vital signs will be collected at each study visit. The 
cardiovascular monitoring plan includes the following:

regular monitoring of lipid levels

potential MACE (cardiovascular death, MI, stroke), other cardiovascular events 
(such as hospitalization for unstable angina, hospitalization for heart failure, 
serious arrhythmia, resuscitated sudden death, cardiogenic shock, coronary 
revascularization such as coronary artery bypass graft or percutaneous coronary 
intervention), VTEs and noncardiovascular deaths will be identified by the 
investigative site or through medical review and will be sent to a blinded Clinical 
Event Committee for adjudication at regular intervals.
9.5.
Pharmacokinetics
Not applicable.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Pharmacogenetics
Not applicable. 
9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, mechanism of action, variability of patient response (including 
safety), and clinical outcome.  Sample collection is incorporated into clinical studies to enable 
examination of these questions through measurement of biomolecules including DNA, RNA, 
proteins, lipids, and other cellular elements.
Blood samples for nonpharmacogenetic biomarker research will be collected at the times
specified in the Schedule of Activities (Section 2) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
baricitinib, pathways associated with AD, mechanism of action of baricitinib, and/or research 
method or in validating diagnostic tools or assay(s) related to AD.


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All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigator site personnel.
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and ethical review boards (ERBs) impose shorter time 
limits, at a facility selected by Lilly.  This retention period enables use of new technologies, 
response to regulatory questions, and investigation of variable response that may not be observed 
until later in the development of baricitinib or after baricitinib becomes commercially available.
9.9.
Medical Resource Utilization and Health Economics
Health Economics will be evaluated in this study utilizing the EQ-5D-5L and WPAI-AD (see 
Section 9.1.3).  Medical Resource Utilization parameters will not be evaluated in this study.


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10. Statistical Considerations
10.1. Sample Size Determination
The study is descriptive in nature and the sample size is not based on any statistical power 
calculations.  All of the approximate 450 patients participating in the originating study can be 
assessed for eligibility to participate in Study JAIX.
10.2. Populations for Analyses
Unless otherwise specified, the efficacy and health outcome analyses will be conducted on all 
enrolled patients who receive at least 1 dose of investigational product in Study JAIX, even if the 
patient does not follow the protocol.  Significant protocol violations will be described in the 
SAP.
Unless otherwise specified, safety analyses will be performed on all enrolled patients who 
receive at least 1 dose of investigational product and who do not discontinue from the study for 
the reason “Lost to Follow-up” at the first postbaseline visit. Further details of other populations 
will be described in the SAP. 
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
As this study is open-label and all patients are receiving baricitinib 2-mg, no hypothesis testing 
will be performed.  Data will be summarized both overall and by prior-treatment-received in 
Study JAIW. Data from this trial may be integrated with other trials.
Statistical analysis of this study will be the responsibility of Lilly or its designee. A detailed 
SAP describing the statistical methodologies will be developed by Lilly or its designee.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol and the justification for making the change will be described 
in the clinical study report (CSR).  Additional exploratory analyses of the data will be conducted 
as deemed appropriate.
All discrete efficacy variables will be summarized using frequencies and percentages.  
Continuous efficacy and health outcome variables will be summarized using number of patients, 
mean, standard deviation, median, minimum, and maximum.
The methods used to handle missing data will be specified in the SAP.
Frequencies and percentages will be computed for AEs, discontinuation, and other categorical 
safety data. 
All patients who discontinue the study or the study treatment at any time for any reason will be 
defined as nonresponders for the NRI summary of categorical efficacy variables such as IGA 0/1 
or EASI 50/75/90 after discontinuation and onward.  


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10.3.2. Descriptive Population Analyses
10.3.2.1. Patient Disposition
All patients who discontinue from the study or the study treatment will be identified, along with 
their reason for discontinuation. Reasons for discontinuation from the study will be summarized. 
Additional summary may be produced by prior treatment received.
10.3.2.2. Patient Characteristics
Descriptive statistics for continuous variables will be produced including number of patients, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized using frequencies and percentages.
10.3.2.3. Concomitant Therapy
Concomitant medications will be descriptively summarized in terms of frequencies and 
percentages using the safety population. Additional summary may be produced by prior 
treatment received.  The medications will be coded accordingly.
10.3.2.4. Treatment Compliance
Treatment compliance with study medication will be evaluated at every clinic visit through the 
counts of returned investigational product tablets. A patient will be considered significantly 
noncompliant if he or she misses more than 20% of the prescribed doses during the study, unless 
the patient’s investigational product is withheld by the investigator for safety reasons; that is, 
compliance <80%.  Similarly, a patient will be considered significantly noncompliant if he or she 
is judged by the investigator to have intentionally or repeatedly taken more than the prescribed 
amount of medication, that is, compliance ≥120%.
10.3.3. Efficacy Analyses
Categorical efficacy variables will be summarized in terms of frequencies and percentages.  
Nonresponder imputation will be used as described in Section 10.3.1. Continuous efficacy 
variables will be descriptively summarized in terms of number of patients, mean, standard 
deviation, median, minimum, and maximum.  


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10.3.4. Safety Analyses
All safety data will be summarized overall and by prior therapy received using the safety 
population. 
Treatment-emergent adverse events (TEAEs) are defined as AEs that first occurred or worsened 
in severity after the first dose of study treatment. The number of TEAEs as well as the number 
and percentage of patients who experienced at least 1 TEAE will be summarized using Medical 
Dictionary for Regulatory Activities (MedDRA) for each system organ class (or a body system) 
and each preferred term. Serious adverse events and AEs that lead to discontinuation of 
investigational product will also be summarized. 
Categorical variables, including the incidence of AEs of special interest, together with individual 
analyses of clinical laboratory results and vital signs are not planned for this Study, but will be 
included in an integrated database.
Further summaries may be performed and will be planned in the SAP.
Data collected after initiation of rescue therapy will be summarized as appropriate.
10.3.5. Other Analyses
10.3.5.1. Health Outcome Measures
The health outcome measures will be summarized using methods described for continuous or
categorical data as described for efficacy measures in Section 10.3.3.
10.3.6. Interim Analyses
10.3.6.1. Adjudication Committee
A Clinical Event Committee will adjudicate potential MACE (cardiovascular death, MI, stroke), 
other cardiovascular events (such as hospitalization for unstable angina, hospitalization for heart 
failure, serious arrhythmia, resuscitated sudden death, cardiogenic shock, coronary 
revascularization such as coronary artery bypass graft or percutaneous coronary intervention), 
VTEs, and noncardiovascular deaths.  Details of membership, operations, recommendations from 
the Committee, and the communication plan will be documented in the Charter.


