Topical Ruxolitinib Evaluation in Atopic Dermatitis Study 2 (TRuE AD2) - A Phase 3, Double-Blind, Randomized, 8-Week, Vehicle-Controlled Efficacy and Safety Study of Ruxolitinib Cream Followed by a Long-Term Safety Extension Period in Adolescents and Adults With Atopic Dermatitis
Phase: PHASE3
Conditions: Atopic Dermatitis
Sponsor: Incyte Corporation

Official Title: ATopical Ruxolitinib Evaluation in Atopic Dermatitis Study 2 (TRuE-AD2)
A Phase 3, Double-Blind, Randomized, 8-Week, Vehicle-Controlled Efficacy and Safety Study
of Ruxolitinib Cream Followed by a Long-Term Safety Extension Period in Adolescents and
Adults With Atopic Dermatitis
NCT Number: NCT03745651
Document Date: 13 FEB 2019

Incyte Co1poration 
Protocol INCB 18424-304 Am 2 
Version 2 
Clinical Study Protocol 
INCB 18424-304 
Page 1 of88 
13 FEB 2019 
Iopical Ruxolitinib E,valuation in ,AtopicJ!ermatitis Study 1, 
(TRuE-AD2) 
A Phase 3, Double-Blind, Randomized, 8-Week, Vehicle-Controlled 
Efficacy and Safety Study ofRuxolitinib Cream Followed by a 
Long-T erm Safety Extension Period in Adolescents and Adults With 
Atopic Dermatitis 
Product: 
Ruxolitinib Cream 
IND Number: 
-
EudraCT Number: 
2018-003713-18 
Phase of Study: 
3 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol (Version 0): 
01 NOV 2018 
Amendment (Version) 1: 
22 JAN 2019 
Amendment (Version) 2: 
13 FEB 2019 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, applicable Good Clinical Practices, and applicable laws 
and country-specific regulations in which the study is being conducted. 
The infonnation in this document is confidential. No pait of this infonnation may be duplicated, referenced, or 
transmitted in any fonn or by any means (electronic, mechanical, photocopy, recording, or otherwise) v.iithout prior 
written consent. 
CONFIDENTIAL 

Incyte Corporation 
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Protocol INCB 18424-304 Am 2 
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CONFIDENTIAL 
INVESTIGATOR'S AGREEMENT 
I have read the INCB 18424-304 Protocol Amendment 2 (Version 2 dated 13 FEB 2019) and 
agree to conduct the study as outlined.  I agree to maintain the confidentiality of all information 
received or developed in connection with this Protocol. 
(Printed Name of Investigator) 
(Signature of Investigator) 
(Date) 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1.
PROTOCOL SUMMARY ..........................................................................................11 
2.
INTRODUCTION ......................................................................................................20 
2.1. 
Background .................................................................................................................20 
2.1.1. 
Atopic Dermatitis ........................................................................................................20 
2.1.2. 
Diagnosis of Atopic Dermatitis ..................................................................................20 
2.1.3. 
Current Treatment and Unmet Needs for Atopic Dermatitis ......................................21 
2.1.4. 
Role of Janus Kinases in Atopic Dermatitis ...............................................................22 
2.2. 
Ruxolitinib ..................................................................................................................22 
2.2.1. 
Oral Ruxolitinib ..........................................................................................................22 
2.2.2. 
Ruxolitinib Cream ......................................................................................................23 
2.2.2.1. 
Preclinical Drug Disposition Summary ......................................................................23 
2.2.2.2. 
Preclinical Safety ........................................................................................................24 
2.2.2.3. 
Clinical Safety ............................................................................................................24 
2.2.2.4. 
Efficacy of Ruxolitinib Cream ....................................................................................25 
2.3. 
Study Rationale ...........................................................................................................28 
2.3.1. 
Scientific Rationale for Study Design ........................................................................28 
2.3.2. 
Justification for Selected Treatment Regimen ............................................................29 
2.4. 
Benefit/Risk Assessment ............................................................................................30 
3.
OBJECTIVES AND ENDPOINTS ............................................................................32 
4.
STUDY DESIGN .......................................................................................................34 
4.1. 
Overall Design ............................................................................................................34 
4.2. 
Overall Study Duration ...............................................................................................35 
4.3. 
Study Termination ......................................................................................................35 
5.
STUDY POPULATION .............................................................................................36 
5.1. 
Inclusion Criteria ........................................................................................................36 
5.2. 
Exclusion Criteria .......................................................................................................37 
5.3. 
Lifestyle Considerations .............................................................................................39 
5.4. 
Screen Failures ............................................................................................................39 
5.5. 
Replacement of Participants .......................................................................................39 
6.
STUDY TREATMENT ..............................................................................................40 

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6.1. 
Study Treatment Administered ...................................................................................40 
6.2. 
Preparation, Handling, and Accountability ................................................................41 
6.3. 
Measures to Minimize Bias:  Randomization and Blinding .......................................42 
6.4. 
Study Treatment Compliance .....................................................................................42 
6.5. 
Modifications to Treatment Regimen .........................................................................43 
6.5.1. 
Criteria and Procedures for Application Interruptions of Study Drug .......................43 
6.5.2. 
Criteria for Permanent Discontinuation of Study Drug Due to an Adverse 
Event ...........................................................................................................................44 
6.6. 
Concomitant Medications and Procedures .................................................................45 
6.6.1. 
Permitted Medications and Procedures ......................................................................45 
6.6.2. 
Restricted Medications and Procedures ......................................................................45 
6.6.3. 
Prohibited Medications and Procedures .....................................................................46 
6.7. 
Treatment After the End of the Study .........................................................................46 
7.
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL ..................................................................47 
7.1. 
Discontinuation of Study Treatment ...........................................................................47 
7.1.1. 
Reasons for Discontinuation .......................................................................................47 
7.1.2. 
Discontinuation Procedures ........................................................................................47 
7.2. 
Participant Withdrawal From the Study .....................................................................48 
7.3. 
Lost to Follow-Up.......................................................................................................48 
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................................49 
8.1. 
Administrative and General Procedures .....................................................................49 
8.1.1. 
Informed Consent Form Process ................................................................................49 
8.1.2. 
Screening Procedures ..................................................................................................50 
8.1.3. 
Interactive Response Technology Procedure ..............................................................50 
8.1.4. 
Distribution of Study Reminder Cards and Diaries ....................................................51 
8.1.5. 
Demography and Medical History ..............................................................................51 
8.1.5.1. 
Demographics and General Medical History .............................................................51 
8.1.5.2. 
Medical and Treatment History ..................................................................................51 
8.2. 
Efficacy Assessments .................................................................................................52 
8.2.1. 
Investigator's Global Assessment ...............................................................................52 
8.2.2. 
Eczema Area and Severity Index Score ......................................................................52 
8.2.3. 
SCORing Atopic Dermatitis .......................................................................................53 

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8.2.4. 
Target Lesion Assessment ..........................................................................................53 
8.2.5. 
Body Surface Area ......................................................................................................54 
8.2.6. 
Photography ................................................................................................................54 
8.2.7. 
Patient-Reported Outcomes ........................................................................................54 
8.2.7.1. 
Dermatology Life Quality Index ................................................................................55 
8.2.7.2. 
Patient Global Impression of Change .........................................................................56 
8.2.7.3. 
Patient-Oriented Eczema Measure .............................................................................56 
8.2.7.4. 
EQ-5D-5L ...................................................................................................................56 
8.2.7.5. 
Work Productivity and Activity Impairment Questionnaire:  Specific Health 
Problem Version 2.0 ...................................................................................................57 
8.2.7.6. 
Itch Numerical Rating Scale .......................................................................................57 
8.2.7.7. 
Skin Pain Numerical Rating Scale ..............................................................................57 
8.2.7.8. 
PROMIS Sleep Questionnaires:  Short Form – Sleep-Related Impairment 
(8a) and Short Form – Sleep Disturbance (8b) ...........................................................57 
8.2.8. 
Health Economics .......................................................................................................58 
8.3. 
Safety Assessments .....................................................................................................58 
8.3.1. 
Adverse Events ...........................................................................................................59 
8.3.2. 
Physical Examinations ................................................................................................59 
8.3.3. 
Vital Signs ..................................................................................................................60 
8.3.4. 
Electrocardiograms .....................................................................................................60 
8.3.5. 
Laboratory Assessments .............................................................................................60 
8.3.5.1. 
Pregnancy Testing ......................................................................................................61 
8.3.5.2. 
Serology ......................................................................................................................61 
8.4. 
Pharmacokinetic Assessments ....................................................................................62 
8.6. 
Unscheduled Visits .....................................................................................................63 
8.7. 
End of Treatment and/or Early Termination ..............................................................63 
8.8. 
Safety Follow-Up ........................................................................................................64 

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9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................64 
9.1. 
Definition of Adverse Event .......................................................................................64 
9.2. 
Definition of Serious Adverse Event ..........................................................................65 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events .........66 
9.4. 
Reporting of Serious Adverse Events .........................................................................68 
9.5. 
Emergency Unblinding of Treatment Assignment .....................................................69 
9.6. 
Pregnancy ...................................................................................................................70 
9.7. 
Warnings and Precautions ..........................................................................................70 
9.8. 
Product Complaints ....................................................................................................71 
10. 
STATISTICS ..............................................................................................................71 
10.1. 
Sample Size Determination ........................................................................................71 
10.2. 
Populations for Analysis .............................................................................................71 
10.3. 
Type I Error Control ...................................................................................................72 
10.4. 
Statistical Analyses .....................................................................................................73 
10.4.1. 
Primary Analysis ........................................................................................................73 
10.4.2. 
Secondary Analysis ....................................................................................................74 
10.4.3. 
Safety Analyses ..........................................................................................................74 
 
 
10.5. 
Interim Analysis ..........................................................................................................75 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................76 
11.1. 
Investigator Responsibilities .......................................................................................76 
11.2. 
Data Management .......................................................................................................77 
11.3. 
Data Privacy and Confidentiality of Study Records ...................................................78 
11.4. 
Financial Disclosure ...................................................................................................79 
11.5. 
Publication Policy .......................................................................................................79 
11.6. 
Study and Site Closure................................................................................................80 
12. 
REFERENCES ...........................................................................................................81 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS ...............................................................................84 
APPENDIX B. PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................85 
 

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LIST OF TABLES 
Table 1: 
Primary and Key Secondary Objectives and Endpoints .............................................11 
Table 2: 
Key Study Design Elements .......................................................................................12 
Table 3: 
Schedule of Activities:  Vehicle-Controlled Period ...................................................14 
Table 4: 
Schedule of Activities:  Long-Term Safety Extension Period....................................17 
Table 5: 
Objectives and Endpoints ...........................................................................................32 
Table 6: 
Study Treatment Information .....................................................................................41 
Table 7: 
Guidelines for Interruption and Restarting of Study Drug .........................................44 
Table 8: 
Investigator's Global Assessment ...............................................................................52 
Table 9: 
Required Laboratory Analytes ....................................................................................61 
Table 10: Populations for Analysis .............................................................................................72 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................13 
Figure 2: 
Stepwise Approach to the Management of Atopic Dermatitis ...................................21 
Figure 3: 
INCB 18424-206 Study Schema ................................................................................26 
Figure 4: 
Control of the Overall Type I Error Rate ....................................................................73 
 

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LIST OF ABBREVIATIONS 
Abbreviations and 
Special Terms 
Definition 
AA 
alopecia areata 
AD 
atopic dermatitis 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BID 
twice daily 
BSA 
body surface area 
BSA assessment – Palmar 
method 
1% BSA for each participant is approximately equal to the surface of their 
palm plus 5 digits; handprint may be used interchangeably 
CFR 
Code of Federal Regulations 
Cmax 
Maximal plasma concentration 
CDLQI 
Children Dermatology Life Quality Index 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLQI 
Dermatology Life Quality Index 
EASI 
Eczema Area and Severity Index 
EASI50 
≥50% improvement in EASI score 
EASI75 
≥75% improvement in EASI score 
EASI90 
≥90% improvement in EASI score 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment  
EQ-5D-5L 
EQ-5D is a validated, self-administered, generic, utility questionnaire 
wherein participants will rate their current health state based on the 
following criteria:  mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. 
ET 
early termination 
FDA 
Food and Drug Administration 
flare 
an episode of worsening of atopic dermatitis, such that it requires 
re-initiation or escalation of treatment (IGA of at least 2) 
GCP 
Good Clinical Practice 
HDL 
high-density lipoprotein 
HIV 
human immunodeficiency virus 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 

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Abbreviations and 
Special Terms 
Definition 
IB 
Investigator's Brochure 
ICF 
informed consent form  
ICH 
International Council on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
IGA 
Investigator's Global Assessment  
IGA-TS 
Investigator's Global Assessment Treatment Success (IGA score of 0 or 1 
with ≥ 2 grade improvement from baseline) 
IL 
interleukin 
IRB 
institutional review board 
IRT 
interactive response technology  
Itch NRS 
Itch Numerical Rating Scale 
ITT 
intent-to-treat 
JAK 
Janus kinase 
LDL 
low-density lipoprotein 
LL 
lower limbs 
LPLV 
last participant last visit 
LTS 
long-term safety 
MedDRA 
Medical Dictionary for Regulatory Activities 
ni. 
non-inferiority 
NOAEL 
no-observed-adverse-effect level 
PASI 
Psoriasis Area Severity Index 
PD 
pharmacodynamic  
PDE 
phosphodiesterase 
PGA 
Physician's Global Assessment 
PGIC 
Patient Global Impression of Change 
PK 
pharmacokinetic 
POEM 
Patient-Oriented Eczema Measure 
PP 
per Protocol 
PROMIS® 
Patient-Reported Outcomes Measurement Information System 
QD 
once daily 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SCORAD 
SCORing Atopic Dermatitis – tool used to assess extent and severity 
(intensity) of eczema 
Skin Pain NRS 
Skin Pain Numerical Rating Scale 

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Abbreviations and 
Special Terms 
Definition 
SoA 
schedule of activities 
SPF 
sun protection factor 
 
 
TARC 
thymus and activation-regulated chemokine 
TC 
triamcinolone 
TEAE 
treatment-emergent adverse event, AEs reported for the first time or 
worsening of a pre-existing event after first dose of study treatment 
 
  
TSH 
thyroid-stimulating hormone 
TSLP 
thymic stromal lymphopoietin 
ULN 
upper limit of normal 
VC 
vehicle-control 
VHP 
Voluntary Harmonisation Procedure 
WPAI:SHP v2.0 
Work Productivity and Activity Impairment Questionnaire:  Specific Health 
Problem Version 2.0 

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1.
PROTOCOL SUMMARY
Protocol Title:  Topical Ruxolitinib Evaluation in Atopic Dermatitis Study 2 (TRuE-AD2) 
A Phase 3, Double-Blind, Randomized, 8-Week, Vehicle-Controlled Efficacy and Safety Study 
of Ruxolitinib Cream Followed by a Long-Term Safety Extension Period in Adolescents and 
Adults With Atopic Dermatitis 
Protocol Number:  INCB 18424-304 
Objectives and Endpoints:  Table 1 presents the primary and key secondary endpoints and 
objectives. 
Table 1: 
Primary and Key Secondary Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To establish the efficacy of ruxolitinib cream in 
participants with AD. 
• Proportion of participants achieving IGA-TS at
Week 8
Key Secondary 
To further assess efficacy of ruxolitinib cream. 
• Proportion of participants who achieve EASI75 at
Week 8.
• Proportion of participants with a ≥ 4-point
improvement in Itch NRS score from baseline to
Week 8.
• Proportion of participants with a clinically
meaningful improvement in the PROMIS Short
Form – Sleep Disturbance (8b) 24-hour recall score
at Week 8.
Overall Design 
Table 2 presents the key study design elements.  Further study details are presented after the 
table.  Table 3 provides the SoA for VC period, and Table 4 provides the SoA for the LTS 
period. 
Adherence to the study design requirements, including those specified in the SoAs, is essential 
and required for study conduct. 

