Conditions: Atopic Dermatitis
Keywords: Atopic Dermatitis Pruritus Eczema Topical Therapy JAK Inhibitor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 631
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the efficacy and safety of twice daily ruxolitinib cream in adolescents and adults with Atopic Dermatitis (AD).

Detailed description:

Arms:
arm 1: Participants received vehicle cream, applied topically to the affected areas as a thin film twice daily (BID) from Day 1 to Week 8 during the Vehicle Control (VC) Period. Participants applied cream BID to areas identified at Baseline even if the areas improved. arm 2: Participants received ruxolitinib 0.75% cream, applied topically to the affected areas as a thin film BID from Day 1 to Week 8 during the VC Period. Participants applied cream BID to areas identified at Baseline even if the areas improved. arm 3: Participants received ruxolitinib 1.5% cream, applied topically to the affected areas as a thin film BID from Day 1 to Week 8 during the VC Period. Participants applied cream BID to areas identified at Baseline even if the areas improved. arm 4: Participants who applied vehicle cream BID during the VC Period, were randomized to apply ruxolitinib 0.75% cream, topically to the affected areas as a thin film BID from Week 8 to 52 during the Long-term Safety (LTS) Period. Participants stopped treatment 3 days after lesions disappeared and restarted at the first sign of recurrence. arm 5: Participants who applied vehicle cream BID during the VC Period, were randomized to apply ruxolitinib 1.5% cream, topically to the affected areas as a thin film BID from Week 8 to 52 during the LTS Period. Participants stopped treatment 3 days after lesions disappeared and restarted at the first sign of recurrence. arm 6: Arm description: Participants who applied ruxolitinib 0.75% cream during VC Period, continued applying ruxolitinib 0.75% cream topically to the affected areas as a thin film BID from Week 8 to 52 during the LTS Period. Participants stopped treatment 3 days after lesions disappeared and restarted at the first sign of recurrence. arm 7: Arm description: Participants who applied ruxolitinib 1.5% cream during VC Period, continued applying ruxolitinib 1.5% cream topically to the affected areas as a thin film BID from Week 8 to 52 during the LTS Period. Participants stopped treatment 3 days after lesions disappeared and restarted at the first sign of recurrence.

Interventions: intervention 1: Ruxolitinib Cream intervention 2: Vehicle Cream
Intervention descriptions: intervention 1: Ruxolitinib cream applied topically to the affected area as a thin film twice daily. intervention 2: Matching vehicle cream applied topically to the affected area as a thin film twice daily.

Protocol document:
Prot_000.pdf: 
Official Title: Topical Ruxolitinib Evaluation in Atopic Dermatitis Study 1 (TRuE-AD1) 
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: NCT03745638
Document Date: 13 FEB 2019 


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Protocol INCB 18424-303 Am 2 
Version 2 
Clinical Study Protocol 
INCB 18424-303 
Page 1 of 88 
13 FEB 2019 
Iopical Ruxolitinib E,valuation in ,AtopicJ!ermatitis Study 1 
(TRuE-ADl) 
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: 
2018-003712-45 
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 part 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 


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Protocol INCB 18424-303 Am 2 
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13 FEB 2019 
CONFIDENTIAL 
INVESTIGATOR'S AGREEMENT 
I have read the INCB 18424-303 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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CONFIDENTIAL 
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 1 (TRuE-AD1) 
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 18424-303 
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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Version 2 
Figure 1: 
Study Design Schema 
Enrollment 
o 
(vehide-control period) 
A5 many treatment eyclesa_s needed 
Page 13 of 88 
13 FEB 2019 
( 
] 
Treatment for 8 weeks 
Lona.. Term Safety (LTS) 
---------
•  12 years
C: 
RUX 1.5% BID
•  2 years with AD
0 
(n=240) 
:;:; 
• AD {Hanifin and Rajka
ro 
N 
criteria) 
.E 
• IGA of 2 or 3
RUX 0.75% BID 
0 
• BSA 3% to 20% at
"'O 
(n=240) 
C: 
ro 
screening and baseline
 
(excluding scalp)
Vehicle• (cream) 
BID (n=120) 
• • 
Dayl 
4 
 "C '!..... 
O O 0 
 -c ai 
<I: 
I!)"' .... 
- 1-: .... 
  ci 
:; ;: er 
;o
 ._ D 
t:: 0 -
..,-
a, 
Q. 	 
41 a> "1 
" 
.2 V X 

 
C:  
w «, 
Primuy 
Endpoint 
.. Recurrence of 
lesions 
Triggers fa 
startire/endi 
cycles 
Clearance of 
lesions .. 
Sit! visits q 
4wks 
] 
treatment • 
52 
*At week 8 {LTS baseline}, participants initially on vehicle will be randomized to either Rux 1.596 or 0.7596 cream BID. Additionally, to
qualify for the LTS period, the /GA score of 0 to 4 and %BSA of 096 to 2096 will be required.
CONFIDENTIAL 


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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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There are also additional systemic drugs being developed for more severe AD, including biologic 
agents against IL-31 and IL-13.  Recent studies with oral JAK inhibitors indicated that these 
drugs may be effective in the treatment of AD (Levy et al 2015) and have triggered further 
interest in their use as topical agents for this skin condition.  A clinical study with topical 
tofacitinib confirmed that JAK inhibitors can be effective in AD also when used topically 
(Bissonnette et al 2016).   
2.1.4. 
Role of Janus Kinases in Atopic Dermatitis 
Ruxolitinib is a small molecule inhibitor of the JAKs, which play an important role in signal 
transduction following cytokine and growth factor binding to their receptors.  Excessive 
production of cytokines and growth factors has been associated with a number of chronic 
inflammatory conditions, including psoriasis, AA, AD, vitiligo, and other potential autoimmune 
diseases of the skin.  
 
 
Th2 cytokines (interleukins IL-4, IL-5, and IL-13) and epithelial cytokines TSLP play a central 
role in the pathogenesis of AD by activating inflammatory pathways in multiple cell types, 
impairing epidermal barrier structure and function, and inducing allergen sensitization 
(Moreno et al 2016). 
A number of drugs currently being developed for AD are designed to block these cytokines and 
are highly promising new biologic agents; in addition to the recently approved dupilumab, 
lebrikizumab and tezepelumab are both being clinically tested (Beck et al 2014).  However, these 
new drugs cannot be used topically and will likely be limited in use in patients with more severe 
AD.  The type 2 cytokines IL-4 and IL-13 signal through JAK1.  Taken together, simultaneous 
disruption of multiple type 2 inflammatory cytokine–associated pathways via JAK inhibition 
may serve as a novel therapeutic modality of a nonsteroidal, anti-inflammatory agent in AD. 
 
 
  To 
date, a topical JAK inhibitor with sufficient skin penetration has not yet been approved in AD.  
 
 
 
2.2. 
Ruxolitinib 
2.2.1. 
Oral Ruxolitinib 
A Phase 1 study of oral ruxolitinib was conducted in 49 children with various malignancies 
(28 with solid tumors and 21 with hematological neoplasms; ADVL1011).  Five dose levels were 
tested (15, 21, 29, 39, and 50 mg/m2 per dose BID) in participants aged 2.4 to 21.4 years.  All 
doses evaluated were tolerated.  The safety profile in these pediatric participants was consistent 
with that seen in adults and did not disclose any abnormalities limited to these age groups only. 
A thorough QT study was conducted in 50 healthy participants.  There was no indication of a 
QT/QTc-prolonging effect of ruxolitinib in single doses up to a supratherapeutic dose of 200 mg, 
indicating that ruxolitinib has no effect on cardiac repolarization. 


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The AE profile of ruxolitinib was also assessed in 198 healthy participants, participants with 
various degrees of renal (n = 32) or hepatic (n = 24) impairment, and participants with 
rheumatoid arthritis (n = 59).  Adverse events were, in general, mild and resolved without 
interventions. 
Ruxolitinib is approved for the treatment of patients with intermediate- or high-risk 
myelofibrosis and for the treatment of patients with polycythemia vera who have had an 
inadequate response to or are intolerant of hydroxyurea. 
In the randomized period of the 2 pivotal studies in myelofibrosis, COMFORT-I and 
COMFORT-II, discontinuation because of AEs regardless of causality was observed in 11.3% of 
participants.  The most frequently reported adverse drug reactions were thrombocytopenia and 
anemia.  Hematological adverse reactions (any CTCAE grade) included anemia (82.4%), 
thrombocytopenia (69.8%), and neutropenia (16.6%).  Anemia, thrombocytopenia, and 
neutropenia are dose-related effects.  The 3 most frequent nonhematological adverse reactions 
were bruising (21.6%), dizziness (15.3%), and headache (14.0%).  The 3 most frequent 
nonhematological laboratory abnormalities were increased ALT (27.2%), increased 
AST (18.6%), and hypercholesterolemia (16.9%). 
Long-term follow-up in participants with myelofibrosis has shown that, as expected, the numbers 
and proportions of AEs and SAEs has increased; however, no new safety signals have emerged 
(median duration of exposure for this population is 27.6 months, with 1345.78 patient-years of 
exposure). 
In Study INCB 18424-258, in participants with myelofibrosis with a platelet count between 
50 and 100 × 109/L, beginning treatment with 5 mg BID was well-tolerated, avoided levels of 
thrombocytopenia associated with a high risk of significant bleeding, and provided an 
opportunity to increase the dose of ruxolitinib in a safe manner. 
Overall, the safety profile of ruxolitinib in the polycythemia vera population is generally 
consistent with that observed in the myelofibrosis population.  Ruxolitinib was generally 
well-tolerated in participants with polycythemia vera, and only a small proportion of participants 
discontinued ruxolitinib because of AEs (3.6%).  Most of the AEs were managed by dose 
modifications.  Hematological toxicities were less frequent and less severe in participants with 
polycythemia vera as compared with those observed in participants with myelofibrosis.  No new 
safety signals emerged from a study in pancreatic cancer in combination with capecitabine. 
Please refer to the ruxolitinib cream IB for more details. 
2.2.2. 
Ruxolitinib Cream 
2.2.2.1. 
Preclinical Drug Disposition Summary 
The relative bioavailability of topical ruxolitinib cream was markedly 
 lower than after 
oral administration.  The primary clearance pathway is via metabolism CYP3A4 is the 
predominant CYP isozyme responsible for the metabolism of ruxolitinib.  Several metabolites of 
ruxolitinib retain JAK-related pharmacological activity. 
 
 
 
 
 


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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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2.2.2.3.1. Systemic Bioavailability 
The PK analysis was performed in 3 clinical studies in psoriasis:  INCB 18424-201, -202, and 
-203.  In summary, the PK of ruxolitinib following topical administration in participants with 
psoriasis was characterized by low systemic bioavailability in the range of 
 and 
consequently plasma concentrations that represent only a fraction of that observed following oral 
administration.  Preliminary PK information from Part A of INCB 18424-204 in participants 
with AA reveals generally comparably low levels of systemic bioavailability when ruxolitinib 
cream is applied to the scalp. 
Pediatric participants are currently being evaluated in a pilot 4-week safety and PK study 
(INCB 18424-102) and, to date, the efficacy, safety, and PK outcomes have been generally 
similar to those seen in adult participants (Study INCB 18424-206). 
Such similarities, particularly for therapeutic responses, are in line with the anticipation based on 
the fact that the skin of children ≥ 2 years old is fully matured and functional and not materially 
different from that of adults (Michel et al 1997).  In general, while the disease presentation may 
show some age-related differences in terms of distribution and chronicity of skin lesions, these 
tend to be minor in nature and do not warrant a different therapeutic approach, particularly for 
pediatric patients above 2 years of age (Akdis et al 2006, Eichenfield et al 2014). 
 
 
 
 
 
 
 
 
 
2.2.2.4. 
Efficacy of Ruxolitinib Cream 
2.2.2.4.1. Atopic Dermatitis 
INCB 18424-206 (see Figure 3) was a Phase 2, randomized, vehicle- and active (TC 0.1% 
cream)-controlled dose-ranging study in participants with AD.  The study was double-blinded for 
vehicle, ruxolitinib doses, and active control.  A total of 307 participants were randomized 
equally to ruxolitinib 1.5% cream BID, 1.5% QD, 0.5% QD, and 0.15% QD; vehicle BID; and 
active control (TC 0.1% cream BID) and stratified by EASI score (≤ 7 and > 7).  Participants 
received blinded study drug for 8 weeks, and those who were randomized to TC applied 
triamcinolone 0.1% cream BID for 4 weeks and vehicle cream for the following 4 weeks, so as 
to not exceed the allowable triamcinolone application duration.  Participants then were permitted 
to enter an open-label extension and apply ruxolitinib 1.5% cream BID for an additional 
4 weeks. 




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In summary, application of ruxolitinib cream 1.5% cream BID for 8 weeks significantly 
(p = 0.0095) reduced TARC levels in circulation as compared with vehicle-treated participants.  
The former was the only treatment group demonstrating a statistically significant difference. 
 
 
 
 
 
Additional details regarding this study can be found in the ruxolitinib cream IB. 
2.2.2.4.2. Psoriasis 
The 3 clinical studies in participants with plaque psoriasis, ruxolitinib cream (0.5%, 1.0%, or 
1.5%) was evaluated in over 200 participants with application of 4 to 12 weeks duration.  
Observed AEs were mild to moderate in intensity and most judged unrelated to study 
medication, with no associated SAEs or withdrawals.  Overall, ruxolitinib cream was 
demonstrated to be safe and well-tolerated when applied QD or BID for 28 days to plaque 
psoriasis affecting 2% to 20% of the BSA. 
Additional details regarding this study can be found in the ruxolitinib cream IB. 
2.2.2.4.3. Alopecia Areata and Vitiligo 
Study INCB 18424-204 is a study in AA where ruxolitinib 1.5% cream BID was also 
well-tolerated, with the majority of participants treated for 48 weeks.  The study was conducted 
in 2015 through 2017 but terminated early in OCT 2017 owing to lack of efficacy in the primary 
Week 24 analysis after all participants completed the Week 48 visit or discontinued. 
Study INCB 18424-211 is an ongoing, 3-part, randomized, double-blind and vehicle-controlled 
study in vitiligo.  Enrollment into the study was completed by 21 MAR 2018 with 
157 participants randomized to treatment groups.  As of 15 JUN 2018, few and only minor 
application site reactions have been observed across treatment groups (study data is blinded).  
Moreover, most of them related to all treated body locations of vitiligo and did not indicate that 
the tolerability of the study drug was any different on the face versus on other body areas. 
Additional details may be found in the ruxolitinib cream IB. 