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11.
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population. Pediatrics. 2008;122(4):812-824.
Kunz B, Oranje A, Labrèze, Stadler JF, Ring J, Taїeb A. Clinical validation and guidelines for 
the SCORAD Index: consensus report of the European Task Force on Atopic Dermatitis. 
Dermatology. 1997;195(1):10-19. 
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12.
Appendices


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Appendix 1.
Abbreviations and Definitions
Term
Definition
AD
atopic dermatitis
ADSS
Atopic Dermatitis Sleep Scale
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BCG
Bacillus Calmette Guérin
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received.
BSA
body surface area
CI
confidence interval
C-SSRS
Columbia Suicide Severity Rating Scale
CSR
clinical study report
DLQI
Dermatology Life Quality Index
EASI
Eczema Area and Severity Index
EASI50
50% improvement from baseline in EASI
EASI75
75% improvement from baseline in EASI
eCOA
electronic clinical outcome assessment


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eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
Enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ePRO
electronic patient-reported outcomes
EQ-5D-5L
European Quality of Life–5 Dimensions–5 Levels
ERB
ethical review board
ETV
early termination visit
GCP
good clinical practice
HADS
Hospital Anxiety Depression Scale
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBV
hepatitis B virus
IB
investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IGA
Investigator’s Global Assessment
IL
interleukin
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
INR
international normalized ratio
Investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IWRS
interactive web-response system
JAK
Janus kinase
LSM
least squares mean


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MACE
major adverse cardiovascular events
MI
myocardial infarction
MMRM
mixed-effects model of repeated measures
NRI
nonresponder imputation
NRS
Numeric Rating Scale
PDE-4
phosphodiesterase type 4
POEM
Patient-Oriented Eczema Measure
QD
once daily
RA
rheumatoid arthritis
SAE
serious adverse event
SAP
statistical analysis plan
SCORAD
SCORing Atopic Dermatitis
SUSAR
suspected unexpected serious adverse reaction
TBL
total bilirubin level
TCNI
topical calcineurin inhibitor
TCS
topical corticosteroids
TEAE
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, which does not necessarily have to have a causal relationship 
with this treatment.
TSLP
thymic stromal lymphopoietin
TYK2
tyrosine kinase 2
VAS
Visual Analog Scale
vIGA-AD
validated Investigator’s Global Assessment for Atopic Dermatitis
VTE
venous thromboembolic event
WPAI-AD
The Work Productivity and Activity Impairment–Atopic Dermatitis


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Appendix 2.
Clinical Laboratory Tests
Hematology
a,b
Clinical Chemistry
a,b
Hemoglobin
Serum concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Absolute reticulocyte count
Total bilirubin
Mean cell volume
Direct bilirubin
Mean cell hemoglobin
Alkaline phosphatase
Mean cell hemoglobin concentration
Alanine aminotransferase (ALT)
Leukocytes (WBC)
Aspartate aminotransferase (AST)
Platelets
Blood urea nitrogen (BUN)
Creatinine
Absolute counts of:
Cystatin C
Neutrophils, segmented
Uric acid
Neutrophils, juvenile (bands)
Calcium
Lymphocytes
Glucose
Monocytes
Albumin
Eosinophils
Total protein
Basophils
Estimated glomerular filtration rate (eGFR)d
Creatine phosphokinase (CPK)
Urinalysis
a,b,c
Color
Lipidsa,e
Specific gravity
Total cholesterol
pH
Low-density lipoprotein
Protein
High-density lipoprotein
Glucose
Triglycerides
Ketones
Bilirubin
Other Testsa
Urobilinogen
HBV DNA
f
Blood
Exploratory storage samples (serum, plasma and mRNA)
Leukocyte esterase
Pregnancy testg
Nitrite
Serum immunoglobulin (IgE)
Abbreviations:  HBcAb+ = hepatitis B core antibody positive; HBV = hepatitis B virus; RBC = red blood cell; WBC 
= white blood cell.
a Assayed by sponsor-designated laboratory.
b Unscheduled or repeat blood chemistry, hematology, and urinalysis panels may be performed at the discretion of 
the investigator, as needed.
c Microscopic examination of sediment performed only if abnormalities are noted on the routine urinalysis.
d eGFR for serum creatinine calculated by the central laboratory using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) Creatinine 2009 equation.
e Fasting lipid profile. Patients should not eat or drink anything except water for 12 hours prior to test.  If a patient 
attends these visits in a nonfasting state, this will not be considered a protocol violation.
f HBV DNA testing will be done in those patients who are HBcAb+ at screening of originating study, Study JAIW.
g For all women of childbearing potential, urine pregnancy tests (local laboratory) will be performed at all specified 
visits.  If required per local regulations and/or institutional guidelines, pregnancy testing can occur at other times 
during the study treatment period.


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Appendix 3.
Study Governance Considerations
Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for ensuring the following:

that the patient understands the potential risks and benefits of participating in 
the study.

that informed consent is given by each patient.  This includes obtaining the 
appropriate signatures and dates on the informed consent form (ICF) prior to 
the performance of any protocol procedures and prior to the administration of 
investigational product.

answering any questions the patient may have throughout the study and 
sharing in a timely manner any new information that may be relevant to the
patient’s willingness to continue his or her participation in the trial.
Appendix 3.1.2.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Council for Harmonisation (ICH)
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Eli Lilly and 
Company (Lilly) before the study may begin at the investigative site(s).  Lilly or its 
representatives must approve the ICF, including any changes made by the ERBs, before it is used 
at the investigative site(s). All ICFs must be compliant with the ICH guideline on Good Clinical 
Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current investigator brochure (IB) and updates during the course of the 
study

ICF

relevant curricula vitae.
Appendix 3.1.3.
Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines


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
applicable ICH GCP Guidelines

applicable laws and regulations.
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.4.
Investigator Information
Physicians with a specialty in dermatology will participate as investigators in this clinical trial.
Appendix 3.1.5.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.6.
Final Report Signature
Lilly will select a qualified investigator(s) from among investigators participating in the design, 
conduct, and/or analysis of the study to serve as the clinical study report (CSR) coordinating 
investigator.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the CSR coordinating investigator.
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

provide sponsor start-up training to instruct the investigators and study 
coordinators.  This training will give instruction on the protocol, the completion 
of the CRFs, and study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and evaluate CRF data and use standard computer edits to detect errors in 
data collection

conduct a quality review of the database.