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Table 2: 
Key Study Design Elements 
Study Phase 
Phase 3 
Clinical Indication 
Atopic Dermatitis 
Population 
Adolescents aged ≥ 12 to 17 years, inclusive, and men and women aged 
≥ 18 years who have been diagnosed with AD of at least 2 years duration, an 
IGA score of 2 to 3, and %BSA involvement (excluding scalp) of 3% to 20%. 
Number of 
Participants 
Approximately 600 participants 
Study Design 
Randomized (2:2:1), double-blind, 8-week VC period followed by a 
randomized, double-blind, 44-week LTS extension period.  In the LTS period, 
participants initially randomized to vehicle will receive either ruxolitinib 0.75% 
or 1.5% cream.   
Estimated Duration 
of Study Participation 
Screening:  up to 28 days 
Vehicle-controlled period:  8 weeks 
Double-blind, randomized LTS period:  44 weeks 
Follow-up:  30 (+ 7) days after last application of study drug or last visit 
Total:  up to 60 weeks 
DSMB/DMC 
No 
Treatment Groups and Duration: 
Adolescents aged ≥ 12 to 17 years, inclusive, and men and women aged ≥ 18 years who meet the 
inclusion criteria and have been diagnosed with AD of at least 2 years duration, an IGA score of 
2 to 3, and %BSA involvement of 3% to 20% (excluding scalp) will be enrolled and receive 
treatment with ruxolitinib 0.75% cream BID, ruxolitinib 1.5% cream BID, or vehicle cream in a 
2:2:1 randomization for a total duration of 8 weeks (with a screening period of approximately 
28 days) during the VC period of the study.  Adolescents will make up approximately 20% of the 
overall study population. 
At Week 8, all participants who successfully complete the VC period of the study and all Week 8 
assessments will be offered participation in the LTS treatment period with ruxolitinib 0.75% or 
1.5% cream BID.  The required %BSA range and IGA score entry into the LTS period is 0% to 
20% and 0 to 4 grade, respectively.  Participants who were initially treated with either ruxolitinib 
0.75% or 1.5% cream will remain in their respective treatment regimen, while those participants 
who were initially treated with vehicle will be randomized to either ruxolitinib 0.75% or 1.5% 
cream BID.  During this LTS period, participants will have study visits every 4 weeks until the 
end of the study (52 weeks total). 
After the Week 8 visit, during the LTS period, participants will self-evaluate recurrence of AD 
and will treat those areas of the skin with active AD changes (not to exceed up to 20% BSA).  If 
lesions clear between study visits, participants will stop treatment application 3 days after they 
have disappeared.  In the event that the new lesions are significantly more extensive than from 
the previous visit, the participant should call the study site to discuss with the investigator 
whether additional evaluation at the clinic is required.  The investigator, if needed, will have the 
option of having the participant return for an unscheduled visit. 
The study schema is shown below in Figure 1.  All participants will have follow-up assessments 
30 (+ 7) days after the last application of study drug. 

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Table 3: 
Schedule of Activities:  Vehicle-Controlled Period 
Visit Day (Range) 
Screening 
Vehicle-Controlled Treatment 
Notes 
Days 
-28 to -1 
Day 1 
(Baseline) 
Week 2 
(± 3 d) 
Week 4 
(± 3 d)  
Week 8*/EOT 
(± 3 d) 
*All assessments for the Week 8 
visit must be performed before 
participants may enter the LTS 
period. 
Administrative procedures 
Informed consent (including assent) 
X 
 
 
 
 
 
Contact IRT 
X 
X 
X 
X 
X 
 
Inclusion/exclusion criteria review 
X 
X 
 
 
 
 
Demography and general and disease 
medical history 
X 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
 
Apply study drug 
 
X 
X 
X 
X 
1st AM application under site 
supervision. 
Weigh/dispense or re-dispense study drug 
and distribute study drug diary and 
reminder card 
 
X 
X 
X 
X 
Used tubes will be replenished, and 
unused tubes may be re-dispensed. 
Collect/weigh study drug and 
collect/review study drug diary 
 
 
X 
X 
X 
 
Assess compliance 
 
X 
X 
X 
X 
 
Safety assessments 
AE assessments and targeted physical 
examinations 
X 
X 
X 
X 
X 
Body systems with symptoms 
should be physically examined. 
Ad hoc photography of skin-related 
AEs should also occur as applicable. 
Comprehensive physical examination 
X 
 
 
 
X 
 
Vital signs/body weight/height 
X* 
X 
X 
X 
X* 
*Height and weight at screening and 
Week 8.  
12-lead ECG 
X 
 
 
 
 
12-lead ECG performed within 
2 months before baseline is 
acceptable. 

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Table 3: 
Schedule of Activities:  Vehicle-Controlled Period (Continued) 
Visit Day (Range) 
Screening 
Vehicle-Controlled Treatment 
Notes 
Days 
-28 to -1 
Day 1 
(Baseline) 
Week 2 
(± 3 d) 
Week 4 
(± 3 d)  
Week 8*/EOT 
(± 3 d) 
*All assessments for the Week 8 visit 
must be performed before participants 
may enter the LTS period. 
Efficacy assessments 
Evaluate %BSA affected by active AD 
X 
X 
X 
X 
X* 
*At Week 8, to qualify for LTS period, 
the %BSA range is 0% to ≤ 20%. 
Target lesion 
X 
X* 
X 
X 
X 
*A lesion of ≥ 10 cm2 needs to be 
identified at baseline (excluding the 
hands, feet and genitalia) 
Photography (target lesion close-up/ 
regional body area) 
 
X 
X 
X 
X 
Ad hoc photography (at selected sites) of 
skin-related AEs is recommended. 
EASI 
X 
X 
X 
X 
X 
 
SCORAD 
 
X 
X 
X 
X 
 
IGA 
X 
X 
X 
X 
X* 
*At Week 8, to qualify for LTS period, 
the IGA range is 0 to 4. 
Itch NRS 
Diary is completed each evening from screening through the last application of study 
drug in the vehicle-controlled period. 
 
Skin Pain NRS 
 
Patient-reported outcome questionnaires – to be evaluated prior to any other study procedures/assessments; see Section 8.2.7 
DLQI/CDLQI 
 
X 
X 
X 
X 
 
PGIC 
 
 
X 
X 
X 
 
POEM 
 
X 
X 
X 
X 
 
EQ-5D-5L questionnaire 
X 
X 
X 
X 
X 
 
WPAI:SHP questionnaire 
X 
X 
X 
X 
X 
 
PROMIS sleep questionnaires (24-hour 
recall) 
Diary is completed daily from screening through the last application of study drug in the 
vehicle-controlled period. 
PROMIS Short Form – Sleep-Related 
Impairment (8a) collected in the evening 
before sleeping. 
PROMIS Short Form – Sleep Disturbance 
(8b) collected in the morning after the 
participant wakes up. 
PROMIS sleep questionnaires (7-day 
recall) 
 
 
 
 
X 
PROMIS Short Form – Sleep-Related 
(8a) and Short Form – Sleep-Disturbance 
(8b) will be completed at Week 8 (this 
will be the baseline assessment for the 
7-day recall questionnaires, collected 
during the Week 8 study visit). 

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Table 3: 
Schedule of Activities:  Vehicle-Controlled Period (Continued) 
Visit Day (Range) 
Screening 
Vehicle-Controlled Treatment 
Notes 
Days 
-28 to -1 
Day 1 
(Baseline) 
Week 2 
(± 3 d) 
Week 4 
(± 3 d)  
Week 8*/EOT 
(± 3 d) 
*All assessments for the Week 8 visit 
must be performed before participants 
may enter the LTS period. 
Laboratory assessments 
Blood draw for clinical laboratory tests must be performed before the in-clinic study 
drug application. 
 
Serum chemistries 
X 
X 
X 
X 
X 
 
Hematology 
X 
X 
X 
X 
X 
 
Serology 
X* 
 
 
 
 
*HIV antibody. 
Pregnancy testing 
X* 
X 
X 
X 
X 
*Female participants of childbearing 
potential will have a serum test at screening 
and follow-up and a urine test at all other 
visits.  A positive urine test must be 
confirmed by a serum test. 
FSH level 
X 
 
 
 
 
For confirmation of nonchildbearing status 
of women who are postmenopausal defined 
as amenorrhea at least 12 months before 
screening. 
Urinalysis 
X 
 
 
 
 
 
PK plasma sampling (trough) 
 
 
X 
X 
X 
Time of last study drug application to be 
written in eCRF. 
Blood samples must not be drawn from the 
area that has been treated with study drug. 

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Table 4: 
Schedule of Activities:  Long-Term Safety Extension Period 
Visit Day (Range) 
LTS Extension Treatment 
Follow-Up 
Notes 
Week 12 
(±7 d) 
Weeks 16, 
20, and 24  
(±7 d) 
Weeks 28, 
32, and 36  
(±7 d) 
Weeks 40, 
44, and 48  
(±7 d) 
Week 52 
ET/EOT 
(±7 d) 
Unscheduled 
Visits 
30 (+7) days 
After Last Dose 
of Study Drug 
Administrative procedures 
Contact IRT 
X 
X 
X 
X 
X 
X 
X 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
Apply study drug 
X 
X 
X 
X 
X 
 
 
1st AM application under 
site supervision. 
Weigh/dispense or re-dispense study 
drug and distribute study drug diary 
and reminder card 
X 
X 
X 
X 
 
X 
 
Used tubes will be 
replenished and unused 
tubes may be re-dispensed 
Collect/weigh study drug and 
collect/review study drug diary 
X 
X 
X 
X 
X 
X 
 
 
Capture start and end date of a 
treatment cycle 
X 
X 
X 
X 
X 
X 
X 
The start/end-date will be 
captured by the participant.  
The end date of a treatment 
cycle will be +3 days after 
lesions clear. 
Refer to Study Manual. 
Safety assessments 
AE assessments and targeted physical 
examinations 
X 
X 
X 
X 
X 
X 
X 
Body systems with 
symptoms should be 
physically examined. 
Ad hoc photography of 
skin-related AEs should 
also occur as applicable. 
Comprehensive physical examination 
 
 
 
 
X 
 
 
 
Vital signs/body weight/height 
X 
X* 
X 
X 
X* 
X 
X 
*Height and weight at 
Weeks 24 and 52/EOT. 
Efficacy assessments 
Evaluate %BSA affected by active 
AD 
X 
X 
X 
X 
X 
X 
X 
Participants may only treat 
up to 20% BSA. 
IGA 
X 
X 
X 
X 
X 
X 
X 
 

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Table 4: 
Schedule of Activities:  Long-Term Safety Extension Period (Continued) 
Visit Day (Range) 
LTS Extension Treatment 
Follow-Up 
Notes 
Week 12 
(±7 d) 
Weeks 16, 
20, and 24  
(±7 d) 
Weeks 28, 
32, and 36  
(±7 d) 
Weeks 40, 
44, and 48  
(±7 d) 
Week 52 
ET/EOT 
(±7 d) 
Unscheduled 
Visits 
30 (+7) days 
After Last Dose 
of Study Drug 
Patient-reported outcome questionnaires – to be evaluated prior to any other study procedures/assessments; see Section 8.2.7  
DLQI/CDLQI 
X 
X* 
 
 
X 
X 
X 
*At Week 24 only. 
POEM 
X 
X* 
 
 
X 
X 
X 
*At Week 24 only. 
EQ-5D-5L questionnaire 
X 
X* 
X* 
 
X 
 
X 
*At Weeks 24 and 36 only  
WPAI:SHP questionnaire 
X 
X* 
X* 
 
X 
 
X 
*At Weeks 24 and 36 only. 
PROMIS sleep questionnaires (7-day 
recall) 
X 
X* 
 
 
X 
 
 
*At Week 24 only. 
PROMIS Short Form –   
Sleep-Related Impairment 
(8a). 
PROMIS Short Form – 
Sleep Disturbance (8b). 
Note:  Recall period 
changed from past 24 hours 
to past 7 days during LTS 
period. 
Laboratory assessments 
Blood draw for clinical laboratory tests must be performed before the in-clinic study drug application. 
 
Serum chemistries 
X 
X 
X 
X 
X 
X 
X 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy testing 
X 
X 
X 
X 
X 
X 
X* 
*Female participants of 
childbearing potential will 
have a serum test at 
screening and follow-up 
and a urine test at all other 
visits.  A positive urine test 
must be confirmed by a 
serum test. 
PK plasma sampling (trough) 
X 
X 
X 
X 
X 
X 
X 
Time of last study drug 
application to be written in 
eCRF. 
Blood samples must not be 
drawn from the area that 
has been treated with study 
drug. 

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2. 
INTRODUCTION 
Ruxolitinib cream is a topical formulation of ruxolitinib phosphate under development for the 
treatment of participants with AD, AA, vitiligo, and plaque psoriasis.  Ruxolitinib phosphate is 
an inhibitor of the JAK family of protein tyrosine kinases.  Isogenic and inflammatory cytokines 
are strongly implicated in the pathogenesis of psoriasis, AA, and AD.  Because JAKs serve to 
translate extracellular signals from a number of relevant cytokines and growth factors 
upregulated in inflammatory diseases such as psoriasis, AA, and AD, JAK inhibitors represent 
potential therapeutic agents for these disease states. 
2.1. 
Background 
2.1.1. 
Atopic Dermatitis 
Atopic dermatitis is a chronic, recurring, inflammatory, and itchy skin condition that affects 
worldwide up to 25% of children and up to 12% of adults (Eichenfield et al 2014, Hanifin 
et al 2007, Harrop et al 2007, Rönmark et al 2012, Vinding et al 2014).  Its incidence in the 
industrialized countries appears to be increasing, and it is associated with substantial cost 
($3.8 billion per year in direct medical costs alone; Ellis et al 2002).  Although AD is not 
life-threatening, patients with AD are at a higher risk for the development of other potentially 
life-threatening disorders such as asthma and/or food allergy (Spergel 2010).  This disease 
evolution leading to the possible development of other atopic conditions, including food allergy, 
asthma, and allergic rhinitis, is often termed as "atopic march." 
According to the recent Global Burden of Disease project, worldwide AD is one of the 50 most 
prevalent diseases, and it has the second highest disability ranking of all nonmalignant skin 
diseases (Hay et al 2014). 
2.1.2. 
Diagnosis of Atopic Dermatitis 
One of the earliest and most recognized sets of diagnostic criteria is the Hanifin and Rajka 
criteria, which requires that 3 of 4 criteria and 3 of 23 minor criteria be met (Purvis 2014). 
Essential features that are present in this disease are pruritus, eczema (acute, subacute, chronic), 
chronic or relapsing history, and typical morphology and age-specific patterns, including the 
following: 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. 
The clinical pattern of AD varies with age.  Infants usually show acute erythematous and often 
develop exudative papules on the face or scalp.  The childhood (age 2 years to puberty) and adult 
phases of AD tend to have less acute or exudative lesions but instead typically present with more 
lichenified and localized lesions (flexural folds, the face and neck, the upper arms and back, and 
the dorsa of the hands, feet, fingers, and toes) that represent a more chronic stage of the condition 
(Akdis et al 2006).  The unifying and cardinal feature of all presentations of AD is the 
pronounced and often unbearable itching. 