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2.3. 
Study Rationale 
Atopic dermatitis is a chronic, relapsing, inflammatory, and itchy skin condition that affect up to 
15% to 20% of children and 5% to 10% of adults.  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 (2 years of age 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. 
Since the early 2000s, only 2 new classes of nonsteroidal topical therapies, topical calcineurin 
inhibitors (with a boxed warning for serious infections and potential for skin carcinogenicity) 
and PDE4 inhibitors, have been introduced and provide a safe treatment alternative (Papier and 
Strowd 2018).  In addition to these 2 therapies, a PDE4 inhibitor ointment was approved at the 
end of 2016 in the United States for patients with AD 2 years and older (crisaborole ointment; 
Eucrisa).  While not associated with any notable safety concerns when used on larger %BSA, it 
showed relatively limited efficacy over its vehicle (approximately 10%; Eucrisa 2016). 
These therapies are limited options; therefore, there is still a significant medical need for topical 
treatments for AD that are both effective and safe, particularly in children.  Janus kinases are 
intracellular signaling enzymes that act downstream of key proinflammatory cytokines known to 
promote AD pathogenesis.  Recent studies suggest that JAK inhibition may have antipruritic 
effects by acting directly on sensory nerve fibers (Oetjen et al 2017).  Ruxolitinib cream is a 
potent, selective inhibitor of JAK1 and JAK2 and may offer a novel therapeutic approach with 
dual anti-inflammatory and antipruritic properties.  Ruxolitinib cream is being developed for 
topical application for AD, a route of administration that should achieve high local 
concentrations of ruxolitinib in the skin while limiting systemic exposure. 
2.3.1. 
Scientific Rationale for Study Design 
This is a confirmatory study in a larger participant population with AD with the objective to 
further evaluate and confirm the prior findings with regard to the efficacy and safety of the 
proposed treatment regimens.  The population to be studied comprises participants amenable to 
topical therapy of their AD, ≥ 12 years of age with AD lesions covering between 3% to 20% of 
the total BSA, and IGA of 2 to 3. 
Ruxolitinib 1.5% cream BID up to 20% BSA has been well-tolerated in participants with 
psoriasis, AA, AD and vitiligo clinical studies with few AEs reported and no evidence of 
systemic effects. 
In the dose-range finding study in AD, 1.5% ruxolitinib cream BID for 8 weeks was found to be 
the most efficacious among investigated study arms with acceptable safety and tolerability 
profile (see Section 2.2.2.4.1 for more details).  The maximum clinical effect with this treatment 
regimen was achieved by Week 8 and did not change significantly thereafter. 
 
 


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The randomized LTS period of the study will provide additional safety information when drug is 
used intermittently for a longer period (up to 44 weeks in total).  It will also provide data about 
the duration of treatment effect after stopping therapy and the nature and number of disease 
exacerbation (flare) episodes. 
2.3.2. 
Justification for Selected Treatment Regimen  
The dose-range finding study, INCB 18424-206, investigated 6 treatment groups (ruxolitinib 
0.15% cream QD, 0.5% QD, 1.5% QD, and 1.5% BID; TC 0.1% BID for 4 weeks then vehicle 
BID for 4 weeks; and vehicle BID) over 8 weeks in a double-blind fashion followed by an 
open-label treatment with ruxolitinib 1.5% cream BID for another 4 weeks.  All ruxolitinib 
cream treatment groups were found to be effective and statistically superior against the vehicle 
with a robust dose response (in mean EASI change and IGA response over baseline).  By 
Week 8, 1.5% BID showed the highest and clearly demarcated efficacy versus other strengths 
with levelling of response thereafter and a prompt and most pronounced decrease on itch versus 
other ruxolitinib cream treatment groups.  Moreover, it demonstrated non-inferiority and 
numerically better efficacy compared with a topical mid-potent corticosteroid (TC 0.1% cream) 
at Week 4. 
Application of ruxolitinib 0.15% cream QD, 0.5% QD, 1.5% QD, and 1.5% BID resulted in 
mean total trough plasma concentrations of 
, 
respectively, after 4 weeks of treatment.  These mean values are at least 
 the 
approximate IC50 for JAK1/2 inhibition in whole blood assays of 
 with about 6% of 
participants receiving 1.5% QD or BID exceeding 
 (half the approximate IC50).  Trough 
plasma concentrations increased as dose strength and frequency of dosing were increased. 
All ruxolitinib cream treatment arms were well-tolerated on application sites and were found to 
have no notable AEs, and vital signs or physical examinations were unremarkable throughout the 
study.  In the laboratory assessments, no changes in chemistry or leukocytes, neutrophils or 
lymphocytes were observed.  Minor changes in hemoglobin 
 and 
platelets 
 were observed primarily in the ruxolitinib 1.5% cream BID 
regimen during the double-blind period, which continued in the open-label extension.  These 
changes were mostly within the limits of normal, transient (platelets), and asymptomatic and 
were not clinically meaningful. 
The proposed treatment regimens of ruxolitinib cream for this study are 0.75% BID and 
1.5% BID.  All study active treatments demonstrated clear and well-demarcated dose responses.  
Although ruxolitinib 0.75% cream BID was not tested, the distinctive dose responses seen 
allowed the projection of its efficacy level to be between 1.5% BID and 0.5% QD.  
 
 
 


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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 
 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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8.2.3. 
SCORing Atopic Dermatitis 
SCORAD is a tool to assess the extent and severity (ie, intensity) of eczema and will be 
completed before, during, and after treatment has begun to determine whether the treatment has 
been effective (Oakley 2009).  This will be performed during all VC study visits (see Table 3), 
starting at baseline. 
 To determine extent, the rule of 9 or handprint method is used to calculate the eczema 
affected area (A) as a percentage of the whole body.  Scores are added up to give a 
possible maximum of 100%. 
 To determine intensity, a representative area of eczema is selected (see below for 
target lesion).  The intensity of each of the following signs of redness, swelling, 
oozing/crusting, scratch marks, skin thickening (lichenification), dryness (this is 
assessed in an area where there is no inflammation) is assessed as follows: 
 None (0) 
 Mild (1) 
 Moderate (2) 
 Severe (3) 
Intensity scores are added together to give “B” (maximum score of 18). 
 Subjective symptoms, that is, itch and sleeplessness, are scored by the participant 
using a visual analogue scale where “0” is no itch (or no sleeplessness) and “10” is 
the worst imaginable itch (or sleeplessness). 
These scores are added to give “C” (maximum score of 20). 
Total score gives approximate weights of 60% to intensity and 20% each to extent and subjective 
signs (ie, insomnia, etc) for the participant and will be calculated as follows:  A/5 + 7B/2 + C. 
8.2.4. 
Target Lesion Assessment 
At baseline, a lesion that is representative of the participant's overall disease and is to be treated 
with study drug will be selected as the target lesion.  This lesion will be identified, measured, and 
documented in the participant's medical record at each subsequent visit during the VC period 
(see Table 3).  A note should be made in their medical record, and baseline photographs can be 
marked with the location of the target lesion.  The target lesion should not be on the hands, feet, 
or genitalia.  The target lesion should have an area of approximately 10 cm2 or more in size.  The 
longest diameter and the measurement perpendicular to the longest diameter will be measured in 
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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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Table 9: 
Required Laboratory Analytes 
Serum Chemistries 
Hematology 
Urinalysis With 
Microscopic 
Examination 
Serology 
Pregnancy Testing 
Albumin 
Alkaline 
phosphatase 
ALT 
AST 
Blood urea nitrogen 
or urea 
Creatinine 
Glucose 
Total bilirubin 
Direct bilirubin (if 
total bilirubin is 
elevated above 
ULN) 
Complete blood 
count, including: 
 Hemoglobin 
 Hematocrit 
 Mean corpuscular 
volume 
 Platelet count 
 Mean platelet 
volume (MPV) 
 Red blood cell 
count 
 Reticulocyte count 
 White blood cell 
(WBC) count 
 
Differential count, 
including: 
 Basophils 
 Eosinophils 
 Lymphocytes 
 Monocytes 
 Neutrophils 
Color and 
appearance 
pH and specific 
gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
HIV antibody 
Female participants 
of childbearing 
potential have a 
serum test at 
screening and a urine 
test at all other visits.  
A positive urine test 
will be confirmed by 
a serum test. 
Lipid Panel 
Other 
Total cholesterol 
Triglycerides 
High-density 
lipoprotein 
Low-density 
lipoprotein 
Very-low density 
lipoprotein 
FSH 
 
 
Note:  Additional tests may be required, as agreed upon by the investigator and sponsor, based on emerging safety data. 
8.3.5.1. 
Pregnancy Testing 
A serum pregnancy test will be required for all female participants of childbearing potential 
during screening and at the safety follow-up visit (30 [+ 7] days after EOT).  Urine pregnancy 
tests will be performed locally, as outlined in the SoAs (see Table 3 and Table 4), and as 
medically indicated (eg, in case of loss of menstrual cycle, when pregnancy is suspected).  If a 
urine pregnancy test is positive, the results must be confirmed with a serum pregnancy test. 
If the serum pregnancy test is negative after a urine test was positive, the investigator will assess 
the potential benefit/risk to the participant and determine whether it is in the participant's best 
interest to resume study drug/treatment and continue participation in the study. 
If a pregnancy is confirmed by a serum pregnancy test, see Section 9.6 for reporting 
requirements. 
8.3.5.2. 
Serology 
HIV assessments will be performed at the screening visit to rule out HIV infection; required 
analytes are shown in Table 9.  Serology and virology tests should be performed early in the 
screening process due to the length of time needed to obtain the results.  Additional tests may be 
performed if clinically indicated. 


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8.4. 
Pharmacokinetic Assessments 
Pharmacokinetic samples will be obtained at the visits and collection times shown in the SoAs 
(see Table 3 and Table 4) for all participants receiving ruxolitinib cream in this study. 
The exact date and time of the PK blood draws and the date and time of the last application of 
study drug preceding the blood draw (if applicable) will be recorded in the eCRF. 
Instructions for sample preparation and shipping will be provided in the Laboratory Manual.  
Participants will receive reminder cards in advance of the study visit providing instruction to 
hold the application of study drug on the day of the visit and a place to record the time of the 
prior dose of study drug. 
Pharmacokinetic blood samples can be collected at any time during study visits noted in the 
SoAs except for baseline prior to the study drug application at the site.  Blood samples must not 
be drawn from the area that has been treated with study drug.  If it is not possible to have an 
access area that is not treated with study drug, the site must adequately document in the eCRF 
and not take the PK blood sample for that visit.  After the PK sample is drawn, participants will 
apply ruxolitinib 0.75% cream, ruxolitinib 1.5% cream, or vehicle cream at the site. 
All analyses will be conducted by Incyte Corporation (Wilmington, DE) or Incyte's designee. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
  
  
 
 




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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 
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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 
cancellation of the code break procedure. 


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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. 
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functional properties of skin equivalent and human skin as a function of donor age. J Cell 
Physiol 1997;171:179-189. 
Moreno AS, McPhee R, Arruda LK, Howell MD. Targeting the T helper 2 inflammatory axis in 
atopic dermatis. Int Arch Allergy Immunol 2016;171:71-80. 
Oakley A. SCORAD. 2009. https://www.dermnetnz.org/topics/scorad/. Accessed November 1, 
2018. 
Oetjen LK, Mack MR, Feng J, et al. Sensory neurons co-opt classical immune signaling 
pathways to mediate chronic itch. Cell 2017;171:217-228. 
Papier A, Strowd C. Atopic dermatitis: a review of topical nonsteroid therapy. Drugs Context 
2018;7:212521. 
Punwani N, Scherle P, Flores R, et al. Preliminary clinical activity of a topical JAK1/2 inhibitor 
in the treatment of psoriasis. J Am Acad Dermatol 2012;67:658-664. 
Purvis D. Guidelines for the diagnosis and assessment of eczema. 2014. 
https://www.dermnetnz.org/topics/guidelines-for-the-diagnosis-and-assessment-of-eczema/. 
Accessed July 17, 2018. 


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Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. PharmacoEconomics 1993;4:353-365. 
Rönmark EP, Ekerljung L, Lötvall J, et al. Eczema among adults: prevalence, risk factors and 
relation to airway diseases. Results from a large-scale population survey in Sweden. Br J 
Dermatol 2012;166:1301-1308. 
Ruxolitinib Cream Investigator's Brochure. Wilmington, DE: Incyte Corporation. 
Spergel JM. Epidemiology of atopic dermatitis and atopic march in children. Immunol Allergy 
Clin North Am 2010;30:269-280. 
Thaçi D, Simpson, EL, Beck LA, et al. Efficacy and safety of dupilumab in adults with 
moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a 
randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet 2016;387:40-52. 
Vestergaard C, Bang K, Gesser B, Yoneyama H, Matsushima K, Larsen CG. A Th2 chemokine, 
TARC, produced by keratinocytes may recruit CLA+CCR4 + lymphocytes into lesional atopic 
dermatitis skin. J Invest Dermatol 2000;115: 640-646. 
Vinding GR, Zarchi K, Ibler KS, Miller IM, Ellervik C, Jemec GB. Is adult atopic eczema more 
common than we think? - A population-based study in Danish adults. Acta Derm Venereol 
2014;94;480-482. 


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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. 