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In addition, Lilly or its representatives will periodically check a sample of the patient data
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Electronic patient-reported outcome (ePRO) measures (e.g., a rating scale) and electronic clinical 
outcome assessments (eCOAs) are entered into an ePRO/eCOA instrument at the time that the 
information is obtained.  In these instances where there is no prior written or electronic source 
data at the site, the ePRO/eCOA instrument record will serve as the source.
If ePRO/eCOA records are stored at a third-party site, investigator sites will have continuous 
access to the source documents during the study and will receive an archival copy at the end of 
the study for retention.
Any data for which the ePRO/eCOA instrument record will serve to collect source data will be 
identified and documented by each site in that site’s study file.
Case report form data will be encoded and stored in InForm.  Data managed by a central vendor, 
such as laboratory test data, will be stored electronically in the central vendor’s database system.  
Data will subsequently be transferred from the central vendor to the Lilly data warehouse.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system.  Data will subsequently be transferred from the central 
vendor to the Lilly data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4.
Hepatic Monitoring Tests for
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly, its designee, or the clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cell; WBC = white blood cell.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
Liver Function Testing and Hepatic Safety 
Monitoring
Liver Function Testing and Hepatic Safety Monitoring
Analyte
Exclusion
Criteria
Additional 
Hepatic 
Testing
Hepatic eCRF 
Reporting
Temporary 
Interruption of 
IP
Permanent Discontinuation 
of IP after Consultation 
with the Lilly-Designated 
Medical Monitor
Protocol 
Section
Section 6.2
Section 9.4.7
Section 9.4.7
Section 8.1.1
Section 8.1.2
ALT/AST
≥2 x ULN
ALT only
≥3 x ULN
ALT only
≥5 x ULN on ≥2 
consecutive tests
≥5 x ULN

>8 x ULN

>5 x ULN for 
>2 weeks

>3 x ULN AND TBL 
>2 x ULN or INR >1.5

>3 x ULN with 
symptomsa
ALP
≥2 x ULN
≥2 x ULN
≥2 x ULN on ≥2 
consecutive tests
No applicable 
criteria

>3 x ULN

>2.5 x ULN AND TBL 
>2 x ULN 

>2.5 x ULN with 
symptomsa
TBL
≥1.5 x ULN
≥2 x ULN
≥2 x ULN
(excluding 
Gilbert’s 
syndrome)
No applicable 
criteria

ALT or AST >3 x ULN 
AND TBL >2 x ULN

ALP >2.5 x ULN AND 
TBL >2 x ULN
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; IP = investigational product; TBL = total bilirubin level; ULN = upper 
level of normal.
a
Fatigue, nausea, vomiting, right upper-quadrant pain or tenderness, fever, and/or rash.


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Appendix 6.
Monitoring Tests for Confirmed VTE
Selected tests may be obtained in the event of a confirmed venous thromboembolic event (VTE)
and may be required in follow-up with patients in consultation with Eli Lilly and Company, its 
designee, or the clinical research physician.  The choice and optimal timing of these tests will be 
directed by the patient’s management and may require ongoing follow-up after study 
discontinuation.
Protein C Functional
Protein S Clottable
Antithrombin III
APC Resistance
PT
APTT
Fibrinogen
Cardiolipin Antibodies
PT Gene
Factor VIII C Assay
Hexagonal Phase Phospholipid Neutralization
C-Reactive Protein
PTT Incubated Mixing 
Dilute Russell Viper Venom 
Platelet Neutralization 
Factor V Leiden 
MTHFR 
Thrombin Time 
Reptilase 
Fibrinogen Antigen 
Protein C Immunologic 
Protein S Immunologic 
Heparin fXa Inhibition 
Abbreviations:  APC = activated protein C; APTT = activated partial thromboplastin time; MTHFR = methylene 
tetrahydrofolate reductase; PT = prothrombin time; PTT = partial thromboplastin time.


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


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Appendix 8.
Investigator Global Assessment


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Appendix 9.
Protocol   I4V MC JAIX(c) Summary - A 
Multicenter, Open-Label, Phase 3 Study to Evaluate 
the Efficacy and Safety of Baricitinib in Adult Patients 
with Moderate to Severe Atopic Dermatitis
Overview
Protocol I4V-MC-JAIX, A Multicenter, Open-Label, Phase 3 Study to Evaluate the Efficacy and 
Safety of Baricitinib in Adult Patients with Moderate to Severe Atopic Dermatitis, has been 
amended.  The new protocol is indicated by amendment (c) and will be used to conduct the study 
in place of any preceding version of the protocol.
There are 3 main changes in this protocol amendment:
1. Study duration extended for all participating patients
2. Study design updated to allow patients who complete Study JAIW to subsequently enter 
Study JAIX
3. Primary efficacy endpoint changed.
Amendment Summary for Protocol I4V-MC-JAIX Amendment (c)
Section # 
Description of Change
Brief Rationale
Section 1,4 and 5
Primary efficacy endpoint was changed.
Updated language to reflect the change in 
eligibility criteria that will allow responders 
who completed Study JAIW through Week 104 
to be enrolled.
Objectives were updated to clarify that 
analyses will consider treatment received and 
responder status.
Exploratory objectives/endpoints were updated 
to reflect the fact that changes in IgE and 
To reflect the change made in the 
originating study, Study JAIW, where the 
primary endpoint was changed from IGA 
0,1 to EASI75.
To allow all patients participating in Study 
JAIW the opportunity to receive IP (2-mg 
QD), the study design has been updated to 
allow “responders” from Study JAIW to 
enter this study (Study JAIX) after 
completing the full treatment period of that 
study.
The change was made to align with the 
study design change which now allows 
inclusion of Study JAIW responders.  Data 
for these patients may be analyzed 
separately from the data for nonresponders 
and partial responders.
Specific analysis of changes in IgE and 
eosinophil levels are not currently planned 