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2.2.2.2. 
Preclinical Safety 
In animal studies, ruxolitinib cream was not a contact sensitizer and did not produce significant 
dermal or ocular irritation, acute phototoxicity, or photoallergic potential.  Ruxolitinib cream (up 
to 1.5%) applied BID for up to 9 months in the Gottingen minipig was not associated with any 
adverse effects.  In a 2-year dermal carcinogenicity study in mice, ruxolitinib was not associated 
with any macroscopic, neoplastic, or nonneoplastic findings. 
The toxicity of ruxolitinib has been evaluated following oral administration to mice, rats, and 
dogs.  Findings in these studies were primarily those associated with the mechanism of action of 
ruxolitinib, including decreases in red blood cells, reticulocytes, eosinophils, and lymphocytes 
have been observed along with lymphoid depletion in bone marrow and lymphoid organs.  
Opportunistic infections considered secondary to immune suppression, were noted in dogs.  
Systemic exposures in these studies exceeded those anticipated with topical application.  
Ruxolitinib was not teratogenic when administered to pregnant rats or rabbits; there were no 
adverse developmental effects at doses below those associated with maternal toxicity.  
Ruxolitinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in 
in vitro chromosomal aberration assay (cultured human peripheral blood lymphocytes) or in vivo 
in a rat bone marrow micronucleus assay. 
In a toxicity study of orally administered ruxolitinib in juvenile rats beginning on Days 7, 14, or 
21 postpartum, dose-related effects on body weight gain and decrements in various bone 
measures were observed in all cohorts.  Hematology and other microscopic findings were similar 
to those previously observed in general toxicology studies.  Other than the bone findings, there 
were no other novel toxicities in juvenile animals.  In animals administered ruxolitinib beginning 
on Day 21 postpartum (considered approximately equivalent to a 2 year old human), bone 
findings occurred at exposures higher than those anticipated with topical application.  The 
clinical relevance of this study in humans is not clear. 
Please refer to the ruxolitinib cream IB for more details. 
2.2.2.3. 
Clinical Safety 
Ruxolitinib is a novel, potent, and selective inhibitor of the JAKs, specifically JAK1 and JAK2 
with modest to marked selectivity against TYK2 and JAK3.  Ruxolitinib potently (IC50 < 5 nM) 
inhibits JAKs, yet it does not significantly inhibit (< 30% inhibition) a broad panel of 26 kinases 
when tested at 200 nM (approximately 100 times the average IC50 value for JAK enzyme 
inhibition).  Ruxolitinib also potently inhibited the phosphorylation of STAT proteins and the 
production of proinflammatory factors induced by cytokines such as IL-23 and interferon γ. 
Topical application of ruxolitinib demonstrated excellent efficacy in an in vivo model of 
immune-based skin inflammation, the delayed-type hypersensitivity model in mice, including 
reduced ear swelling, reduced immune cell infiltrates, and normalization of tissue histology.  
Furthermore, ruxolitinib was also efficacious in the inflammatory phase of the dorsal 
delayed-type hypersensitivity model when applied in a clinically relevant cream formulation. 

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2.4. 
Benefit/Risk Assessment 
Ruxolitinib presents a low risk of cutaneous toxicity both in animals and clinical studies.  
Ruxolitinib cream tested positive in a photoclastogenicity assay; hence, there may be a risk of 
skin reaction to the combined exposure of ruxolitinib and sunlight.  Ruxolitinib cream did not act 
as a contact sensitizer nor did it produce significant dermal irritation or demonstrate 
phototoxicity or photoallergenic potential.  This lack of adverse cutaneous effects has been 
supported by clinical studies to date, where cutaneous AEs have been infrequent and of similar 
frequency and severity as with vehicle control treatment.  Participants should be cautioned to 
avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun 
lamps, etc). 
The primary clinical risks noted with orally administered ruxolitinib treatment for polycythemia 
vera or myelofibrosis are the potential sequelae of decreased hematopoietic proliferation 
secondary to the inhibition of growth factor pathways by JAK2 antagonism.  Dose-dependent, 
reversible thrombocytopenia has been observed in participants with myelofibrosis, as well as 
anemia and less frequently neutropenia.  An increased rate of infection is an additional potential 
risk of immunomodulation.  In healthy participants and rheumatoid arthritis participants with 
greater bone marrow reserve, the effects on hematopoietic proliferation appear to be less 
pronounced.  Ruxolitinib cream has 3% to 5% of the relative systemic availability of oral 
treatment, which was studied in participants with psoriasis.  Owing to its low systemic 
bioavailability, ruxolitinib cream is not expected to bring about clinically significant changes in 
hematology laboratory investigations. 
The results of the INCB 18424-206 dose range-finding study in adults with AD are provided and 
discussed in more detail in Section 2.2.2.4.1.  The efficacy outcomes for all treatment groups can 
be summarized as follows: 
• IGA response and EASI50/75/90 response rates showed all ruxolitinib cream 
treatment regimens to be efficacious and statistically superior to its vehicle. 
• Efficacy was time- and regimen-related, with 1.5% cream QD and 1.5% cream BID 
numerically greater than the other treatment groups, including the active control (TC 
0.1% cream BID). 
• All ruxolitinib cream strengths continued to demonstrate improvement through 
Week 8. 
• Prompt effect on itch was observed with all active treatment groups within 24 hours 
after study baseline. 
• The therapeutic response to 1.5% ruxolitinib cream BID plateaued after Week 8 (in 
IGA response and mean EASI change; note:  this was the only treatment applied 
continuously for 12 weeks). 
All active treatment groups were found to have no notable AEs and were well-tolerated on 
application sites.  They were also unremarkable for laboratory values, vital signs, or physical 
examinations.  

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While minor changes in select hematology parameters (red blood cells and platelet counts) were 
noted in the laboratory assessments (primarily on 1.5% cream BID regimen), they were mostly 
within the limits of normal range of values, transient (platelets), asymptomatic, and clinically 
insignificant and did not necessitate any remedial action.  
Based on the above information, ruxolitinib up to 1.5% cream BID can be safely used as a 
topical medication for AD and represents the treatment regimen with the best benefit-to-risk ratio 
from among those investigated. 
More detailed information can be found in the ruxolitinib cream IB. 

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3. 
OBJECTIVES AND ENDPOINTS 
Table 5 presents the objectives and endpoints. 
Table 5: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To establish the efficacy of ruxolitinib cream in participants 
with AD. 
• Proportion of participants achieving IGA-TS at Week 8. 
Key Secondary 
To further assess the treatment effects of ruxolitinib cream. 
• Proportion of participants who achieve EASI75 at Week 8. 
• Proportion of participants with a ≥ 4-point improvement in 
Itch NRS score from baseline to Week 8. 
• Proportion of participants with a clinically meaningful 
improvement in the PROMIS Short Form – Sleep 
Disturbance (8b – 24-hour recall) score at Week 8. 
Secondary 
To evaluate the safety and tolerability of ruxolitinib cream. 
The frequency, duration, and severity of AEs; performing 
physical examinations; collecting vital signs; and collecting 
laboratory data for hematology, serum chemistry, and 
urinalysis. 
To further evaluate efficacy of ruxolitinib cream. 
• Proportion of participants achieving an IGA-TS at Weeks 2 
and 4. 
• Proportion of participants achieving an IGA of 0 or 1 at each 
visit. 
• Proportion of participants with a ≥ 4-point improvement in 
Itch NRS score from baseline to Weeks 2 and 4. 
• Proportion of participants who achieve EASI50 at each visit 
during the VC period. 
• Proportion of participants who achieve EASI75 at Weeks 2 
and 4. 
• Proportion of participants who achieve EASI90 at each visit 
during the VC period. 
• Mean percentage change from baseline in EASI score at 
each visit during the VC period. 
• Mean percentage change from baseline in SCORAD score at 
each visit during the VC period. 
• Change from baseline in Itch NRS score at each visit during 
the VC period. 
• Time to achieve Itch NRS score improvement of at least 2, 
3, or 4 points. 
• Change from baseline in Skin Pain NRS score at each visit 
during the VC period. 
• Proportion of participants with a clinically meaningful 
improvement in the PROMIS Short Form – Sleep-Related 
Impairment (8a) 24-hour recall score at Weeks 2, 4, and 8. 
• Change from baseline in PROMIS Short Form – 
Sleep-Related Impairment (8a) 24-hour recall and Short 
Form – Sleep Disturbance (8b) 24-hour recall score at 
Weeks 2, 4, and 8. 
• PROMIS Short Form – Sleep-Related Impairment (8a) 7-day 
recall and Short Form – Sleep Disturbance (8b) 7-day recall 
score at Weeks 8, 12, 24, and 52. 
• Change from baseline in AD afflicted %BSA at every visit. 

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Table 5: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
To evaluate the participants' Quality of Life and other patient-
reported outcomes. 
• Change from baseline in POEM score at each visit. 
• Change from baseline in DLQI score at Weeks 2, 4, 8, 12, 
24, and 52 and at unscheduled visits. 
• Mean PGIC score at Weeks 2, 4, and 8. 
• Proportion of participants with each score on the PGIC at 
Weeks 2, 4, and 8. 
• Proportion of participants with a score of either 1 or 2 on the 
PGIC at Weeks 2, 4, and 8. 
• Change from baseline in EQ-5D-5L score during the VC 
period. 
• Change from baseline in WPAI-SHP v2.0 at Weeks 2, 4, 8, 
12, 24, 36, and 52. 
To evaluate the pharmacokinetics of ruxolitinib cream in 
plasma. 
Trough plasma concentrations of ruxolitinib at all study visits. 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a randomized, VC study in adolescent and adult (≥ 12 years old) participants with AD 
eligible for topical therapy.  Approximately 600 participants will be randomized 2:2:1 to 
ruxolitinib 0.75% cream BID, ruxolitinib 1.5% cream BID, or vehicle cream.  In addition, 
approximately 20% of the overall study population will consist of adolescents.  Participants with 
baseline IGA score of 2 will constitute up to approximately 25% of the overall study population.  
Participants with AD involvement of 3% to 20% BSA and IGA score of 2 to 3 will receive 
blinded study treatment for 8 weeks. 
For participants who have met all study inclusion criteria and none of the exclusion criteria, 
study drug assignment will be obtained.  Key entry criteria for participants to be eligible for the 
8-week VC treatment period is a diagnosis of AD (as defined by the Hanifin and Rajka criteria) 
with a duration of disease for at least 2 years, IGA score of 2 to 3, and a %BSA involvement of 
3% to 20% (excluding scalp) at screening and baseline. 
Participants who develop additional areas of AD may treat these additional areas with approval 
by the investigator as long as the total treated BSA does not exceed 20%, and there are no safety 
concerns regarding the additional application of study drug.  Approval to treat additional areas 
may occur via telephone during the VC period, although the investigator, at his/her discretion, 
may ask the participant to return for an unscheduled visit.  Through Week 8, participants should 
continue to treat areas identified for treatment at baseline even if the areas begin to improve. 
At Week 8, the study's primary endpoint, participants will be assessed for efficacy with a 
percentage of participants achieving a treatment response in IGA score.  Participants will also be 
assessed for safety and tolerability by monitoring the frequency, duration, and severity of AEs; 
performing physical examinations; and collecting vital signs and clinical/laboratory assessments 
at various timepoints during the study. 
Participants who complete Week 8 assessments with no additional safety concerns will be 
offered to continue into the LTS period with the same treatment regimen, except for those 
initially on vehicle, who will be equally assigned at Week 8 to 1 of the 2 active treatment groups.  
At that time, the IGA score required for the participants to enter the LTS period is 0 to 4.  With 
regard to %BSA, there is no required lower limit; participants may have BSA in the range of 0% 
to 20%. 
In the LTS period, participants will have study visits every 4 weeks until the end of the study 
(52 weeks total).  At those visits, AD lesions will be evaluated by the investigator to confirm if 
the participant still requires continuation of therapy (IGA ≥ 1) or can otherwise (re)enter the 
observation/no treatment cycle (IGA = 0). 

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During the LTS period (ie, after the Week 8 visit), participants will self-evaluate recurrence of 
AD and will treat areas of the skin with active AD changes (not to exceed 20% BSA).  If lesions 
clear between study visits, participants will stop treatment applications 3 days after they have 
disappeared.  Participants will restart treatment of their AD at the first sign of recurrence.  In the 
event that new lesions are outside of the usual location and/or are more wide spread than at 
baseline, the participant is required to contact the site for approval.  Approval to treat additional 
areas may occur via telephone during the LTS period, although the investigator, at his/her 
discretion, may ask the participant to return for an unscheduled visit.  This is a close reflection of 
the clinical practice of managing AD in the outpatient setting. 
4.2. 
Overall Study Duration 
Participants will be on study for a duration of up to 60 weeks (28 days screening, 8 weeks of 
treatment in the VC period, 44 weeks of treatment in the LTS period, and a 30 (+ 7)-day safety 
follow-up; see Figure 1). 
The study will begin when the first participant (or parent or guardian) signs the ICF (and if 
needed, an assent form).  The end of the study is defined as the date of the last visit of the last 
participant in the study or discontinued study drug and have completed applicable follow-up 
assessments. 
A participant is considered to have completed the study if he/she has completed all study visits, 
including the follow-up visit. 
The investigator will be expected to monitor for and report any SAEs and pregnancies, as 
detailed in Section 9.  The remaining participants are considered to be on study until a 
discontinuation criterion is met and written notification is provided to the sponsor. 
4.3. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator is to notify the IRB/IEC in writing of the 
study's completion or early termination, send a copy of the notification to the sponsor or 
sponsor's designee, and retain 1 copy for the site study regulatory file. 
The sponsor may terminate the study electively, or if required by regulatory agency.  In the event 
of significant safety findings, the study will be terminated.  If the study is terminated 
prematurely, the sponsor will notify the investigators, the IRBs and IECs, and regulatory bodies 
of the decision and reason for termination of the study. 