SAP_001.pdf: 
Official Title: Topical Ruxolitinib ,Evaluation in A,topic Dermatitis Study 1/2 (TRuE-AD 1/2) 
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: NCT03745638/NCT03745651
Document Date: 08NOV2019 


Incyte Co1poration 
INCB 18424-303/304 Statistical Analysis Plan 
STATISTICAL ANALYSIS PLAN 
Page 1 of 47 
08 NOV 2019 
Iopical Ruxolitinib ,Evaluation in A,topic U,ermatitis Study 1/2 
(TRuE-AD 1/2) 
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 
IND Number 
-
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Protocol Version: 
Protocol Amendment 2 dated 13 FEB 2019 
CRF Approval Date: 
05 MAR 2019 
SAP Version: 
Original 
SAP Author: 
Date of Plan: 
08NOV2019 
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 
CONFIDENTIAL 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1.
INTRODUCTION ........................................................................................................8 
2.
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS .................................8 
2.1. 
Protocol and Case Report Form Version ......................................................................8 
2.2. 
Objectives and Endpoints .............................................................................................8 
3.
STUDY DESIGN .......................................................................................................11 
3.1. 
Randomization ............................................................................................................11 
3.2. 
Control of Type I Error ...............................................................................................11 
3.3. 
Sample Size Considerations .......................................................................................13 
3.4. 
Schedule of Assessments ............................................................................................14 
4.
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................14 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................14 
4.1.1. 
Day 1 ...........................................................................................................................14 
4.1.2. 
Study Day ...................................................................................................................14 
4.1.3. 
Baseline Value ............................................................................................................14 
4.1.4. 
Last Available Value ..................................................................................................15 
4.1.5. 
Handling of Missing and Incomplete Data .................................................................15 
4.2. 
Variable Definitions ....................................................................................................15 
4.2.1. 
Body Mass Index ........................................................................................................15 
4.2.2. 
Prior and Concomitant Medication .............................................................................15 
5.
STATISTICAL METHODOLOGY ...........................................................................16 
5.1. 
General Methodology .................................................................................................16 
5.2. 
Treatment Groups .......................................................................................................16 
5.3. 
Analysis Populations ..................................................................................................16 
5.3.1. 
Intent-to-Treat Population ..........................................................................................16 
5.3.2. 
Per Protocol Population ..............................................................................................16 
5.3.3. 
Safety Population ........................................................................................................16 
5.3.4. 
Pharmacokinetic/Pharmacodynamic Evaluable Population .......................................17 
6.
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND
ANALYSES ...............................................................................................................17 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease History .............17 
6.1.1. 
Demographics .............................................................................................................17 


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6.1.2. 
Baseline Disease Characteristics ................................................................................17 
6.1.3. 
Medical History ..........................................................................................................18 
6.2. 
Disposition of Participants ..........................................................................................18 
6.3. 
Protocol Deviations ....................................................................................................18 
6.4. 
Exposure .....................................................................................................................18 
6.5. 
Study Drug Compliance .............................................................................................18 
6.6. 
Prior and Concomitant Medication .............................................................................19 
7.
EFFICACY .................................................................................................................19 
7.1. 
General Considerations ...............................................................................................19 
7.2. 
Analysis of the Primary Efficacy Parameters .............................................................19 
7.2.1. 
Primary Efficacy Measures .........................................................................................19 
7.2.1.1. 
Investigator's Global Assessment ...............................................................................19 
7.2.1.2. 
Eczema Area and Severity Index Score ......................................................................20 
7.2.2. 
Primary Efficacy Analyses .........................................................................................20 
7.2.3. 
Subgroup Analyses for Primary Endpoints ................................................................20 
7.2.4. 
Sensitivity and Supportive Analyses for Primary Endpoints .....................................21 
7.2.4.1. 
Longitudinal Logistic Regression With Repeated Measures ......................................21 
7.2.4.2. 
Multiple Imputation ....................................................................................................21 
7.2.4.3. 
Last Observation Carry Forward ................................................................................21 
7.2.4.4. 
Tipping Point Analysis ...............................................................................................22 
7.3. 
Analysis of the Key Secondary Efficacy Parameters .................................................22 
7.3.1. 
Key Secondary Efficacy Measures .............................................................................22 
7.3.1.1. 
Itch Numerical Rating Scale Score .............................................................................22 
7.3.1.2. 
PROMIS Short Form – Sleep Disturbance (8b) .........................................................22 
7.3.1.3. 
PROMIS Short Form – Sleep-Related Impairment (8a) .............................................23 
7.3.2. 
Key Secondary Efficacy Analysis ..............................................................................23 
7.4. 
Analysis of Secondary Efficacy Parameters ...............................................................23 
7.4.1. 
Secondary Efficacy Measures .....................................................................................23 
7.4.1.1. 
SCORing Atopic Dermatitis .......................................................................................23 
7.4.1.2. 
Time to Itch Response ................................................................................................24 
7.4.1.3. 
Skin Pain Numerical Rating Scale ..............................................................................24 
7.4.1.4. 
Body Surface Area ......................................................................................................24 
7.4.1.5. 
Patient-Oriented Eczema Measure .............................................................................24 


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7.4.1.6. 
Dermatology Life Quality Index and Children's Dermatology Life Quality 
Index ...........................................................................................................................25 
7.4.1.7. 
Patient Global Impression of Change .........................................................................27 
7.4.1.8. 
EQ-5D-5L ...................................................................................................................27 
7.4.1.9. 
Work Productivity and Activity Impairment Questionnaire:  Specific Health 
Problem Version 2.0 ...................................................................................................27 
7.4.2. 
Secondary Efficacy Analysis ......................................................................................28 
7.4.2.1. 
Continuous Efficacy Endpoints ..................................................................................28 
7.4.2.2. 
Daily Continuous Efficacy Endpoints ........................................................................29 
7.4.2.3. 
Categorical Efficacy Endpoints ..................................................................................29 
7.4.2.4. 
Time-To-Event Efficacy Endpoints ............................................................................30 
7.6. 
Pharmacokinetic Analyses ..........................................................................................31 
8.
SAFETY AND TOLERABILITY ..............................................................................31 
8.1. 
General Considerations ...............................................................................................31 
8.2. 
Adverse Events ...........................................................................................................31 
8.2.1. 
Adverse Event Definitions ..........................................................................................31 
8.2.2. 
Adverse Event Summaries ..........................................................................................32 
8.3. 
Clinical Laboratory Tests ...........................................................................................33 
8.3.1. 
Laboratory Value Definitions .....................................................................................33 
8.3.2. 
Laboratory Value Summaries .....................................................................................33 
8.4. 
Vital Signs ..................................................................................................................34 
9.
PLANNED ANALYSES ............................................................................................35 
10.
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................36 
10.1. 
Changes to Protocol-Defined Analyses ......................................................................36 
10.2. 
Changes to the Statistical Analysis Plan .....................................................................36 
11.
REFERENCES ...........................................................................................................37 
APPENDIX A. PLANNED TABLES AND FIGURES .............................................................38 


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LIST OF TABLES 
Table 1: 
Objectives and Endpoints .............................................................................................9 
Table 2: 
Investigator's Global Assessment ...............................................................................19 
Table 3: 
Criteria for Clinically Notable Vital Sign Abnormalities for 12 to 15 Years 
Old ..............................................................................................................................34 
Table 4: 
Criteria for Clinically Notable Vital Sign Abnormalities for 16 to 17 Years 
Old ..............................................................................................................................34 
Table 5: 
Criteria for Clinically Notable Vital Sign Abnormalities for ≥ 18 Years Old ............34 
Table 6: 
Statistical Analysis Plan Versions ..............................................................................36 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................11 
Figure 2: 
Control of the Overall Type I Error Rate ....................................................................13 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AD 
atopic dermatitis 
AE 
adverse event 
ANOVA 
analysis of variance 
BID 
twice daily 
BMI 
Body Mass Index 
BSA 
body surface area 
CDLQI 
Children Dermatology Life Quality Index 
CI 
confidence interval 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
diastolic blood pressure 
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 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
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. 
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) 
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) 
ITT 
intent-to-treat 
KM 
Kaplan-Meier 
LTS 
long-term safety 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-model repeated measures 
NCI 
National Cancer Institute 
NRI 
nonresponder imputation 
NRS 
numerical rating scale 


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Abbreviation 
Term 
PD 
pharmacodynamic 
PGIC 
Patient Global Impression of Change 
PK 
pharmacokinetics 
POEM 
Patient-Oriented Eczema Measure 
PP 
per Protocol 
PROMIS® 
Patient-Reported Outcomes Measurement Information System 
PT 
preferred term 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SCORAD 
SCORing Atopic Dermatitis – tool used to assess extent and severity 
(intensity) of eczema 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
VAS 
Visual Analogue Scale 
VC 
vehicle-control 
WHO 
World Health Organization 
WPAI:SHP v2.0 
Work Productivity and Activity Impairment Questionnaire:  Specific 
Health Problem Version 2.0 


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1.
INTRODUCTION
INCB 18424-303 is a randomized, vehicle-controlled 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 followed by a randomized 
44-week LTS extension period.  In the LTS period, participants initially randomized to vehicle
will receive either ruxolitinib 0.75% or 1.5% cream BID.
The purpose of this SAP is to provide details of the statistical analyses that have been outlined in 
the study Protocol.  The scope of this plan will be executed by the Department of Biostatistics or 
designee, and the analyses of PK will be executed by the Department of Clinical 
Pharmacokinetics or designee. 
Another Phase 3 study, INCB 18424-304, has the identical study design as INCB 18424-303.  
This SAP applies to both INCB 18424-303 and INCB 18424-304 studies. 
2.
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS
2.1. 
Protocol and Case Report Form Version
This SAP is based on INCB 18424-303 and -304 Protocol Amendment 2 dated 13 FEB 2019 and 
CRFs approved 05 MAR 2019.  Unless superseded by an amendment, this SAP will be effective 
for all subsequent Protocol amendments and CRF versions. 
2.2. 
Objectives and Endpoints 
Table 1 presents the objectives and endpoints. 


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Table 1: 
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.a
Key Secondary 
To further assess the treatment effects of 
ruxolitinib cream. 
• Proportion of participants who achieve EASI75 at
Week 8.a
• Proportion of participants with a ≥ 4-point
improvement in Itch NRS score from baseline to
Week 8.
• Proportion of participants with a clinically meaningful
(≥ 6-point) improvement in the PROMIS Short Form –
Sleep Disturbance (8b – 24-hour recall) score at
Week 8.
• Proportion of participants with a clinically meaningful
(≥ 6-point) improvement in the PROMIS Short Form –
Sleep-Related Impairment (8a – 24-hour recall) score at
Week 8.
Secondary 
To evaluate the safety and tolerability of 
ruxolitinib cream. 
The frequency and severity of AEs; physical 
examinations; vital signs; and 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.


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Table 1: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
To further evaluate efficacy of ruxolitinib cream. 
• Proportion of participants with a clinically meaningful
(≥ 6-point) improvement in the PROMIS Short Form –
Sleep-Related Impairment (8a) and Sleep Disturbance
(8b) 24-hour recall score at Weeks 2 and 4.
• 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.
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 PK of ruxolitinib cream in 
plasma. 
• Trough plasma concentrations of ruxolitinib at all study
visits.
 For an EMA submission, if applicable, the primary endpoint is changed to the proportion of participants who 
achieve EASI75 at Week 8, and the first key secondary endpoint is changed to the proportion of participants 
achieving IGA-TS at Week 8. 


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3.
STUDY DESIGN
This is a randomized, vehicle-controlled 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 followed by a randomized, 
double-blinded, 44-week LTS extension period.  In the LTS period, participants initially 
randomized to vehicle will receive either ruxolitinib 0.75% or 1.5% cream BID. 
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. 
Figure 1: 
Study Design Schema 
3.1. 
Randomization 
In the treatment period, approximately 600 participants will be randomized 2:2:1 to ruxolitinib 
0.75% cream BID, ruxolitinib 1.5% cream BID, or vehicle cream.  Participants will be stratified 
at randomization based on baseline IGA (2, 3) and region (North America or other).  
3.2. 
Control of Type I Error 
For the primary and key secondary endpoints, the overall 2-sided Type I error is 0.05. 
A graphical procedure with gatekeeping testing strategy for the primary and key secondary 
analyses, as specified in Protocol Section 10.3, will be implemented to control the overall Type I 
error.  The underlying procedure is derived using the methodology developed in Bretz et al 
(2009).  The method will guarantee a strong control of the family-wise error rate. 


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In Step 1, two families of 8 elementary hypotheses tests are grouped according to treatment 
comparison between each ruxolitinib cream group to vehicle group, 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 ≥ 6-point 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 ≥ 6-point improvement in the PROMIS
Sleep Disturbance score.
Step 2 has one family of 2 hypotheses tests: 
•
Family 3 (1.5% BID vs vehicle and 0.75% BID vs vehicle on PROMIS Sleep-Related
Impairment score):
−
H31:  Proportion of participants with a clinically meaningful improvement
(≥ 6-point change over baseline) in Sleep-Related Impairment (8a) score between
1.5% BID vs vehicle;
−
H32:  Proportion of participants with a clinically meaningful improvement
(≥ 6-point change over baseline) in Sleep-Related Impairment (8a) score between
0.75% BID vs vehicle.
To control the overall Type I error rate, 2-sided α = 0.05, the Bonferroni's method will be used.  
In Step 1, within Family 1 and 2, the endpoints are tested in a fixed sequence at Bonferronized 
2-sided α = 0.025 level.  The endpoint will be tested only if the associated primary (and
secondary in previous steps) are rejected.  For any dose level, if the 4 related null hypotheses can
be rejected, then the fixed sequence for the other dose level can be conducted at 2-sided
α = 0.05 level.  If all null hypotheses in Family 1 and 2 are rejected, in Step 2, H31 and H32 will
be tested using Bonferroni- Hochberg’s procedure with overall 2-sided α = 0.05 level.  The
approach is visualized in Figure 2.
For an EMA submission, if applicable, the primary endpoint is changed to the proportion of 
participants who achieve EASI75 at Week 8, and the first key secondary endpoint is changed to 
the proportion of participants achieving IGA-TS at Week 8, and the hypotheses are changed 
accordingly. 