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Section # 
Description of Change
Brief Rationale
eosinophil levels will not be considered.  
to be considered as exploratory 
objectives/endpoints.
Section 1
Extended treatment duration by approximately 
2 years.
The treatment period was extended to allow 
for continued efficacy and safety data 
collection as well as to allow patients to 
continue to receive baricitinib treatment for 
up to another 2 years.
Section 2, Table
JAIX.1. Schedule 
of Activities
Added scheduled study visits every 4 months 
to the end of the study treatment period for a 
total of 6 new visits (Visits 12 through 17)
during the 2-year extension.
Treatment visits were added at a frequency 
of every 4-months to allow for appropriate 
ongoing safety monitoring during the study.
Section 5 and 
Figure JAIX 1
Updated to reflect the 2-year treatment 
extension and associated visit schedule.
Figure was updated to include the additional 
visits.
As described above, the treatment period 
was extended to allow for continued 
efficacy and safety data collection as well 
as to allow patients to continue to receive 
baricitinib treatment for up to another 2 
years.
Section 1, 3.2, 5.1, 
5.2, 5.4, 6 and 
10.1
Updated the number of patients that may be 
enrolled.
Updated language to reflect the change in 
eligibility criteria that will allow responders 
who completed Study JAIW through Week 104
to be enrolled.
The study design has been updated to allow 
“responders” from Study JAIW to enter this 
study (Study JAIX) after completing the 
full treatment period of that study. This 
change, in effect, makes all patients 
enrolled in Study JAIW eligible for 
assessment to enter Study JAIX at some 
point at or after JAIW Visit 8.  The 
approximate sample size in Study JAIW is 
450 patients.   
To allow all patients participating in Study 
JAIW the opportunity to receive IP (2-mg 
QD), the study design has been updated to 
allow “responders” from Study JAIW to 
enter this study (Study JAIX) after 
completing the full treatment period of that 
study.
Section 5.1.1
Added text that will allow Study JAIW 
“responders” to take a voluntary drug 
interruption between Study JAIW Visit 15 and 
Study JAIX Visit 1.
Some patients who have achieved and 
maintained treatment response in Study 
JAIW may be receiving placebo or 1-mg 
baricitinib QD.  This voluntary interruption 
will give patients and investigators time to 
see if the patients’ condition changes after 
stopping treatment which may inform their 
decision to enter into Study JAIX.
Section 6.1
Eligibility criteria were updated to include 
responders who completed Study JAIW 
through Week 104.
To allow all patients participating in Study 
JAIW the opportunity to receive IP (2-mg 
QD), the study design has been updated to 
allow “responders” from Study JAIW to 
enter this study (Study JAIX) after 


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Section # 
Description of Change
Brief Rationale
completing the full treatment period of that 
study.
Section 7.6
Treatment period was updated.
Section was updated to reflect the extension
of the treatment period for the reasons 
described above.  There is no change to 
how treatment compliance is assessed nor 
what is considered significant 
noncompliance. 
Section 7.7.3
Updated language to reflect that TCS will not 
be provided or reimbursed by the sponsor for 
visit 11 and after (i.e., dispensed at Visits 1-10 
only).
The purpose for this extension is to allow 
patients the opportunity to continue to 
receive baricitinib while allowing clinicians 
and patients freedom to use a low potency 
TCS product/dosing form (e.g., cream, 
ointment) that is preferred and is available 
as part of local standard of care.
Section 8.2
Added that study termination may occur based 
on regulatory disapproval, or approval and 
reimbursement and commercial availability of 
baricitinib for the treatment of AD, in a 
country or region.
Early termination of the study in a 
country/region as a result of a favorable or 
unfavorable regulatory opinion will allow 
patients to receive treatment that is in line 
with what the local or regional regulatory 
agency consider appropriate standard of 
care. 
Section 9.1.1 and
9.1.2
Updated efficacy assessment descriptions and 
section heading numbering.
To reflect the change made in the 
originating study, Study JAIW, where the 
primary endpoint was changed from IGA 
0,1 to EASI75.
Section 10.3.1 and 
10.3.4
Updated safety analyses description.
Safety endpoints are better assessed in the 
context of combining the safety data from 
the originating study with the safety data 
from an extension study. Therefore, some 
of the planned safety analyses (e.g., clinical 
laboratory analysis, vital signs, and AEs of 
special interest) will now be conducted as 
part of the integrated safety database and 
not at the study level. 


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
1. Synopsis
Objectives/Endpoints:
Objectives
Endpoints
Primary
To describe the clinical response to baricitinib 2-mg 
QD in patients with moderate to severe AD by prior 
treatment received (ie., baricitinib 2-mg, 1-mg, or 
placebo) received and responder status achieved in 
Study I4V-MC-JAIW (JAIW).

Proportion of patients achieving IGAEASI75 from 
baseline of 0 or 1originating study, assessed at 
Week 16
Secondary
To describe the clinical response to baricitinib 2-mg 
QD in AD as measured by improvement in signs and 
symptoms of AD by prior treatment received (ie., 
baricitinib 2-mg, 1-mg, or placebo) received and 
responder status achieved in Study JAIW.

Proportion of patients achieving IGA of 0 or 1 
assessed at Week 16 

Proportion of patients achieving IGA of 0 or 1 
assessed at or before Week 16

Proportion of patients achieving EASI75 from 
baseline of originating study, assessed at Week 16

Proportion of patients achieving EASI75 from 
baseline of originating study, assessed at or before 
Week 16

Mean percent change from baseline in EASI score 
from baseline of originating study, assessed at 
Week 16 

Proportion of patients achieving a BSA of ≤3% 
assessed at or before Week 16
To describe the clinical response to baricitinib 2-mg 
QD in AD as assessed by patient-reported outcome 
measures by prior treatment received (ie., baricitinib 
2-mg, 1-mg, or placebo) received and responder 
status achieved in Study JAIW.

Proportions of patients achieving a ≥4-point 
improvement in Itch NRS from baseline of 
originating study, assessed at Week 16

Proportions of patients achieving a ≥4-point 
improvement in Itch NRS from baseline of 
originating study, assessed at or before Week 16

Mean percent change from baseline of originating 
study, in Itch NRS assessed at Week 16
Abbreviations:  AD = atopic dermatitis; BSA = body surface area; EASI = Eczema Area and Severity Index; 
EASI75 = 75% improvement from baseline in EASI; IGA = Investigator’s Global Assessment; NRS = numeric 
rating scale; QD = once daily.
Summary of Study Design:
Study I4V-MC-JAIX (JAIX) is a Phase 3, multicenter, open-label outpatient study evaluating the efficacy and safety 
of baricitinib 2-mg once daily (QD) in adult patients with moderate to severe AD.  The study population will include 
patients 18 years or older with a history of inadequate response or intolerance to existing topical therapies, and who 
have completed at least Visit 8protocol-defined minimal participation in Study JAIW based on responder status.