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5. 
STUDY POPULATION 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or participant safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential.  Prospective approval of 
Protocol deviations to recruitment and enrollment criteria, also known as Protocol waivers or 
exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Adolescents aged ≥ 12 to 17 years, inclusive, and men and women aged ≥ 18 years. 
2. Participants diagnosed with AD as defined by the Hanifin and Rajka (1980) criteria. 
3. AD duration of at least 2 years. 
4. Participants with an IGA score: 
a. VC period:  2 to 3 at screening and baseline  
b. LTS period:  0 to 4 at Week 8 
5. Participants with %BSA (excluding scalp) of AD involvement: 
a. VC period:  3% to 20% at screening and baseline 
b. LTS period:  0% to 20% at Week 8 
6. Participants who agree to discontinue all agents used to treat AD from screening through 
the final follow-up visit. 
7. Participants who have at least 1 "target lesion" that measures approximately 10 cm2 or 
more at screening and baseline.  Lesion must be representative of the participant's disease 
state and not be located on the hands, feet, or genitalia. 
8. Willingness to avoid pregnancy or fathering of children based on the criteria below: 
a. Woman of nonchildbearing potential (surgically sterile with a hysterectomy and/or 
bilateral oophorectomy OR postmenopausal, defined by last menstrual period 
≥ 12 months of amenorrhea before screening confirmed by FSH levels at screening) 
and at least 50 years of age) are exempt from pregnancy testing. 
b. Woman of childbearing potential who has a negative serum pregnancy test at 
screening and a negative urine pregnancy test before the first dose on Day 1 and who 
agrees to take appropriate precautions to avoid pregnancy (with at least 99% 
certainty) from screening through safety follow-up (30 [+ 7] days after EOT) 
(see Appendix A).  Permitted methods that are at least 99% effective in preventing 
pregnancy should be communicated to the participant and their understanding 
confirmed. 
c. Adolescents who are prepubescent. 

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d. Man who agrees to take appropriate precautions to avoid fathering children (with at 
least 99% certainty) or from sperm donation from screening through 90 days after 
treatment with ruxolitinib cream.  Permitted methods that are at least 99% effective in 
preventing pregnancy (see Appendix A) should be communicated to the participant 
and their understanding confirmed. 
9. Ability to comprehend and willingness to sign an ICF or written informed consent of the 
parent(s) or legal guardian and written assent from the participant when possible. 
Note:  Adolescent participants who become legal adults during the study will be asked for 
their signed consent to continue the study, and in the event of lack thereof, will be 
discontinued from further participation. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Participants who have an unstable course of AD (spontaneously improving or rapidly 
deteriorating) as determined by the investigator in the 4 weeks prior to baseline. 
2. Participants with concurrent conditions and history of other diseases: 
a. Immunocompromised (eg, lymphoma, acquired immunodeficiency syndrome, 
Wiskott-Aldrich syndrome). 
b. Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, 
antiparasitics, antiprotozoals, or antifungals within 2 weeks before baseline. 
c. Active acute bacterial, fungal, or viral skin infection (eg, herpes simplex, herpes 
zoster, chicken pox) within 1 week before baseline. 
d. Any other concomitant skin disorder (eg, generalized erythroderma such as Netherton 
syndrome), pigmentation, or extensive scarring that, in the opinion of the investigator, 
may interfere with the evaluation of AD lesions or compromise participant safety. 
e. Presence of AD lesions only on the hands or feet without prior history of involvement 
of other classical areas of involvement such as the face or the folds. 
f. Other types of eczema. 
3. Any serious illness or medical, physical, or psychiatric condition(s) that, in the 
investigator's opinion, would interfere with full participation in the study, including 
administration of study drug and attending required study visits; pose a significant risk to 
the participant; or interfere with interpretation of study data.  For example: 
a. Clinically significant or uncontrolled cardiac disease, including unstable angina, acute 
myocardial infarction within 6 months from Day 1 of study drug administration, New 
York Heart Association Class III or IV congestive heart failure, and arrhythmia 
requiring therapy or uncontrolled hypertension (blood pressure > 150/90 mmHg) 
unless approved by medical monitor/sponsor. 
b. Participants with a history of malignancy in the 5 years preceding enrollment into this 
study, except for adequately treated, nonmetastatic malignancies. 
c. Low hemoglobin (< 10 g/dL). 

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d. Severe renal disease on dialysis (serum creatinine > 2 mg/dL). 
e. Current and/or liver disease history, including known hepatitis B or C, with hepatic or 
biliary abnormalities. 
4. Participants using any of the following treatments within the indicated washout period 
before baseline: 
a. 5 half-lives or 12 weeks, whichever is longer – biologic agents (eg, dupilumab). 
b. 4 weeks – systemic corticosteroids or adrenocorticotropic hormone analogs, 
cyclosporin, methotrexate, azathioprine, or other systemic immunosuppressive or 
immunomodulating agents (eg, mycophenolate or tacrolimus). 
c. 2 weeks – immunizations and sedating antihistamines, unless on long-term stable 
regimen (nonsedating antihistamines are permitted). 
d. 1 week – use of other topical treatments for AD (other than bland emollients), such as 
corticosteroids, calcineurin inhibitors, coal tar (shampoo), antibiotics, antibacterial 
cleansing body wash/soap.  Diluted sodium hypochlorite "bleach" baths are allowed 
as long as they do not exceed 2 baths per week and their frequency remains the same 
throughout the study. 
5. Participants who have previously received JAK inhibitors, systemic or topical. 
6. Ultraviolet light therapy or prolonged exposure to natural or artificial sources of UV 
radiation (eg, sunlight or tanning booth) within 2 weeks prior to baseline and/or intention 
to have such exposure during the study, which is thought by the investigator to 
potentially impact the participant's AD. 
7. Positive serology test results at screening for HIV antibody. 
8. Liver function tests:  AST or ALT ≥ 2 × ULN; alkaline phosphatase and/or bilirubin 
> 1.5 × ULN (isolated bilirubin > 1.5 × ULN is acceptable if bilirubin is fractionated and 
direct bilirubin < 35%). 
9. Pregnant or lactating participants, or those considering pregnancy. 
10. History of alcoholism or drug addiction within 1 year before screening or current alcohol 
or drug use that, in the opinion of the investigator, will interfere with the participant's 
ability to comply with the administration schedule and study assessments. 
11. Current treatment or treatment within 30 days or 5 half-lives (whichever is longer) before 
baseline with another investigational medication or current enrollment in another 
investigational drug protocol. 
12. Participants who, in the opinion of the investigator, are unable or unlikely to comply with 
the administration schedule and study evaluations. 
13. Participants who are committed to a mental health institution by virtue of an order issued 
either by the judicial or the administrative authorities. 
14. Employees of the sponsor or investigator or are otherwise dependents of them. 

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5.3. 
Lifestyle Considerations 
Prolonged exposure to natural or artificial sources of ultraviolet radiation (including sun lamps, 
tanning booths, etc) is prohibited from 2 weeks prior to baseline through the last study visit.  
When outdoors, participants will be advised to wear loose-fitting clothing that protects the 
treated area from the sun. 
If sunscreen, makeup, or other cosmetics has been applied to the areas to be treated, participants 
should wash the treatment areas with mild soap and water and pat dry before application of study 
drug. 
Use of swimming pools during the VC period of the study is not recommended.  If unavoidable, 
it is recommended that swimming should not take place within 2 hours before and after the 
planned study drug application. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. 
Tests with results that fail eligibility requirements may be repeated once during screening if the 
investigator believes the result to be in error.  Additionally, a participant who fails screening may 
repeat the screening process 1 time if the investigator believes that there has been a change in 
eligibility status.  Participants who rescreen must be assigned a new screening number. 
5.5. 
Replacement of Participants 
Participants will not be replaced during the study. 

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6. 
STUDY TREATMENT 
6.1. 
Study Treatment Administered 
In this study, ruxolitinib cream or matching vehicle will be applied as a thin film BID, with 
applications at least 8 hours apart in the morning and in the evening at least 1 hour before 
bedtime.  The strengths for ruxolitinib cream are 0.75% and 1.5% in a cream formulation and the 
matching vehicle cream formulation that does not contain active drug. 
On the first clinic visit day and subsequent study visits, the participant or guardian applies a thin 
film of study drug by applying small amounts of study drug until all the affected areas to be 
treated are covered.  The amount of study drug used per application will be determined by 
weighing a tube before and after the participant or guardian applies study drug to the affected 
areas. 
On subsequent study visit days, participants should not apply the study drug at home (morning 
application).  The first application of the day will be done at the clinic. 
In general, the amount of study drug used per day (BID application) should not exceed 
one-fourth (1/4) of the 60 g tube per day.  One 60 g tube should be sufficient for approximately 
4 days of applications for those participants who have approximately 20% BSA of lesions on 
their body. 
At the baseline visit, an estimate of the %BSA to be treated will be used by the IRT system to 
calculate the number of tubes of study drug to be dispensed.  All areas identified at baseline 
should continue to be treated through the end of the VC period (Week 8) unless the participant 
meets criteria for stopping study drug.  If there are new areas to be treated, including expansion 
of existing areas or development of new areas, after consultation with the investigator, study 
drug should be applied to these areas in addition to the areas treated at baseline (up to 20% 
BSA), and the percentage of BSA to be treated will be recalculated and increased.  This new 
estimate will be entered into the IRT system to calculate the number of tubes of study drug to be 
dispensed. 
During the LTS period starting at the Week 8 visit, participants will have study visits every 
4 weeks until the end of the study (52 weeks total).  At those visits, AD lesions will be evaluated 
by the investigator to confirm whether the participant still requires continuation of therapy 
(IGA ≥ 1) or can otherwise (re)enter the observation/no treatment cycle (IGA = 0).  At Week 8, a 
participant will receive a prespecified number of tubes with study medication corresponding to a 
lower %BSA affected (up to 5%) or higher number of tubes corresponding to their affected 
%BSA (> 5%).  This new estimate will be entered into the IRT system to calculate the number of 
tubes of study drug to be dispensed.   
In-between study visits, the participant will self-evaluate recurrence of AD and will treat all 
areas identified with active AD changes (not to exceed 20% BSA).  If lesions clear between 
study visits, participants will stop treatment applications 3 days after they have disappeared.  
Participants will restart treatment of their AD at the first sign of recurrence.  In the event that 
new lesions are outside of the usual location and/or are more widespread than at baseline, the 
participant is required to contact the site for approval.  Approval to treat additional areas may 

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occur via telephone during the LTS period, although the investigator, at his/her discretion, may 
ask the participant to return for an unscheduled visit. 
Application instructions will be provided by the site study staff, and the participant will record 
their daily applications via a diary card given to the participants during each study visit.  Refer to 
the Study Pharmacy Manual for participant instructions for handling study of drug.  Table 6 
presents the study treatment information. 
Table 6: 
Study Treatment Information 
 
Study Treatment 1 
Study Treatment 2 
Study Treatment 3 
Study treatment name: 
Ruxolitinib 
Ruxolitinib 
Vehicle 
Dosage formulation: 
Cream 
Cream 
Cream 
Unit dose strength(s)/dosage 
level(s): 
0.75% 
1.5% 
Not applicable 
Administration instructions: 
Topical: 
BID (morning and 
evening applications). 
A thin film is applied to 
the affected areas in the 
morning and in the 
evening at least 1 hour 
before bedtime. 
Topical: 
BID (morning and 
evening applications). 
A thin film is applied to 
the affected areas in the 
morning and in the 
evening at least 1 hour 
before bedtime. 
Topical: 
VC period:  BID (morning 
and evening application). 
A thin film is applied to 
the affected areas in the 
morning and in the 
evening at least 1 hour 
before bedtime. 
LTS period:  Not 
applicable   
Packaging and labeling: 
Study treatment 1 will be 
provided in 60 g tube. 
Each tube will be labeled 
as required per country 
requirement. 
Study treatment 2 will be 
provided in 60 g tube. 
Each tube will be labeled 
as required per country 
requirement. 
Vehicle will be provided 
in 60 g tube. 
Each tube will be labeled 
as required per country 
requirement. 
Storage: 
15°C-30°C (59°F-86°F) 
15°C-30°C (59°F-86°F) 
15°C-30°C (59°F-86°F) 
Status of treatment in 
participating countries: 
Investigational 
Investigational  
Not applicable 
6.2. 
Preparation, Handling, and Accountability 
The investigator or designee must confirm appropriate temperature conditions (both ruxolitinib 
cream and vehicle cream are to be stored between 15°C and 30°C [59°F-86°F]) have been 
maintained during transit for all study treatments received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment, and only authorized site 
staff may supply study treatment.  Immediately after application of ruxolitinib cream, 
participants are to wash hands thoroughly with soap and warm water.  Refer to the Study 
Pharmacy Manual for participant instructions for handling of study drug. 
All study treatment must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff.  Participants should store study treatment at ambient 
temperature conditions. 

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The investigator (or designee) is responsible for study treatment accountability, reconciliation, 
and record maintenance (ie, receipt, reconciliation, and final disposition records).  Inventory and 
accountability records must be maintained and readily available for inspection by the study 
monitor and are open to inspection at any time by any applicable regulatory authorities.  The 
investigator or designee must maintain records that document: 
• Delivery of study drug(s) to the study site. 
• Inventory of study drug(s) at the site. 
• Participant use of the study drug(s) including tube counts from each supply 
dispensed. 
• Return of study drug(s) to the investigator or designee by participants.  
The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the participants were provided the 
specified study drug.  These records should include dates, quantities, and any available batch or 
serial numbers or unique code numbers assigned to the investigational product and study 
participants. 
Completed accountability records will be archived by the site.  The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of study drug 
until verified by the study monitor (unless otherwise agreed to by the sponsor).  At the 
conclusion of the study, the investigator or designee will oversee shipment of any remaining 
study drug back to the sponsor or its designee for destruction according to institutional standard 
operating procedures.  If local procedures mandate on-site destruction of investigational supply, 
the site should (where local procedures allow) maintain the investigational supply until the study 
monitor inspects the accountability records in order to evaluate compliance and accuracy of 
accountability by the investigative site.  At sites where the study drug is destroyed before 
monitor inspection, the monitors rely on documentation of destruction per the site SOP. 
Further guidance and information for the final disposition of unused study treatments are 
provided in the study materials provided to sites. 
6.3. 
Measures to Minimize Bias:  Randomization and Blinding 
All participants will be centrally assigned to study treatment using an IRT system.  The system 
will assign in a 2:2:1 ratio, stratified by baseline IGA (2, 3) and region (North America or other), 
the participant study number, track participant visits, randomize according to the defined 
parameters, maintain the blinding, and manage study drug inventory.  Full details will be 
provided in the IRT Manual.  Study treatment will be dispensed at the study visits summarized in 
the SoAs (see Table 3 and Table 4). 
6.4. 
Study Treatment Compliance 
Compliance with all study-related treatments must be emphasized to the participant by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study.  
Compliance with ruxolitinib cream will be evaluated by participants' adherence to the application 
regimen and drug accountability documented by the site staff and monitored by the 
sponsor/designee (tube counts). 