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INCB 18424-303/304 Statistical Analysis Plan 
Figure 2: 
Control of the Overall Type I Error Rate 
Step 1: 
Hll 
11
H12 
11
H13 
11
H14 
Step 2: 
Family3 
3-3_
Sample Size Considerations 
H21 
11
H22 
l 
H23 
11
H24 
Page 13 of 47 
08 NOV 2019 
Approximately 600 paiiicipants will be randomized 2:2:1 to rnxolitinib 0.75% BID, 1.5% BID, 
or vehicle and strntified by baseline IGA (2, 3) and region (No1th America or Europe). The 
sample size calculation is based on the Fisher exact test for the statistical comparison on the 
primaiy 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 aims 
(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 dete1mined to provide an adequate database for safety evaluation. 
CONFIDENTIAL 


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3.4. 
Schedule of Assessments 
Refer to Protocol Amendment 2 dated 13 FEB 2019 for a full description of all study procedures 
and assessment schedules (Protocol Tables 3 and 4) for this study. 
4.
DATA HANDLING DEFINITIONS AND CONVENTIONS
4.1. 
Scheduled Study Evaluations and Study Periods 
4.1.1. 
Day 1 
Day 1 is the date that the first application of ruxolitinib cream or vehicle cream is administered 
to the participants in the specific period. 
For randomized participants not treated with any study drug, Day 1 is defined as the day of 
randomization.  
4.1.2. 
Study Day 
If a visit/reporting date is on or after Day 1, then the study day at the visit/reporting date will be 
calculated as  
Day # = (Visit/Reporting Date – Day 1 date + 1).  
If the visit/reporting date is before Day 1, then the study day at the visit/reporting date will be 
calculated as  
Day # = (Visit/Reporting Date – Day 1 date). 
A study day of -1 indicates 1 day before Day 1. 
4.1.3. 
Baseline Value 
Baseline is the last nonmissing measurement obtained before or on the day of first application of 
ruxolitinib cream or vehicle cream. 
For participants who cross-over treatment in LTS period, baseline is the last nonmissing 
measurement obtained before or on the day of first application of study treatment in LTS period. 
For randomized participants not treated with any study drug, baseline is defined as the last 
nonmissing assessment before or on the day of randomization for all parameters. 
When scheduled assessments and unscheduled assessments occur on the same day and time of 
the assessment or time of first application is not available, use the following convention to 
determine baseline: 
•
If both a scheduled and an unscheduled visit are available on the day of the first
application and the time is missing, use the scheduled assessment as baseline.
•
If all scheduled assessments are missing on the day of the first application and an
unscheduled assessment is available, use the unscheduled assessment as baseline.


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4.1.4. 
Last Available Value 
The last available value is the last nonmissing measurement obtained after starting ruxolitinib 
cream or vehicle cream and within 30 days after the last application of ruxolitinib cream or 
vehicle cream, or before the first application of ruxolitinib cream in the next period, whichever is 
earlier. 
4.1.5. 
Handling of Missing and Incomplete Data 
For response endpoints, all nonresponders, as well as all participants who are missing 
postbaseline values, will be defined as nonresponders for the NRI analysis. 
For continuous endpoints, any participant who is missing postbaseline values may have missing 
data handled using MMRM under the missing-at-random assumption.  MMRM model implicitly 
adjusts for missing data through a variance-covariance structure. 
For other endpoints, missing observations will be handled as detailed in the specific sections 
addressing each analysis. 
4.2. 
Variable Definitions 
4.2.1. 
Body Mass Index 
Body mass index (BMI) will be calculated as follows: 
BMI (kg/m2) = [weight (kg)] / [height (m)]2 
4.2.2. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication started before the first application of study 
treatment. 
Concomitant medication is defined as any nonstudy medication that is started accordingly: 
•
Before the date of first application of study treatment and is ongoing throughout the
study or ends on/after the date of first application of study treatment.
•
On/after the date of first application of study treatment and is ongoing or ends during
the course of study treatment.
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after the first application of study treatment.  In the listing, it will be indicated whether 
a medication is prior-only, concomitant-only, or both prior and concomitant. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant. 


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5.
STATISTICAL METHODOLOGY
5.1. 
General Methodology
Unless otherwise noted, SAS software (SAS Institute Inc, Cary, NC; Version 9.1 or later) will 
be used for the generation of all tables, graphs, and statistical analyses.  Descriptive summaries 
for continuous variables will include, but not be limited to, the number of observations, mean, 
standard deviation, median, minimum, maximum, 1st quartile, 3rd quartile and 95% CI.  
Descriptive summaries for categorical variables will include the number and percentage of 
participants in each category.  
5.2. 
Treatment Groups 
This is a randomized, double-blinded vehicle-controlled study followed by a LTS extension 
period.  Data will be summarized based on treatment regimen that was assigned (ITT) or that the 
participant actually applied (safety). 
During the VC period, the treatment groups will be 1.5% BID, 0.75% BID, and Vehicle. 
During the LTS period, the treatment groups will be 1.5% BID, 0.75% BID, Vehicle to 1.5% 
BID, and Vehicle to 0.75% BID. 
5.3. 
Analysis Populations 
5.3.1. 
Intent-to-Treat Population 
All participants who are randomized to the study constitute the ITT population.  Treatment 
groups for this population will be defined according to the treatment assignment at the time of 
randomization regardless of the actual study treatment the participant might apply during his/her 
participation in the study. 
The ITT population will be used for the summary of demographics, baseline characteristics, 
participant disposition, and analyses of all efficacy data. 
5.3.2. 
Per Protocol Population 
Participants in the ITT population who are considered to be sufficiently compliant with the 
Protocol compose the PP population, which is defined for supportive sensitivity analyses for 
efficacy endpoints in the treatment period.  Participants with important protocol deviations, as 
defined in Section 6.3, will be excluded from the PP population. 
5.3.3. 
Safety Population 
All randomized participants who applied at least 1 application of ruxolitinib cream or vehicle 
cream will constitute the safety population.  Treatment groups for this population will be 
determined according to the actual treatment the participant applied on Day 1 regardless of 
assigned study treatment. 
All safety analyses will be conducted using the safety population. 


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5.3.4. 
Pharmacokinetic/Pharmacodynamic Evaluable Population 
The PK/PD evaluable population will include all participants who applied at least 1 application 
of ruxolitinib cream and provided at least 1 postdose plasma sample (1 PK/PD measurement) 
that complies with the instruction in the Protocol.  Participants in whom it is not possible to 
obtain a blood sample for PK/PD from an area of the body that was not treated with (exposed to) 
study drug (eg, due to difficulties of technical/ procedural nature) will not be included in the 
PK/PD evaluable population because of the material risk of the contamination of such a sample 
with study drug from the skin through which a needle is passed.  The study pharmacokineticist 
will review data listings of study drug application and sample records to identify participants to 
be excluded from PK data analyses.  The study research investigator will review data listings of 
PD data and sample records to identify participants to be excluded from analyses of PD data. 
6.
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND
ANALYSES
Appendix A provides a list of planned tables, figures, and listings.  Sample data displays are 
included in a separate document.  
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease 
History 
6.1.1. 
Demographics 
The following demographics will be summarized for the ITT population during the VC period:  
age, age group, sex, race, ethnicity, region, weight, height, and BMI. 
6.1.2. 
Baseline Disease Characteristics 
Baseline disease characteristics summarized for the ITT population during the VC period include 
but are not limited to the following: 
•
Time since first onset of AD
•
Prior history of asthma (No/Yes)
•
Prior allergies (food, environmental) (No/Yes)
•
History of contact dermatitis (No/Yes)
•
Common complications of AD
•
Prior treatments for AD
•
Time since onset of current AD
•
Prior therapy for AD given in the past 30 days (No/Yes)
•
Total %BSA involvement in current AD episode
•
Facial involvement (No/Yes)
•
Number of AD episodes/flare-ups over the last 12 months


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•
Baseline IGA score (2, 3)
•
Baseline EASI score
6.1.3. 
Medical History
For participants in the ITT population during the VC period, medical history will be summarized 
by assigned treatment groups.  This summary will include the number and percentage of 
participants with medical history for each body system/organ class as documented in the eCRF.  
6.2. 
Disposition of Participants 
The number and percentage of participants who were randomized, treated, and completed the VC 
period; were treated in the LTS period; completed the LTS period; discontinued the treatment or 
withdrew from the study during the VC period; and discontinued treatment or withdrew from the 
study during the LTS period with a primary reason for discontinuation will be summarized for 
the ITT population during the VC and LTS periods. 
6.3. 
Protocol Deviations 
In general, the following are important protocol deviations that may significantly affect the 
primary and gated secondary analyses: 
•
Missing data for the primary endpoint;
•
Overall application compliance less than 60%;
•
Key inclusion/exclusion criteria deviations;
•
Use of restricted or prohibited medications.
Participants with one or more such deviations will be excluded from the PP population. 
6.4. 
Exposure 
For participants in the safety population during the VC and LTS periods, descriptive statistics 
will be provided by treatment group for duration of treatment, average daily dose, and total dose.  
Duration of treatment with ruxolitinib cream or vehicle cream is defined as the number of days 
from Day 1 to the last record of ruxolitinib cream or vehicle cream application in the specific 
period. 
6.5. 
Study Drug Compliance 
Overall compliance (%) for the application of ruxolitinib cream or vehicle cream during the VC 
period will be calculated for all participants in the safety population as follows: 
Overall application compliance (%) = 100 × [total number of nonmissing applications] / 
[total number of intended applications] 
where the total number of nonmissing applications is the total number of applications that the 
participant actually applied during the study. 


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6.6. 
Prior and Concomitant Medication 
For participants in the ITT population during the VC period, prior medications and concomitant 
medications will be coded using the WHO Drug Dictionary and summarized as number and 
percentage of participants with prior and concomitant medications by WHO drug class and 
WHO drug term.  For participants in the LTS period, only concomitant medications will be 
summarized. 
Prior medications for AD will be summarized by treatment group as well as listed. 
7.
EFFICACY
Appendix A provides a list of planned tables, figures, and listings.  Sample data displays are 
included in a separate document.  
7.1. 
General Considerations 
For all continuous variables, both the actual value and change and/or percentage from baseline 
(if available) will be analyzed. 
All by-visit analyses will include the follow-up period if the data are available. 
7.2. 
Analysis of the Primary Efficacy Parameters 
For FDA submission, the primary endpoint is IGA-TS at Week 8.  For EMA submission, if 
applicable, the primary endpoint is EASI75 at Week 8. 
7.2.1. 
Primary Efficacy Measures 
7.2.1.1. 
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 2. 
Table 2: 
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:  University of Nottingham. 


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The IGA-TS is defined as an IGA score of 0 or 1 with ≥ 2 grade improvement from baseline. 
7.2.1.2. 
Eczema Area and Severity Index Score 
Atopic dermatitis will be assessed using EASI scoring system, which is a validated disease 
measurement for clinical studies 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 disease 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. 
The categorical variable EASI75 will be equal to 1 for percentage improvement from baseline in 
EASI score of 75% or greater and will be equal to 0 for percentage improvement of less than 
75%.  EASI50 are EASI90 are defined with the same pattern. 
7.2.2. 
Primary Efficacy Analyses 
The primary analysis will be based on the ITT population in the VC period.  The primary 
alternative hypothesis (superiority of ruxolitinib 1.5% BID or 0.75% BID compared with 
vehicle) will be tested using logistic regression.  This model will include the treatment group 
(1.5% BID, 0.75% BID, and vehicle) and stratification factors (baseline IGA and region).  The 
unadjusted p-values between each treatment group versus vehicle will be calculated based on 
Wald test, which will be compared with the procedure defined in Section 3.2.  Exact logistic 
regression (Mehta and Patel 1995) will be used for all of the comparisons if any of the dose 
levels have an expected cell count less than 5. 
Odds ratio and 95% CI in response rates (ruxolitinib cream vs vehicle) at Week 8 will also be 
computed.  All nonresponders in the VC treatment period, as well as all participants who are 
missing postbaseline values, will be defined as nonresponders for the nonresponder imputation 
analysis. 
The primary outcome will also be examined for PP population using the same model as the 
primary analysis. 
7.2.3. 
Subgroup Analyses for Primary Endpoints 
Subgroups will be formed based on the following participant characteristics and baseline 
variables for those participants whose data are available: 
•
Baseline IGA score (2, 3)
•
Baseline EASI score (≤ 7, >7)
•
Region (North America, Europe)
•
Categorical age
•
Sex
•
Race


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7.2.4. 
Sensitivity and Supportive Analyses for Primary Endpoints 
7.2.4.1. 
Longitudinal Logistic Regression With Repeated Measures 
To adjust for the dependence underlying the hierarchical multilevel data structure (visit, 
participant, and site), a longitudinal logistic regression with repeated measures will be applied. 
The 3 level structures in the model are: 
•
Level 1:  visit;
•
Level 2:  participant; and
•
Level 3:  site,
where visits are nested within participants, which are further nested within sites. 
The binary response (IGA-TS or EASI75) of each participant at Week 2, Week 4, and Week 8 
will be included as the dependent variable.  Treatment (1.5% BID, 0.75% BID, and vehicle 
BID), the randomization stratification factors (baseline IGA and region), visit, and treatment by 
visit interaction will be included as fixed effects.  Site level intercept and participant nested in 
site level intercept will be included as random effects.  The within-participant and within-site 
errors will be modeled by an unstructured variance-covariance matrix.  The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom for this model. 
7.2.4.2. 
Multiple Imputation 
Multiple imputation with missing at random assumption will be used as an alternative method to 
handle missing data.  The imputation method of choice depends on the type of missing data 
pattern: 
•
For data sets with monotone missing patterns, the variables with missing values will
be imputed sequentially with covariates constructed from their corresponding sets of
preceding variables.  With IGA score (0-4) or EASI (0-72), a monotone method
(Rubin 1987) with treatment group and stratification factors as predictors will be
used.
•
For data sets with arbitrary missing patterns, a fully conditional specification method
(van Buuren 2007) that assumes the existence of a joint distribution for all variables
will be used to impute IGA or EASI score.
After the missing values have been imputed, the binary variable IGA-TS or EASI75 response 
will be derived based on the definition specified in Section 7.2.1.  The imputation will be 
repeated a number of times to generate  corresponding complete data sets, in order to reflect the 
uncertainty around the true value.  The proposed logistic regression described in Section 7.2.2 
will be applied to each imputed datasets, and then the results will be combined for the inference. 
7.2.4.3. 
Last Observation Carry Forward 
For the participants who are missing postbaseline values, the last observed nonmissing value will 
be used to fill in missing values at Week 8.  Then the proposed logistic regression described in 
Section 7.2.2 will applied to the imputed dataset. 