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The study duration will be up to 108204 weeks over 2 study periods:

Period 1:  Open-Label Treatment Period, lasting from Week 0 (baseline, Visit 1) through Week 104200
(Visit 1117).
Period 2:  Post-Treatment Follow-Up Period (Visit 801), spanning the period from the last treatment visit at 
Week 104200 (Visit 1117) or Early Termination Visit (ETV) to approximately 4 weeks following the last dose of 
investigational product
Treatment Arms and Duration:
Patients will be assigned at baseline to open-label treatment with baricitinib 2-mg QD.  The study duration will be 
up to 108204 weeks (Open-Label Treatment Period:  104200 weeks; Post-Treatment Follow-Up Period:  
approximately 4 weeks after the last dose of investigational product).
Number of Patients:
This study will include approximately 300up to 450 patients with AD who will be treated with baricitinib 2-mg QD.
Statistical Analysis:
Unless otherwise specified, the efficacy and health outcomes summaries will be conducted on all enrolled patients
who receive at least 1 dose of investigational product in Study JAIX, even if the patient does not follow the protocol, 
and safety analyses will be conducted on all enrolled patients who receive at least 1 dose of investigational product
and who do not discontinue from the study for the reason “Lost to Follow-up” at the first postbaseline visit.  
Treatment comparisons of discrete efficacy variables between prior-treatment-received groups may be performed 
using group percentages.    All patients who discontinue the study or study treatment at any time for any reason will 
be defined as nonresponders for the nonresponder imputation (NRI) analysis for categorical variables after 
discontinuation onward.  
Continuous efficacy variables will be descriptively summarized in terms of number of patients, mean, standard 
deviation, median, minimum, and maximum.   
Frequencies and percentages will be computed for adverse event (AE), discontinuation, and other categorical safety 
data.  Continuous vital signs, body weight, and other safety variables including laboratory variables will be 
summarized by mean, standard deviation, median, minimum and maximum.  






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b
An ET visit should be conducted if a patient discontinues from the study before Week 104200.  Early termination visit activities do not need to be duplicated 
if occurring at the time of a scheduled visit. Weighing of TCS and collection of HADS, EQ-5D-5L, and WPAI-AD are not a component of study visit 17, only 
the ETV at or before Week 104.
c
Visit 801 is the PTFU visit, which occurs after the patient has been off baricitinib/IP for approximately 4 weeks.  Patients who have permanently discontinued 
IP but remain in the study for more than 28 days without IP will only complete Visit 1117/ET; Visit 801 (follow-up visit) is not required.
d
Screening should occur during the LPV of the originating study.   It may be permissible for screening to occur after the last visit of the originating study if 
needed, upon approval from the sponsor.
e Applies to ET visit if conducted prior to Week 16 only.
f
Only required at investigator discretion. Sponsor provided low potency TCS will be available to dispense to patients at anytime prior to study visit 11.  At 
visit 11 and after, low potency TCS is allowed as background therapy but will not be provided by the sponsor or reimbursed by the sponsor.  
g
The following measures (POEM, DLQI, HADS, EQ-5D-5L, WPAI-AD) should be completed prior to any clinical assessments being performed on days when
study visits occur.
h
Suicidal ideation and behavior subscales excerptadapted for the assessment of 11 preferred ideation and behavior categories.
i
The Self-Harm Follow-Up Form is required only if triggered by the Self-Harm Supplement Form.
j
Fasting lipid profile.  Patients should not eat or drink anything except water for 12 hours prior to sample collection.  If a patient attends these visits in a 
nonfasting state, this will not be considered a protocol violation.  Unscheduled lipid testing can be performed at the discretion of the investigator.
k
If laboratory examinations have been performed ≤4 weeks from previous study visit, then they do not need to be repeated.
l
For ET visits, collect fasting lipids when possible. 
m Clinical chemistry will include the following value calculated from serum creatinine:  estimated glomerular filtration rate (eGFR; calculated using the Chronic 
Kidney Disease Epidemiology Collaboration [CKD-EPI] Creatinine 2009 equation).
n
Patients who are positive for HBcAb and negative for HBV DNA may be enrolled.  Any enrolled patient who is HBcAb positive as determined at screening 
of originating study, Study JAIW, regardless of HBsAb status or level, must undergo HBV DNA testing per the schedule.
o
Urinalysis, serum IgE, exploratory storage samples, and RNA and biomarker samples are only collected for ET visits occurring at or before Week 104.  These 
samples are not collected as a component of Visit 17For all women of childbearing potential, urine pregnancy tests (local laboratory) will be performed at all 
specified visits.  If required per local regulations and/or institutional guidelines, pregnancy testing can occur at other times during the study treatment period.
p
For all women of childbearing potential, urine pregnancy tests (local laboratory) will be performed at all specified visits.  If required per local regulations 
and/or institutional guidelines, pregnancy testing can occur at other times during the study treatment period.


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3.2
Study Rationale
The recently completed Phase 2 study of baricitinib in AD, Study JAHG, met its primary 
objective of proportion of patients achieving a 50% improvement from baseline in Eczema Area 
and Severity Index (EASI50) scores compared to placebo.  Baricitinib also showed statistically 
significant improvements for other disease severity analyses as well as multiple different patient 
reported outcome scales compared to placebo, further validating the hypothesis that JAK1/JAK2 
signaling plays a key role in AD pathogenesis. Phase 3 placebo-controlled studies are ongoing to 
define baricitinib efficacy in AD.  This open-label, long-term extension study is designed to 
further assess long-term efficacy and safety of baricitinib in patients with moderate to severe 
AD, who did not achieve the primary end point (Investigator’s Global Assessment [IGA] 0, or 1)
in the originating study, Study I4V-MC-JAIW (JAIW).  This will allow patients originally 
randomized to baricitinib 1-mg or placebo in Study JAIW to have the opportunity for treatment 
with baricitinib 2-mg QD, and also assess the longer-term clinical utility of the 2-mg dose 
beyond achieving an IGA 0,1.  In addition, this study will give patients completing Study JAIW 
as responders the opportunity for ongoing access to baricitinib 2-mg.
4.
Objectives and Endpoints
Table JAIX.2.
Objectives and Endpoints
Objectives
Endpoints
Primary
To describe the clinical response to baricitinib 2-mg 
QD in patients with moderate to severe AD by prior 
treatment received (ie., baricitinib 2-mg, 1-mg, or 
placebo) received and responder status achieved in 
Study I4V-MC-JAIW (JAIW).) 

Proportion of patients achieving IGAEASI75 from 
baseline of 0 or 1originating study, assessed at 
Week 16
Secondary
To describe the clinical response to baricitinib 2-mg 
QD in AD as measured by improvement in signs and 
symptoms of AD by prior treatment received (ie., 
baricitinib 2-mg, 1-mg, or placebo) received and 
responder status achieved in Study JAIW.