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In general, the application compliance will be determined by the number of actual versus 
anticipated number of applications, which should be within 80% to 120% of the prescribed 
number of applications during the VC period, unless otherwise discussed/approved by the 
sponsor.  Participants will be instructed to bring all study drugs with them to the study visits in 
order for site personnel to conduct tube counts to assess study drug accountability.  The drug 
accountability documentation will be used by the sponsor to calculate treatment compliance. 
6.5. 
Modifications to Treatment Regimen 
Through Week 8, participants should continue to treat areas identified for treatment at baseline 
even if the area begins to improve.  Participants who develop new AD lesions during the course 
of the study may treat these additional areas, with approval by the investigator, as long as the 
total treated BSA does not exceed 20% and there are no safety concerns.  Approval to treat 
additional areas may occur via telephone during the VC period, although the investigator may 
request to have the participant come in to have an unscheduled visit, if needed. 
After Week 8, for participants enrolled in the LTS period, only areas with active disease should 
be treated.  Once the lesions are cleared, participants should continue to apply study drug for an 
additional 3 days on the areas of the body where lesions were last present before discontinuing 
the treatment.  In the event that the new lesions are significantly more extensive than from the 
previous visit, the participant should call the study site to discuss with the investigator whether 
additional evaluation at the clinic is required. 
6.5.1. 
Criteria and Procedures for Application Interruptions of Study Drug 
Safety concerns should be discussed with the sponsor immediately upon occurrence or awareness 
to determine whether the participant should continue or discontinue study treatment. 
In some circumstances, it may be necessary to temporarily interrupt treatment with ruxolitinib 
cream.  Except in cases of emergency, it is recommended that any findings of concern (eg, AE) 
be confirmed and that the investigator consult with the sponsor medical monitor (or other 
representative of the sponsor) before interrupting study drug.  Additionally, the investigator must 
obtain approval from the sponsor before restarting study drug.  Participants who experience a 
recurrence of the initial AEs upon restarting the study drug may need the study drug to be 
permanently discontinued. 
Instructions for application interruptions for ruxolitinib cream are outlined in Table 7.  Individual 
decisions regarding interruptions should be made using clinical judgment in consultation with the 
medical monitor (whenever possible), taking into account relatedness of the AE to the study 
treatment and the participant's underlying condition. 

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Table 7: 
Guidelines for Interruption and Restarting of Study Drug 
ADVERSE EVENT
a 
ACTION TAKEN 
Chemistry 
ALT (> 3 × ULN) or AST (> 3 × ULN) 
• Laboratory abnormalities should be confirmed with repeat 
testing within 48 hours whenever possible and immediate 
delivery of the laboratory results requested. 
• Study drug applications must be interrupted.   
• At the discretion of the investigator, after consultation 
with the sponsor, study drug application may be restored 
once these have resolved. 
Hematology 
Grade 2 decrease in ANC (< 1.5 × 109/L) 
• Laboratory abnormalities should be confirmed with 
repeat testing within 48 hours whenever possible and 
immediate delivery of the laboratory results requested. 
• Study drug applications must be interrupted.  At the 
discretion of the investigator, after consultation with the 
sponsor, study drug application may be restored once 
these have resolved. 
Any other Grade 3 or higher laboratory abnormality 
(eg, hemoglobin with the exception of asymptomatic 
elevations in triglyceride, cholesterol, or amylase) 
• Laboratory abnormalities should be confirmed with 
repeat testing within 48 hours whenever possible and 
immediate delivery of the laboratory results requested. 
• Study drug applications must be interrupted.  At the 
discretion of the investigator, after consultation with the 
sponsor, study drug application may be restored once 
these have resolved. 
Any Grade 4 laboratory abnormality or AST or ALT 
(> 5 × ULN) 
• Laboratory abnormalities should be confirmed with 
repeat testing within 48 hours whenever possible and 
immediate delivery of the laboratory results requested. 
• Discontinue study drug if lab abnormalities are 
confirmed. 
a In the opinion of the investigator related to study drug. 
6.5.2. 
Criteria for Permanent Discontinuation of Study Drug Due to an Adverse Event 
The occurrence of unacceptable severity of an AE not caused by the underlying disease will be 
presumed to be related to study drug treatment and will require that the study drug be 
permanently discontinued.  Unacceptable severity is defined as follows: 
• Occurrence of an AE that is related to treatment with the study drug that, in the 
judgment of the investigator or the sponsor's medical monitor, compromised the 
participant's ability to continue study-specific procedures, or is considered to not be in 
the participant's best interest.  
• Participant presents with a worsening of AD that requires treatment with a prohibited 
concomitant medication. 
• Persistent AE requiring a delay of therapy for more than 2 weeks without resolution 
of the AE. 
See Section 7 for discontinuation procedures. 

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6.6. 
Concomitant Medications and Procedures 
All concomitant medications and treatments (including over-the-counter or prescription 
medicines, vitamins, vaccines, and/or herbal supplements) must be recorded in the eCRF.  Any 
prior medication received up to 28 days before the first dose of study treatment and within 
30 days after the last dose of study treatment will be recorded in the eCRF. 
Any addition, deletion, or change in the dose of these medications will also be recorded.  
Concomitant medications administered after 30 days after the last dose of study treatment should 
be recorded for SAEs as defined in Section 9.3.  Concomitant treatments/procedures that are 
required to manage a participant's medical condition during the study will also be recorded in the 
eCRF.  The medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.6.1. 
Permitted Medications and Procedures 
The following are permitted during the study: 
• Participants may use bland emollients such as Eucerin® cream. 
Note:  Emollients should not be used within the following periods from the 
application of study drug:  4 hours before and 2 hours after application. 
• Bathing during the study should be limited to once daily for no longer than 
15 minutes.  During baths, tepid (not hot) water and mild cleansing agents (eg, Basis® 
bar or Dove®) should be used.  (See Section 5.3 for swimming guidance.)  Showers 
should be limited in time with warm water and mild cleansing agents used.  
• If sunscreen is needed, a mineral-based sunscreen (such as zinc oxide– or titanium 
oxide–based) with SPF of at least 30 may be used not less than 4 hours before and at 
least 2 hours after study drug application. 
• Participants may use nonsedating, over-the-counter antihistamines. 
6.6.2. 
Restricted Medications and Procedures 
The following are permitted during the study under specified conditions: 
• Use of any over-the-counter, nonprescription preparations (including vitamins, 
minerals, and phytotherapeutic, herbal, or plant derived preparations) within 7 days 
before the baseline visit through the follow-up visit, unless deemed acceptable by the 
investigator. 
• Use of any prescription medication (including immunizations, phytotherapeutic, 
herbal, or plant-derived preparations) within 7 days before the baseline visit through 
the follow-up visit, unless deemed acceptable by the investigator. 
• Bleach baths are allowed as long as they do not exceed 2 baths per week and their 
frequency remains the same throughout the study. 
• Participants should not take baths or showers within 2 hours after study drug 
application. 
• Topical anti-infectives or other topical treatments applied to active AD lesions should 
not be used for at least 4 hours before and 2 hours after application of study drug. 

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6.6.3. 
Prohibited Medications and Procedures 
The following are not permitted during the study:  
• Any investigational medication other than the study drug. 
• Topical corticosteroids, tacrolimus, pimecrolimus, and PDE4-inhibitors (Eucrisa®). 
• Other topical agents for AD (except bland emollients as noted in Section 6.6.1). 
• Treatment known to affect the course of AD. 
• Systemic corticosteroids, methotrexate, cyclosporine A, azathioprine and biological 
therapies, or other immunosuppressant agents. 
• Allergen immunotherapy 
• Phototherapy or tanning beds. 
• Live or live-attenuated vaccination. 
6.7. 
Treatment After the End of the Study 
 There will be no treatment provided after the end of the study. 

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7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
7.1.1. 
Reasons for Discontinuation 
Participants must be discontinued from study treatment for the following reasons: 
• Due to lack of efficacy response during the LTS (defined as no change/improvement 
in either %BSA or IGA when treated continuously for 8 weeks).   
• The participant becomes pregnant. 
• Consent is withdrawn.   
Note:  Consent withdrawn means that the participant has explicitly indicated that they 
do not want to be followed any longer; in this case no further data, except data in 
public domain, may be solicited from or collected on the participant.  Participants 
may choose to discontinue study treatment and remain in the study to be followed for 
progression and survival. 
• Further participation would be injurious to the participant's health or well-being, in 
the investigator's medical judgment. 
• Any adverse event of unacceptable severity as noted in Section 6.5.2. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
A participant may be discontinued from study treatment as follows: 
• If, at 2 consecutive study visits, a participant's drug usage exceeds one 60 g tube per 
4 days.  The medical monitor should be consulted for instruction on handling the 
participant. 
• If, during the course of the study, a participant is found not to have met eligibility 
criteria, the medical monitor, in collaboration with the investigator, will determine 
whether the participant should be withdrawn from study treatment. 
• If a participant is noncompliant with study procedures or study drug/treatment 
administration in the investigator's opinion, the medical monitor should be consulted 
for instruction on handling the participant. 
7.1.2. 
Discontinuation Procedures 
In the event that the decision is made to permanently discontinue the study treatment, the EOT 
visit should be conducted.  Reasonable efforts should be made to have the participant return for a 
follow-up visit.  The last date of the last dose of study drug(s)/treatment and the reason for 
discontinuation of study treatment will be recorded in the eCRF. 

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If a participant is discontinued from study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal must be documented in the participant's medical record 
and the primary reason for withdrawal must be included in the eCRF. 
• The EOT visit should be performed. 
• The date of the EOT visit should be recorded in the eCRF. 
• Participants must be followed for safety until the time of the follow-up visit or until 
study drug/treatment–related AEs resolve, return to baseline, or are deemed 
irreversible, whichever is longest. 
If the participant discontinues study treatment and actively withdraws consent for collection of 
follow-up data (safety follow-up), then no additional data collection should occur; however, 
participants will have the option of withdrawing consent for study treatment but continuing in the 
follow-up period of the study for safety assessments.   
7.2. 
Participant Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.  If a participant 
withdraws from the study, he/she may request destruction of any samples taken and not tested, 
and the investigator must document this in the site study records. 
Data to be collected at the time of study discontinuation and follow-up and for any further 
evaluations should conform to the requirements of the ET/EOT visit (see Table 3 and Table 4). 
7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  The following actions must be 
taken if a participant fails to return to the clinic for a required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make reasonable effort to regain contact with the participant (where possible, 
3 telephone calls and, if unsuccessful, a certified letter to the participant's last known 
mailing address or local equivalent methods).  These contact attempts should be 
documented in the participant's medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Administrative and General Procedures 
8.1.1. 
Informed Consent Form Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. 
− Informed consent/assent must be obtained from the participant and/or parent or 
guardian before any study-related procedures are conducted, unless otherwise 
specified by the Protocol. 
Note:  Adolescent participants who become legal adults during the study will be 
asked for their signed consent to continue the study, and in the event of lack 
thereof, will be discontinued from further participation. 
− Informed consent/assent must be obtained using the IRB/IEC-approved version in 
a language that is native and understandable to the participant.  A template will be 
provided by the sponsor or its designee.  The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF/assent template.  The 
ICF/assent must include a statement that the sponsor or its designee and 
regulatory authorities have direct access to participant records. 
− The ICF/assent must contain all required elements and describe the nature, scope, 
and possible consequences of the study in a form understandable to the study 
participant. 
• Participants must be informed that their participation is voluntary.  Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent/assent that meets the applicable requirements and regulations for the 
countries in which the study is being conducted as well as the IRB/IEC or study 
center. 
• The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection laws.  The level of disclosure 
must also be explained to the participant. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
• The medical record must include a statement that written informed consent/assent 
was obtained before the participant was enrolled in the study and the date the written 
consent was obtained.  The authorized person obtaining the informed consent must 
also sign the ICF/assent. 

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• Participants must provide consent to the most current version of the ICF(s)/assent(s) 
during their participation in the study. 
• A copy of the signed ICF(s)/assent(s) must be provided to the participant or the 
participant's legally authorized representative. 
• Participants who are rescreened are required to sign a new ICF/assent and must be 
assigned a new participant number. 
8.1.2. 
Screening Procedures 
Screening is the interval between signing the ICF/assent and the day the participant is enrolled in 
the study (Day 1).  Informed consent (or assent) must be obtained before performing any 
study-specific procedures.  Screening may not exceed 28 days.  Assessments that are required to 
demonstrate eligibility may be performed over the course of 1 or more days during the screening 
process. 
Procedures conducted as part of the participant's routine clinical management by their healthcare 
provider (eg, blood count) and obtained before signing of informed consent/assent may be used 
for screening or baseline purposes provided the procedure meets the Protocol-defined criteria and 
has been performed in the timeframe of the study (ie, within 28 days of Day 1).  For participants 
who are enrolled in the study, information associated with eligibility requirements must be 
entered into the appropriate eCRF pages. 
Results from the screening visit evaluations will be reviewed to confirm eligibility before 
enrollment or the administration of study drug.  Tests with results that fail eligibility 
requirements may be repeated once during screening if the investigator believes the results to be 
in error.  For screening assessments that are repeated, the most recent available result before 
randomization/treatment assignment will be used to determine eligibility. 
See Section 5.4 for information regarding screen failures and the rescreening procedure for 
participants. 
8.1.3. 
Interactive Response Technology Procedure 
Each participant will be identified in the study by a participant ID number, which is a 
combination of the site ID and participant number.  Site staff should contact the IRT system to 
obtain the participant ID number during screening.  Upon determining that the participant is 
eligible for study entry, the IRT system will be contacted to obtain the study medication kit 
assignment.  Additionally, the IRT system will be contacted at each regular study visit during 
both the VC period and the LTS period to update the study drug supply.  Additional details are 
provided in the IRT Manual. 

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8.1.4. 
Distribution of Study Reminder Cards and Diaries 
Starting at the Day 1 visit and each visit thereafter, a study drug–specific diary will be given to 
each participant in order to record use of the study drug.  The completed diary will be collected 
during each of the participant's visits.   
Qualified clinical site staff will review the participants' entries for compliance.  Participants who 
are noncompliant with their study drug schedule (defined as < 80% or > 120% of the expected 
number of applications between study visits) will have their administration instructions 
reinforced by the investigator or a qualified designee.  Participants will be considered compliant 
with the treatment regimen if they apply at least 80% but no more than 120% of the expected 
applications during participation in the treatment period of the study. 
Participants will be provided with a reminder card starting on Day 1 and at all VC visits.  The 
reminder card will indicate the date/time of the next visit and will also remind the participant that 
they should have their 1st morning application at the clinic under site supervision after their 
blood draws for PK and safety evaluations have been completed. 
8.1.5. 
Demography and Medical History 
8.1.5.1. 
Demographics and General Medical History 
Demographic data and general medical history will be collected at screening by the investigator 
or qualified designee and will include year of birth/age, race, ethnicity, medical and surgical 
history, and current illnesses.  Medical history will include relevant medical or surgical treatment 
within the last 2 years that are considered to be clinically significant by the investigator. 
8.1.5.2. 
Medical and Treatment History 
Relevant medical and treatment history for the past year will be collected at screening by the 
investigator or qualified designee.  Details regarding the participant's history of AD, including 
date of diagnosis, relevant disease characteristics, and prior treatments, including systemic 
treatments, radiation, and surgical procedures, will be recorded.  A medical history of other 
conditions related to AD will also be collected at this time. 