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7.2.4.4. 
Tipping Point Analysis 
A tipping point sensitivity analysis will be conducted to examine the potential effects of missing 
data.  The missing IGA-TS or EASI75 response at Week 8 in each treatment group will be 
replaced by a range of values to see how far we must change them for the results of the study to 
tip from significant to not.  Between-treatment comparisons will be performed using a chi-square 
test. 
7.3. 
Analysis of the Key Secondary Efficacy Parameters 
7.3.1. 
Key Secondary Efficacy Measures 
7.3.1.1. 
Itch Numerical Rating Scale Score 
The Itch NRS is a once-per-24 hours ("daily") patient-reported measure of itch intensity assessed 
using an 11-point scale (0 = no itch to 10 = worst imaginable itch).  Participants will be asked to 
record their highest (worst) level of itch in the evening over the 24-hour recall period. 
The Itch NRS score for baseline will be determined by averaging the 7 daily NRS scores before 
Day 1 (Day –7 to Day –1).  The by-visit Itch NRS score for postbaseline visits will be 
determined by averaging the 7 daily NRS scores before the visit day.  If 4 or more daily scores 
are missing (out of the 7), the Itch NRS score at the visit will be set to missing. 
The proportion of participants with a clinically relevant change in itch – defined as a ≥ 4-point 
improvement in Itch NRS score from baseline to Week 8 – will be summarized by treatment 
groups for participants with baseline Itch NRS ≥ 4.  
7.3.1.2. 
PROMIS Short Form – Sleep Disturbance (8b) 
The PROMIS Short Form – Sleep Disturbance (8b) is an 8-item questionnaire.  Each item on the 
measure is rated on a 5-point scale with a range in score from 8 to 40 with higher scores 
indicating greater severity of sleep disturbance.  The recall period will be the past 24 hours for 
the VC period and the past 7 days for the LTS period.  The raw scores on the 8 items should be 
summed to obtain a total raw score.  If 4 or more of the total items on the measure are missing 
for a given day/assessment, the scores should not be used.  
For total raw score, the baseline will be determined by averaging the 7 daily scores on and before 
Day 1 (Day –6 to Day 1).  The by-visit score for post-baseline visits will be determined by 
averaging the 7 daily scores before the visit day.  If 4 or more daily scores are missing (out of 
the 7), the by-visit score at the visit will be set to missing. 
Clinically meaningful difference is defined as a ≥ 6-point change over baseline.  The total raw 
score will be summarized by visit and by treatment.  The proportion of participants with a 
≥ 6-point improvement in the PROMIS Short Form – Sleep Disturbance (8b – 24-hour recall) 
score will be summarized by treatment group for participants with baseline ≥ 6. 


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7.3.1.3. 
PROMIS Short Form – Sleep-Related Impairment (8a) 
The PROMIS Short Form – Sleep-Related Impairment (8a) is an 8-item questionnaire.  Each 
item on the measure is rated on a 5-point scale (1 = Not at all; 2 = A little bit; 3 = Somewhat; 
4 = Quite a bit; and 5 = Very much) with a range in score from 8 to 40 with higher scores 
indicating greater severity of sleep-related impairment.  The recall period will be the past 
24 hours for the VC period and the past 7 days for the LTS period.  The raw scores on the 
8 items should be summed to obtain a total raw score.  If 4 or more of the total items on the 
measure are missing, the scores should not be used. 
For total raw score, the baseline will be determined by averaging the 7 daily scores before Day 1 
(Day –7 to Day –1).  The by-visit score for post-baseline VC visits will be determined by 
averaging the 7 daily scores before the visit day.  If 4 or more daily scores are missing (out of the 
7), the by-visit score at the visit will be set to missing. 
Clinical meaningful difference is defined as a ≥ 6-point change over baseline.  The total raw 
score will be summarized by visit and by treatment.  The proportion of participants with a 
≥ 6-point (clinically meaningful) improvement in the PROMIS Short Form – Sleep-Related 
Impairment (8a – 24-hour recall) score will be summarized by treatment group for participants 
with baseline ≥ 6.  
7.3.2. 
Key Secondary Efficacy Analysis 
Key secondary efficacy analyses will be conducted in the ITT population in the VC period.  If 
the primary objective is achieved, the statistical comparisons for key secondary endpoints will be 
tested with the procedures specified in Figure 2.  All of the key secondary endpoints will be 
analyzed using the similar logistic regression models as specified in the primary efficacy 
analysis. 
7.4. 
Analysis of Secondary Efficacy Parameters 
7.4.1. 
Secondary Efficacy Measures 
7.4.1.1. 
SCORing Atopic Dermatitis 
SCORAD is a tool to assess the extent and severity (ie, intensity) of eczema and will be 
completed before, during, and after treatment has begun to determine whether the treatment has 
been effective.  This will be performed during all VC study visits, starting at baseline. 
•
To determine extent, the rule of 9 or handprint method is used to calculate the eczema
affected area (A) as a percentage of the whole body.
•
To determine intensity, the intensity of each of the following signs of redness,
swelling, oozing/crusting, scratch marks, skin thickening (lichenification), dryness
(this is assessed in an area where there is no inflammation) is assessed as follows:
−
None (0)
−
Mild (1)
−
Moderate (2)
−
Severe (3)


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Intensity scores are added together to give “B” (maximum score of 18). 
•
Subjective symptoms, that is, itch and sleeplessness, are scored by the participant
using a VAS where “0” is no itch (or no sleeplessness) and “10” is the worst
imaginable itch (or sleeplessness).
These scores are added to give “C” (maximum score of 20).
Total score gives approximate weights of 60% to intensity and 20% each to extent and subjective 
signs (ie, insomnia, etc) for the participant and will be calculated as follows:   
Total score = A / 5 + (7 × B) / 2 + C. 
7.4.1.2. 
Time to Itch Response 
Time to Itch NRS response is defined as the number of days between the day of randomization 
and the day of achieving a daily Itch NRS score improvement of at least 2, 3, and 4 points. 
7.4.1.3. 
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.” 
The Skin Pain NRS score for baseline will be determined by averaging the 7 daily NRS scores 
before Day 1 (Day –7 to Day –1).  The by-visit Skin Pain NRS score for postbaseline visits will 
be determined by averaging the 7 daily NRS scores before the visit day.  If 4 or more daily 
scores are missing (out of the 7), the Skin Pain NRS score at the visit will be set to missing.  
7.4.1.4. 
Body Surface Area 
Total %BSA afflicted by AD will be estimated at each visit in the VC and LTS periods.  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. 
7.4.1.5. 
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 (Charman 
et al 2004). 
Each of the 7 questions carries equal weight and is scored from 0 to 4 as follows: 
•
No days = 0
•
1 to 2 days = 1
•
3 to 4 days = 2
•
5 to 6 days = 3
•
Every day = 4


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The POEM is calculated by summing the score of each question resulting in a maximum of 
28 and a minimum of 0.  The meaning of POEM scores can be categorized as follows: 
•
0 to 2 = Clear or almost clear
•
3 to 7 = Mild eczema
•
8 to 16 = Moderate eczema
•
17 to 24 = Severe eczema
•
25 to 28 = Very severe eczema
If 1 question is left unanswered, this is scored 0, and the scores are summed and expressed as 
usual out of a maximum of 28.  If 2 or more questions are left unanswered, the questionnaire is 
not scored.  If 2 or more response options are selected, the response option with the highest score 
should be recorded. 
The total POEM score and POEM scores in each category will be summarized by visit and by 
treatment. 
7.4.1.6. 
Dermatology Life Quality Index and Children's Dermatology Life Quality Index 
The DLQI (Finlay and Khan 1994) is a simple 10-question validated questionnaire for use in 
participants aged 16 years and over to measure how much the skin problem has affected the 
participant over the previous 7 days. 
The scoring of each question is as follows:  Very much = 3; A lot = 2; A little = 1; Not at all = 0; 
Not relevant = 0; Question 7, “Prevented work or studying” = 3. 
The following imputation will be applied for incorrectly completed questionnaires: 
•
If 1 question is left unanswered, this is scored 0 and the scores are summed and
expressed as usual out of a maximum of 30.
•
If 2 or more questions are left unanswered, the questionnaire is not scored.
•
If question 7 is answered “yes,” this is scored 3.  If Question 7 is answered “no,” but
then either “a lot” or “a little” is ticked, this is then scored 2 or 1.  If “Not relevant” is
ticked, the score for Question 7 is 0.  If it is answered “no,” but the second half is left
incomplete, the score will remain 0.
•
If 2 or more response options are ticked, the response option with the highest score
should be recorded.
•
If there is a response between 2 tick boxes, the lower of the 2 score options should be
recorded.
•
For DLQI 6 subscales, if the answer to one question in a subscale is missing, that
subscale should not be scored.
The DLQI is calculated by summing the score of each question resulting in a maximum of 
30 and a minimum of 0.  The higher the score, the more quality of life is impaired. 


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The meaning of total DLQI scores can be categorized as follows: 
•
0 to 1 = No effect
•
2 to 5 = Small effect
•
6 to 10 = Moderate effect
•
11 to 20 = Very large effect
•
21 to 30 = Extremely large effect
A change from baseline in DLQI and CDLQI score of at least 4 points is considered clinically 
important (Basra et al 2015, Waters et al 2010). 
The questionnaire is also analyzed under 6 sub-scales 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)
CDLQI (Lewis‐Jones and Finlay 1995) is the youth/children’s version of the DLQI and will be 
completed by adolescents aged ≥ 12 years to < 16 years.  The scoring of each question is Very 
much = 3; Quite a lot = 2; Only a little  = 1; Not at all = 0; Question unanswered = 0; 
Question 7:  “Prevented school” = 3.  The CDLQI is calculated by summing the score of each 
question resulting in a maximum of 30 and a minimum of 0.  The higher the score, the more 
quality of life is impaired. 
The questionnaire is also analyzed under 6 subscales 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)
The severity banding for CDLQI scores: 
•
0 to 1 = No effect on child’s life
•
2 to 6 = Small effect
•
7 to 12 = Moderate effect


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•
13 to 18 = Very large effect
•
19 to 30 = Extremely large effect
The following imputation will be applied for incorrectly completed questionnaires for CDLQI: 
1. If one question is left unanswered, this is scored 0, and the scores are summed and
expressed as usual out of a maximum of 30.
2. If 2 or more questions are left unanswered, the questionnaire is not scored.
3. If both parts of Question 7 are completed, the higher of the 2 scores should be counted.
7.4.1.7. 
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 (1, very much improved; 2, much 
improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; 7, very 
much worse).  Missing values will not be imputed. 
A participant is said to be a PGIC responder or have achieved a PGIC response if he or she has 
achieved PGIC of (1) very much improved or (2) much improved. 
7.4.1.8. 
EQ-5D-5L 
The EQ-5D-5L (EuroQol Research Foundation 2017) 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. 
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. 
Missing values will not be imputed.  The categorical outcomes for the 5 dimensions (mobility, 
self-care, usual activity, pain/discomfort, and anxiety/depression) will be summarized.  The 
change from baseline in EQ-5D VAS score will be analyzed. 
7.4.1.9. 
Work Productivity and Activity Impairment Questionnaire:  Specific Health 
Problem Version 2.0 
The WPAI:SHP v2.0 (Reilly et al 1993) 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. 


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WPAI outcomes are expressed as impairment percentages, with higher numbers indicating 
greater impairment and less productivity, i.e., worse outcomes, as follows:  
Questions: 
•
1 = currently employed
•
2 = hours missed due to AD
•
3 = hours missed other reasons
•
4 = hours actually worked
•
5 = degree AD affected productivity while working
•
6 = degree AD affected regular activities
Scores: 
Multiply scores by 100 to express in percentages. 
•
Percent work time missed due to AD:  Q2 / (Q2 + Q4)
•
Percent impairment while working due to AD:  Q5 / 10
•
Percent overall work impairment due to AD:  [Q2 / (Q2 + Q4)] +
({1 – [Q2 / (Q2 + Q4)]} × {Q5 / 10})
•
Percent activity impairment due to AD:  Q6 / 10
These impairment percentages will be summarized by visit and by treatment.  Missing values 
will not be imputed. 
7.4.2. 
Secondary Efficacy Analysis 
All secondary efficacy analyses will be conducted based on the ITT population in the VC and 
LTS periods. 
7.4.2.1. 
Continuous Efficacy Endpoints 
By-visit summary statistics for the following continuous measurements, including change from 
baseline and percentage change from baseline will be presented: 
•
EASI score
•
By-visit Itch NRS score
•
By-visit Skin Pain NRS score
•
By-visit PROMIS Short Form – Sleep-Related Impairment (8a) 24-hour recall total
raw score
•
By-visit PROMIS Short Form – Sleep Disturbance (8b) 24-hour recall total raw score
The summary statistics includes sample size, mean, median, standard deviation, minimum, 
maximum, 1st quartile, 3rd quartile, and 95% CI will be presented by visits.  An MMRM may be 
fit for the comparisons between ruxolitinib cream groups and vehicle cream group at Week 8.  
The MMRM will include the fixed effect of treatment, stratification factor, the visit, and 


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treatment by visit interaction.  The variance-covariance matrix of the within-participant errors in 
MMRM will be modeled as unstructured. 
For the following continuous measurements, the change from baseline to Week 8 will be 
analyzed using an ANCOVA model with treatment and stratification factors and baseline score 
as covariates if applicable. 
•
Total AD afflicted %BSA
•
Total SCORAD score
•
Total POEM score
•
Total DLQI/CDLQI score
•
DLQI/CDLQI subscores
•
EQ VAS score
•
WPAI:SHP v2.0 scores
For the above continuous measurements during the LTS period, only summary statistics will be 
presented.  
7.4.2.2. 
Daily Continuous Efficacy Endpoints 
For the following daily continuous measurements, summary statistics including sample size, 
mean, median, standard deviation, minimum, maximum, 1st quartile, 3rd quartile, and 95% CI 
will be presented by day.  An ANOVA model will be fit for the comparisons between ruxolitinib 
cream and vehicle cream at Week 8 on change and percentage from baseline.  The ANOVA 
model will include treatment groups. 
•
Daily Itch NRS score
•
Daily Skin Pain NRS score
•
Daily PROMIS Short Form – Sleep-Related Impairment (8a) 24-hour recall total raw
score
•
Daily PROMIS Short Form – Sleep Disturbance (8b) 24-hour recall total raw score
7.4.2.3. 
Categorical Efficacy Endpoints 
For the following categorical parameters, summary statistics including sample size, frequency, 
and percentages will be presented by visits.  
•
Proportion of participants achieving an IGA of 0 or 1
•
Proportion of participants with a ≥ 2-point improvement in Itch NRS score
•
Proportion of participants with a ≥ 3-point improvement in Itch NRS score
•
Proportion of participants with a ≥ 4-point improvement in Itch NRS score
•
Proportion of participants achieving EASI50
•
Proportion of participants achieving EASI75