Proportion of patients achieving IGA of 0 or 1 
assessed at Week 16

Proportion of patients achieving IGA of 0 or 1 
assessed at or before Week 16

Proportion of patients achieving EASI75 from 
baseline of originating study, assessed at Week 16

Proportion of patients achieving EASI75 from 
baseline of originating study, assessed at or before 
Week 16

Mean percent change from baseline in EASI score 
from baseline of originating study, assessed at 
Week 16 

Proportion of patients achieving a BSA of ≤3% 
assessed at or before Week 16
To describe the clinical response to baricitinib 2-mg 
QD in AD as assessed by patient-reported outcome 

Proportions of patients achieving a ≥4-point 
improvement in Itch NRS from baseline of 


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Objectives
Endpoints
measures by prior treatment received (ie., baricitinib 
2-mg, 1-mg, or placebo) received and responder 
status achieved in Study JAIW.
originating study, assessed at Week 16

Proportions of patients achieving a ≥4-point 
improvement in Itch NRS from baseline of 
originating study, assessed at or before Week 16

Mean percent change from baseline of originating 
study, in Itch NRS assessed at Week 16
Exploratory Objectives/Endpoints

Exploratory objectives may include evaluating the response to baricitinib treatment regimens on clinical 
measures and patient reported outcomes.  These endpoints may include dichotomous endpoints or change 
from baseline for the following measures:  IGA, EASI, SCORAD, POEM, HADS, DLQI, WPAI-AD, EQ-
5D-5L, Itch NRS, ADSS Item 2 score, Skin Pain NRS, PGI-S-AD.

To evaluate changes from baseline in IgE levels during the study.

To evaluate changes from baseline in eosinophil levels during the study.  
Abbreviations:  AD = atopic dermatitis; ADSS = Atopic Dermatitis Sleep Scale; BSA = body surface area; DLQI = 
Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; EASI75 = 75% improvement from 
baseline in EASI; EQ-5D-5L = the European Quality of Life–5 Dimensions–5 Levels; HADS = Hospital Anxiety 
Depression Scale; IGA = Investigator’s Global Assessment; IgE = immunoglobulin E; NRS = numeric rating 
scale; QD = once daily; PGI-S-AD = Patient Global Impression of Severity–Atopic Dermatitis; POEM = 
Patient-Oriented Eczema Measure; SCORAD = SCORing Atopic Dermatitis; WPAI-AD = Work Productivity 
and Activity Impairment – Atopic Dermatitis.
5.
Study Design
5.1
Overall Design
Study I4V-MC-JAIX (JAIX) is a Phase 3, multicenter, open-label, outpatient study evaluating 
the efficacy and safety of baricitinib 2-mg QD in adult patients with moderate to severe AD.  The 
study is divided into 2 periods; a 104200-week Open-Label Treatment period, and a 4-week 
Post-Treatment Follow-Up period. The following patients will be eligible to participate in this 
study:

Partial Responders (IGA 2 at Week 16 of Study JAIW)

Previous Responders at Week 16 of Study JAIW (IGA 0 or 1): Patients who were 
responders at Week 16 of Study JAIW, and thus remain in Study JAIW but later 
experience loss of response resulting in an IGA ≥3 (or requiring more than low-potency 
TCS after Week 16 to manage symptoms)

Nonresponders (IGA 3 or 4 at Week 16 of Study JAIW or rescued with topical [e.g. TCS, 
TCNI] or systemic therapies prior to Week 16)

Responders who completed Study JAIW through Week 104 (Visit 15)
Approximately 300 patients who have been discontinued from Study JAIW may be eligible to 
enroll in this study.  Patients who complete Study JAIW through Visit 8 (Week 16) can enter 
Study JAIX.  In addition, patients who complete Study JAIW as responders may be eligible to 
enroll in this study.  For most patients, the last visit of the originating study will be the first visit 
and screening/baseline period for Study JAIX.  Patients will have been using emollients daily in 


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their originating study and this will continue during Study JAIX participation. Starting at 
baseline, patients will be treated with open-label baricitinib 2-mg QD for up to 104200 weeks.
All procedures to be conducted during the study, including timing of all procedures, are indicated 
in the Schedule of Activities (Section 2).  Section 9.4.3 describes collection of laboratory 
samples; Appendix 2, Appendix 4, Appendix 5, and Appendix 6 list the specific laboratory tests 
that will be performed for this study.  Study governance considerations are described in detail in 
Appendix 3. The IGA tool to be used in this study is included in Appendix 8.
Figure JAIX.1 illustrates the study design.  The dosing regimen is described in Section 7.1. 
Abbreviations:  AD = atopic dermatitis; QD = once daily; V = visit; W = week.
a
Occurs approximately 28 days after the last dose of investigational product.
Figure JAIX.1.
Illustration of study design for Clinical Protocol I4V-MC-JAIX.


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5.1.1.Period 1:  Open-Label Treatment, Weeks 0 to 200104
Screening should occur during the last visit of the originating study. Study eligibility for each 
patient will be reviewed based on all enrollment criteria (Section 6). Patients who meet all 
criteria will have treatment allocated by interactive web-response system (IWRS) and begin their 
treatment period at Visit 1. Patients who meet all of the inclusion and none of the exclusion 
criteria (Section 6) will be enrolled in the study.  It may be permissible for screening to occur 
after the last visit of the originating study if needed, upon approval from the sponsor. For 
example, patients requiring elective procedures may want to have those in between studies.  , or 
responders who complete Visit 15 of Study JAIW have the option to delay enrollment into open-
label Study JAIX to assess response while off investigational product.
Patients who received oral systemic AD treatment and/or topical rescue therapy during the 
originating study must discontinue use of the prohibited medications listed in Section 7.7.1 prior 
to initiating IP in Study JAIX.  Low-potency TCS (e.g., hydrocortisone 2.5% ointment) is 
permitted (Section 7.7.2).
Patients will receive open-label baricitinib 2–mg QD.  Investigational product will be 
administered daily for a maximum of 104200 weeks (treatment period Visits 1 through 1117; see 
Section 7).  All patients will be required to use emollients daily.  Daily diaries will continue to be 
utilized through Week 16.  Download of this data will be required at study visits.  Patients are 
allowed to use low potency TCS (e.g., hydrocortisone 2.5% ointment) in combination with 
investigational product.  Rescue with higher potency TCS, topical calcineurin inhibitors 
(TCNIs), or systemic therapies is not allowed.  Assessments of disease severity will be 
performed by the investigator as described in the Schedule of Activities (Section 2).
The primary efficacy endpoint will be at Week 16 (Visit 4).  All patients who permanently 
discontinue investigational product prior to the primary endpoint should complete an ETV and 
post-treatment follow-up visit.  
At Week 16, all patients should be formally assessed to determine if sufficient clinical benefit 
has been observed to justify continuing in this study.  Clinical benefit is defined as meeting at 
least 1 of the following criteria during the first 16 weeks:

IGA score of 0 or 1 with a ≥2-point improvement from baseline of originating study, 

≥4-point improvement from baseline of originating study in Itch NRS, 

EASI-75 from baseline of originating study, or

BSA involvement of ≤3%. 
If a patient achieves any of these treatment goals during the first 16 weeks of the treatment 
period, the patient will be allowed to continue in the study. Although formal criteria for 
sufficient clinical benefit should be assessed at Week 16, investigators are strongly encouraged 
to discontinue patients who have not shown signs of clinical benefit by Week 8 of Study JAIX, 
defined as improvement in IGA, itch NRS, EASI, or BSA. Attention should be given to patients 
treated continuously for 16 weeks during Study JAIW (no IP discontinuation for systemic rescue 


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therapy) and who then show no benefit in Study JAIX, to avoid exposing patients to a potentially 
ineffective therapy for an additional 16 weeks before discontinuation.  Since no rescue therapies 
are available during this study, patients requiring more than low-potency TCS at any time during 
the study will be discontinued.
5.1.2.Period 2:  Post-Treatment Follow-Up
Patients who complete the study through Visit 1117 (Week 104200) will have a post-treatment
follow-up visit (Visit 801) approximately 28 days after the last dose of investigational product.
Patients who have received at least 1 dose of investigational product and discontinue early from 
the study should have an ETV, and return for the post-treatment safety follow-up visit (Visit 801) 
approximately 28 days after the last dose of investigational product.
Patients who have discontinued investigational product but remain in the study for more than 
28 days without investigational product will have an ETV if they choose to discontinue early; 
however, a separate follow-up visit (V801) is not required.
Patients should not initiate new systemic AD treatment during this period.  However, if patients 
or investigators must initiate treatment, investigators should make every attempt to conduct 
efficacy and safety assessments immediately before administering any new treatment. 
An unscheduled visit can be used for this purpose if necessary. 
5.2.
Number of Participants
Approximately 300Up to 450 participants willmay be enrolled, although final number of patients 
will be determined by response rate observed in the originating Study JAIW.
5.4.
Scientific Rationale for Study Design
This open-label long-term extension study will enroll moderate to severe AD patients who have 
completed treatment visits until at least the primary endpoint of an originating study (i.e., Visit 8, 
Week 16 of Study JAIW) but who did not achieve the primary endpoint of IGA 0,1, or who 
experience loss of response after Week 16, or who complete Study JAIW as responders at Visit 
15, Week 104. This study will further assess long-term efficacy and safety of baricitinib in this 
population.  This will allow patients originally randomized to baricitinib 1-mg or placebo in 
Study JAIW to have the opportunity for treatment with baricitinib 2-mg QD, and also assess the 
longer-term clinical utility of the 2-mg dose beyond achieving an IGA 0,1.
During the open-label treatment period, patients will be treated with baricitinib 2-mg, which has 
been shown to be efficacious in the Phase 2 study in AD (JAHG). Patients will also be allowed 
to use low-potency TCS (e.g., hydrocortisone 2.5% ointment) as background therapy for comfort 
if needed. Daily treatment with emollient will continue. To avoid confounding effect of topical 
therapies, higher-potency TCS, as well as TCNIs and topical phosphodiesterase type 4 (PDE-4) 
inhibitors are not allowed at any time during the study. If a patient does not experience sufficient 
clinical benefit during the study, the patient should be discontinued.  The criteria for determining 
sufficient clinical benefit are discussed in Section 5.1.1.  This 24-year-long study will generate
important long-term efficacy and safety data in AD.


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The post-treatment follow-up period (Period 2) is for safety monitoring after the patient has been 
off investigational product for approximately 28 days.
6. Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
The study population will comprise patients diagnosed with AD who have completed at least 
Visit 8 (Week 16) of Study JAIW.  Study investigator(s) will determine if the patient meets all 
inclusion criteria and none of the exclusion criteria to qualify for enrollment in the study.  All 
screening activities must be completed and reviewed before the patient is enrolled.
6.1.
Inclusion Criteria
Type of Patient and Disease Characteristics
[1]
have completed the minimum number of visits based on responder status in 
Study JAIW

nonresponder/partial responder: have completed at least 16 weeks of 
treatment in Study JAIW (i.e., Visit 8, Week 16) and
A nonresponder/partial responder is defined as a patient who met at least 1 
of the following in Study JAIW: 

did not achieve an IGA of 0 or 1 at Week 16, or

achieved an IGA ≥3 after Week 16, or

required rescue therapy at any time.
or

responder: have completed the full treatment period of Study JAIW (i.e., 
Visit 15, week 104)
A responder is defined as a patient who achieved IGA 0 or 1 and who did 
not require rescue therapy at or before Week 16 in Study JAIW.
7.6
Treatment Compliance
Patient compliance with study medication will be assessed at each visit during the treatment 
period (Visit 2 through Visit 1117) by counting returned tablets.  
A patient will be considered significantly noncompliant if he or she misses more than 20% of the 
prescribed doses of investigational product during the study, unless the patient’s investigational 
product is withheld by the investigator for safety reasons.  Similarly, a patient will be considered 
significantly noncompliant if he or she is judged by the investigator to have intentionally or 
repeatedly taken 20% more than the prescribed amount of medication during the study.
Patients will be counseled by study staff on the importance of taking the investigational product 
as prescribed, as appropriate.


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Patients’ compliance will be further defined in the statistical analysis plan (SAP).
7.7.3. Rescue Therapy
No rescue therapy options are available during the study.  Patients are allowed to use low-
potency TCS as background therapy for comfort if needed. Patients who experience worsening 
and unacceptable symptoms of AD should consider discontinuing from the study.  Patients 
requiring more than low-potency TCS to manage their symptoms should also be discontinued.
Hydrocortisone 2.5% ointment will be supplied by the sponsor. for use during the first 2 years of 
the treatment period (dispensed at Visits 1-10 only).  In the event that providing this topical 
formulation during the first 2 years is not possible, an alternate, equivalent potency TCS cream 
and/or ointment may be provided by the sponsor.  Use of sponsor-supplied TCS should be 
recorded via weight of returned tubes as indicated in the Schedule of Activities (Section 2).  
Sponsor will not provide or reimburse the cost of TCS at Visit 11 or after.
In the event that the sponsor is unable to supply TCS during the first 2 years of the treatment 
period, commercially available hydrocortisone 2.5% ointment or an equivalent-potency TCS 
cream and/or ointment that is in line with local practices can be supplied by the sponsor or the 
sites. Refer to Appendix 7 for guidance on potency equivalence.  
On the days of study visits, topical therapy should not be applied before the patient has 
undergone all study procedures and clinical evaluations to allow adequate assessment of skin 
dryness.
8.2
Discontinuation From the Study 
Patients may choose to withdraw from the study for any reason at any time, and the reason for 
early withdrawal will be documented.
Some possible reasons that may lead to permanent discontinuation include the following:

enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study

participation in the study needs to be stopped for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and good clinical 
practice

study termination may occur in a specific country or region when baricitinib is approved 
for the treatment of AD and becomes reimbursed or commercially available in that 
country or region, or a negative regulatory opinion is received in that country or region  

investigator decision
o
The investigator decides that the patient should be discontinued from the 
study.


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o
If the patient, for any reason, requires treatment with another therapeutic 
agent (not allowed as part of rescue therapy [Section 7.7.3]) that has been 
demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new 
agent.

patient decision
o
The patient requests to be withdrawn from the study.
Patients discontinuing from the study prematurely for any reason should complete AE and other 
safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety) of this protocol.
9.1.1 Primary Efficacy Assessments
Eczema Area and Severity Index Scores (EASI): The EASI assesses extent of disease at 4
body regions and measures 4 clinical signs:  (1) erythema, (2) induration/papulation, (3) 
excoriation, and (4) lichenification, each on a scale of 0 to 3.  The EASI confers a maximum 
score of 72.  The EASI evaluates 2 dimensions of AD:  disease extent and clinical signs (Hanifin 
et al. 2001).Validated Investigator’s Global Assessment for Atopic Dermatitis (vIGA AD):  
The IGA used in this study, the vIGA AD (referred to as the IGA throughout the protocol) 
measures the IGA of the patient’s overall severity of their AD, based on a static, numeric 5 point 
scale from 0 (clear skin) to 4 (severe disease).  The score is based on an overall assessment of the 
degree of erythema, papulation/induration, oozing/crusting, and lichenification.
9.1.2 Secondary Efficacy Assessments
9.1.2.1. Eczema Area and Severity Index scoresValidated Investigator’s Global 
Assessment for Atopic Dermatitis (vIGA-AD)
The IGA used in this study, the vIGA-AD (referred to as the IGA throughout the protocol) 
measures the IGA of the patient’s overall severity of their AD, based on a static, numeric 5-point 
scale from 0 (clear skin) to 4 (severe disease).  The score is based on an overall assessment of the 
degree of erythema, papulation/induration, oozing/crusting, and lichenification.
9.1.2.12. Eczema Area and Severity Index scores
9.1.2.23. SCORing Atopic Dermatitis
9.1.2.34. Hospital Anxiety Depression Scale
10.1. Sample Size Determination
It is anticipated that approximately 90% of enrolled patients will complete Week 16 of 
Study JAIW; of these patients, it is expected that approximately 75% will roll over into 
Study JAIX.  Assuming that approximately 90% of the nonresponders and partial responders join 
Study JAIX, then the planned enrollment will be approximately 300 patients.  The study is 


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descriptive in nature and the sample size is not based on any statistical power calculations.  The 
final sample size will depend on the response rate in Study JAIW.All of the approximate 450 
patients participating in the originating study can be assessed for eligibility to participate in 
Study JAIX.
10.3.1 General Statistical Considerations
As this study is open-label and all patients are receiving baricitinib 2-mg, no hypothesis testing 
will be performed.  Data will be summarized both overall and by prior-treatment-received in 
Study JAIW. Data from this trial may be integrated with other trials.
Statistical analysis of this study will be the responsibility of Lilly or its designee. A detailed 
SAP describing the statistical methodologies will be developed by Lilly or its designee.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol and the justification for making the change will be described 
in the clinical study report (CSR).  Additional exploratory analyses of the data will be conducted 
as deemed appropriate.
All discrete efficacy variables will be summarized using frequencies and percentages.  
Continuous efficacy and health outcome variables will be summarized using number of patients, 
mean, standard deviation, median, minimum, and maximum.
The methods used to handle missing data will be specified in the SAP.
Frequencies and percentages will be computed for AEs, discontinuation, and other categorical 
safety data. Continuous vital signs, body weight, and other safety variables including laboratory 
variables will be summarized using mean, standard deviation, median, minimum and maximum.  
Shift tables for categorical safety analyses (e.g., “high” or “low” laboratory results) will also be 
produced.
All patients who discontinue the study or the study treatment at any time for any reason will be 
defined as nonresponders for the NRI summary of categorical efficacy variables such as IGA 0/1 
or EASI 50/75/90 after discontinuation and onward.  
10.3.4. Safety Analyses
All safety data will be summarized overall and by prior therapy received using the safety 
population.
Treatment-emergent adverse events (TEAEs) are defined as AEs that first occurred or worsened 
in severity after the first dose of study treatment. The number of TEAEs as well as the number 
and percentage of patients who experienced at least 1 TEAE will be summarized using Medical 
Dictionary for Regulatory Activities (MedDRA) for each system organ class (or a body system) 
and each preferred term. Serious adverse events and AEs that lead to discontinuation of 
investigational product will also be summarized. 


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Categorical variables, including the incidence of AEs of special interest, together with individual 
analyses of clinical laboratory results and vital signs are not planned for this Study, but will be 
included in an integrated database.
All clinical laboratory results will be descriptively summarized.  Additional summary may be 
produced by prior treatment received.  Individual results that are outside of normal reference 
ranges will be flagged in data listings.  Quantitative clinical hematology, chemistry, and 
urinalysis variables obtained at the baseline to postbaseline visits will be summarized as changes 
from baseline.  Categorical variables, including the incidence of abnormal values and incidence 
of AEs of special interest, will be summarized by frequency and percentage of patients in 
corresponding categories.  Shift tables will be presented for selected measures.
Observed values and changes from baseline (predose or screening if missing) for vital signs and 
physical characteristics will be summarized by visit.  Change from baseline to postbaseline in 
vital signs, and body weight will be summarized using mean, standard deviation, median, 
minimum, and maximum.  The incidence and average duration of investigational product 
interruptions will be summarized. Various techniques may be used to estimate the effects of 
investigational product interruptions on safety measures.  Further summaries may be performed 
and will be planned in the SAP.
Data collected after initiation of rescue therapy will be summarized as appropriate.


Leo Document ID = c2a9e61c-547d-4bef-81eb-2753ad40062b
Approver: 
Approval Date & Time: 28-Oct-2019 16:36:52 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 28-Oct-2019 21:37:07 GMT
Signature meaning: Approved
PPD
PPD