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8.2. 
Efficacy Assessments 
8.2.1. 
Investigator's Global Assessment 
The IGA is an overall eczema severity rating on a 0 to 4 scale that will be assessed during site 
visits.  The grades for the IGA are shown in Table 8. 
Table 8: 
Investigator's Global Assessment 
Grade 
Severity 
Status 
0 
Clear 
No erythema or induration/papulation, no oozing/crusting; there may be minor 
residual discoloration. 
1 
Almost 
clear 
There may be trace faint pink erythema, with almost no induration/papulation, and 
no oozing/crusting. 
2 
Mild 
There may be faint pink erythema, with mild induration/papulation and no 
oozing/crusting. 
3 
Moderate 
There may be pink-red erythema with moderate induration/papulation and there 
may be some oozing/crusting. 
4 
Severe 
There may be deep or bright red erythema with severe induration/papulation and 
with oozing/crusting. 
Source:  www.homeforeczema.org. 
The IGA-TS is defined as an IGA score of 0 or 1 with ≥ 2 grade improvement from baseline. 
8.2.2. 
Eczema Area and Severity Index Score 
Atopic dermatitis will be assessed as outlined in the SoA (see Table 3) using EASI scoring 
system (refer to Study Manual), which is a validated disease measurement for clinical studies 
(Hanifin et al 2001) that examines 4 areas of the body and weights them for participants of at 
least 8 years of age.  Each of the 4 body regions is assessed separately for erythema (E), 
induration/papulation/edema (I), excoriations (Ex), and lichenification (l) for an average degree 
of severity of each sign in each region. 
The severity strata for the EASI are as follows:  0 = clear; 0.1 to 1.0 = almost clear; 1.1 to 
7.0 = mild; 7.1 to 21.0 = moderate; 21.1 to 50.0 = severe; 50.1 to 72.0 = very severe 
(Leshem et al 2015). 

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8.2.5. 
Body Surface Area 
Total %BSA afflicted by AD will be estimated at each visit in the VC period as outlined in the 
SoAs (see Table 3 and Table 4).  Body surface area assessment will be approximated to the 
nearest 0.1% using the Palmar Method as guides, the palm plus 5 digits, with fingers tucked 
together and thumb tucked to the side (handprint), as 1% BSA and the thumb as 0.1% BSA. 
8.2.6. 
Photography 
At selected sites, for each visit with photography (baseline and Weeks 2, 4, and 8), photography 
of the target lesion will be conducted via 2 views (close-up and regional body area).  Ad hoc 
photography of skin-related AEs is recommended at selected sites to provide additional 
photographic documentation. 
8.2.7. 
Patient-Reported Outcomes 
Quality of life (QoL) will be assessed (see SoAs Table 3 and Table 4) using the following tools:  
DQLI, PGIC, POEM, EQ-5D-5L, WPAI:SHP, Itch NRS, Skin Pain NRS, PROMIS Short 
Form – Sleep-Related Impairment (8a), and PROMIS Short Form – Sleep Disturbance (8b). 
In order to avoid bias in the participants' responses to the questionnaires, all these assessments 
should be completed before any other evaluations or study procedures on the day of the study 
visit and prior to discussions with the investigator or study site staff. 
At the baseline visit, all patient-reported outcomes must be completed before the participant's 
first study drug application. 
Participants will be issued a paper questionnaire or hand-held device (eDiary) for daily 
assessments.  The participant will be instructed to complete the diary during specific timepoints 
needed for each assessment beginning on the day of screening through Week 8 or treatment 
discontinuation.  Detailed directions for the administration of an eDiary will be provided in the 
Study Manual. 
Daily assessments will be performed by participants via a diary starting at the screening visit and 
all visits during the VC period: 
• The participant will rate (during the past 24 hours) the following: 
− Itch NRS – the worst level of itch will be recorded in the evening. 
− Skin Pain NRS – the worst level of pain will be recorded in the evening. 
− PROMIS questionnaires: 
 Short Form – Sleep-Related Impairment (8a) will be completed in the 
evening. 
 Short Form – Sleep-Disturbance (8b) will be assessed in the morning. 
Note:  At Week 8 only (LTS baseline) for both PROMIS Short Form – 
Sleep-Related Impairment (8a) and Short Form – Sleep-Disturbance (8b), the 
“past 7-day recall” assessment will also be completed using the tablet during the 
site visit. 

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• Assessments to be completed during all VC site visits include the following: 
− EQ-5D-5L – starts at screening 
− WPAI:SHP – starts at screening 
− DLQI/CDLQI – starts at Day 1 
− POEM – starts at Day 1 
− PGIC – starts at Week 2 
Assessments to be completed at the site during the LTS period (see SoA Table 4 for timepoints): 
• EQ-5D-5L  
• WPAI:SHP  
• DLQI/CDLQI 
• POEM 
• PROMIS Short Form – Sleep-Related Impairment (8a) and Short Form – 
Sleep-Disturbance (8b): 
− As stated above, this assessment will be completed during the LTS site visits 
(except for unscheduled visits) starting at Week 8. 
Note:  The recall period for Weeks 8, 12, 24, and 52 during the LTS period changes 
to the “past 7 days” from “the previous 24 hours” in the VC period. 
Refer to the Study Manual for detailed instructions. 
8.2.7.1. 
Dermatology Life Quality Index 
The DLQI is a simple, 10-question validated questionnaire to measure how much the skin 
problem has affected the participant over the previous 7 days as outlined in the SoAs (see 
Table 3 and Table 4; Finlay and Khan 1994).  The participant, aged ≥ 16 years and over, will 
answer the questionnaire with either (1) very much, (2) a lot, (3) a little, or (4) not at all. 
The questionnaire is analyzed under 6 headings as follows: 
• Symptoms and feelings (Questions 1 and 2) 
• Daily activities (Questions 3 and 4) 
• Leisure (Questions 5 and 6) 
• Work and school (Question 7) 
• Personal relations  (Questions 8 and 9) 
• Treatment (Question 10) 

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CDLQI is the youth/children’s version of the DLQI and will be completed by adolescents aged 
≥ 12 years to < 16 years.  It is self-explanatory and can be simply given to the participant who is 
asked to fill it in and who may ask the help of the parent or guardian.  The questionnaire is 
analyzed under 6 headings as follows: 
• Symptoms and feelings (Questions 1 and 2) 
• Leisure (Questions 4, 5, and 6) 
• School or holidays (Question 7) 
• Personal relationships (Questions 3 and 8) 
• Sleep (Question 9) 
• Treatment (Question 10) 
8.2.7.2. 
Patient Global Impression of Change 
The PGIC is a participants' self-reporting measure that reflects their belief about the efficacy of 
treatment.  The PGIC is a 7-point scale depicting a participant's rating of overall improvement 
and will be captured during site visits during the VC period (Hurst and Bolton 2004). 
The participant will answer the following: 
"Since the start of the treatment you've received in this study, your atopic dermatitis in areas 
treated with the study drug is:  (1) very much improved, (2) much improved, (3) minimally 
improved, (4) no change, (5) minimally worse, (6) much worse, and (7) very much worse." 
8.2.7.3. 
Patient-Oriented Eczema Measure 
The POEM is a 7-question quality-of-life assessment that asks how many days the participant 
has been bothered by various aspects of their skin condition during the past 7 days obtained as 
outlined in the SoAs (see Table 3 and Table 4; Charman et al 2004). 
8.2.7.4. 
EQ-5D-5L 
The EQ-5D is a validated, self-administered, generic utility questionnaire wherein participants 
(adolescents and adults) rate their current health state based on the following criteria 
(dimensions):  mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. 
The 5L indicates that for each dimension, there are 5 levels, which are as follows:  no problems, 
slight problems, moderate problems, severe problems, and extreme problems.   
During all VC period study visits (starting at screening) and at specific LTS visits (Weeks 12, 24, 
36, 52, and follow-up visit), the participant will be asked to indicate his/her health state over the 
past 7 days, by ticking the box next to the most appropriate statement in each of the 5 
dimensions.  The digits for the 5 dimensions can be combined into a 5-digit number that 
describes the participant's health state (EuroQol Research Foundation 2017). 

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8.2.7.5. 
Work Productivity and Activity Impairment Questionnaire:  Specific Health 
Problem Version 2.0 
The WPAI:SHP v2.0 questionnaire is a validated 6-item instrument, completed during all site 
visits starting at screening, during the VC period, and at specific LTS visits (Weeks 12, 24, 36, 
52 and follow-up visit) that measures the effect of overall health and specific symptoms on 
productivity at work and regular activities outside of it during the past 7 days (Reilly et al 1993). 
8.2.7.6. 
Itch Numerical Rating Scale 
The Itch NRS is a daily patient-reported measure (24-hour recall) of the worst level of itch 
intensity.  Participants will be asked to rate the itching severity because of their AD by selecting 
a number from 0 (no itch) to 10 (worst imaginable itch) that best describes their worst level of 
itching in the past 24 hours as outlined in the SoA (see Table 3). 
Participants will be issued a diary in which to record itch severity.  The participants will be 
instructed to complete the diary each night beginning on the day of screening through the last 
application of study drug in the VC period.  Detailed directions for the administration of an 
eDiary will be provided in the Study Manual. 
8.2.7.7. 
Skin Pain Numerical Rating Scale 
The Skin Pain NRS is a daily patient-reported measure (24-hour recall) of the worst level of pain 
intensity from 0 (no pain) to 10 (worst imaginable pain).  Participants will be asked, “Rate the 
pain severity from your atopic dermatitis skin changes by selecting a number that best describes 
your worst level of pain in the past 24 hours,” as outlined in the SoA (see Table 3). 
Participants will be issued a diary in which to record skin pain severity each evening, rating the 
worst pain in the past 24-hours.  The participants will be instructed to complete the diary each 
night beginning on the day of screening through the last application of study drug in the VC 
period.  Detailed directions for the administration of an eDiary will be provided in the Study 
Manual. 
8.2.7.8. 
PROMIS Sleep Questionnaires:  Short Form – Sleep-Related Impairment (8a) 
and Short Form – Sleep Disturbance (8b) 
PROMIS® (Patient-Reported Outcomes Measurement Information System) is a set of widely 
used and accepted patient-reported outcome measurements that have been developed with strong 
clinical outcome assessment development methods and are psychometrically supported.   
Note:  The selected PROMIS Short Form – Sleep-Related Impairment (8a) and Short Form – 
Sleep-Disturbance (8b) questionnaires have been modified to be completed with a diary on a 
daily basis with a 24-hour recall:  Short Form – Sleep-Related Impairment (8a) is collected in the 
evening, and Short Form – Sleep-Disturbance (8b) is collected in the morning during the VC 
period. 
Starting at Week 8 and during the LTS period, these will be done with a 7-day recall period and 
be completed at the site during study visits.  For timing, see SoAs Table 3 and Table 4. 

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These measures will be collected from both adolescents and adults via a diary during the VC 
period and on a tablet at the site during scheduled LTS period study visits.  Refer to the Study 
Manual for detailed instructions. 
8.2.7.8.1. PROMIS Short Form – Sleep-Related Impairment (8a) 
The PROMIS Short Form – Sleep-Related Impairment (8a) questionnaire, is to be completed in 
the evening during the VC period.  This assessment focuses on self-reported perceptions of 
alertness, sleepiness, and tiredness during usual waking hours and the perceived functional 
impairments during wakefulness associated with sleep problems or impaired alertness 
(Buysse et al 2010). 
The questionnaire has 8 simple questions with a 5-point scale with a range in score from 8 to 40, 
with higher scores indicating greater severity of sleep-related impairment.  Each item asks the 
participant to rate the severity of the participant's sleep impairment.  The recall period will be the 
past 24 hours for the VC period and the past 7 days for the LTS period. 
8.2.7.8.2. PROMIS Short Form – Sleep Disturbance (8b) 
The PROMIS Short Form – Sleep Disturbance (8b) questionnaire is to be completed in the 
morning during the VC period.  This assessment is self-reported perceptions of sleep quality, 
sleep depth, and restoration associated with sleep.  Sleep disturbance does not focus on 
symptoms of specific sleep disorders and does not provide subjective estimates of sleep 
quantities (eg, total amount of sleep, time to fall asleep, amount of wakefulness during sleep; 
Buysse et al 2010).  The sleep disturbance short form is generic rather than disease-specific. 
The questionnaire is also 5-point scale with a range in score from 8 to 40, with higher scores 
indicating greater severity of sleep disturbance.  Each item asks the participant to rate the 
severity of the participant's sleep disturbance.  The recall period will be the past 24 hours for the 
VC period and the past 7 days for the LTS period. 
8.2.8. 
Health Economics 
Health economic data will be assessed through the WPAI and EQ-5D-5L Questionnaires (see 
Section 8.2.7.4 and 8.2.7.5). 
8.3. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoAs in Table 3 and Table 4. 
See Section 6.5 for guidelines regarding the management of relevant laboratory or other safety 
assessment abnormalities. 

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8.3.1. 
Adverse Events 
Adverse events will be monitored from the time the participant signs the ICF/assent until at least 
30 (+ 7) days after the last dose of study drug.  Adverse events that begin or worsen after 
informed consent/assent should be recorded on the Adverse Events Form in the eCRF regardless 
of the assumption of a causal relationship with the study drug.  Conditions that were already 
present at the time of informed consent/assent should be recorded on the Medical History Form 
in the eCRF.  Adverse events (including laboratory abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible rather than by individual underlying signs and 
symptoms. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).  The investigator and any 
qualified designees are responsible for detecting, documenting, and recording events that meet 
the definition of an AE or SAE and remain responsible for following-up on AEs that are serious, 
considered related to the study treatment/procedures, or that caused the participant to discontinue 
the study drug.  Care will be taken not to introduce bias when detecting AEs and/or SAEs.  
Open-ended and nonleading verbal questioning of the participant, such as "How are you 
feeling?" is the preferred method to inquire about AE occurrences.  Adverse events may also be 
detected when they are volunteered by the participant during the screening process or between 
visits, or through physical examinations, laboratory tests, or other assessments.  The definition, 
reporting, and recording requirements for AEs are described in Section 9. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours.  The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
8.3.2. 
Physical Examinations 
At the screening visit and at Weeks 8 and 52/EOT, a comprehensive physical examination 
should be conducted.  The comprehensive physical examination will include assessment(s) of the 
following organ or body systems:  skin; head, eyes, ears, nose, and throat; thyroid; lungs; 
cardiovascular system; abdomen (liver, spleen); extremities; and lymph nodes; as well as a brief 
neurological examination. 
During the study, participants will be assessed by the investigator or medically qualified 
designee per institutional standard of care.  These assessments should be an evaluation as 
indicated by participant symptoms, AEs, or other findings and documented on the AE eCRF. 
Physical examinations will be conducted at the timepoints listed in Table 3 and Table 4. 