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Proportion of participants achieving EASI90
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•
Propo1tion of pa1ticipants with av 6-point improvement in the PRO MIS Sho1t Form
(8a)- Sleep-Related Impainnent 24-hour recall score
•
Propo1tion of pa1ticipants with av 6-point improvement in the PRO MIS Sho1t Form
(8b) - Sleep Disturbance 24-hour recall score
•
Proportion of participants with a score of either 1 or 2 of PGIC
•
Propo1tion of pa1ticipants with a clinically meaningful improvement (v 4-point
improvement) in DLQI/CDLQI
A logistic regression model with ti·eatment and sti·atification factors as covariates will be fit at 
Week 8. The p-values between each mxolitinib group versus vehicle will be calculated based on 
Wald test. Exact logistic regression will be used for all of the comparisons if any of the dose 
levels have an expected cell count less than 5. The NRI will be used to impute postbaseline 
missing values for bina1y outcomes based on IGA, EASI, Itch NRS, PRO MIS Sho1t Fo1m -
Sleep-Related Impai1ment (8a) scores, PROMIS Sho1t Fo1m - Sleep Disturbance (8b) scores. 
For the following categorical endpoints, the number and percentage of paiticipants will be 
summarized by ti·eatment at each postbaseline visit. 
•
Proportion of paiticipants in each catego1y of EASI score
•
Proportion of paiticipants in each catego1y ofIGA score
•
Propo1tion of pa1ticipants in each catego1y of PGIC score
•
Proportion of paiticipants in each catego1y of POEM score
•
Proportion of paiticipants in each catego1y ofDLQI/CDLQI score
•
Propo1tion of pa1ticipants in each catego1y of each EQ-5D dimension
7.4.2.4. 
Time-To-Event Efficacy Endpoints
For the time to achieve Itch NRS score improvement of at least 2, 3, or 4 points, a log-rank test 
sti·atified by randomization sti·atification factors will be used for between ti·eatment group 
comparisons. The hazard ratio and its 95% CI will be estimated based on the stratified Cox 
regression model using Efron's method accounting for ties. Kaplan-Meier curves will be 
presented by ti·eatment groups. The number of paiticipants, number of events and number of 
censoring will be summarized by u-eatment groups. The KM estimate of median time will be 
presented with its 95% CI. The 95% CI will be calculated using the method by Brookmeyer and 
Crowley (1982). 
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Pharmacokinetic Analyses 
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Trough plasma concentrations of rnxolitinib at all study visits will be summarized using 
descriptive statistics by treatment group. 
8_ 
SAFETY AND TOLERABILITY 
Appendix A provides a list of planned tables figures, and listings. Sample data displays are 
included in a separate document. 
8-L
General Considerations 
The analyses in this section will be provided for the safety population in the VC and LTS 
periods. Summaiy tables may be replaced with listings when appropriate. For instance, an AE 
frequency table may be replaced with a listing if it only contains a few unique PTs repo1ied on 
relatively few pa1iicipants. 
Unless othe1wise stated, table summaries will be limited to AEs occuning within 30 days of the 
last application of study diug or the first application in the LTS period (if available) of the study, 
whichever is earlier. 
8-2-
Adverse Events 
8.2.1. 
Adverse Event Definitions 
A TEAE is any AE either repo1ied for the first time or worsening of a pre-existing event after 
first adininistration of study di11g. Analysis of AEs (as discussed below) will be liinited to 
TEAEs, but data. listings will include all AEs regardless of their tiining in relation to study diug 
adininistration. 
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Adverse events will be tabulated by MedDRA PT and SOC.  Severity of AEs will be graded 
using the NCI CTCAE.  The CTCAE v4.03 is used for this study.  The CTCAE reporting 
guidelines and grading details are available on the Cancer Therapy Evaluation Program website. 
The subset of AEs considered by the investigator to be related 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, the AE will be considered to be treatment-related.  The incidence of AEs and 
treatment-related AEs will be tabulated.  Serious AEs will also be tabulated. 
Any missing onset date, causality, or severity must be queried for resolution.  Unresolved 
missing causality and severity will be handled according to the following rules: 
•
An unresolved missing causality will be considered treatment-related.
•
An unresolved missing severity will be identified as an unknown severity.
For purposes of analysis, all AEs will be considered TEAEs unless the AE can unequivocally be 
defined as not treatment-emergent. 
8.2.2. 
Adverse Event Summaries 
An overall summary of AEs by treatment group will include: 
•
Number (%) of participants reporting any TEAEs
•
Number (%) of participants reporting any serious TEAEs
•
Number (%) of participants reporting any Grade 3 or higher TEAEs
•
Number (%) of participants reporting any treatment-related TEAEs
•
Number (%) of participants who temporarily interrupted study drug because of
TEAEs
•
Number (%) of participants who permanently discontinued study drug because of
TEAEs
•
Number (%) of participants who had a fatal TEAE
The following summaries will be produced by MedDRA term (if 2 or fewer participants appear 
in a table, a listing may be appropriate): 
•
Summary of TEAEs by SOC and PT
•
Summary of TEAEs by PT in decreasing order of frequency
•
Summary of Grade 3 or higher AEs by SOC and PT
•
Summary of Grade 3 or higher AEs by PT in decreasing order of frequency
•
Summary of serious TEAEs by SOC and PT
•
Summary of serious TEAEs by PT in decreasing order of frequency
•
Summary of treatment-related TEAEs by SOC and PT
•
Summary of treatment-related TEAEs by PT in decreasing order of frequency


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•
Summary of Grade 3 or higher treatment-related TEAEs by SOC and PT
•
Summary of treatment-related serious TEAEs by SOC and PT
•
Summary of TEAEs with a fatal outcome by SOC and PT
•
Summary of TEAEs leading to dose interruption of study drug by SOC and PT
•
Summary of TEAEs leading to discontinuation of study drug by SOC and PT
•
Summary of TEAEs requiring concomitant medications by SOC and PT
Subgroup analysis for TEAEs by age categories will also be provided. 
8.3. 
Clinical Laboratory Tests 
8.3.1. 
Laboratory Value Definitions 
All laboratory assessments will be performed using a central laboratory except for urine 
pregnancy tests (as applicable).  Laboratory values and change from baseline values will be 
summarized descriptively by visit, and non-numeric test values will be tabulated when necessary. 
The baseline value will be determined using the last nonmissing value collected before the first 
application, prioritizing scheduled assessments for baseline identification over unscheduled 
visits.  The last record before administration in the highest priority will be considered the 
baseline record.  For baseline laboratory candidates with the same date and time in the same 
priority category, additional rules may be provided after consultation with the medical monitor to 
delineate which value will be defined as baseline. 
8.3.2. 
Laboratory Value Summaries 
Clinical laboratory tests, including hematology and serum chemistry, will be performed at the 
Protocol-specified visits.  If specific safety issues arise, additional unscheduled laboratory 
tests/analyses may be performed at the discretion of the investigator. 
All test results and associated normal ranges from central laboratories will be reported in 
SI units.  All tests with numeric values will have a unique unit per test.  Any laboratory test 
results and associated normal ranges from local laboratories will be converted to SI units. 
When there are multiple laboratory nonmissing values for a participant's particular test within a 
visit window, the laboratory value with the smallest laboratory sequence number will be used in 
by-visit summaries. 
For test results that will be summarized with available normal ranges, the number and percentage 
of participants with the laboratory values being low (but never high), normal, high (but never 
low), and both low and high will be calculated for each test.  This shift summary will be 
produced for each test for the safety population in VC period.  Shift tables will be presented 
showing change in CTCAE grade from baseline to worst grade postbaseline as well.  The 
denominator for the percentage calculation will use the number of participants in the baseline 
category. 
Subgroup analysis for laboratory results by age categories will also be provided. 


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8.4. 
Vital Signs 
Values at each scheduled visit, change, and percentage change from baseline for vital signs, 
including SBP, DBP, pulse, respiratory rate, and body temperature will be summarized 
descriptively. 
Criteria for clinically notable vital sign abnormalities are defined in Table 3, Table 4, and 
Table 5.  The abnormal values for participants exhibiting clinically notable vital sign 
abnormalities will be listed along with their assigned treatment group.  Alert vital signs are 
defined as an absolute value outside the defined range and percentage change greater than 25%.  
The abnormal values for participants exhibiting alert vital sign abnormalities will be listed. 
Table 3: 
Criteria for Clinically Notable Vital Sign Abnormalities for 12 to 15 Years 
Old 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 131 mmHg
< 110 mmHg 
Diastolic blood pressure 
> 83 mmHg
< 64 mmHg 
Pulse 
> 100 bpm
< 60 bpm 
Temperature 
> 38.0ºC
< 35.5ºC 
Respiratory rate 
> 20 breaths/min
< 8 breaths/min 
Table 4: 
Criteria for Clinically Notable Vital Sign Abnormalities for 16 to 17 Years 
Old 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 120 mmHg
< 90 mmHg 
Diastolic blood pressure 
> 85 mmHg
< 50 mmHg 
Pulse 
> 100 bpm
< 45 bpm 
Temperature 
> 38.0ºC
< 35.5ºC 
Respiratory rate 
> 20 breaths/min
< 8 breaths/min 
Table 5: 
Criteria for Clinically Notable Vital Sign Abnormalities for ≥ 18 Years Old 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg
< 40 mmHg 
Pulse 
> 100 bpm
< 45 bpm 
Temperature 
> 38ºC
< 35.5ºC 
Respiratory rate 
> 20 breaths/min
< 8 breaths/min 


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9.
PLANNED ANALYSES
No formal interim analysis is planned.  There are 3 formal planned analyses: 
•
The primary analysis will occur after the primary database lock, when all participants
have completed the vehicle-controlled, double-blind treatment period.  The sponsor
will be unblinded after the primary database lock; however, investigators and
participants will remain blinded to the individual study treatment assignment;
•
An analysis will occur when approximately 200 participants (≥ 20% adolescents)
complete 12 months of treatment across both INCB 18424-303 and INCB 18424-304
studies;
•
The final analysis will occur when all participants have completed or withdrew from
the study.


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10.
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN
All versions of the SAP are listed in Table 6. 
Table 6: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
08 NOV 2019 
10.1. 
Changes to Protocol-Defined Analyses 
•
The LTS evaluable population will not be used.  Efficacy and safety in LTS will be
evaluated in the ITT and safety populations to keep consistency with the
measurements in VC.
•
Duration of AEs will not be analyzed.
•
The sleep-related impairment is considered as an important endpoint.  The proportion
of participants with a clinically meaningful improvement (≥ 6-point) in the PROMIS
Short Form – Sleep-Related Impairment (8a-24-hour recall) score at Weeks 8 has
been moved into the list of key secondary endpoints with alpha control.
10.2. 
Changes to the Statistical Analysis Plan 
Not applicable. 


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11.
REFERENCES
Basra MK, Salek MS, Camilleri L, Sturkey R, Finlay AY. Determining the minimal clinically 
important difference and responsiveness of the Dermatology Life Quality Index (DLQI): further 
data. Dermatology 2015;230:27-33. 
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med 2009;28:586-604. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29-41. 
Charman CR, Venn AJ, Williams HC. The patient-oriented eczema measure: development and 
initial validation of a new tool for measuring atopic eczema severity from the patients' 
perspective. Arch Dermatol 2004;140:1513-1519. 
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. 
Lewis‐Jones MS, Finlay AY. The Children's Dermatology Life Quality Index (CDLQI): initial 
validation and practical use. Br J Dermatol 1995;132:942-949. 
Mehta CR, Patel NR. Exact logistic regression: theory and examples. Stat Med 
1995;14:2143-2160. 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. PharmacoEconomics 1993;4:353-365. 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York, NY: John Wiley & 
Sons;1987. 
University of Nottingham. Harmonising Outcome Measures for Eczema (HOME). 
www.homeforeczema.org. Accessed November 6, 2019. 
van Buuren S. Multiple imputation of discrete and continuous data by fully conditional 
specification. Stat Methods Med Res 2007;16:219-242. 
Waters A, Sandhu D, Beattie P, Ezughah F, Lewis-Jones S. Severity stratification of Children's 
Dermatology Life Quality Index (CDLQI) scores. Br J Dermatol 2010;163(suppl 1):121. 


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APPENDIX A. PLANNED TABLES AND FIGURES 
This appendix provides a list of the planned tables, figures, and listing for the clinical study 
report.  Standard tables will follow the conventions in the Standard Safety Tables initial version.  
Shells are provided for nonstandard tables.  In-text tables are identical in structure and content as 
appendix tables, but follow a Rich Text Format. 
The list of tables, figures, listings, and the shells are to be used as guideline.  Modifications of 
the list or shells that do not otherwise affect the nature of the analysis will not warrant an 
amendment to the SAP. 
Tables 
Table No. 
Title 
Population 
Baseline Demographic and Characteristic 
1.1.1 
Analysis Populations 
All 
1.1.2 
Summary of Participant Disposition 
ITT 
1.1.3 
Summary of Number of Participants Enrolled by Country and Site 
ITT 
1.1.4 
Summary of Protocol Deviations 
ITT 
1.2 
Summary of Demographics and Baseline Characteristics 
ITT 
1.3 
Summary of Baseline Disease Characteristics 
ITT 
1.4.1 
Summary of Prior Medications 
ITT 
1.4.2 
Summary of Prior Medications for Atopic Dermatitis 
ITT 
1.4.3.1 
Summary of Concomitant Medications in VC Period 
ITT 
1.4.3.2 
Summary of Concomitant Medications from Baseline to Week 52 
ITT 
1.4.3.3 
Summary of Concomitant Medications in LTS Period 
ITT 
1.5 
Summary of General Medical History 
ITT 
Efficacy 
IGA 
2.1.1.1 
Summary and Analysis of Participants Achieving IGA-TS From Baseline to 
Week 52 
ITT 
2.1.1.2 
Summary of Participants Achieving IGA-TS in LTS Period 
ITT 
2.1.2 
Summary and Sensitivity Analysis of Participants Achieving IGA-TS at 
Week 8 by Tipping Point Analysis 
ITT 
2.1.3.1 
Summary and Analysis of Participants Achieving IGA-TS From Baseline to 
Week 52 
PP 
2.1.4 
Summary and Analysis of Participants Achieving IGA-TS by Baseline IGA 
Score From Baseline to Week 52 
ITT 
2.1.5 
Summary and Analysis of Participants Achieving IGA-TS by Baseline EASI 
Score From Baseline to Week 52 
ITT 
2.1.6 
Summary and Analysis of Participants Achieving IGA-TS by Region From 
Baseline to Week 52 
ITT 
2.1.7 
Summary and Analysis of Participants Achieving IGA-TS by Age Group From 
Baseline to Week 52 
ITT 
2.1.8 
Summary and Analysis of Participants Achieving IGA-TS by Sex From 
Baseline to Week 52 
ITT 
2.1.9 
Summary and Analysis of Participants Achieving IGA-TS by Race From 
Baseline to Week 52 
ITT 


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Table No. 
Title 
Population 
2.1.10.1 
Summary of Participants in Each Category of IGA Score From Baseline to 
Week 52 
ITT 
2.1.10.2 
Summary of Participants in Each Category of IGA Score in LTS Period 
ITT 
2.1.11.1 
Summary and Analysis of Participants Achieving an IGA of 0 or 1 From 
Baseline to Week 52 
ITT 
2.1.11.2 
Summary of Participants Achieving an IGA of 0 or 1 in LTS Period 
ITT 
2.1.12 
Shift Summary of IGA at Week 8 
ITT 
EASI 
2.2.1 
Summary and Analysis of Participants Achieving EASI75 in VC Period 
ITT 
2.2.2 
Summary and Analysis of Participants Achieving EASI50 in VC Period 
ITT 
2.2.3 
Summary and Analysis of Participants Achieving EASI90 in VC Period 
ITT 
2.2.4 
Summary and Analysis of EASI Score in VC Period 
ITT 
2.2.5 
Summary of Participants in Each Category of EASI Score in VC Period 
ITT 
Itch NRS Score 
2.3.1 
Summary and Analysis of Participants Achieving ≥ 2-Point Improvement in 
Itch NRS Score in VC Period 
ITT 
2.3.2 
Summary and Analysis of Participants With a ≥ 3-Point Improvement in Itch 
NRS Score in VC Period 
ITT 
2.3.3 
Summary and Analysis of Participants With a ≥ 4-Point Improvement in Itch 
NRS Score in VC Period 
ITT 
2.3.4 
Summary and Analysis of Itch NRS Score in VC Period 
ITT 
2.3.5 
Summary and Analysis of Daily Itch NRS Score in VC Period 
ITT 
2.3.6 
Summary and Analysis of Time to ≥ 2-Point Improvement in Itch NRS Score in 
VC Period 
ITT 
2.3.7 
Summary and Analysis of Time to ≥ 3-Point Improvement in Itch NRS Score in 
VC Period 
ITT 
2.3.8 
Summary and Analysis of Time to ≥ 4-Point Improvement in Itch NRS Score in 
VC Period 
ITT 
PROMIS Sleep Disturbance Score (8b) 
2.4.1.1 
Summary and Analysis of Participants Achieving a ≥ 6-point Improvement in 
the PROMIS Sleep Disturbance Score (8b) From Baseline to Week 52 
ITT 
2.4.1.2 
Summary of Participants Achieving a ≥ 6-point Improvement in the PROMIS 
Sleep Disturbance Score (8b) in LTS Period 
ITT 
2.4.2.1 
Summary and Analysis of By-Visit PROMIS Sleep Disturbance Score (8b) 
From Baseline to Week 52 
ITT 
2.4.2.2 
Summary of By-Visit PROMIS Sleep Disturbance Score (8b) in LTS Period 
ITT 
2.4.3 
Summary and Analysis of Daily PROMIS Sleep Disturbance Score (8b) in VC 
Period 
ITT 
PROMIS Sleep-Related Impairment Score (8a) 
2.5.1.1 
Summary and Analysis of Participants Achieving a ≥ 6-point Improvement in 
the PROMIS Sleep-Related Impairment Score (8a)From Baseline to Week 52 
ITT 
2.5.1.2 
Summary of Participants Achieving a ≥ 6-point Improvement in the PROMIS 
Sleep-Related Impairment Score (8a) in LTS Period 
ITT 
2.5.2.1 
Summary and Analysis of By-Visit PROMIS Sleep-Related Impairment Score 
(8a) From Baseline to Week 52 
ITT 


Incyte Corporation 
Page 40 of 47 
INCB 18424-303/304 Statistical Analysis Plan 
08 NOV 2019 
CONFIDENTIAL 
Table No. 
Title 
Population 
2.5.2.2 
Summary of By-Visit PROMIS Sleep-Related Impairment Score (8a) in LTS 
Period 
ITT 
2.5.3 
Summary and Analysis of Daily PROMIS Sleep-Related Impairment Score (8a) 
in VC Period 
ITT 
SCORAD 
2.6 
Summary and Analysis of SCORAD Score in VC Period 
ITT 
Skin Pain NRS Score 
2.7.1 
Summary and Analysis of By-Visit Skin Pain NRS Score in VC Period 
ITT 
2.7.2 
Summary and Analysis of Daily Skin Pain NRS Score in VC Period 
ITT 
BSA 
2.8.1.1 
Summary and Analysis of Total %BSA Afflicted by AD From Baseline to 
Week 52 
ITT 
2.8.1.2 
Summary of Total %BSA Afflicted by AD in LTS Period 
ITT 
POEM 
2.9.1.1 
Summary and Analysis of Total POEM Score From Baseline to Week 52 
ITT 
2.9.1.2 
Summary of Total POEM Score in LTS Period 
ITT 
2.9.2.1 
Summary of Participants in Each Category of POEM Score From Baseline to 
Week 52 
ITT 
2.9.2.2 
Summary of Participants in Each Category of POEM Score in LTS Period 
ITT 
DLQI/CDLQI 
2.10.1.1 
Summary and Analysis of Total DLQI Score From Baseline to Week 52 
ITT 
2.10.1.2 
Summary and Analysis of Total CDLQI Score From Baseline to Week 52 
ITT 
2.10.1.3 
Summary of Total DLQI Score in LTS Period 
ITT 
2.10.1.4 
Summary of Total CDLQI Score in LTS Period 
ITT 
2.10.2.1 
Summary and Analysis of DLQI Subscore From Baseline to Week 52 
ITT 
2.10.2.2 
Summary and Analysis of CDLQI Subscore From Baseline to Week 52 
ITT 
2.10.2.3 
Summary of DLQI Subscore in LTS Period 
ITT 
2.10.2.4 
Summary of CDLQI Subscore in LTS Period 
ITT 
2.10.3.1 
Summary of Participants in Each Category of DLQI Score From Baseline to 
Week 52 
ITT 
2.10.3.2 
Summary of Participants in Each Category of CDLQI Score From Baseline to 
Week 52 
ITT 
2.10.3.3 
Summary of Participants in Each Category of DLQI Score in LTS Period 
ITT 
2.10.3.4 
Summary of Participants in Each Category of CDLQI Score in LTS Period 
ITT 
2.10.4.1 
Summary and Analysis of Participants Achieving ≥ 4 Improvement in DLQI 
Score From Baseline to Week 52 
ITT 
2.10.4.2 
Summary and Analysis of Participants Achieving ≥ 4 Improvement in CDLQI 
Score From Baseline to Week 52 
ITT 
2.10.4.3 
Summary of Participants Achieving ≥ 4 Improvement in DLQI Score in LTS 
Period 
ITT 
2.10.4.4 
Summary of Participants Achieving ≥ 4 Improvement in CDLQI Score in LTS 
Period 
ITT 
PGIC 
2.11.1 
Summary and Analysis of Participants Achieving a PGIC Score of 1 or 2 in VC 
Period 
ITT 
2.11.2 
Summary of Participants in Each Category of PGIC Score in VC Period 
ITT 
2.11.3 
Summary of PGIC Score in VC Period 
ITT 


Incyte Co1poration 
INCB 18424-303/304 Statistical Analysis Plan 
Table No. 
Title 
EQ-5D-SL 
2.12.1 
Summaiy and Analysis ofEQ VAS Score From Baseline to Week 52 
2.12.2 
Summaiy ofEQ VAS Score in LTS Period 
WPAI-SHP 
2.13.1.1 
Summaiy and Analysis ofWPAI-SHP v2.0 Score From Baseline to Week 52 
Summaiy ofWPAI-SHP v2.0 Score in LTS Period 
Exposure, Adverse Events, Laborato1-y, and Vital Signs 
Exposure 
3.1.1.1 
Summaiy of Exposure in VC Period 
3.1.1.2 
Summaiy of Exposure From Baseline to Week 52 
3.1.1.3 
Summaiy of Exposure in LTS Period 
3.1.2 
Summaiy of Study Drug Compliance in VC Period 
Adverse Events 
3.2.1.1 
3.2.1.1.1 
3.2.1.2 
3.2.1.2.1 
3.2.1.3 
3.2.2.1 
3.2.2.1.1 
3.2.2.2 
3.2.2.2.1 
3.2.2.3 
3.2.3.1 
3.2.3.1.1 
3.2.3.2 
3.2.3.2.1 
3.2.3.3 
Overall Summa1y of Treatment-Emergent Adverse Events in VC Period 
Overall Summa1y of Treatment-Emergent Adverse Events by Age Group in VC 
Period 
Overall Summa1y of Treatment-Emergent Adverse Events From Baseline to 
Week 52 
Overall Summa1y of Treatment-Emergent Adverse Events by Age Group From 
Baseline to Week 52 
Overall Summa1y of Treatment-Emergent Adverse Events in L TS Period 
Summaiy of Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Prefen-ed Te1m in VC Period 
Summaiy of Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Prefen-ed Te1m by Age Group in VC Period 
Summaiy of Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Prefen-ed Te1m From Baseline to Week 52 
Summaiy of Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Prefen-ed Te1m by Age Group From Baseline to Week 52 
Summaiy of Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Prefen-ed Te1m in LTS Period 
Summaiy of Treatment-Emergent Adverse Events by MedDRA Prefen-ed Term 
in Decreasing Order of Frequency in VC Period 
Summaiy of Treatment-Emergent Adverse Events by MedDRA Prefen-ed Term 
in Decreasing Order of Frequency by Age Group in VC Period 
Summaiy of Treatment-Emergent Adverse Events by MedDRA Prefen-ed Term 
in Decreasing Order of Frequency From Baseline to Week 52 
Summaiy of Treatment-Emergent Adverse Events by MedDRA Prefen-ed Term 
in Decreasing Order of Frequency by Age Group From Baseline to Week 52 
Summaiy of Treatment-Emergent Adverse Events by MedDRA Prefen-ed Term 
in Decreasing Order of Frequency in LTS Period 
CONFIDENTIAL 
Page 41 of 47 
08 NOV 2019 
Population 
ITT 
ITT 
ITT 
ITT 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 
Safety 


Incyte Corporation 
Page 42 of 47 
INCB 18424-303/304 Statistical Analysis Plan 
08 NOV 2019 
CONFIDENTIAL 
Table No. 
Title 
Population 
3.2.6.1 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term in VC Period 
Safety 
3.2.6.1.1 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term by Age Group in VC Period 
Safety 
3.2.6.2 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term From Baseline to Week 52 
Safety 
3.2.6.2.1 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term by Age Group From 
Baseline to Week 52 
Safety 
3.2.6.3 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term in LTS Period 
Safety 
3.2.7.1 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency in VC Period 
Safety 
3.2.7.1.1 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency by Age Group in 
VC Period 
Safety 
3.2.7.2 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency From Baseline to 
Week 52 
Safety 
3.2.7.2.1 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency by Age Group 
From Baseline to Week 52 
Safety 
3.2.7.3 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency in LTS Period 
Safety 
3.2.8.1 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term in VC Period 
Safety 
3.2.8.1.1 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term by Age Group in VC Period 
Safety 
3.2.8.2 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term From Baseline to Week 52 
Safety 
3.2.8.2.1 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term by Age Group From Baseline to Week 52 
Safety 
3.2.8.3 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term in LTS Period 
Safety 
3.2.9.1 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency in VC Period 
Safety 
3.2.9.1.1 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency by Age Group in VC Period 
Safety 
3.2.9.2 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency From Baseline to Week 52 
Safety 
3.2.9.2.1 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency by Age Group From 
Baseline to Week 52 
Safety 
3.2.9.3 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency in LTS Period 
Safety 
3.2.10.1 
Summary of Treatment-Related Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term in VC Period 
Safety 
3.2.10.1.1 
Summary of Treatment-Related Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term by Age Group in VC Period 
Safety 


Incyte Corporation 
Page 43 of 47 
INCB 18424-303/304 Statistical Analysis Plan 
08 NOV 2019 
CONFIDENTIAL 
Table No. 
Title 
Population 
3.2.10.2 
Summary of Treatment-Related Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term From Baseline to Week 52 
Safety 
3.2.10.2.1 
Summary of Treatment-Related Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term by Age Group From 
Baseline to Week 52 
Safety 
3.2.10.3 
Summary of Treatment-Related Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term in LTS Period 
Safety 
3.2.11.1 
Summary of Treatment-Related Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency in VC Period 
Safety 
3.2.11.1.1 
Summary of Treatment-Related Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency by Age Group in 
VC Period 
Safety 
3.2.11.2 
Summary of Treatment-Related Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency From Baseline to 
Week 52 
Safety 
3.2.11.2.1 
Summary of Treatment-Related Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency by Age Group 
From Baseline to Week 52 
Safety 
3.2.11.3 
Summary of Treatment-Related Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency in LTS Period 
Safety 
3.2.14.1 
Summary of Grade 3 or Higher Treatment-Related Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred Term in VC 
Period 
Safety 
3.2.14.1.1 
Summary of Grade 3 or Higher Treatment-Related Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred Term by Age 
Group in VC Period 
Safety 
3.2.14.2 
Summary of Grade 3 or Higher Treatment-Related Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred Term From 
Baseline to Week 52 
Safety 
3.2.14.2.1 
Summary of Grade 3 or Higher Treatment-Related Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred Term by Age 
Group From Baseline to Week 52 
Safety 
3.2.14.3 
Summary of Grade 3 or Higher Treatment-Related Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred Term in LTS 
Period 
Safety 
3.2.15.1 
Summary of Treatment-Related Serious Treatment-Emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term in VC Period 
Safety 
3.2.15.1.1 
Summary of Treatment-Related Serious Treatment-Emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term by Age Group in VC 
Period 
Safety 
3.2.15.2 
Summary of Treatment-Related Serious Treatment-Emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term From Baseline to 
Week 52 
Safety 
3.2.15.2.1 
Summary of Treatment-Related Serious Treatment-Emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term by Age Group From 
Baseline to Week 52 
Safety 
3.2.15.3 
Summary of Treatment-Related Serious Treatment-Emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term in LTS Period 
Safety 
3.2.16.1 
Summary of Treatment-Emergent Adverse Events With a Fatal Outcome by 
MedDRA System Organ Class and Preferred Term in VC Period 
Safety 


Incyte Corporation 
Page 44 of 47 
INCB 18424-303/304 Statistical Analysis Plan 
08 NOV 2019 
CONFIDENTIAL 
Table No. 
Title 
Population 
3.2.16.1.1 
Summary of Treatment-Emergent Adverse Events With a Fatal Outcome by 
MedDRA System Organ Class and Preferred Term by Age Group in VC Period 
Safety 
3.2.16.2 
Summary of Treatment-Emergent Adverse Events With a Fatal Outcome by 
MedDRA System Organ Class and Preferred Term From Baseline to Week 52 
Safety 
3.2.16.2.1 
Summary of Treatment-Emergent Adverse Events With a Fatal Outcome by 
MedDRA System Organ Class and Preferred Term by Age Group From 
Baseline to Week 52 
Safety 
3.2.16.3 
Summary of Treatment-Emergent Adverse Events With a Fatal Outcome by 
MedDRA System Organ Class and Preferred Term in LTS Period 
Safety 
3.2.19.1 
Summary of Treatment-Emergent Adverse Events Leading to Dose Interruption 
by MedDRA System Organ Class and Preferred Term in VC Period 
Safety 
3.2.19.1.1 
Summary of Treatment-Emergent Adverse Events Leading to Dose Interruption 
by MedDRA System Organ Class and Preferred Term by Age Group in VC 
Period 
Safety 
3.2.19.2 
Summary of Treatment-Emergent Adverse Events Leading to Dose Interruption 
by MedDRA System Organ Class and Preferred Term From Baseline to 
Week 52 
Safety 
3.2.19.2.1 
Summary of Treatment-Emergent Adverse Events Leading to Dose Interruption 
by MedDRA System Organ Class and Preferred Term by Age Group From 
Baseline to Week 52 
Safety 
3.2.19.3 
Summary of Treatment-Emergent Adverse Events Leading to Dose Interruption 
by MedDRA System Organ Class and Preferred Term in LTS Period 
Safety 
3.2.20.1 
Summary of Treatment-Emergent Adverse Events Leading to Discontinuation 
of Study Drug by MedDRA System Organ Class and Preferred Term in VC 
Period 
Safety 
3.2.20.1.1 
Summary of Treatment-Emergent Adverse Events Leading to Discontinuation 
of Study Drug by MedDRA System Organ Class and Preferred Term by Age 
Group in VC Period 
Safety 
3.2.20.2 
Summary of Treatment-Emergent Adverse Events Leading to Discontinuation 
of Study Drug by MedDRA System Organ Class and Preferred Term From 
Baseline to Week 52 
Safety 
3.2.20.2.1 
Summary of Treatment-Emergent Adverse Events Leading to Discontinuation 
of Study Drug by MedDRA System Organ Class and Preferred Term by Age 
Group From Baseline to Week 52 
Safety 
3.2.20.3 
Summary of Treatment-Emergent Adverse Events Leading to Discontinuation 
of Study Drug by MedDRA System Organ Class and Preferred Term in LTS 
Period 
Safety 
3.2.21.1 
Summary of Treatment-Emergent Adverse Events Requiring Concomitant 
Medications by MedDRA System Organ Class and Preferred Term in VC 
Period 
Safety 
3.2.21.1.1 
Summary of Treatment-Emergent Adverse Events Requiring Concomitant 
Medications by MedDRA System Organ Class and Preferred Term by Age 
Group in VC Period 
Safety 
3.2.21.2 
Summary of Treatment-Emergent Adverse Events Requiring Concomitant 
Medications by MedDRA System Organ Class and Preferred Term From 
Baseline to Week 52 
Safety 
3.2.21.2.1 
Summary of Treatment-Emergent Adverse Events Requiring Concomitant 
Medications by MedDRA System Organ Class and Preferred Term by Age 
Group From Baseline to Week 52 
Safety 


Incyte Corporation 
Page 45 of 47 
INCB 18424-303/304 Statistical Analysis Plan 
08 NOV 2019 
CONFIDENTIAL 
Table No. 
Title 
Population 
3.2.21.3 
Summary of Treatment-Emergent Adverse Events Requiring Concomitant 
Medications by MedDRA System Organ Class and Preferred Term in LTS 
Period 
Safety 
Laboratory 
3.3.1.1 
Summary of Laboratory Values – Hematology From Baseline to Week 52 
Safety 
3.3.1.1.1 
Summary of Laboratory Values – Hematology by Age Group From Baseline to 
Week 52 
Safety 
3.3.1.2 
Summary of Laboratory Values – Hematology in LTS Period 
Safety 
3.3.2.1 
Summary of Laboratory Values – Chemistry From Baseline to Week 52 
Safety 
3.3.2.1.1 
Summary of Laboratory Values – Chemistry by Age Group From Baseline to 
Week 52 
Safety 
3.3.2.2 
Summary of Laboratory Values – Chemistry in LTS Period 
Safety 
3.3.3 
Shift Summary of Hematology Laboratory Values in CTC Grade – To the 
Worst Abnormal Value From Baseline to Week 8 
Safety 
3.3.4 
Shift Summary of Chemistry Laboratory Values in CTC Grade – To the Worst 
Abnormal Value From Baseline to Week 8 
Safety 
3.3.5 
Shift Summary of Hematology Values – To the Worst Abnormal Value 
Safety 
3.3.6 
Shift Summary of Chemistry Values – To the Worst Abnormal Value 
Safety 
Vital Signs 
3.4.1.1 
Summary of Systolic Blood Pressure From Baseline to Week 52 
Safety 
3.4.1.2 
Summary of Systolic Blood Pressure in LTS Period 
Safety 
3.4.2.1 
Summary of Diastolic Blood Pressure From Baseline to Week 52 
Safety 
3.4.2.2 
Summary of Diastolic Blood Pressure in LTS Period 
Safety 
3.4.3.1 
Summary of Pulse From Baseline to Week 52 
Safety 
3.4.3.2 
Summary of Pulse in LTS Period 
Safety 
3.4.4.1 
Summary of Respiratory Rate From Baseline to Week 52 
Safety 
3.4.4.2 
Summary of Respiratory Rate in LTS Period 
Safety 
3.4.5.1 
Summary of Body Temperature From Baseline to Week 52 
Safety 
3.4.5.2 
Summary of Body Temperature in LTS Period 
Safety 
Figure 
Figure No. 
Title 
Population 
4.1 
Proportion of Participants Achieving IGA-TS From Baseline to Week 52 
ITT 
4.2.1 
Proportion of Participants Achieving EASI75 in VC Period 
ITT 
4.2.2.1 
Mean and Standard Error Plot of EASI Score in VC Period 
ITT 
4.2.2.2 
Mean and Standard Error Plot of Change From Baseline in EASI Score in VC 
Period 
ITT 
4.2.2.3 
Mean and Standard Error Plot of Percent Change From Baseline in EASI Score in 
VC Period 
ITT 
4.3.1 
Proportion of Participants Achieving ≥ 4-point Improvement in Itch NRS Score in 
VC Period 
ITT 
4.3.2.1 
Mean and Standard Error Plot of Itch NRS Score in VC Period 
ITT 
4.3.2.2 
Mean and Standard Error Plot of Change From Baseline in Itch NRS Score in VC 
Period 
ITT 
4.3.2.3 
Mean and Standard Error Plot of Percent Change From Baseline in Itch NRS 
Score in VC Period 
ITT 


Incyte Corporation 
Page 46 of 47 
INCB 18424-303/304 Statistical Analysis Plan 
08 NOV 2019 
CONFIDENTIAL 
Figure No. 
Title 
Population 
4.3.3.1 
Mean and Standard Error Plot of Daily Itch NRS Score in VC Period 
ITT 
4.3.3.2 
Mean and Standard Error Plot of Change From Baseline in Daily Itch NRS Score 
in VC Period 
ITT 
4.3.3.3 
Mean and Standard Error Plot of Percent Change From Baseline in Daily Itch 
NRS Score in VC Period 
ITT 
4.3.4.1 
Kaplan-Meier Curve of the Time to ≥ 2-Point Improvement in Itch NRS Score in 
VC Period 
ITT 
4.3.4.2 
Kaplan-Meier Curve of the Time to ≥ 3-Point Improvement in Itch NRS Score in 
VC Period 
ITT 
4.3.4.3 
Kaplan-Meier Curve of the Time to ≥ 4-Point Improvement in Itch NRS Score in 
VC Period 
ITT 
4.4.1 
Proportion of Participants Achieving a ≥ 6-Point Improvement in the PROMIS 
Sleep Disturbance Score (8b) From Baseline to Week 52 
ITT 
4.4.2.1 
Mean and Standard Error Plot of PROMIS Sleep Disturbance Score (8b)  From 
Baseline to Week 52 
ITT 
4.4.2.2 
Mean and Standard Error Plot of Change From Baseline in PROMIS Sleep 
Disturbance Score (8b) From Baseline to Week 52 
ITT 
4.4.2.3 
Mean and Standard Error Plot of Percentage Change From Baseline in PROMIS 
Sleep Disturbance Score (8b) From Baseline to Week 52 
ITT 
4.4.3.1 
Mean and Standard Error Plot of Daily PROMIS Sleep Disturbance Score (8b) 
From Baseline to Week 52 
ITT 
4.4.3.2 
Mean and Standard Error Plot of Change From Baseline in Daily PROMIS Sleep 
Disturbance Score (8b) From Baseline to Week 52 
ITT 
4.4.3.3 
Mean and Standard Error Plot of Percent Change From Baseline in Daily 
PROMIS Sleep Disturbance Score (8b) From Baseline to Week 52 
ITT 
4.5.1 
Proportion of Participants Achieving a ≥ 6-point Improvement in the PROMIS 
Sleep-Related Impairment (8a) From Baseline to Week 52 
ITT 
4.5.2.1 
Mean and Standard Error Plot of PROMIS Sleep-Related Impairment (8a) From 
Baseline to Week 52 
ITT 
4.5.2.2 
Mean and Standard Error Plot of Change From Baseline in PROMIS 
Sleep-Related Impairment (8a) From Baseline to Week 52 
ITT 
4.5.2.3 
Mean and Standard Error Plot of Percentage Change From Baseline in PROMIS 
Sleep-Related Impairment (8a) From Baseline to Week 52 
ITT 
4.5.3.1 
Mean and Standard Error Plot of Daily PROMIS Sleep-Related Impairment (8a) 
From Baseline to Week 52 
ITT 
4.5.3.2 
Mean and Standard Error Plot of Change From Baseline in Daily PROMIS 
Sleep-Related Impairment (8a) From Baseline to Week 52 
ITT 
4.5.3.3 
Mean and Standard Error Plot of Percent Change From Baseline in Daily 
PROMIS Sleep-Related Impairment (8a) From Baseline to Week 52 
ITT 
4.6 
Kaplan-Meier Curve of the Time to First Retreatment in LTS Period 
ITT 
Listings 
Listing No. 
Title 
Baseline Demographic and Characteristic 
2.1.1 
Participant Enrollment and Disposition Status 
2.1.2 
Participant Inclusion and Exclusion Criteria Violations 
2.2 
Protocol Deviations 
2.3 
Analysis Populations 


Incyte Corporation 
Page 47 of 47 
INCB 18424-303/304 Statistical Analysis Plan 
08 NOV 2019 
CONFIDENTIAL 
Listing No. 
Title 
2.4.1 
Demographic Characteristics 
2.4.2 
Baseline Disease Characteristics 
2.4.3 
Prior and Concomitant Medications 
2.4.4 
Prior Medications for Atopic Dermatitis 
2.4.5 
Medical History 
2.5 
Study Drug Exposure and Compliance 
Efficacy 
2.6.1 
IGA Score 
2.6.2 
EASI Score 
2.6.3.1 
Itch NRS Score 
2.6.3.2 
Time to Itch Response 
2.6.4 
PROMIS Sleep Disturbance Score (8b) 
2.6.5 
PROMIS Sleep-Related Impairment Score (8a) 
2.6.6 
SCORAD Score 
2.6.7 
Skin Pain NRS Score 
2.6.8 
AD Afflicted %BSA 
2.6.9 
POEM Score 
2.6.10.1 
DLQI Score 
2.6.10.2 
CDLQI Score 
2.6.11 
EQ-5D-5L Score 
2.6.12 
WPAI-SHP v2.0 Score 
2.6.13 
PGIC Score 
2.6.14 
Treatment Cycle in LTS Period 
Adverse Events 
2.7.1 
Adverse Events 
2.7.2 
Adverse Events Leading to Drug Discontinuation 
2.7.3 
Serious Adverse Events 
2.7.4 
Treatment-Related Adverse Events 
2.7.5 
Adverse Events With a Fatal Outcome 
2.7.6 
Adverse Events Leading to Interruption of Study Drug 
2.7.7 
Adverse Events Requiring Concomitant Medications 
2.7.8 
Adverse Events with Grade 3 or Higher 
Laboratory Data 
2.8.1 
Clinical Laboratory Values - Hematology 
2.8.2 
Clinical Laboratory Values - Serum Chemistry 
2.8.3 
Abnormal Clinical Laboratory Values - Hematology 
2.8.4 
Abnormal Clinical Laboratory Values - Serum Chemistry 
2.8.5 
PK Blood Sampling Times 
Vital Signs 
2.9.1 
Vital Signs 
2.9.2 
Abnormal Vital Sign Values 
2.9.3 
Alert Vital Sign Values 


Document Number: IC-STS-SAP-0168
Title: 18424-303 and -304 SAP
Signature Manifest 
All dates and times are in Eastern Standard Time. 
18424-303 and -304 SAP 
Approval and Release 
Name/Signature 
Title 
Date 
08 Nov 2019, 02:57:20 PM 
08 Nov 2019, 03:16:04 PM 
11 Nov 2019, 10:06:50 AM 
11 Nov 2019, 10:52:11 AM 
Meaning/Reason 
Approved 
Approved 
Approved 
Approved 
Revision: 0