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8.3.3. 
Vital Signs 
Vital sign measurements (to be taken before blood collection for laboratory tests), include blood 
pressure, pulse, respiratory rate, and body temperature.  Blood pressure and pulse will be taken 
with the participant in the sitting position after 5 minutes of rest.  Height and weight will also be 
assessed at screening, Weeks 8, 24 and 52/EOT.  Abnormal vital sign results identified after the 
first dose of study treatment constitute an AE if they are considered clinically meaningful, induce 
clinical signs or symptoms, or require concomitant therapy. 
8.3.4. 
Electrocardiograms 
A single 12-lead ECG will be obtained at screening (12-lead ECG performed within 2 months 
before baseline is acceptable) using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTc intervals.  All 12-lead ECGs will be performed with the 
participant in a recumbent or semirecumbent position after 5 minutes of rest. 
The decision to include or exclude a participant or withdraw a participant from the study 
treatment based on an ECG flagged as "Abnormal, Clinically Significant" is the responsibility of 
the investigator, in consultation with the sponsor's medical monitor, as appropriate.  Clinically 
notable abnormalities that are considered clinically significant in the judgment of the investigator 
are to be reported as AEs. 
8.3.5. 
Laboratory Assessments 
See Table 9 for the list of clinical laboratory tests to be performed and to the SoAs (see Table 3 
and Table 4) for the timing and frequency.  A central laboratory will perform all clinical 
laboratory assessments for safety (ie, blood chemistries, hematology assessments, coagulation 
tests, endocrine function, and urinalysis), and will store the samples for PK and PD.  Additional 
testing may be required by the sponsor based on emerging safety data.  All Protocol-required 
laboratory assessments must be conducted in accordance with the laboratory manual and the 
SoAs (see Table 3 and Table 4).  Information regarding collection, processing, and shipping of 
laboratory assessments is provided in the Laboratory Manual. 
Clinically significant abnormal laboratory findings are those that are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.  All laboratory tests with values considered clinically significantly 
abnormal during participation in the study, or within 30 days after the last dose of study 
treatment, should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor. 
See Section 9.1 for information regarding laboratory abnormalities that should be recorded as an 
AE in the eCRF. 

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8.8. 
Safety Follow-Up 
The safety follow-up period is the interval between the EOT visit and the scheduled follow-up 
visit, which should occur 30 (+ 7) days after the EOT visit (or after the last dose of study 
drug/treatment if the EOT visit was not performed. 
Adverse events and SAEs must be reported up until at least 30 days after the last dose of study 
drug/treatment, the date of the follow-up visit, or until toxicities resolve, return to baseline, or are 
deemed irreversible, whichever is longer.  Reasonable efforts should be made to have the 
participant return for the follow-up visit and report any AEs that may occur during this period. 
9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
9.1. 
Definition of Adverse Event 
Adverse Event Definition 
• An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug-related. 
• An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
treatment. 
Events Meeting the Adverse Event Definition  
• Any safety assessments (eg, ECG, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the investigator (ie, 
not related to progression of underlying disease). 
• Abnormal laboratory test results constitute an AE if they are considered clinically meaningful, induce 
clinical signs or symptoms, require concomitant therapy, or require changes in study drug.  Whenever 
possible, a diagnosis (eg, anemia, thrombocytopenia) should be recorded in the eCRF rather than the 
abnormal lab result (eg, low hemoglobin, platelet count decreased). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study treatment administration even though they may have 
been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication.  Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent.  Such overdoses should be reported 
regardless of sequelae. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE 
or SAE.  Such instances will be captured in the efficacy assessments.  However, the signs, symptoms, 
and/or clinical sequelae resulting from lack of efficacy will be reported as an AE or SAE if they fulfill 
the definition of an AE or SAE. 

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Events NOT Meeting the Adverse Event Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety assessments that are 
associated with the underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder 
being studied, unless more severe than expected for the participant's condition or considered to be 
treatment-related by the investigator. 
• Efficacy endpoints as outlined in Section 2 will not be reported as AE/SAEs, specifically, any event 
that is related to disease progression.  Unblinded aggregated efficacy endpoint events and safety data 
will be monitored to ensure the safety of the participants in the study.  Any suspected endpoint that 
upon review is not progression of the disease under study will be forwarded to Incyte 
Pharmacovigilance as a SAE within 24 hours of determination that the event is not progression of the 
disease under study. 
• Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that leads to the 
procedure is the AE if it occurred after signing informed consent/assent.  If present before entering the 
study, the condition should be captured as medical history. 
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the 
start of the study that do not worsen. 
9.2. 
Definition of Serious Adverse Event 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A Serious Adverse Event is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an adverse drug experience that places the 
participant, in the opinion of the initial reporter, at immediate risk of death from the adverse experience as 
it occurred.  This does not include an adverse drug experience that, had it occurred in a more severe form, 
might have caused death. 
c.  Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician's office or outpatient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether "hospitalization" occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 

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d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person's ability to conduct normal life functions. 
• This definition is not intended to include experiences of relatively minor medical significance, such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained 
ankle), that may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
e.  Is a congenital anomaly/birth defect 
f. Other situations (Important Medical Event) 
An event that may not result in death, be immediately life-threatening, or require hospitalization, but may 
be considered serious when, based on appropriate medical judgment, the event may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in the 
above definition.  Examples of such events include invasive or malignant cancers (excluding the 
disease[s] under study in oncology protocols), intensive treatment in an emergency department or at home 
for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse 
Events 
Adverse Event and Serious Adverse Event Recording 
• An AE/SAE that begins or worsens after informed consent/assent is signed should be recorded on the 
Adverse Event Form in the eCRF.  Conditions that were present at the time informed consent/assent 
was given should be recorded on the Medical History Form in the eCRF. 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (eg, 
hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• The investigator (or delegate) will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the investigator to send photocopies of the participant's medical records in lieu 
of completing the AE eCRF page. 
• There may be instances when copies of medical records for certain cases are requested.  In this case, all 
participant identifiers, with the exception of the participant number, will be redacted on the copies of 
the medical records before submission. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information.  Whenever possible, the diagnosis (not the individual signs/symptoms) will 
be documented as the AE/SAE.  When a clear diagnosis cannot be identified, each sign or symptom 
should be reported as a separate AE/SAE. 
To the extent possible, each AE/SAE should be evaluated to determine: 
• The severity grade (CTCAE v4.03 Grade 1 to 5).  See below for further instructions on the assessment 
of intensity. 
• Whether there is at least a reasonable possibility that the AE is related to the study treatment:  suspected 
(yes) or not suspected (no).  See below for further instructions on the assessment of causality. 
• The start and end dates, unless unresolved at final follow-up. 
• The action taken with regard to study drug as a result of the AE/SAE(s). 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown). 

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• The seriousness, as per the SAE definition provided in Section 9.2. 
• The action taken with regard to the event.  Note:  If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on Adverse Event Form and the treatment should be 
specified on the appropriate eCRF (eg, Prior/Concomitant Medications, Procedures and Non-Drug 
Therapy). 
Assessment of Intensity 
The severity of AEs will be assessed using CTCAE v4.03 Grades 1 through 5.  If an event is not 
classified by CTCAE, the severity of the AE will be graded according to the scale below to estimate the 
grade of severity: 
The investigator will make an assessment of intensity for each AE and SAE reported during the study and 
assign it to 1 of the following categories: 
• Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment 
not indicated. 
• Grade 2:  Moderate; minimal, local, or noninvasive treatment indicated; limiting age appropriate 
activities of daily living. 
• Grade 3:  Severe or medical significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. 
• Grade 4:  Life-threatening consequences; urgent treatment indicated. 
• Grade 5:  Fatal. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study treatment and each occurrence of 
each AE/SAE.   
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or arguments to 
suggest a causal relationship, rather than that a relationship cannot be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• The investigator will also consult the RSI in the IB and/or Product Information, for marketed products, 
in his/her assessment. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as 
the temporal relationship of the event to study treatment administration, will be considered and 
investigated. 
• For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• With regard to assessing causality of SAEs: 
− There may be situations in which an SAE has occurred and the investigator has minimal information 
to include in the initial report.  However, the causality assessment is one of the criteria used when 
determining regulatory reporting requirements.  Therefore, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE. 
− The investigator may change his/her opinion of causality in light of follow-up information and send a 
follow-up SAE report with the updated causality assessment. 

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Follow-Up of Adverse Events and Serious Adverse Events 
• The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the sponsor to elucidate the nature and/or 
causality of the AE or SAE as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the sponsor with a copy of any postmortem findings including histopathology.   
• New or updated information will be recorded in the originally completed eCRF. 
• Any updated SAE data will be submitted to the sponsor (or designee) within 24 hours of receipt of the 
information. 
• Once an AE is detected, it should be followed until it has resolved or until it is judged to be permanent; 
assessment should be made at each visit (or more frequently if necessary) of any changes in severity, 
the suspected relationship to the study drug, the interventions required to treat the event, and the 
outcome. 
• When the severity of an AE changes over time for a reporting period (eg, between visits), each change 
in severity will be reported as a separate AE until the event resolves. 
9.4. 
Reporting of Serious Adverse Events 
All SAEs, regardless of suspected causality (eg, relationship to study drug or study 
procedure[s]), occurring after the participant has signed the ICF/assent through the last study 
visit or 30 (+ 7) days after the last dose of study drug, whichever occurs later, must be reported 
to the sponsor (or designee) within 24 hours of learning of its occurrence, unless otherwise 
specified by the Protocol.  The investigator will submit any updated SAE data to the sponsor (or 
designee) within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation.  However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the investigator must notify the 
sponsor (or designee) within 24 hours of becoming aware of the event. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
treatment under clinical investigation are met. 
If the SAE is not documented in the ruxolitinib cream IB for the study drug (new occurrence) 
and is thought to be related to the sponsor's study drug, the sponsor or its designee may urgently 
require further information from the investigator for reporting to health authorities.  The sponsor 
or its designee may need to issue an Investigator Notification to inform all investigators involved 
in any study with the same drug that this SAE has been reported.  Suspected Unexpected Serious 
Adverse Reactions will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC, or as per national regulatory requirements 
in participating countries. 

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The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg summary or listing of SAEs) from the sponsor will review and then file it 
along with the Investigator's Brochure and will notify the IRB/IEC, if appropriate according to 
local requirements. 
Serious Adverse Event Reporting 
• Information about all SAEs is collected and recorded on the Adverse Event Form in the eCRF. 
• The investigator must also complete the Incyte Serious Adverse Event Report Form, in English.  Refer 
to the Incyte Reference Guide for Completing the Serious Adverse Event Report Form. 
• Facsimile or email transmission of the Serious Adverse Event Report Form is the preferred method to 
transmit this information to the PhV/designee (eg, C3i/Telerx).  The contact information of the 
sponsor's study-specific representatives is listed in the investigator manual provided to each site.  The 
original copy of the Serious Adverse Event Report Form and the confirmation sheet must be kept at the 
study site. 
• Follow-up information is recorded on an amended or new Serious Adverse Event Report Form, with an 
indication that it is follow-up to the previously reported SAE and the date of the original report.  The 
follow-up report should include information that was not provided on the previous Serious Adverse 
Event Report Form, such as the outcome of the event (eg, resolved or ongoing), treatment provided, 
action taken with study drug because of the SAE (eg, dose reduced, interrupted, or discontinued), or 
participant disposition (eg, continued or withdrew from study participation).  Each recurrence, 
complication, or progression of the original event should be reported as follow-up to that event, 
regardless of when it occurs. 
• In rare circumstances and in the absence of facsimile or computer equipment, notification by telephone 
is acceptable with a copy of the Incyte Serious Adverse Event Report Form sent by overnight mail or 
courier service.  Initial notification via telephone does not replace the need for the investigator to 
complete and sign the Serious Adverse Event Report Form within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the Study Manual. 
9.5. 
Emergency Unblinding of Treatment Assignment 
In a medical emergency during the study, if the investigator deems it necessary to determine 
optimal medical management of the participant, emergency unblinding will be performed 
exclusively by the Principal Investigator and subinvestigator as described in the IRT Study 
Manual.  The IRT system has an option to select for "Emergency Code Break" action for a given 
participant.  After entering the 6-digit study drug tube number and verification of the unmasking 
information, the investigator/subinvestigator will proceed to either final confirmation or 
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If a participant's treatment assignment is unblinded, the sponsor or its designee must be notified 
immediately by telephone followed-up with an email. 
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be withdrawn from the study treatment, unless there are ethical reasons to have 
the participant remain on the study treatment.  In these cases, the investigator must obtain 
specific approval from the sponsor's (or its designee's) medical monitor for the participant to 
continue in the study. 
9.6. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a participant during maternal or paternal exposure to study 
drug, the following procedures should be followed in order to ensure safety: 
• The study drug must be discontinued immediately. 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy Form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
Data on fetal outcome are collected for regulatory reporting and drug safety evaluation.  
Follow-up should be conducted for each pregnancy to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications, by following until the first 
well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported 
by the investigator to the sponsor or its designee.  Pregnancy follow-up information should be 
recorded on the same form and should include an assessment of the possible causal relationship 
to the sponsor's study drug to any pregnancy outcome, as well as follow-up to the first well-baby 
visit or the duration specified in local regulations, whichever is later.  Refer to the Incyte 
Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy of a study participant must be recorded on the 
Serious Adverse Event Report Form and submitted to the sponsor or designee. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, or ectopic pregnancy) are considered SAEs (if occurring in the study participant) and 
must be reported as described in Section 9.4.  If an abnormal pregnancy outcome is reported in a 
study participant's partner, the event should be reported to the sponsor on the Clinical Trial 
Pregnancy Form. 
9.7. 
Warnings and Precautions 
Special warnings or precautions for the study drug, derived from safety information collected by 
the sponsor or its designee, are presented in the IB.  Additional safety information collected 
between IB updates will be communicated in the form of Investigator Notifications.  Any 
important new safety information should be discussed with the participant during the study, as 
necessary.  If new significant risks are identified, they will be added to the ICF/assent. 
There are no study-specific special warnings or precautions in this study. 

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9.8. 
Product Complaints 
The sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor.  All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 
The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint via email or other written communication to the sponsor contact or respective 
manufacturer as noted in the packaging information.  Any AE associated with a product 
complaint should be recorded as described in Section 9.3. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 
10. 
STATISTICS 
10.1. 
Sample Size Determination 
Approximately 600 participants will be randomized 2:2:1 to ruxolitinib 0.75% BID, 1.5% BID, 
or vehicle and stratified by baseline IGA (2, 3) and region (North America or other).  The sample 
size calculation is based on the Fisher exact test for the statistical comparison on the primary 
efficacy endpoint.  The Fisher exact test is used to provide a conservative evaluation of statistical 
power, and it is accurate when there is a small expected number of responders in the vehicle 
group.  Based on the results from a Phase 2, randomized, dose-ranging study (INCB 18424-206), 
the IGA-TS at Week 8 is assumed to be 45% and 30% for active arms (1.5% BID and 0.75% 
BID, respectively) versus 10% for placebo.  Using a 2-sided alpha of 0.025, the sample size will 
have > 95% power to detect a difference between each of the 2 active treatment groups versus 
vehicle.  In addition to provide adequate power for efficacy variables, the sample size is 
determined to provide an adequate database for safety evaluation. 
10.2. 
Populations for Analysis 
Table 10 presents the populations for analysis. 

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Table 10: 
Populations for Analysis 
Population 
Description 
ITT 
The ITT population includes all randomized participants.  Treatment groups for this 
population will be defined according to the treatment assignment at randomization. 
PP 
The PP population includes randomized participants who are considered to be 
sufficiently compliant with the Protocol. 
Safety 
The safety population includes all participants who applied at least 1 dose of study 
drug.  Treatment groups for this population will be determined according to the 
actual treatment the participant received on Day 1. 
LTS evaluable 
The LTS evaluable population includes all participants who applied at least 1 dose 
of ruxolitinib 0.75% or 1.5 % cream during the LTS period.  All analyses for the 
LTS period will be conducted with the LTS evaluable population. 
PK/ 
pharmacodynamic 
evaluable 
The PK/pharmacodynamic evaluable population includes participants who applied 
at least 1 dose of ruxolitinib cream and provided at least 1 postdose blood sample 
for PK.  The study pharmacokineticist will review data listings of participant 
administration and sample records to identify participants to be excluded from the 
analysis. 
10.3. 
Type I Error Control 
A graphical procedure with gatekeeping testing strategy for the primary and key secondary 
analyses will be implemented.  The underlying procedure is derived using the methodology 
developed in Bretz et al (2009).  This method will guarantee a strong control of the family-wise 
error rate. 
Two families of 8 elementary hypotheses tests are grouped according to treatment comparison 
between each active dose group to vehicle, where 
• Family 1 (1.5% BID vs vehicle): 
− H11:  proportion of participants who achieve IGA-TS; 
− H12:  proportion of participants who achieve EASI-75; 
− H13:  proportion of participants with a ≥ 4-grade improvement in Itch NRS over 
baseline; 
− H14:  proportion of participants with a clinically meaningful improvement in the 
PROMIS Sleep Disturbance score. 
• Family 2 (0.75% BID vs vehicle): 
− H21:  proportion of participants who achieve IGA-TS; 
− H22:  proportion of participants who achieve EASI-75; 
− H23:  proportion of participants with a ≥ 4-grade improvement in Itch NRS over 
baseline; 
− H24:  proportion of participants with a clinically meaningful improvement in the 
PROMIS Sleep Disturbance score. 

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The difference in IGA-TS rates (ruxolitinib cream vs vehicle) at Week 8 will also be computed.  
The 95% confidence interval for the difference will be computed based on a large-sample normal 
approximation with continuity correction.  All nonresponders in the VC treatment period, as well 
as all participants who discontinue study treatment at any time before the timepoint of interest, or 
discontinue from the study for any reason, will be defined as nonresponders for the nonresponder 
imputation analysis.  Sensitivity analyses, including longitudinal logistic regression with 
repeated measurements and multiple imputation, may be performed.  In addition, a tipping point 
analysis will be conducted to examine the potential effects of missing data.  Subgroup analysis 
by baseline characteristic (eg, IGA, region, and age) will be performed.  Details will be provided 
in the Statistical Analysis Plan. 
10.4.2. 
Secondary Analysis 
Secondary efficacy analyses will be conducted in the ITT population.  If the primary objective is 
achieved, the statistical comparisons for key secondary endpoints will be tested with the 
procedures specified in Figure 4.  The endpoints will be analyzed using the similar method as 
specified in the primary analysis. 
All other secondary and exploratory efficacy variables will be summarized using descriptive 
statistics.  For categorical measurements, summary statistics will include sample size, frequency, 
and percentages.  Similar logistic regression models as specified in the primary and key 
secondary analysis will be used if applicable.  For continuous measurements, summary statistics 
will include sample size, mean, median, standard deviation, standard error of the mean, 
minimum, and maximum.  Continuous efficacy endpoints, including the actual measurement, 
change from baseline, and percentage change from baseline may also be analyzed by the 
mixed-effect model with repeat measurement. 
10.4.3. 
Safety Analyses 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first dose of study drug.  Analysis of AEs will be limited to TEAEs, but data listings will include 
all AEs regardless of their timing to study drug administration.  Adverse events will be tabulated 
by the MedDRA preferred term and system organ class.  Severity of AEs will be based on the 
National Cancer Institute CTCAE v4.03 using Grades 1 through 5. 
The subset of AEs considered by the investigator to have a relationship to study drug will be 
considered to be treatment-related AEs.  If the investigator does not specify the relationship of 
the AE to study drug, then the AE will be considered treatment-related.  The incidence of AEs 
and treatment-related AEs will be tabulated. 
The clinical laboratory data will be analyzed using summary statistics; no formal treatment group 
comparisons are planned.  Laboratory test values outside the normal range will be assessed for 
severity based on the normal ranges for the clinical reference laboratory.  The incidence of 
abnormal laboratory values and shift tables relative to baseline will be tabulated. 
Descriptive statistics and mean change from baseline will be determined for vital signs (blood 
pressure, pulse, respiratory rate, and body temperature) at each assessment time. 

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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
11.1. 
Investigator Responsibilities 
• The Protocol, Protocol amendments, ICF/assent, IB, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements, the 
policies and procedures established by the IRB/IEC, and institutional requirements. 
• Any amendments to the Protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 
• The investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
− Providing oversight of the conduct of the study at the site and adherence to GCP, 
IRB/IEC requirements, institutional requirements, and applicable laws and 
country-specific regulations. 
• Adhering to the Protocol as described in this document and agreeing that changes to 
the Protocol procedures, with the exception of medical emergencies, must be 
discussed and approved, first, by the sponsor or its designee and, second, by the 
IRB/IEC.  Each investigator is responsible for enrolling participants who have met 
the specified eligibility criteria. 
• Retaining records in accordance with all local, national, and regulatory laws, but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
− The investigator must not destroy any records associated with the study without 
receiving approval from the sponsor.  The investigator must notify the sponsor or 
its designee in the event of accidental loss or destruction of any study records.  If 
the investigator leaves the institution where the study was conducted, the sponsor 
or its designee must be contacted to arrange alternative record storage options. 

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− All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations.  
The sponsor will retain the original eCRF data and audit trail. 
11.2. 
Data Management 
Data management will be performed in a validated EDC system.  The investigator will be 
provided with access to an EDC system so that an eCRF can be completed for each participant. 
The site will be provided eCRF completion guidelines for instructions on data entry in the eCRF.  
The study monitor will reference the Monitoring Plan in order to ensure that each issue identified 
is appropriately documented, reported, and resolved in a timely manner in accordance with the 
plan's requirements. 
The sponsor (or designee) will be responsible for: 
• The data management of this study including quality checking of the data. 
• Ensuring that study monitors perform ongoing source data verification to confirm that 
data entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
The investigator will be responsible for: 
• Ensuring participant data relating to the study is recorded in the eCRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, diary data) 
or as otherwise specified in the Protocol.  The investigator is responsible for verifying 
that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
• Maintaining accurate documentation (source data) that supports the information 
entered in the eCRF. 
− Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected.  Source documents are filed at the 
investigator's site. 
− Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical 
records or transfer records, depending on the study.  Also, current medical records 
must be available. 

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• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring:  Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan.  The 
investigator must allow the study monitors to review any study materials and 
participant records at each monitoring visit. 
− Auditing:  Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct.  The 
investigator must allow the auditors to review original source records and study 
documentation for all participants. 
− Regulatory inspection:  Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product.  The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other 
study-related documents.  The investigator must immediately notify the sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection. 
11.3. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data protection laws 
and regulations.  The investigator and the sponsor or its designee are responsible for ensuring 
that sensitive personal information is handled in accordance with local data protection laws  
(including, but not limited to, HIPAA and GDPR).  Appropriate consent for collection, use, and 
disclosure and/or transfer (if applicable) of personal information must be obtained in accordance 
with local data protection laws. 
Participant names will not be supplied to the sponsor or its designee.  Only the participant 
number will be recorded in the eCRF; if the participant's name appears on any other document 
(eg laboratory report), it must be obliterated on the copy of the document to be supplied to the 
sponsor or its designee.  Study findings stored on a computer will be stored in accordance with 
appropriate technical and organizational measures as required by local data protection laws. 
Records and documents, including signed ICFs/assents, pertaining to the conduct of this study 
must be retained by the investigator for 30 years after study completion unless local regulations 
or institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the sponsor.  No records may be transferred 
to another location or party without written notification to the sponsor. 

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11.4. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies participant to 
FDA Regulation Title 21 CFR Part 54 – Financial Disclosure by Clinical Investigators (ie, 
"covered studies") are required to submit a completed Clinical Investigator Financial Disclosure 
form that sufficiently details any financial interests and arrangements that apply.  For the purpose 
of this regulation, "clinical investigator" is defined as any investigator or subinvestigator who is 
directly involved in the treatment or evaluation of research participants, including the spouse and 
each dependent child of the clinical investigator or subinvestigator.  These requirements apply to 
both US and foreign clinical investigators conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Investigator Financial Disclosure Form.  During a covered clinical study, 
any changes to the financial information previously reported by a clinical investigator must be 
reported to the sponsor or its designee.  At the conclusion of the covered clinical study, the 
clinical investigators will be reminded of their obligations.  In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
11.5. 
Publication Policy 
By signing the study Protocol, the investigator and his/her institution agree that the results of the 
study may be used by the sponsor, Incyte Corporation for the purposes of national and 
international registration, publication, and information for medical and pharmaceutical 
professionals.  Study results will be published in accordance with applicable local and national 
regulations.  If necessary, the authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement.  The terms regarding the publication of study results 
are contained in the agreement signed with the sponsor or its designee.  A signed agreement will 
be retained by the sponsor or its designee. 
The results of this study may be published or presented at scientific meetings.  If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission.  
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined in line with International Committee of Medical Journal Editors 
authorship requirements. 

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11.6. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines. 
• Inadequate recruitment of participants by the investigator. 
• Discontinuation of further study treatment development. 

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12. 
REFERENCES 
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Beck LA, Thaçi D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe 
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Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
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Buysse DJ, Yu L, Moul DE. Development and validation of patient-reported outcome measures 
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initial validation of a new tool for measuring atopic eczema severity from the patients' 
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Clinical Trial Facilitation Group. Recommendations related to contraception and pregnancy 
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Contraception.pdf. Accessed October 2, 2017. 
Dupixent® (dupilumab) [prescribing information]. Regeneron Pharmaceuticals, Inc.; 2017. 
Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care for the management of atopic 
dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol 
2014;70:338-351. 
Ellis CN, Drake LA, Prendergast MM, et al. Cost of atopic dermatitis and eczema in the United 
States. J Am Acad Dermatol 2002;46:361-370. 
Eucrisa® (crisaborole) [prescribing information]. Pfizer Inc.; 2016. 
EuroQol Research Foundation. EQ-5D-5L. 2017. https://euroqol.org/eq-5d-instruments/eq-5d-5l-
about/. Accessed July 17, 2018. 
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)-- a simple practical measure for 
routine clinical use. Clin Exp Dermatol 1994;19:210-216. 
Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol Suppl 
(Stockh) 1980;92:44-47. 
Hanifin JM, Reed ML, Eczema Prevalence and Impact Working Group. A population-based 
survey of eczema prevalence in the United States. Dermatitis 2007;18:82-91. 

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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;10:11-18. 
Harrop J, Chinn S, Verlato G, et al. Eczema, atopy and allergen exposure in adults: a 
population-based study. Clin Exp Allergy 2007;37:526-535. 
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For male participants in the study: 
Male participants should use a condom from screening through 90 days after the end of systemic 
exposure.  If the male participant has a partner that is of child-bearing potential, the partner should also 
use contraception through 90 days after the end of relevant systemic exposure.  In addition, male 
participants must refrain from donating sperm from screening through 90 days after the end of relevant 
systemic exposure.  Males who have had a vasectomy qualify as having met the requirement for a 
highly effective birth control method. 
For female participants in the study: 
Precautions to avoid pregnancy should be followed until the end of safety follow-up period 
(30 [+7] days after EOT). 
The following methods that can achieve a failure rate of less than 1% per year when used consistently 
and correctly are considered as highly effective birth control methods: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
− oral 
− injectable 
− implantable
a 
• Intrauterine devicea 
• Intrauterine hormone-releasing systema 
• Bilateral tubal occlusiona 
• Vasectomized partnerab 
• Sexual abstinence
c 
a Contraception methods that in the context of this guidance are considered to have low user dependency. 
b Vasectomized partner is a highly effective method of avoiding pregnancy provided that partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the vasectomized partner has received 
medical assessment of the surgical success. 
c In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the participant. 
Source:  Clinical Trial Facilitation Group 2014. 

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APPENDIX B. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment (Version) 1: 
22 JAN 2019 
Amendment (Version) 2: 
13 FEB 2019 
Amendment 2 (13 FEB 2019) 
Overall Rational for the Amendment: 
The primary purpose of this amendment is to incorporate revisions requested by the second 
review of the Voluntary Harmonisation Procedure (VHP). 
1. Section 1, Protocol Summary (Table 4, Schedule of Activities:  Long-Term Safety 
Extension Period); Section 8.3.3, Vital Signs 
Description of change:  Updated to indicate that height and weight are assessed at 
screening and Weeks 8, 24, and 52/EOT. 
Rationale for change:  To address VHP request. 
2. Section 5.1, Inclusion Criteria 
Description of change:  Fixed a number formatting error for inclusion criterion 7. 
Rationale for change:  To correct. 
3. Section 6.1, Study Treatment Administered 
Description of change:  Added text to clarify treatment application process for the 
participant. 
Rationale for change:  To clarify. 
4. Section 6.6.3, Prohibited Medications and Procedures 
Description of change:  Deleted text to clarify that allergen immunotherapies are 
prohibited throughout the study. 
Rationale for change:  To address VHP request. 
5. Section 9.5, Emergency Unblinding of Treatment Assignment 
Description of change:  Revised to be clear that emergency unblinding is permitted at 
any stage of the entire study and not only during the VC period. 
Rationale for change:  To address VHP request. 

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6. Section 8.3.4, Electrocardiograms 
Description of change:  Deleted text to clarify the electrocardiogram process. 
Rationale for change:  To clarify. 
7. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 

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6. Section 5.2, Exclusion Criteria (Criterion 3b) 
Description of change:  Text added to limit the history of malignancy to within the past 
5 years.  
Rationale for change:  To address VHP request and to provide additional detail 
regarding what was intended by history of malignancy. 
7. Section 5.2, Exclusion Criteria (Criteria 13 and 14) 
Description of change:  Addition of criteria to exclude participants who have been 
committed to a mental institution due to an order from judicial or administrative 
authorities.  In addition, participants should be excluded if they are employees or 
dependents of the sponsor or investigator. 
Rational for change:  To address VHP request. 
8. Section 6.6.3, Prohibited Medications and Procedures 
Description of change:  Text added to clarify that allergen immunotherapies are 
prohibited unless the participant is on a stable and established regimen. 
Rationale for change:  Additional clarification for the use allergen immunotherapies. 
9. Section 9.5, Emergency Unblinding of Treatment Assignment 
Description of change:  Text revised to indicate that an emergency unblinding procedure 
is possible during the entire clinical study and that the sponsor must be notified by 
telephone with a follow-up email. 
Rationale for change: To address VHP request. 
10. Section 10.1, Sample Size Determination 
Description of change:  Updated to include additional information about the Fisher exact 
test and a Phase 2 study reference for the IGA-TS values at Week 8.   
Rationale for change:  To address VHP request.  
11. Section 10.4.1, Primary Analysis 
Description of change:  Text added to clarify the analysis to be performed. 
Rationale for change: To address VHP request. 
12. Appendix A, Information Regarding Effectiveness of Contraceptive Methods 
Description of change:  Removed the footnote regarding hormonal contraception and 
the section containing acceptable birth control with failure rate of more than 1% per year. 
Rationale for change:  To address VHP request. 
13. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment.