Clinical trial NCT04921969
Conditions: Atopic Dermatitis
Keywords: Atopic Dermatitis Ruxolitinib
Sponsor: Incyte Corporation
Start date: 2021-07-19; Completion date: 2024-04-08
Enrollment: 330 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to assess the efficacy and safety of ruxolitinib cream in children with Atopic Dermatitis. This is a randomized, double-blind, Vehicle Controlled study. Participants will be randomized 2:2:1 to blinded treatment with ruxolitinib cream 0.75% ,1.5% , or vehicle cream, with stratification by baseline IGA score and age. At Week 8, efficacy will be evaluated. Participants who complete Week 8 assessments with no additional safety concerns will continue into the 44-week Long Term Safety (LTS) period with the same treatment regimen, except those initially randomized to vehicle cream will be rerandomized (1:1) in a blinded manner to 1 of the 2 active treatment groups (ruxolitinib cream 0.75% or 1.5%).

Detailed description:

Arms: arm 1: Study drug will be administered twice daiily. arm 2: Study drug will be administered twice daily. arm 3: Vehicle cream will be administered twice daily.
Interventions: intervention 1: Ruxolitinib intervention 2: Vehicle Cream
Intervention descriptions: intervention 1: The study cream will be applied topically twice a day for up to 52 weeks. intervention 2: Matching vehicle cream will be applied topically twice a day for up to 8 weeks.

Protocol documents:
Prot_000.pdf: 
Official Title:    A Phase 3, Double-Blind, Randomized, Vehicle-Controlled, Efficacy 
and Safety Study of Ruxolitinib Cream Followed by a Long-Term Safety 
Extension Period in Children (Ages ≥ 2 Years to < 12 Years) With Atopic 
Dermatitis
NCT Number: 
 NCT04921969 
Document Date: 
 Protocol Amendment 6: 23-February-2023


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Clinical Study Protocol 
TITLE PAGE 
INCB 18424-305 
Topical Ruxolitinib Evaluation in Atopic Dermatitis Study 3 
(TRuE-AD3) 
A Phase 3, Double-Blind, Randomized, Vehicle-Controlled, Efficacy 
and Safety Study of Ruxolitinib Cream Followed by a Long-Term 
Safety Extension Period in Children (Ages ≥ 2 Years to < 12 Years) 
With Atopic Dermatitis
Product: 
Ruxolitinib Cream 
IND Number: 
 
EudraCT number: 
2021‐000489‐14 
Phase of Study: 
3 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, Delaware, USA 19803 
Original Protocol: 
25 MAR 2021 
Protocol Amendment 1: 
06 MAY 2021 
Protocol Amendment 2: 
02 AUG 2021 
Protocol Amendment 3: 
19 AUG 2021 
Protocol Amendment 4: 
06 APR 2022 
Protocol Amendment 5: 
29 JUL 2022 
Protocol Amendment 6: 
22 FEB 2023 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki (Brazil 2013) and conducted in adherence to the study Protocol, applicable Good Clinical Practices, and 
applicable laws and country-specific regulations, including WMO (Medical Research Involving Human Participants 
Act) and Clinical Trials Regulation (EU) No. 536/2014, in which the study is being conducted. 
The information in this document is confidential.  No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without prior 
written consent. 


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INVESTIGATOR'S AGREEMENT 
 
I have read the INCB 18424-305 Protocol (Amendment 6 dated 22 FEB 2023) 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 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR'S AGREEMENT ................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................9 
1. 
PROTOCOL SUMMARY ..........................................................................................11 
2. 
INTRODUCTION ......................................................................................................21 
2.1. 
Background .................................................................................................................21 
2.2. 
Pivotal Phase 3 Studies and Pilot Pediatric Study ......................................................22 
2.2.1. 
INCB 18424-303 and INCB 18424-304:  Phase 3 Adolescent/Adult Studies ...........22 
2.2.1.1. 
Safety ..........................................................................................................................22 
2.2.1.2. 
Efficacy .......................................................................................................................23 
2.2.2. 
INCB 18424-102:  Pharmacokinetic Pediatric Study .................................................25 
2.2.2.1. 
Pharmacology Results ................................................................................................26 
 
28 
2.3. 
Study Rationale ...........................................................................................................29 
2.3.1. 
Scientific Rationale for Study Design ........................................................................29 
2.3.2. 
Justification for the Selected Treatment Regimen ......................................................30 
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 ......................................................................................................36 
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 TREATMENTS............................................................................................40 
6.1. 
Study Treatments Administered .................................................................................40 


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6.1.1. 
Study Treatment Application Guidance .....................................................................41 
6.2. 
Preparation, Handling, and Accountability ................................................................42 
6.3. 
Measures to Minimize Bias:  Randomization and Blinding .......................................43 
6.4. 
Study Treatment Compliance .....................................................................................43 
6.5. 
Dose Modifications .....................................................................................................44 
6.5.1. 
Criteria and Procedures for Application Interruptions and Adjustments of 
Study Cream ...............................................................................................................44 
6.5.2. 
Criteria for Permanent Discontinuation of Study Cream Due to an Adverse 
Event ...........................................................................................................................45 
6.6. 
Concomitant Medications and Procedures .................................................................46 
6.6.1. 
Permitted Medications and Procedures ......................................................................46 
6.6.2. 
Restricted Medications and Procedures ......................................................................46 
6.6.3. 
Prohibited Medications and Procedures .....................................................................47 
6.7. 
Treatment After the End of the Study .........................................................................47 
7. 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
WITHDRAWAL ........................................................................................................48 
7.1. 
Discontinuation of Study Treatment ...........................................................................48 
7.1.1. 
Reasons for Discontinuation .......................................................................................48 
7.1.2. 
Discontinuation Procedures ........................................................................................49 
7.2. 
Participant Withdrawal From the Study .....................................................................49 
7.3. 
Lost to Follow-Up.......................................................................................................49 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................50 
8.1. 
Administrative and General Procedures .....................................................................50 
8.1.1. 
Informed Consent Process ..........................................................................................50 
8.1.2. 
Screening Procedures ..................................................................................................51 
8.1.3. 
Interactive Response Technology Procedure ..............................................................51 
8.1.4. 
Distribution of Reminder Cards and Diaries ..............................................................52 
8.1.5. 
Demography and Medical History ..............................................................................52 
8.1.5.1. 
Demographics and General Medical History .............................................................52 
8.1.5.2. 
Medical and Treatment History ..................................................................................52 
8.2. 
Efficacy Assessments .................................................................................................53 
8.2.1. 
Health Economics .......................................................................................................53 
8.2.2. 
Body Surface Area ......................................................................................................53 


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8.2.3. 
Target Lesion Identification .......................................................................................53 
8.2.4. 
Photography ................................................................................................................54 
8.2.5. 
Investigator's Global Assessment ...............................................................................54 
8.2.6. 
Eczema Area and Severity Index ................................................................................54 
8.2.7. 
Itch Numerical Rating Scale .......................................................................................55 
 
55 
8.3. 
Patient-Reported Outcome Assessments ....................................................................56 
 
56 
 
56 
 
 
57 
 
58 
 
58 
 
58 
8.4. 
Safety Assessments .....................................................................................................58 
8.4.1. 
Adverse Events ...........................................................................................................59 
8.4.2. 
Physical Examinations ................................................................................................59 
8.4.2.1. 
Comprehensive Physical Examination .......................................................................59 
8.4.2.2. 
Targeted Physical Examination ..................................................................................59 
8.4.3. 
Vital Signs, Height, and Weight .................................................................................60 
8.4.4. 
Laboratory Assessments .............................................................................................60 
 
61 
8.4.4.2. 
Pregnancy Testing ......................................................................................................61 
8.4.4.3. 
Serology ......................................................................................................................61 
 
62 
 
62 
 
62 
8.7. 
Unscheduled Visits .....................................................................................................62 
8.8. 
End of Treatment and/or Early Termination ..............................................................63 
8.9. 
Follow-Up ...................................................................................................................63 
8.9.1. 
Safety Follow-Up ........................................................................................................63 
9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................64 


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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 ..........................................................................................71 
9.8. 
Treatment of Excessive Use .......................................................................................71 
9.9. 
Product Complaints ....................................................................................................71 
10. 
STATISTICS ..............................................................................................................72 
10.1. 
Sample Size Determination ........................................................................................72 
10.2. 
Populations for Analysis .............................................................................................72 
10.3. 
Level of Significance ..................................................................................................73 
10.4. 
Statistical Analyses .....................................................................................................74 
10.4.1. 
Primary Analysis ........................................................................................................75 
10.4.2. 
Secondary Analyses ....................................................................................................76 
10.4.3. 
Safety Analyses ..........................................................................................................77 
10.4.4. 
Biomarker Analyses ....................................................................................................77 
10.5. 
Interim Analysis ..........................................................................................................77 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................78 
11.1. 
Investigator Responsibilities .......................................................................................78 
11.1.1. 
Identification of the Coordinating Principal Investigator ...........................................79 
11.2. 
Data Management .......................................................................................................79 
11.3. 
Data Quality Assurance ..............................................................................................81 
11.4. 
Data Privacy and Confidentiality of Study Records ...................................................81 
11.5. 
Financial Disclosure ...................................................................................................82 
11.6. 
Publication Policy .......................................................................................................82 
11.7. 
Study and Site Closure................................................................................................83 
12. 
REFERENCES ...........................................................................................................84 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS ...............................................................................87 


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88 
APPENDIX C. COVID-19 PANDEMIC MITIGATION STRATEGIES AND 
INSTRUCTIONS .......................................................................................................90 
APPENDIX D. BODY SURFACE AREA CALCULATION GUIDES ....................................93 
APPENDIX E. ECZEMA AREA AND SEVERITY INDEX ....................................................95 
APPENDIX F. PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................97 
 
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 Period.....................................................18 
Table 5: 
Summary of Treatment-Emergent Adverse Events Occurring in ≥ 1% of 
Participants in Any Treatment Group (Phase 3 Atopic Dermatitis 
Vehicle-Controlled Population) ..................................................................................23 
Table 6: 
Study INCB 18424-303 and Study INCB 18424-304:  Primary and Key 
Secondary Endpoints – Responders at Week 8 ..........................................................24 
Table 7: 
Objectives and Endpoints ...........................................................................................32 
Table 8: 
Study Treatment Information .....................................................................................40 
Table 9: 
Guidelines for Interruption and Restarting of Treatment Applications if 
Adverse Event Is Deemed Related to the Study Cream .............................................45 
Table 10: Investigator's Global Assessment ...............................................................................54 
Table 11: Required Laboratory Analytes ....................................................................................61 
Table 12: Populations for Analysis .............................................................................................72 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................13 
Figure 2: 
Study INCB 18424-303 and Study INCB 18424-304:  Proportions of 
Participants Who Achieved IGA-TS ..........................................................................24 
Figure 3: 
Study INCB 18424-303 and Study INCB 18424-304:  Change From 
Baseline in Daily Itch NRS Score ..............................................................................25 
Figure 4: 
Box Plots of Steady-State Plasma Concentrations Overlaid With Mean 
Values (Log10 Scale) ...................................................................................................26 


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Figure 5: 
Study 18424-102:  P1NP Concentrations for Individual Participants in 
Cohort 6 by Visit ........................................................................................................27 
 
 
28 
 
 
29 
Figure 8: 
Study Cream Application Using a Fingertip ..............................................................41 
Figure 9: 
Control of the Overall Type I Error Rate ....................................................................74 


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LIST OF ABBREVIATIONS 
Abbreviations and 
Special Terms 
Definition 
AD 
atopic dermatitis 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BID 
twice daily 
BSA 
body surface area 
 
 
CFR 
Code of Federal Regulations 
COVID-19 
coronavirus disease 2019 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
EASI 
Eczema Area and Severity Index  
EASI50/75/90 
≥ 50%/75%/90% improvement in Eczema Area and Severity Index score 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GFR 
glomerular filtration rate 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
IB 
Investigator's Brochure 
ICF 
informed consent form  
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
 
 
IEC 
independent ethics committee 
IGA 
Investigator's Global Assessment 
IGA-TS 
Investigator's Global Assessment Treatment Success  


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Abbreviations and 
Special Terms 
Definition 
IL 
interleukin 
IRB 
institutional review board 
IRT 
interactive response technology  
ITT 
intent-to-treat 
JAK 
Janus kinase 
LLN 
lower limit of normal 
LTS 
long-term safety 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numerical Rating Scale 
P1NP 
procollagen type 1 N-terminal propeptide 
PD 
pharmacodynamic 
PDE4 
phosphodiesterase 4 
 
 
PK 
pharmacokinetics 
 
   
PP 
per protocol 
 
 
 
 
 
 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SoA 
schedule of activities 
SOP 
standard operating procedure 
SPF 
sun protection factor 
Study cream 
This term refers to Incyte medicinal investigational product(s) or matching 
placebo(s) used for this study. 
Study treatment 
This term refers to all medications that the participant is required to receive 
as part of this study. 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
UV 
ultraviolet 
 
 
VC 
vehicle-controlled 


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1. 
PROTOCOL SUMMARY 
Protocol Title: 
Topical Ruxolitinib Evaluation in Atopic Dermatitis Study 3 (TRuE-AD3) 
A Phase 3, Double-Blind, Randomized, Vehicle-Controlled, Efficacy and Safety Study of 
Ruxolitinib Cream Followed by a Long-Term Safety Extension Period in Children (Ages 
≥ 2 Years to < 12 Years) With Atopic Dermatitis 
Protocol Number:  INCB 18424-305 
Objectives and Endpoints: 
Table 1 presents the primary and key secondary objectives and endpoints. 
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 who achieve IGA-TS at 
Week 8. 
Key Secondary 
To further assess the treatment effects of 
ruxolitinib cream. 
Proportion of participants with a ≥ 4-point 
improvement in Itch NRS score from baseline to 
Week 8. 
Proportion of participants with a ≥ 4-point 
improvement in Itch NRS score from baseline to 
Day 7 (Week 1). 
Proportion of participants with a ≥ 4-point 
improvement in Itch NRS score from baseline to 
Day 3. 
Overall Design: 
Table 2 presents the key study design elements.  Further study details are presented after the 
table. 


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Table 2: 
Key Study Design Elements 
Study Phase 
Phase 3 
Clinical Indication 
Atopic dermatitis 
Population 
Children aged ≥ 2 years to < 12 years (with at least 40% of 
participants ages ≥ 2 years to 6 years) who have been diagnosed 
with AD for at least 3 months, have an IGA score of 2 to 3, and have 
%BSA involvement (excluding the scalp) of 3% to 20%. 
Number of Participants 
Approximately 315 participants will be randomized 2:2:1 to 1 of 
3 treatment groups (ruxolitinib cream 0.75% BID [n = 126], 
ruxolitinib cream 1.5% BID [n = 126], or vehicle cream BID 
[n = 63]).  The study will be conducted at approximately 60 sites in 
the United States and Canada. 
Study Design 
Randomized (2:2:1), double-blind, VC period (8 weeks) followed by 
an LTS period (44 weeks) and a 30-day safety follow-up period after 
the last application of study cream.  In the LTS period, participants 
initially randomized to vehicle cream will be rerandomized (1:1) in a 
blinded manner to ruxolitinib cream 0.75% or 1.5%, and participants 
initially randomized to an active treatment group will continue in the 
same treatment group.  
Estimated Duration of Study 
Participation 
Screening period:  up to 28 (+ 7) days 
VC period:  approximately 8 weeks 
LTS period:  approximately 44 weeks 
Safety follow-up period:  30 days after the last application of study 
treatment or last study visit 
Total:  up to approximately 61 weeks 
Data Safety Monitoring 
Board/Data Monitoring 
Committee 
No 
Coordinating Principal 
Investigator 
, MD 
Treatment Groups and Duration: 
Male and female children aged ≥ 2 years to < 12 years who have been diagnosed with AD for at 
least 3 months and have an IGA score of 2 to 3 and %BSA involvement (excluding the scalp) of 
3% to 20% will be eligible to participate in the study.  Participants who have met all of the 
inclusion criteria during the screening period (up to 28 days or up to 35 days for participants 
taking prior medications that require a 4-week washout period [see Section 5.2, Exclusion 
Criterion 6b]) will be enrolled (randomized 2:2:1) and receive blinded treatment with ruxolitinib 
0.75% cream BID, ruxolitinib 1.5% cream BID, or vehicle cream for a total treatment duration of 
8 weeks during the VC period of the study. 
Participants who complete the Week 8 assessments with no additional safety concerns will 
continue into the 44-week LTS period with the same treatment regimen, except those initially 
treated with vehicle cream will be rerandomized (1:1) in a blinded manner to 1 of the 2 active 


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treatment groups (ruxolitinib cream 0.75% or 1.5% BID).  The IGA score required for 
participants to enter the LTS period is 0 to 4, and participants must have a %BSA in the range of 
0% to 20% (excluding the scalp). 
Following the end of treatment (Week 52/EOT or ET), all participants will have a safety 
follow-up visit 30 days later (or 30 days after the last application of study treatment if the 
Week 52/EOT or ET visit was not performed). 
Figure 1 presents the study design schema, and Table 3 (VC period) and Table 4 (LTS period) 
present the SoA.  Adherence to the study design requirements, including those specified in the 
SoA, is essential and required for study conduct. 
Figure 1: 
Study Design Schema 
 
 


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Table 3: 
Schedule of Activities:  Vehicle-Controlled Period 
Visit Day (Range) 
Screening 
VC Period 
Notes and Protocol Section 
Days −28 
(+ 7a) to −1 
Day 1/ 
Baseline 
Wk 2 
(± 3 d) 
Wk 4 
(± 3 d) 
Wk 8b/ET 
(± 3 d) 
Administrative procedures 
Informed consent/assent 
X 
 
 
 
 
Section 8.1.1. 
Contact IRT 
X 
X 
X 
X 
X 
Section 8.1.3. 
Inclusion/exclusion criteria 
X 
X 
 
 
 
Section 5. 
Demography and general medical 
history 
X* 
 
 
 
 
Section 8.1.5.1. 
*Height and weight of both parents, if available, should be obtained and 
entered into the EDC. 
Relevant AD medical and 
treatment history 
X 
 
 
 
 
Section 8.1.5.2. 
Collect/obtain growth 
measurements for the year prior to 
study entry 
X* 
X* 
 
 
 
Section 8.4.3. 
*Collected at either screening or baseline.  A reasonable effort must be 
made to collect and document measurements prior to baseline.  If unable 
to obtain, the reason should be documented. 
Prior/concomitant medications and 
procedures 
X 
X 
X 
X 
X 
Section 6.6. 
Apply study cream at site 
 
X 
X 
X 
X* 
Section 6.1; at each visit (except for the Week 8 visit if IGA is 0), 
starting at Day 1, the participant should apply the first (morning) 
application under direct site staff supervision to all areas identified at 
Day 1, even if the AD lesion is cleared or disappeared. 
*Not applicable to the ET visit. 
Weigh and dispense study cream; 
dispense diary cards 
 
X 
X 
X 
X* 
Section 6.1 and Section 8.1.4. 
* Not applicable to the Week 8 visit if IGA score = 0 or to the ET visit. 
Collect and weigh study cream; 
collect diary cards 
 
 
X 
X 
X 
Section 6.1. 
Assess compliance 
 
 
X 
X 
X 
Section 6.4. 
Safety assessments 
AE assessment 
X 
X 
X 
X 
X 
Section 8.4.1. 
Comprehensive physical 
examination 
X 
 
 
 
X* 
Section 8.4.2.1. 
*For the ET visit only. 


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Table 3: 
Schedule of Activities:  Vehicle-Controlled Period (Continued) 
Visit Day (Range) 
Screening 
VC Period 
Notes and Protocol Section 
Days −28 
(+ 7a) to −1 
Day 1/ 
Baseline 
Wk 2 
(± 3 d) 
Wk 4 
(± 3 d) 
Wk 8b/ET 
(± 3 d) 
Safety assessments (continued) 
Targeted physical examination* 
 
X 
X 
X 
X† 
Section 8.4.2.2.  
*Conducted only when indicated by symptoms reported by participant 
(ie, AEs or other findings); clinically significant abnormalities (in the 
investigator's judgment) are to be reported as AEs. 
†Not done for the ET visit. 
Height and weight 
 
X 
 
 
X 
Section 8.4.3; height should be measured with a stadiometer. 
Vital signs 
X 
X 
X 
X 
X 
Section 8.4.3; vital signs are taken before blood sampling and other 
procedures. 
Efficacy assessments 
Evaluate %BSA affected by AD 
(excluding skin dryness) 
X 
X 
X 
X 
X* 
Section 8.2.2; evaluate %BSA (excluding the scalp) affected by active 
AD lesions using the handprint method. 
*At Week 8, the %BSA range is 0% to ≤ 20% for the LTS period.  
Target lesion identification 
X 
X* 
 
 
 
Section 8.2.3; the longest diameter and the span perpendicular to the 
longest diameter will be measured in centimeters. 
*For photography participants, a lesion of ≥ 5 cm2 (target lesion) is to be 
identified at screening and confirmed at the baseline visit (excluding the 
hands, feet, and genitalia). 
Photography (target lesion and 
regional body area)* 
 
X 
X 
X 
X 
Section 8.2.4; photography of the target lesion area identified at 
Day 1/baseline even if the lesion has cleared. 
*Performed only for photography participants at selected sites. 
IGA 
X 
X 
X 
X 
X* 
Section 8.2.5. 
*At Week 8, the IGA range is 0 to 4 for the LTS period. 
EASI 
X 
X 
X 
X 
X 
Section 8.2.6; evaluate EASI in 4 regions (head/neck, upper limbs, 
trunk, and lower limbs) and overall. 
Itch NRS 
eDiary is completed each evening from screening through 
the last application of study cream during the VC period 
(night prior to Week 8 visit). 
Section 8.2.7; baseline itch (defined as the average of at least 4 of the 
7 days directly before Day 1) must be NRS ≥ 4. 
Note:  Itch is collected from participants ≥ 6 years of age. 


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Table 3: 
Schedule of Activities:  Vehicle-Controlled Period (Continued) 
Visit Day (Range) 
Screening 
VC Period 
Notes and Protocol Section 
Days −28 
(+ 7a) to −1 
Day 1/ 
Baseline 
Wk 2 
(± 3 d) 
Wk 4 
(± 3 d) 
Wk 8b/ET 
(± 3 d) 
Laboratory assessments 
Blood draws for clinical laboratory tests must be performed before the 
in-clinic study cream application. 
Use of a topical anesthetic prior to blood draw is recommended. 
Serum chemistries 
X 
X* 
X 
 
X 
Section 8.4.4. 
*Day 1 testing will be performed only if the interval between this visit 
and the screening visit is > 2 weeks. 
Hematology 
X 
X* 
X 
 
X 
Section 8.4.4. 
*Day 1 testing will be performed only if the interval between this visit 
and the screening visit is > 2 weeks. 
Serology 
X* 
 
 
 
 
Section 8.4.4.3.  
*HIV antibody. 
Pregnancy testing 
X 
X* 
 
 
X 
Section 8.4.4.2; at the indicated visits, only female participants who 
have reached menarche will undergo a urine pregnancy test.  A positive 
urine test must be confirmed by a serum test. 
*Day 1 testing will be performed only if the interval between this visit 
and screening is > 2 weeks. 


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Table 3: 
Schedule of Activities:  Vehicle-Controlled Period (Continued) 
Visit Day (Range) 
Screening 
VC Period 
Notes and Protocol Section 
Days −28 
(+ 7a) to −1 
Day 1/ 
Baseline 
Wk 2 
(± 3 d) 
Wk 4 
(± 3 d) 
Wk 8b/ET 
(± 3 d) 
Note:  Unscheduled visits may occur at any time at the investigator's discretion, and appropriate clinical and laboratory tests may be performed as clinically indicated. 
a For prior medications that require a 4-week washout period (see Section 5.2, Exclusion Criterion 6b), a 35-day screening period is allowed. 
b Week 8 is the baseline for participants eligible to continue in the LTS period (IGA score = 0-4 and BSA = 0%-20%). 


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Table 4: 
Schedule of Activities:  Long-Term Safety Period 
Visit Day (Range) 
LTS Period 
Unscheduled 
Visit 
Safety Follow-Up 
Notes and Protocol Section 
Wk 12 
(± 7 d) 
Wk 16, 
20, and 24 
(± 7 d) 
Wk 28, 
32, and 36 
(± 7 d) 
Wk 40, 
44, and 48 
(± 7 d) 
Wk 52/ 
EOT/ET 
(± 7 d) 
30 (+ 7) Days After 
Last Study Cream 
Applicationa 
Administrative procedures 
Contact IRT 
X 
X 
X 
X 
X 
X 
X 
Section 8.1.3. 
Prior/concomitant 
medications and procedures 
X 
X 
X 
X 
X 
X 
X 
Section 6.6. 
Apply study cream at site 
X 
X 
X 
X 
 
 
 
Section 6.1; only for participants with active 
AD lesions at time of visit; apply the first 
(morning) application under direct site staff 
supervision. 
Weigh and dispense study 
cream; dispense diary cards 
X 
X 
X 
X 
 
 
 
Section 6.1 and Section 8.1.4. 
Collect and weigh study 
cream; collect diary cards 
X 
X 
X 
X 
X 
 
 
Section 6.1. 
Record start and end dates 
of treatment cycle(s) 
X 
X 
X 
X 
X 
 
 
Section 6.1; the start/end date will have been 
recorded by the participant.  The end date 
should be 3 days after lesions clear; however, 
if this 3-day window is during a study visit 
and IGA score = 0, stop treatment and record 
the date of the study visit as the treatment 
cycle end date. 
Assess compliance 
X 
X 
X 
X 
X 
 
 
Section 6.4. 
Safety assessments 
AE assessments 
X 
X 
X 
X 
X 
X 
X 
Section 8.4.1. 
Comprehensive physical 
examination 
 
 
 
 
X 
 
 
Section 8.4.2.1. 
Targeted physical 
examination 
X 
X 
X 
X 
 
X 
X 
Section 8.4.2.2; conducted only when 
indicated by symptoms reported by 
participant (AEs or other findings); clinically 
significant abnormalities (in the investigator's 
judgment) are to be reported as AEs. 


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Table 4: 
Schedule of Activities:  Long-Term Safety Period (Continued) 
Visit Day (Range) 
LTS Period 
Unscheduled 
Visit 
Safety Follow-Up 
Notes and Protocol Section 
Wk 12 
(± 7 d) 
Wk 16, 
20, and 24 
(± 7 d) 
Wk 28, 
32, and 36 
(± 7 d) 
Wk 40, 
44, and 48 
(± 7 d) 
Wk 52/ 
EOT/ET 
(± 7 d) 
30 (+ 7) Days After 
Last Study Cream 
Applicationa 
Safety assessments (continued) 
Height and weight 
 
X* 
 
 
X 
 
 
Section 8.4.3; height should be measured 
with a stadiometer. 
*Only at Week 24. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Section 8.4.3; vital signs are taken before 
blood sampling and other procedures.  
Disease severity assessments 
Evaluate %BSA affected by 
active AD lesions 
X 
X 
X 
X 
X 
X 
X 
Section 8.2.2; evaluate %BSA (excluding the 
scalp) affected by active AD lesions using 
the handprint method. 
IGA 
X 
X 
X 
X 
X 
X 
X 
Section 8.2.5. 


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Table 4: 
Schedule of Activities:  Long-Term Safety Period (Continued) 
Visit Day (Range) 
LTS Period 
Unscheduled 
Visit 
Safety Follow-Up 
Notes and Protocol Section 
Wk 12 
(± 7 d) 
Wk 16, 
20, and 24 
(± 7 d) 
Wk 28, 
32, and 36 
(± 7 d) 
Wk 40, 
44, and 48 
(± 7 d) 
Wk 52/ 
EOT/ET 
(± 7 d) 
30 (+ 7) Days After 
Last Study Cream 
Applicationa 
Laboratory assessments 
Blood draws for clinical laboratory tests must 
be performed before the in-clinic study 
cream application. 
Serum chemistries 
X 
X* 
X* 
X* 
X 
X 
X 
Section 8.4.4. 
*Only at Weeks 16, 24, 32, 40, and 48. 
Hematology 
X 
X* 
X* 
X* 
X 
X 
X 
Section 8.4.4. 
*Only at Weeks 16, 24, 32, 40, and 48. 
Pregnancy testing 
 
X* 
X* 
X* 
 
 
X 
Section 8.4.4.2; at the indicated visits, only 
female participants who have reached 
menarche will have urine pregnancy test.  A 
positive urine test must be confirmed by a 
serum test. 
*Only at Weeks 16, 24, 32, 40, and 48. 
Note:  Unscheduled visits may occur at any time at the investigator's discretion, and appropriate clinical and laboratory tests may be performed as clinically indicated. 
a Except for participants who have been in an observation/no treatment cycle with a total IGA score of 0 (clear) from Week 48 or earlier until Week 52; such participants should 
complete the safety follow-up and Week 52/EOT visits together. In practice, this would mean conducting all Week 52/EOT visit assessments plus the pregnancy test at the 
Week 52/EOT visit. 


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2. 
INTRODUCTION 
2.1. 
Background 
Ruxolitinib cream is a topical formulation of ruxolitinib phosphate under development for the 
treatment of patients with AD and vitiligo and was investigated earlier in alopecia areata and 
plaque psoriasis.  Ruxolitinib phosphate is an inhibitor of the JAK family of protein tyrosine 
kinases.  Inflammatory cytokines are strongly implicated in the pathogenesis of several 
dermatologic diseases.  Because JAKs serve to translate extracellular signals from a number of 
relevant cytokines and growth factors upregulated in inflammatory diseases such as AD, alopecia 
areata, plaque psoriasis, and vitiligo, JAK inhibitors represent potential therapeutic agents for 
these disease states (Howell et al 2019). 
Atopic dermatitis is a chronic, recurring, inflammatory, and highly pruritic skin condition that 
affects up to 25% of children and up to 12% of adults worldwide (Eichenfield et al 2014, Hanifin 
et al 2007, Harrop et al 2007, Rönmark et al 2012, Vinding et al 2014) and is one of the most 
common dermatoses encountered by pediatric health care providers.  Although 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).  According to the 
recent Global Burden of Disease project, AD is one of the 50 most prevalent diseases worldwide 
and has the second highest disability ranking of all nonmalignant skin diseases (Hay et al 2014). 
The clinical pattern of AD varies with age and generally develops during the first 5 years of life 
in 90% of patients (but not in the first weeks of life, as seen in the autosomal dominant 
hyper-immunoglobulin E syndrome; Lyons et al 2015).  Infants usually show acute erythematous 
and often exudative papules on the face or scalp, which are often intensely pruritic.  The 
childhood phase (2 years of age to puberty) and adult phase 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), which 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. 
In addition to the allergy-related sequelae of AD affecting the skin, recent reports have shown 
that children with AD, compared to those without AD, are at a higher risk of developing 
psychosocial comorbidities such as attention-deficit/hyperactivity disorder and depression 
(de la O-Escamilla and Sidbury 2020, Hong et al 2019, van der Schans et al 2017, 
Yaghmaie et al 2013).  Sleep disturbance, both in pediatric patients and their parents/caregivers, 
is also common and can significantly impair quality of life (Chang and Chiang 2018, 
Ramirez et al 2019, Yang et al 2019). 
Despite the availability of a number of treatment options, there is still a significant medical need 
for safe topical therapies that provide rapid and effective control of the signs and symptoms of 
AD and that are also both effective and safe, particularly in children.  Moderate to potent topical 
corticosteroids and calcineurin inhibitors have well-known safety restrictions limiting their use to 
4 and 8 weeks, respectively.  In addition, a PDE4 inhibitor, 2% crisaborole (Eucrisa®) ointment, 
was recently approved in the United States for patients aged 3 months and older with mild to 


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moderate AD and has no such safety limitations but was shown to have modest efficacy 
(Eucrisa 2020). 
For patients with more severe AD, the most recent addition to the systemic drug armamentarium 
is dupilumab (Dupixent® 2020).  Dupilumab is a monoclonal humanized antibody against 
IL-4Rα that blocks the action of IL-4 and IL-13 and was approved for adult patients with 
moderate to severe AD in 2017 and most recently in children aged 6 years and older in the 
United States (Dupixent 2020). 
Studies with oral JAK inhibitors (tofacitinib and baricitinib) indicated that these drugs may be 
effective in the treatment of patients with AD (Levy et al 2015, Napolitano et al 2020) 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).  Consequently, efforts have been made to find new treatment 
possibilities that would more appropriately address the medical needs of patients with AD. 
Janus kinases are intracellular signaling enzymes that act downstream of key proinflammatory 
cytokines known to promote the pathogenesis of AD.  Ruxolitinib (INCB018424) is a potent and 
selective JAK1 and JAK2 inhibitor that is currently approved for use in tablet form for the 
treatment of patients with myelofibrosis and polycythemia vera in multiple countries and acute 
graft-versus-host disease in the United States.  Recent studies suggest that JAK inhibition may 
have antipruritic effects by acting directly on sensory nerve fibers and may offer a novel 
therapeutic approach with dual anti-inflammatory and antipruritic properties. 
Nonclinical pharmacology, PK/PD, and toxicology data for ruxolitinib cream from in vitro and 
in vivo model systems support the use of topically applied ruxolitinib cream for the treatment of 
patients with AD, psoriasis, vitiligo, and other inflammatory diseases of the skin.  Refer to the 
ruxolitinib cream IB for a summary of findings from the nonclinical studies. 
2.2. 
Pivotal Phase 3 Studies and Pilot Pediatric Study 
2.2.1. 
INCB 18424-303 and INCB 18424-304:  Phase 3 Adolescent/Adult Studies 
The ruxolitinib cream Phase 3 studies (INCB 18424-303 and INCB 18424-304) confirmed that 
1.5% ruxolitinib cream applied BID for 8 weeks is a highly effective treatment for participants 
with AD and is not associated with safety concerns.  A lower strength of ruxolitinib cream 
(0.75% BID for 8 weeks) was also investigated in these trials.  While its safety profile was not 
different from that of 1.5% cream, it was less efficacious than the higher strength. 
2.2.1.1. 
Safety 
The primary analysis of the safety of ruxolitinib cream is based on pooled data from the VC 
period of the 2 confirmatory Phase 3 studies, INCB 18424-303 and INCB 18424-304 (ie, the 
Phase 3 AD VC population), in 1249 adolescents and adults with AD.  Participants were 
randomized 2:2:1 to ruxolitinib 0.75% cream BID (500 participants), ruxolitinib 1.5% cream 
BID (499 participants), or vehicle cream BID (250 participants). 
The most frequently reported TEAEs during the VC period are summarized in Table 5 and were 
consistent with the types of events that are common in patients with AD.  The overall rate of 


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TEAEs in both studies after 8 weeks of treatment was comparable between the ruxolitinib cream 
regimens (0.75% BID, 29.0%; 1.5% BID, 26.5%) and vehicle cream (33.2%). 
Table 5: 
Summary of Treatment-Emergent Adverse Events Occurring in ≥ 1% of 
Participants in Any Treatment Group (Phase 3 Atopic Dermatitis 
Vehicle-Controlled Population) 
MedDRA Preferred Term, n (%) 
Vehicle Cream 
BID 
(N = 250) 
Ruxolitinib Cream Regimen 
Ruxolitinib 
Cream Total 
(N = 999) 
0.75% BID 
(N = 500) 
1.5% BID 
(N = 499) 
Participants with any TEAE 
83 (33.2) 
145 (29.0) 
132 (26.5) 
277 (27.7) 
Nasopharyngitis 
2 (0.8) 
15 (3.0) 
13 (2.6) 
28 (2.8) 
Upper respiratory tract infection 
5 (2.0) 
7 (1.4) 
12 (2.4) 
19 (1.9) 
Headache 
5 (2.0) 
4 (0.8) 
11 (2.2) 
15 (1.5) 
Oropharyngeal pain 
3 (1.2) 
3 (0.6) 
5 (1.0) 
8 (0.8) 
Application site paina 
12 (4.8) 
3 (0.6) 
4 (0.8) 
7 (0.7) 
Application site pruritus 
7 (2.8) 
5 (1.0) 
1 (0.2) 
6 (0.6) 
Pruritus 
4 (1.6) 
2 (0.4) 
4 (0.8) 
6 (0.6) 
Dermatitis atopicb 
11 (4.4) 
1 (0.2) 
2 (0.4) 
3 (0.3) 
a  Event lowest level terms included application site burning, application site stinging, and pain after application. 
b Reported terms of atopic dermatitis flare, atopic dermatitis exacerbation, exacerbation of atopic dermatitis, intensification of 
atopic dermatitis, worsening of atopic dermatitis, flare of atopic dermatitis. 
The frequency of application site reactions was low (1.6% and 1.0% in participants who applied 
ruxolitinib 0.75% and 1.5% cream BID, respectively, and 7.6% in participants who applied 
vehicle cream BID); no clinically significant application site reactions were observed, including 
areas of sensitive skin (eg, the face).  The rate of SAEs was comparable among all treatment 
groups (0.75% ruxolitinib BID, 0.8%; 1.5% ruxolitinib BID, 0.6%; vehicle cream BID, 0.8%).  
Long-term safety data (44-week extension period of both studies) did not identify any safety 
concerns with prolonged intermittent use of ruxolitinib cream. 
2.2.1.2. 
Efficacy 
In Study INCB 18424-303 and Study INCB 18424-304, significantly more participants achieved 
IGA-TS with application of ruxolitinib cream 0.75% BID (50.0% and 39.0%) and 1.5% BID 
(53.8% and 51.3%) versus vehicle cream (15.1% and 7.6%; all p < 0.0001; see Figure 2), 
respectively. 


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Figure 2: 
Study INCB 18424-303 and Study INCB 18424-304:  Proportions of 
Participants Who Achieved IGA-TS 
INCB 18424-303  
 
 
 
 
 
 
 
INCB 18424-304 
 
In Study INCB 18424-303 and Study INCB 18424-304, EASI75 was achieved by 56.0% and 
51.5% of participants applying ruxolitinib cream 0.75% BID, 62.1% and 61.8% of participants 
applying ruxolitinib cream 1.5% BID, and 24.6% and 14.4% of participants applying vehicle 
cream (all p < 0.0001), respectively.  A summary of the primary and select key secondary 
endpoints of responders at Week 8 is shown in Table 6. 
Table 6: 
Study INCB 18424-303 and Study INCB 18424-304:  Primary and Key 
Secondary Endpoints – Responders at Week 8 
 
INCB 18424-303 
INCB 18424-304 
Vehicle 
Cream 
BID 
(N = 126) 
Ruxolitinib 
0.75% 
Cream BID 
(N = 252) 
Ruxolitinib 
1.5% 
Cream BID 
(N = 253) 
Vehicle 
Cream 
BID 
(N = 118) 
Ruxolitinib 
0.75% 
Cream BID 
(N = 231) 
Ruxolitinib 
1.5% 
Cream BID 
(N = 228) 
IGA-TSa 
15.1% 
50.0%b 
53.8%b 
7.6% 
39.0%b 
51.3%b 
EASI75c 
24.6%  
56.0%b 
62.1%b 
14.4% 
51.5%b 
61.8%b 
Itch NRS (≥ 4-point 
reduction)d 
15.4%  
40.4%e 
52.2%b 
16.3% 
42.7%b 
50.7%b 
a IGA-TS was defined as an IGA score of 0 or 1 with a ≥ 2-grade improvement from baseline. 
b p < 0.0001, ruxolitinib cream versus vehicle. 
c An EASI75 responder was defined as a participant achieving ≥ 75% improvement from baseline in EASI score. 
d An Itch 4 NRS responder was defined as a participant achieving a ≥ 4-point improvement from baseline in Itch NRS score.  
The denominator includes participants in the ITT population with baseline Itch NRS score ≥ 4. 
e p < 0.001, ruxolitinib cream versus vehicle cream. 
In both studies, significantly greater itch reduction was observed within 12 hours of the first 
application of ruxolitinib cream 1.5% BID versus vehicle cream (p < 0.05; see Figure 3).  At 
Week 8, clinically meaningful reduction (≥ 4-point improvement in Itch NRS score) was 
achieved by more participants who applied ruxolitinib cream (0.75% BID, 40.4% and 42.7%; 
1.5% BID, 52.2% and 50.7%) versus vehicle cream (15.4% and 16.3%, respectively; all 
p < 0.0001). 


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Figure 3: 
Study INCB 18424-303 and Study INCB 18424-304:  Change From Baseline 
in Daily Itch NRS Score 
INCB 18424-303  
 
 
 
 
 
 
 
INCB 18424-304 
 
Overall, ruxolitinib cream demonstrated superior efficacy versus vehicle cream for endpoints 
including IGA-TS, EASI75, and ≥ 4-point improvement in Itch NRS score.  The safety profile 
was similar to that of vehicle cream and consistent between the 2 studies, and the rate of 
application site reactions was low. 
2.2.2. 
INCB 18424-102:  Pharmacokinetic Pediatric Study 
The pilot pediatric study (INCB 18424-102), an open-label, descending age (≥ 12 to 17 years, 
≥ 7 to < 12 years, and ≥ 2 to < 7 years), and increasing treatment strength (0.5%, 0.75%, or 
1.5%) trial, was conducted to explore primarily the safety of several treatment regimens with 
ruxolitinib cream.  Although not a dose range–finding study, it showed that the efficacy and 
safety of ruxolitinib cream 0.75% and 1.5% BID were similar in this pediatric age population to 
that in adolescents and adults with AD. 
The results of Study INCB 18424-102 indicate that ruxolitinib cream at the 0.5%, 0.75%, and 
1.5% strengths was safe and well-tolerated when administered BID for 4 weeks to pediatric 
participants with AD (aged ≥ 2 to 17 years).  A summary of the results is listed below: 
• There were no serious TEAEs or TEAEs with a fatal outcome.  One participant 
(7.1%) in Cohort 6 (≥ 2 to < 7 years; ruxolitinib 1.5% cream BID) had a 
treatment-related TEAE of decreased neutrophil count with onset on Day 9 that led to 
study cream discontinuation.  The event was Grade 1 in severity and resolved after 
49 days. 
• The overall incidences of TEAEs were highest among participants ≥ 12 to 17 years 
old (50.0% and 45.5% for Cohorts 1 and 2, respectively) and did not vary according 
to ruxolitinib cream strength.  Treatment-emergent AEs were Grade 1 or 2 in severity 
with the exception of 2 Grade 3 events, tooth fracture and lip injury, in a participant 
in Cohort 3 (≥ 7 to < 12 years; ruxolitinib 0.75% cream BID). 


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• The most frequently reported TEAEs overall were headache (5.6%), atopic dermatitis 
(reported as worsening, flares, or exacerbations of atopic dermatitis; 4.2%), and otitis 
media and upper respiratory tract infection (2.8% each). 
• The incidence of application site reaction TEAEs was low:  1 participant (10.0%) in 
Cohort 1 (≥ 12 to 17 years; ruxolitinib 0.5% cream BID) had an event of application 
site urticaria, and 1 participant (7.1%) in Cohort 4 (≥ 7 to < 12 years; ruxolitinib 1.5% 
cream BID) had 2 events of application site pain (reported term:  stinging sensation).  
All application site reaction TEAEs were Grade 1 in severity and resolved on the 
same day as the event onset. 
• There were no clinically meaningful changes in mean chemistry or hematology 
parameters over time, and no clinically meaningful changes were noted for vital signs 
or height. 
2.2.2.1. 
Pharmacology Results 
Plasma concentrations of ruxolitinib were in general low and showed substantial interindividual 
variability in all cohorts.  The steady-state plasma concentrations of ruxolitinib increased in a 
less than proportional manner as the formulation strength increased.  Mean steady-state plasma 
concentrations of ruxolitinib are shown in Figure 4. 
Figure 4: 
Box Plots of Steady-State Plasma Concentrations Overlaid With Mean 
Values (Log10 Scale) 
 
Note:  Gray circles represent outliers (> 1.5 × interquartile range). 


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Overall, plasma PK of ruxolitinib in adolescent participants aged ≥ 12 to 17 years who applied 
ruxolitinib cream were similar to those previously observed in adult patients with AD. 
Evaluation of serum bone markers related to bone development was included in the safety 
assessments for Cohorts 3 to 6 to provide safety monitoring for early detection of possible bone 
effects on P1NP and BSAP (bone formation markers) and CTx (a bone resorption marker). 
A percentage decrease from the pretreatment levels (average of screening and baseline values) 
was used to monitor bone biomarker fluctuations in each participant. 
Bone biomarker values were variable between participants.  The normal ranges of serum bone 
biomarkers in children typically show high intraparticipant and interparticipant levels.  Spaghetti 
plots of BSAP, CTx, and P1NP serum concentrations were used to illustrate the changes in these 
bone markers.  A spaghetti plot from the youngest age group treated with 1.5% ruxolitinib cream 
(Cohort 6; ≥ 2 to < 7 years) is shown in Figure 5.  This was the youngest age group treated with 
the highest strength of ruxolitinib cream and thus the most vulnerable from a safety point of 
view.  This plot was also representative of the other cohorts in which bone markers were 
evaluated (Cohorts 3-5). 
Figure 5: 
Study 18424-102:  P1NP Concentrations for Individual Participants in 
Cohort 6 by Visit 
 
These analyses did not reveal any pattern of change that would indicate any effect of ruxolitinib 
cream on bone growth. 


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2.3. 
Study Rationale 
Ruxolitinib cream is a potent inhibitor of JAK1 and JAK2 with dual anti-inflammatory and 
antipruritic properties and has been recently shown to be an effective and safe therapy for AD in 
patients ≥ 12 years of age (Kim et al 2020a, Kim et al 2020b, Papp et al 2020).  Given its topical 
application, treatment of AD with ruxolitinib cream selectively targets the diseased skin and 
minimizes the chance of safety concerns associated with the systemic administration of JAK 
inhibitors. 
Five studies have been conducted to date evaluating the safety and efficacy of ruxolitinib cream 
in patients with AD (see Section 2.2):  a Phase 1 maximum use trial (INCB 18424-103), a 
Phase 2 study (INCB 18424-206), 2 Phase 3 studies (INCB 18424-303 and -304; TRuE-AD1 and 
TRuE-AD2), and a Phase 1 pediatric PK study (INCB 18424-102).  The results consistently 
demonstrated that ruxolitinib 1.5% cream is a safe and efficacious treatment of AD in adolescent 
participants and are in line with similar outcomes in adult participants. 
This Phase 3 pediatric trial is a part of the pediatric clinical program with the objective to 
evaluate the efficacy and safety of ruxolitinib cream in children with AD ≥ 2 years to < 12 years 
of age. 
2.3.1. 
Scientific Rationale for Study Design 
Two identical Phase 3 studies (TRuE AD-1 and TRuE AD-2) were conducted to evaluate the 
efficacy of ruxolitinib cream in adolescents and adults ≥ 12 years of age with AD.  The present 
study is intended to investigate and eventually confirm the findings of the above studies in a 
pediatric population ≥ 2 years to < 12 years of age.  Owing to the prevalence of AD in patients 
< 12 years of age and the unmet need for novel topical therapies with improved efficacy/safety 


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ratios in this age group, this study will evaluate the safety and efficacy profile of ruxolitinib 
cream in younger children. 
This Phase 3 pediatric trial (INCB 18424-305) is a double-blind study composed of sequential 
VC and LTS periods lasting 8 and 44 weeks, respectively, and replicates the design of the earlier 
pivotal studies in adolescent and adults with AD. 
The VC period of the study will provide efficacy and safety data, and the LTS period will 
provide safety information when ruxolitinib cream is used intermittently for a longer period.  It 
will also provide data about the duration of treatment effect after stopping therapy following 
lesion clearance and the nature and number of new disease exacerbation (flare) episodes.  
Additionally, this treat/re-treat manner of administration may reflect the likely use of the product 
in the post-approval, real-world setting.  Other measures included in this study are Itch 
 
, 
 
 
 
 
2.3.2. 
Justification for the Selected Treatment Regimen 
The ruxolitinib cream Phase 2 dose range–finding study (INCB 18424-206) in adult participants 
with AD was the basis for the treatment strength selection for the Phase 3 studies.  There were no 
meaningful differences in safety between all treatment regimens, and all treatment arms 
demonstrated unremarkable safety profiles with good tolerability on application sites. 
The 1.5% BID regimen was found to be the most efficacious, with the near-maximal treatment 
effect obtained within 8 weeks of therapy and the leveling of response thereafter.  In addition, 
a prompt and pronounced decrease in itch was observed relative to the other active treatment 
groups.  Given that the 1.5% strength (BID, for up to 8 weeks) demonstrated the highest 
efficacy/safety ratio, this particular regimen was selected for the consecutive clinical studies. 
Although ruxolitinib 0.75% BID was not tested in the earlier phase 2 dose range–finding study, 
the distinctive dose responses seen allowed the projection of its efficacy level to be intermediate 
between the 0.5% once daily and 1.5% BID strengths.  It was also anticipated that reducing the 
ruxolitinib cream strength would lead to reduced systemic exposure. 
While the efficacy of 1.5% ruxolitinib cream in the Phase 3 studies in adults and adolescents 
with AD was superior to that of 0.75% ruxolitinib cream, there were no meaningful differences 
in the safety profiles of these 2 regimens.  However, there is a possibility that plasma levels of 
ruxolitinib may be relatively higher, especially in younger children (with a higher BSA/body 
mass ratio), than those observed in adolescent and adult participants.  Therefore, both regimens 
will be evaluated in subsequent studies. 
2.4. 
Benefit/Risk Assessment 
See Appendix C for COVID-19–related guidance. 
Despite available treatment options, there is still a significant medical need for topical therapies 
for AD that are both effective and safe, particularly in children.  The overall benefit/risk 
assessment of ruxolitinib cream favors its use in adolescent and adult patients with AD, 
including those with involvement of sensitive skin areas (eg, the face).  Ruxolitinib cream 


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rapidly and effectively treats both signs (erythema, induration/papulation, and oozing/crusting) 
and symptoms, most importantly pruritus, of AD. 
All clinical studies with ruxolitinib cream in AD conducted to date confirm that both the 0.75% 
and 1.5% BID treatment regimens are most efficacious, compared with lower strengths of 
ruxolitinib cream evaluated, and are not associated with any concerning safety findings.  
Treatment with ruxolitinib cream 1.5% BID for 8 weeks demonstrated better efficacy and similar 
safety to the 0.75% BID treatment regimen, resulting in a better benefit/risk ratio in adolescents 
and adults. 
A pilot pediatric study (INCB 18424-102) demonstrated a similar risk/benefit ratio for each 
treatment strength in pediatric participants (aged ≥ 2 to 17 years, inclusive).  See Section 2.2.2. 
The Phase 3 pivotal studies of ruxolitinib cream (INCB 18424-303 and INCB 18424-304) in 
adolescents and adults with AD are ongoing.  However, the preliminary data are in line with the 
findings from other studies in terms of the efficacy and safety of this drug.  See Section 2.2. 
Based on the above information, ruxolitinib cream up to 1.5% BID can be safely used as a 
topical medication for AD and represents the treatment regimen with the best benefit/risk ratio 
from among those investigated. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of ruxolitinib cream may be found in the ruxolitinib cream IB. 


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3. 
OBJECTIVES AND ENDPOINTS 
Table 7 presents the objectives and endpoints. 
Table 7: 
Objectives and Endpoints 
Objectives  
Endpoints 
Primary 
To establish the efficacy of ruxolitinib cream in 
participants with AD. 
Proportion of participants who achieve IGA-TS at 
Week 8. 
Key Secondary 
To further assess the treatment effects of ruxolitinib 
cream. 
• Proportion of participants with a ≥ 4-point 
improvement in Itch NRS score from baseline to 
Week 8.  
• Proportion of participants with a ≥ 4-point 
improvement in Itch NRS score from baseline to 
Day 7 (Week 1). 
• Proportion of participants with a ≥ 4-point 
improvement in Itch NRS score from baseline to 
Day 3.  
Secondary 
To evaluate the safety and tolerability of ruxolitinib 
cream. 
The type, frequency, and severity of AEs and changes 
from baseline in physical examinations, vital signs, 
height, weight, and laboratory data for hematology and 
serum chemistry. 
To further evaluate the efficacy of ruxolitinib cream. 
• Proportion of participants who achieve IGA-TS at 
Weeks 2 and 4. 
• Proportion of participants with a ≥ 4-point 
improvement in Itch NRS score from baseline to 
Weeks 2 and 4. 
• Proportion of participants who achieve EASI75 at 
Weeks 2, 4, and 8. 
• Time to achieve Itch NRS score improvement of at 
least 2 or 4 points. 


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Table 7: 
Objectives and Endpoints (Continued) 
Objectives  
Endpoints 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a randomized, double-blind, VC study with an LTS period in pediatric participants with 
AD eligible for topical therapy, to be conducted at approximately 60 sites in the United States 
and Canada.  For participants who meet all study inclusion criteria and none of the exclusion 
criteria, study cream will be assigned at the Day 1/baseline visit.  Participants will be randomized 
2:2:1 to blinded treatment with ruxolitinib cream 0.75% BID, ruxolitinib cream 1.5% BID, or 
vehicle cream BID, with stratification by baseline IGA score and age.  Enrollment will be capped 
such that no more than approximately 25% of randomized participants have a baseline IGA score 
of 2.  At least 40% of the overall study population will consist of children aged ≥ 2 years to 
6 years. 
During the 8-week VC period, participants will apply study treatment BID to all areas identified 
for treatment at the Day 1/baseline visit even if the AD begins to improve and lesions decrease in 
size.  Note:  Throughout this protocol, the term "participant" refers either to the participants 
themselves or, in the case of younger children, their parent or legal guardian. 
At Week 8, efficacy (the primary endpoint of the study) will be evaluated as the proportion of 
participants achieving treatment success (IGA score of 0 or 1 with ≥ 2-grade improvement from 
baseline). 
Participants who complete Week 8 assessments with no additional safety concerns will continue 
into the 44-week LTS period with the same treatment regimen, except those initially randomized 
to vehicle cream will be rerandomized (1:1) in a blinded manner to 1 of the 2 active treatment 
groups (ruxolitinib cream 0.75% or 1.5% BID).  The IGA score required for participants to enter 
the LTS period is 0 to 4, and participants must have a %BSA in the range of 0% to 20% 
(excluding the scalp). 
During the LTS period, participants will have study visits every 4 weeks until the end of the 
study (52 weeks total).  At each of these visits, including Week 8 (baseline visit for the LTS 
period), the participant's AD lesions will be evaluated by the investigator to determine whether 
the participant requires continuation of treatment or should (re)enter an observation/no treatment 
cycle.  If the IGA score is ≥ 1, the participant will start or continue active treatment with 
ruxolitinib cream (0.75% or 1.5%) BID.  If the IGA score is 0 (clear), the participant will 
(re)enter an observation/no treatment cycle. 
During the LTS period (ie, starting at the Week 8 visit), participants will self-evaluate the 
recurrence of AD and will treat areas of the skin with active AD changes only (not to exceed 
20% BSA).  If AD lesions clear between study visits, participants will stop treatment 
applications 3 days after the lesions have disappeared and record the dates of these events in their 
diaries.  Similarly, those participants whose AD lesions recurred and who were previously in an 
observation/no treatment cycle will restart treatment at home at the first sign of recurrence and 
record the date of the new treatment cycle.  All cycles of treatment will be captured in the study 
database with their beginning and end dates. 
Throughout the study (VC period or LTS period), participants who develop new or expanded 
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 


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application of study cream.  Approval to treat additional areas may occur via telephone, 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. 
If the participant does not have a response during the LTS period (defined as no 
change/improvement in either %BSA or IGA score when treated continuously for 8 weeks 
during the LTS period), the participant must be discontinued from study treatment and an ET 
visit performed. 
Throughout the study, participants will be assessed for safety and tolerability by monitoring the 
type, frequency, and severity of AEs; performing physical examinations; measuring vital signs, 
height, and weight; and conducting clinical and laboratory assessments as outlined in the SoA 
(see Table 3 [VC period] and Table 4 [LTS period]).  Additional disease severity assessments, 
including PROs, will be conducted as outlined in the SoA (see Table 3 and Table 4). 
 
 
Following the end of treatment (Week 52/EOT or ET), all participants will have a safety 
follow-up visit 30 days later to evaluate safety and duration of response.  One exception to this 
would be for participants who have been in an observation/no treatment cycle with an IGA score 
of 0 (clear) from Week 48 or earlier until Week 52; such participants could complete the safety 
follow-up and Week 52/EOT visits together.  In practice, this would mean conducting all 
Week 52/EOT visit assessments plus the pregnancy test at the Week 52/EOT visit. 
Figure 1 presents the study design schema, and Table 3 (VC period) and Table 4 (LTS period) 
present the SoA. 
4.2. 
Overall Study Duration 
Participants will participate in the study for a duration of up to approximately 61 weeks: 
28 (+ 7) days in the screening period, 8 weeks in the VC period, 44 weeks in the LTS period, and 
30 days in the safety follow-up period (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 the date that the last participant has discontinued study cream and has 
completed applicable safety follow-up assessments or is lost to follow-up. 
A participant is considered to have completed the study if he/she has completed all study visits, 
including the safety 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. 


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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 of the study's 
completion or early termination in writing, 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. 
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. Male and female children aged ≥ 2 years to < 12 years (at the screening visit). 
2. Diagnosis of AD as defined by the Hanifin and Rajka (1980) criteria. 
3. AD duration of at least 3 months (participant/parent/guardian may verbally report signs 
and symptoms of AD with onset at least 3 months prior). 
4. IGA score of 2 to 3 at the screening and baseline visits. 
5. %BSA (excluding the scalp) with AD involvement of 3% to 20% at the screening and 
baseline visits. 
6. For children aged 6 years to < 12 years, baseline itch NRS score ≥ 4 (see Section 8.2.7).  
Note: Participants who are aged 6 years to < 12 years must record Itch NRS scores for at 
least 4 of the 7 days immediately prior to the Day 1/baseline visit. 
7. Participants/guardians who agree to discontinue all agents used by the participant to treat 
AD from the screening visit through the final safety follow-up visit. 
8. For participants who sign photography consent, at least 1 target lesion that measures at 
least 5 cm2 at the screening and baseline visits.  The target lesion must be representative 
of the participant's disease state but not located on the hands, feet, or genitalia. 


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9. For sexually active participants, willingness to take appropriate contraceptive measures 
(see Appendix A) to avoid pregnancy or fathering a child for the duration of study 
participation with the exception of male and female participants who are prepubescent. 
Note:  Female participants who have reached menarche must have a negative urine 
pregnancy test at the screening and baseline visits before the first application of study 
cream on Day 1.  They must also take appropriate precautions to avoid pregnancy from 
the screening visit through the safety follow-up visit. 
10. Ability to comprehend and willingness to sign an ICF or written informed consent of the 
parent(s) or legal guardian and a verbal or written assent from the participant when 
possible. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. An unstable course of AD (spontaneously improving or rapidly deteriorating) as 
determined by the investigator over the previous 4 weeks before the baseline visit. 
2. Concurrent conditions and history of other diseases as follows: 
a. Immunocompromised (eg, lymphoma, acquired immunodeficiency syndrome, 
Wiskott-Aldrich syndrome) or a history of malignant disease within 5 years before 
the baseline visit. 
b. Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, 
antiparasitics, antiprotozoals, or antifungals within 2 weeks before the baseline visit. 
c. Active acute bacterial, fungal, or viral skin infection (eg, herpes simplex, herpes 
zoster, chicken pox, clinically infected AD, impetigo) within 1 week before the 
baseline visit. 
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 classic areas of involvement such as the face or the flexural folds. 
f. Other types of eczema. 
g. Chronic asthma requiring more than 880 µg/day of inhaled budesonide or equivalent 
high dose of other inhaled corticosteroids. 
h. Any participant on maintenance dialysis. 
i. A medical history of hepatitis B virus or hepatitis C virus infection. 
3. Any of the following clinical laboratory test results at screening: 
a. Removed during Protocol Amendment 2. 
b. Removed (modified and moved to Exclusion Criterion 3d) during Protocol 
Amendment 2. 
c. Cytopenias at screening, defined as follows: 
− Hemoglobin < 10 g/dL 
− ANC < 1000/µL 
− Platelet count < 100,000/µL 


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d. Liver function tests: 
− AST or ALT ≥ 2.5 × ULN 
− Total bilirubin > 1.5 × ULN (isolated bilirubin > 1.5 × ULN is acceptable if 
bilirubin is fractionated and direct bilirubin is < 35%) 
e. Estimated GFR < 30 mL/min/1.73 m2 (using the Modification of Diet in Renal 
Disease equation). 
f. Positive serology test results at screening for HIV antibody. 
g. Any other clinically significant laboratory result that, in the opinion of the 
investigator, poses a significant risk to the participant. 
4. Removed (moved to Exclusion Criterion 2i) during Protocol Amendment 2. 
5. 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 cream and attending required study visits; pose a significant risk 
to the participant; or interfere with interpretation of study data. 
6. Use of any of the following treatments within the indicated washout period before the 
baseline visit: 
a. 5 half-lives or 12 weeks, whichever is longer – biologic agents (eg, dupilumab). 
b. 4 weeks – systemic corticosteroids or adrenocorticotropic hormone analogues, 
cyclosporin, methotrexate, azathioprine, or other systemic immunosuppressive or 
immunomodulating agents (eg, mycophenolate or tacrolimus). 
c. 2 weeks – immunizations with live-attenuated vaccines; sedating antihistamines 
unless on a long-term stable regimen (nonsedating antihistamines are permitted). 
Note:  Live-attenuated vaccines are not recommended during the VC period. 
Note:  COVID-19 vaccination is allowed. 
d. 1 week – use of topical treatments for AD (other than bland emollients, eg, Aveeno® 
creams, ointments, sprays, soap substitutes), such as topical antipruritics (eg, doxepin 
cream), corticosteroids, calcineurin inhibitors, PDE4 inhibitors, coal tar (shampoo), 
topical antibiotics, or antibacterial cleansing body wash/soap. 
Note:  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. 
7. Previous treatment with systemic or topical JAK inhibitors (eg, ruxolitinib, tofacitinib, 
baricitinib, filgotinib, lestaurtinib, pacritinib). 
8. Ultraviolet light therapy or prolonged exposure to natural or artificial sources of UV 
radiation (eg, sunlight or tanning booth) within 2 weeks prior to the baseline visit and/or 
intention to have such exposure during the study, which is thought by the investigator to 
potentially impact the participant's AD. 
9. Removed (moved to Exclusion Criterion 3f) during Protocol Amendment 2. 
10. Current treatment or treatment within 30 days or 5 half-lives (whichever is longer) before 
the baseline visit with another investigational medication or current enrollment in another 
investigational drug protocol. 
11. Removed during Protocol Amendment 4. 


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12. In the opinion of the investigator, unable or unlikely to comply with the administration 
schedule and study evaluations. 
13. Employees of the sponsor or investigator or otherwise dependents of them. 
5.3. 
Lifestyle Considerations 
Prolonged exposure to natural or artificial sources of UV radiation (including sun lamps, tanning 
booths, etc) is prohibited from 2 weeks prior to the baseline visit through the last study visit.  
When outdoors, participants will be advised to wear loose-fitting clothing that protects the 
treated areas from the sun. 
If sunscreen, makeup, or other cosmetics have 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 
cream.  See Section 6.6.1 for additional guidance. 
Participants should abstain from physical activity that can cause significant sweating for 
approximately 2 hours following study cream application. 
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 study 
cream application. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered into 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 reconsent (if rescreened ≥ 28 days after the 
initial screening or ≥ 35 days after the initial screening for those participants on prior 
medications requiring a 4-week washout period, as described in Section 5.2, Exclusion 
Criterion 6b) and be assigned a new screening number. 
5.5. 
Replacement of Participants 
Participants are not anticipated to be replaced during the study.  However, as noted in 
Appendix C (COVID-19–related guidance), due to the evolving situation of the COVID-19 
pandemic, the sponsor may decide to recruit additional participants in the study beyond the 
expected number (eg, if a substantial number of participants withdraw early from the study). 


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6. 
STUDY TREATMENTS 
See Appendix C for COVID-19–related guidance. 
6.1. 
Study Treatments Administered 
Table 8 presents the study treatment information. 
Table 8: 
Study Treatment Information 
 
Study Treatment 1 
Study Treatment 2 
Study Treatment 3 
Study treatment name: 
Ruxolitinib cream 1.5% 
Ruxolitinib cream 0.75% 
Vehicle 
Treatment strength: 
1.5% 
0.75% 
Not applicable 
Mechanism of action: 
Inhibitor of the JAK 
family of protein 
tyrosine kinases 
Inhibitor of the JAK 
family of protein  
tyrosine kinases 
Not applicable 
Dosage formulation: 
Cream 
Route of administration:  
Topical 
Administration instructions: 
VC period:  BID (morning and evening applications at least 1 hour before 
bedtime); a thin film is applied to affected areas. 
LTS period:  BID (morning and evening applications 
at least 1 hour before bedtime); a thin film is applied 
to affected areas. 
LTS period:  Not 
applicable. 
Packaging and labeling: 
Ruxolitinib cream and vehicle cream will be provided in 60-g tubes.  Each tube 
will be labeled as required per country requirements. 
Storage: 
Ambient (15°C-30°C/59°F-86°F) 
Status of treatment in 
participating countries: 
Investigational 
Investigational 
Not applicable 
Study treatments (ruxolitinib cream 1.5%, ruxolitinib cream 0.75%, and matching vehicle cream 
formulation that does not contain active drug) will be supplied in 60-g tubes and applied 
topically as a thin film BID (optimally at equal intervals, eg, ideally 12 hours apart but with at 
least 8 hours between applications) to the affected areas in the morning and in the evening, with 
the evening application at least 1 hour before bedtime. 
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 cream to be dispensed.  All areas identified at the baseline 
visit should continue to be treated through the end of the VC period (at Week 8), even if the area 
begins to improve or the AD resolves completely, unless the participant meets criteria for 
stopping study cream. 
If there are new areas to be treated, including expansion of existing areas or development of new 
areas, after consultation with the investigator, study cream should be applied to these areas in 
addition to the areas identified at the baseline visit (up to 20% BSA) for the remainder of the VC 
period, 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 cream to 
be dispensed.  Approval to treat these additional areas may occur via telephone, although the 
investigator, at their 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.  Participants 


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whose additional new areas to be treated in addition to the areas identified at the baseline visit 
exceed 20% BSA should be discontinued from study treatment and complete the EOT 
assessments. 
During the LTS period starting at the Week 8 visit, participants will have study visits every 
4 weeks until the end of the study (44 weeks total).  At those visits, AD lesions will be evaluated 
by the investigator to confirm whether the participant still requires continuation of therapy 
(IGA score ≥ 1) or can otherwise (re)enter the observation/no treatment cycle (IGA score = 0).  
During this period, only areas with active disease need to be treated.  Participants who develop 
new or expanded 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 cream.  At Week 8, each participant will receive a 
prespecified number of tubes of study cream 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 cream to be 
dispensed. 
The start and end dates of treatment applications will be captured by the participant.  Once the 
lesions clear, participants should continue to apply study cream for an additional 3 days to the 
areas of the body where lesions were last present before discontinuing treatment.  If this 3-day 
window is during a study visit and the IGA score is 0, as assessed by the investigator, treatment 
is to be stopped.  The date of the study visit will be recorded as the treatment cycle end date.  If a 
lesion recurs, then treatment should be resumed at the first sign of recurrence. 
At any time during the LTS period, if a participant's new areas to be treated in addition to the 
areas identified at the previous visit exceed 20% BSA, then the participant should be 
discontinued from study treatment and complete the EOT assessments. 
No study treatment adjustments are allowed except for temporary drug discontinuation, if needed 
(eg, for management of an AE; see Section 6.5). 
6.1.1. 
Study Treatment Application Guidance 
Participants should remove Study Cream from the tube and apply the Study Cream with their 
fingertip in small amounts until all of the areas to be treated are covered by a thin, even film (see 
Figure 8). 
Figure 8: 
Study Cream Application Using a Fingertip 
 
Source:  DermNet New Zealand (www.dermnetnz.org). 


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In the clinic, the amount of study cream used will be determined by weighing a tube(s) before 
and after the participant or guardian applies a thin film of study cream to the affected areas. 
On the day of a visit, the participant should not apply their morning application of study cream 
at home; instead, study cream will be applied in the clinic during the visit, under direct 
supervision of the site staff.  The tube will be weighed before and after application to determine 
the participant's usage. 
Application instructions will be provided by the site study staff, and the participants will record 
their daily applications via a diary card provided at each study visit.  Participants must not apply 
study cream more often than BID.  Refer to the Study Reference Manual for participant 
instructions for handling study cream. 
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 cream, and only authorized site staff 
may distribute study cream.  The cream will be applied by the participant or her/his parent/legal 
guardian.  Immediately after application of study cream, the hands should be thoroughly washed 
with soap and water.  Note that the study cream is for exclusive use on the skin.  In case of 
accidental exposure to the eyes or mucous membranes, the cream should be immediately 
removed from that area and necessary supportive measures taken.  Refer to the Study Reference 
Manual for participant instructions for handling of study cream. 
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 cream at ambient 
temperature conditions. 
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 the following: 
• Delivery of study cream to the study site. 
• Inventory of study cream at the site. 
• Participant use of the study cream, including tube counts from each supply dispensed. 
• Return of study cream 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 cream.  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. 


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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 cream 
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 cream back to the sponsor or its designee for destruction according to institutional SOPs.  
If local procedures mandate on-site destruction of the 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 cream 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 
included 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 score (2 or 3) and age, assign the 
participant study number, track participant visits, randomize according to the defined parameters, 
maintain the blinding, and manage study cream inventory.  Full details will be provided in the 
IRT Manual.  Study treatment will be dispensed at the study visits summarized in the SoA (see 
Table 3 and Table 4). 
6.4. 
Study Treatment Compliance 
Compliance will be assessed for frequency of administration of study cream by reviewing the 
participants' diaries.  Participants will also be questioned regarding study cream application 
technique, missed applications, and use of any additional topical or systemic prescriptions of 
other products or over-the-counter products.  Compliance with study cream will be evaluated by 
the participant's adherence to the BID application regimen (evaluation of actual number vs 
prescribed number of applications) and documented by the site staff and monitored by the 
sponsor/designee. 
Qualified clinical staff will review the diary entries for compliance.  Participants will be 
considered compliant with the treatment regimen if they apply at least 80% but no more than 
120% of the prescribed number of applications during participation in the VC period of the 
study.  Participants who are noncompliant during the VC period and LTS period (if on a 
treatment cycle) will be reinstructed by the investigator (or designee), and the sponsor should be 
consulted by the investigator for instruction on the proper handling of the participant. 
Drug accountability will be assessed by documenting the quantities of drug used between study 
visits (tube counts and weighing).  At the first clinic visit and subsequent study visits, the amount 
of study cream to be applied is to be determined by weighing a tube before and after the 
participant applies a thin film of study cream to the affected areas.  Participants will be instructed 
to bring all study cream with them to the study visits in order for site personnel to assess study 
cream accountability. 


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6.5. 
Dose Modifications 
Application adjustments/modifications (decrease or increase in study cream strength or 
frequency of application) are not allowed except for study cream interruption or permanent 
discontinuation if needed (eg, for management of an AE). 
Temporary study cream interruption could be due to an AE during the VC or LTS periods or due 
to clearance of the AD lesions during the LTS period, as described in Section 6.1. 
6.5.1. 
Criteria and Procedures for Application Interruptions and Adjustments of 
Study Cream 
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 as a result of AEs 
or laboratory abnormalities that may have an unclear relationship to study cream.  In the event of 
an AE is present at a specific site of application, treatment may be temporarily withheld only at 
that lesional site and continued elsewhere.  This should be recorded as a dose interruption on the 
AE eCRF page.  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 cream applications.  Additionally, 
the investigator must obtain approval from the sponsor before restarting study cream.  
Participants who experience a recurrence of the initial AEs upon restarting the study cream may 
need to permanently discontinue treatment with the study cream. 
Participants should be closely monitored for the development of signs and symptoms of infection 
during treatment with the study cream and up to the safety follow-up visit. Study cream should 
be interrupted if a participant develops a serious infection, an opportunistic infection, or sepsis. 
Study cream application should not be resumed until the infection is controlled. 
Instructions for application interruptions of study cream are outlined in Table 9.  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 
cream and the participant's underlying condition. 


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Table 9: 
Guidelines for Interruption and Restarting of Treatment Applications if 
Adverse Event Is Deemed Related to the Study Cream 
Adverse Event Related to Study Creama 
Action Taken 
ANC < 750/µL (without fever); < 1000/µL (with 
fever) 
• Laboratory abnormalities should be confirmed 
with repeat testing within 48 hours whenever 
possible and immediate delivery of the 
laboratory results requested. 
• Study cream applications must be interrupted.   
At the discretion of the investigator, after 
consultation with the sponsor, study cream 
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 cream applications must be interrupted.   
At the discretion of the investigator, after 
consultation with the sponsor, study cream 
application may be restored once these have 
resolved. 
Any Grade 4 laboratory abnormality or AST or 
ALT (> 20 × ULN) 
• Laboratory abnormalities should be confirmed 
with repeat testing within 48 hours whenever 
possible and immediate delivery of the 
laboratory results requested. 
• Discontinue study cream if laboratory 
abnormalities are confirmed. 
a In the opinion of the investigator. 
6.5.2. 
Criteria for Permanent Discontinuation of Study Cream 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 cream and will require that the study cream be permanently 
discontinued.  Unacceptable severity is defined as follows: 
• Occurrence of an AE that is related to treatment with the study cream 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. 
• Any Grade 4 laboratory abnormality related to the study cream (see Table 9). 
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 application of study treatment and any 
new or ongoing medication used during the study through 30 days after the last application 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 application 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 (except those containing urea, salicylic acid, or 
lactic acid) such as Eucerin® cream.  Participants should continue to use the bland 
emollient/moisturizer in the same manner they did before entering the study and 
throughout the course of the study. 
Note:  Emollients should not be used within 4 hours before and 2 hours after 
application of study cream. 
• Bathing during the study should be limited to once daily for no longer than 
15 minutes and not within 2 hours following study cream application.  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 cream 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: 
• Short-term use of systemic corticosteroids may be permitted to treat acute AEs 
(eg, asthma, croup) during the LTS period, and the decision to keep the participant in 
the study (or to permanently discontinue study cream) will be made in consultation 
with the medical monitor. 
• Participants may continue using sedating antihistaminic drugs as long as their use is 
part of a preexisting and well-established regimen.  There are no restrictions for use 
of nonsedating antihistamines. 


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• Use of any over-the-counter, nonprescription preparations deemed acceptable by the 
investigator is permitted under an established and stable treatment regimen. 
• Use of any prescription medication (including phytotherapeutic, herbal, or 
plant-derived preparations) within 7 days before the baseline visit through the safety 
follow-up visit, unless deemed acceptable by the investigator. 
• Immunizations with a live-attenuated vaccine are not recommended during the VC 
period (first 8 weeks) unless deemed necessary by the investigator. 
• Allergen immunotherapy (desensitization) that is ongoing at a stable dose at the time 
of study entry may be continued while on study but only at the same dose. 
• 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 cream 
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 cream. 
6.6.3. 
Prohibited Medications and Procedures 
The following are not permitted during the study: 
• Any investigational medication other than the study cream. 
• 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 (except the example stated in Section 6.6.2), methotrexate, 
cyclosporin A, azathioprine and biologic therapies, or other immunosuppressant 
agents. 
• Phototherapy or tanning beds. 
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 WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
7.1.1. 
Reasons for Discontinuation 
Participants must be discontinued from study treatment for the following reasons: 
• Lack of efficacy response during the LTS period (defined as no change/improvement 
in either %BSA or IGA when treated continuously for 8 weeks). 
• AD worsens during either the VC period or the LTS period, to the point where the 
extent of AD to be treated (ie. all areas excluding the scalp) exceeds 20% BSA. 
• The participant becomes pregnant. 
• Consent is withdrawn. 
Note:  Consent withdrawn means that the participant has explicitly indicated that 
he/she does not want to be followed any longer; in this case, no further data, except 
data in the 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 safety monitoring. 
• Further participation would be injurious to the participant's health or well-being, in 
the investigator's medical judgment. 
• Any AE 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, after 2 consecutive study visits and reinforcement of study cream application by 
site staff, a participant's drug usage exceeds one 60-g tube every 4 days, a participant 
who again fails to meet compliance benchmarks at a subsequent visit may be 
considered for withdrawal from the study.  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 cream administration 
in the investigator's opinion, the medical monitor should be consulted for instruction 
on handling the participant. 


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7.1.2. 
Discontinuation Procedures 
In the event that the decision is made to permanently discontinue the study treatment prior to the 
Week 52/EOT study visit, the ET visit should be conducted.  Reasonable efforts should be made 
to have the participant return for a follow-up visit.  The date of the last application of study 
cream and the reason for discontinuation of study cream will be recorded in the eCRF. 
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 ET visit should be performed. 
• The date of the ET visit should be recorded in the eCRF. 
• Participants must be followed for safety until the time of the follow-up visit or until 
study 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. 


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• Before a participant is deemed lost to follow-up, the investigator or designee must 
make a 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. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
See Appendix C for COVID-19–related guidance. 
8.1. 
Administrative and General Procedures 
8.1.1. 
Informed Consent 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 before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 
− 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 
must include a statement that the sponsor or its designee and regulatory 
authorities have direct access to participant records. 
− The ICF 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. 


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• 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. 
• 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 (if rescreened 
> 28 days after the initial screening [or > 35 days for participants on prior 
medications requiring a 4-week washout period as described in Section 5.2, Exclusion 
Criterion 6b]) 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 assessments for determination of eligibility may be 
performed over a period of up to 28 days, or up to 35 days for participants on prior medications 
requiring a 4-week washout period as described in Section 5.2 (Exclusion Criterion 6b).  
Assessments that are required to demonstrate eligibility may be performed over the course of 
1 or more days during the screening process. 
Results from the screening visit evaluations will be reviewed to confirm eligibility before 
enrollment or the administration of study cream.  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 laboratory results 
before randomization/treatment assignment will be used to determine eligibility.  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 (eg, after recovery from an infection).  
The participant is not required to sign another ICF if the rescreening occurs within 28 days (or 
35 days for participants on prior medications requiring a 4-week washout period) of the previous 
ICF signature date (screening period). 
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 as indicated in Table 3 and Table 4 to update the study 
cream supply.  The IRT system will also be used during the study visits to recalculate the amount 
of study cream to be dispensed if the participant's %BSA of AD lesions to be treated has 


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increased (during the VC period) or has either increased or decreased (during the LTS period).  
Additional details are provided in the IRT Manual. 
8.1.4. 
Distribution of Reminder Cards and Diaries 
Starting at Day 1 visit and each visit thereafter, a study cream–specific diary will be given to 
each participant in order to record use of the study cream.  The completed diary will be reviewed 
during each of the participant's study visits and data uploaded will be confirmed by the study 
staff. 
Qualified clinical study staff will review the participants' entries for compliance.  Participants 
who are noncompliant with their study cream 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 VC period of the study. 
Participants will be provided with a reminder card starting on Day 1 and at all VC and all LTS 
visits through Week 48.  The reminder card will indicate the date and time of the next visit and 
will also remind the participant that their morning application of study cream will be take place 
at the clinic under site supervision 
 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 past 2 years that are considered to be clinically significant by the investigator. 
The height and weight of both parents, if available, should be obtained and entered into the EDC. 
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 for the previous year prior 
to enrollment, including systemic treatments, radiation, and surgical procedures, will be 
recorded.  Acceptable documentation includes contemporaneous chart notes that record topical 
medication prescription and treatment outcome, or investigator documentation based on 
communication with the participant's treating physician.  A medical history of other conditions 
related to AD will also be collected at this time. 
In addition, information about previous AD treatment (within 12 months prior to screening) and 
their outcomes will be collected.  For participants with safety issues (side effects) and/or 
insufficient therapeutic response, a collective term of inadequate response will be used. 
Inadequate response is defined as inability of a given topical therapy to induce and maintain 
remission or to contain the disease severity at an acceptable level (comparable to IGA score of 


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0-2; none to mild eczema lesions) despite continuous treatment with a topical corticosteroid and 
a topical calcineurin inhibitor (if applicable) for at least 2 weeks or for the maximum duration 
recommended by the product prescribing information (whichever is shorter). 
Participants with documented systemic treatment for AD can also be considered as inadequate 
responders to topical treatments. 
Clinically relevant side effects/safety risks and/or skin tolerability issues are those that outweigh 
the potential treatment benefits and are the reason why a topical treatment cannot be initiated or 
continued. 
8.2. 
Efficacy Assessments 
8.2.1. 
Health Economics 
Not applicable. 
8.2.2. 
Body Surface Area 
Total %BSA affected by AD will be estimated at each visit as outlined in the SoA (see Table 3 
[VC period] and Table 4 [LTS period]).  Body surface area assessment will be approximated to 
the nearest 0.1% using the handprint (Palmar) method as a guide.  The approximate size of the 
participant's entire palmar surface (ie, the palm plus 5 digits, with fingers tucked together and 
thumb tucked to the side) should be considered as 1% BSA, and the approximate size of the 
participant's thumb should be considered as 0.1% BSA. 
Alternatively, %BSA affected by AD may be measured using the calculation guidance of the 
diagrams, based on age group, in Appendix D.  One of these 2 methods should be selected and 
consistently used throughout the study. 
Participants must have BSA involvement (excluding scalp) of 3% to 20% at the screening and 
baseline visits for the VC period to enroll in the study; they may have 0% to 20% BSA 
involvement at Week 8 (baseline for the LTS period) to enter the LTS period. 
During the LTS period, including Week 8 (baseline for the LTS period), %BSA will be 
evaluated by the investigator to determine whether the participant requires continuation of 
treatment or should (re)enter an observation/no treatment cycle. 
8.2.3. 
Target Lesion Identification 
A representative target lesion for participants who consent to photography will be identified 
during the screening visit, and the measurements of the same lesion will be confirmed/updated at 
the baseline visit (procedure is optional for nonphotography participants). The target lesion 
should be representative of the participant's overall disease and is to be treated with study cream.  
The target lesion should approximately measure at least 5 cm2 in size and should not be on the 
hands, feet, or genitalia.  A note should be made in the participant's source documents, and the 
photographs (at selected sites) can be marked with the location of the target lesion at each visit.  
The longest diameter and the span perpendicular to the longest diameter will be measured in 
centimeters. 


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8.2.4. 
Photography 
At selected sites, participants will be asked but will not be required to consent to photography.  
For each visit with photography (baseline and Weeks 2, 4, and 8), a photograph of the target 
lesion (identified at the baseline visit, at least 5 cm2 in size; see Section 8.2.3) will be taken via 
2 views (close-up and regional body area) before any study procedure, even if the AD lesion has 
cleared or disappeared.  A note should be made in the participant's source documents of the 
target lesion location, and the photographs can be marked with the location of the target lesion at 
each visit. 
8.2.5. 
Investigator's Global Assessment 
Investigator's Global Assessment is an overall eczema severity rating on a 0 to 4 scale that will 
be assessed during site visits as outlined in the SoA (see Table 3 [VC period] and Table 4 [LTS 
period]).  The severity strata for the IGA are shown in Table 10. 
Table 10: 
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:  FDA 2012. 
The IGA-TS is defined as an IGA score of 0 or 1 with a ≥ 2-grade improvement from baseline. 
Participants must have an IGA score of 2 or 3 at the screening and baseline visits for the VC 
period to enroll in the study; they may have an IGA score of 0 to 4 at Week 8 (baseline for the 
LTS period) to enter the LTS period. 
During the LTS period, including Week 8 (baseline for the LTS period), IGA will be evaluated 
by the investigator to determine whether the participant requires continuation of treatment or 
should (re)enter an observation/no treatment cycle.  If the IGA score is ≥ 1, the participant will 
start or continue active treatment with ruxolitinib cream (0.75% or 1.5%) BID.  If the IGA score 
is 0 (clear), the participant will (re)enter an observation/no treatment cycle. 
8.2.6. 
Eczema Area and Severity Index 
Atopic dermatitis will be assessed as outlined in the SoA (see Table 3) using the EASI scoring 
system, which is a validated scoring system that grades the physical signs of AD to provide a 
measure of AD severity (ranging from 0 to 72).  The EASI scoring system examines 4 regions of 
the body (head/neck, upper limbs, trunk, and lower limbs) and weights them.  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 


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multiplier used in the scoring is based on age (< 8 years or ≥ 8 years).  See Appendix E for the 
EASI calculation guides by age group. 
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; and 50.1 to 72.0 = very severe. 
8.2.7. 
Itch Numerical Rating Scale 
The Itch NRS will be administered based on the participant's age (at the time of consent), as 
follows: 
• For participants ≥ 6 years of age, collect the Itch NRS.  Baseline itch (defined as the 
average of the 7 days directly before Day 1, with Itch NRS values available for at 
least 4 of the 7 days) must be ≥ 4 on NRS. 
• For participants < 6 years of age, do not collect the Itch NRS. 
The Itch NRS is a daily participant-reported measure (24-hour recall) of the worst level of itch 
intensity (Pruritus Resources).  Participants will be asked to rate the itch severity 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 
cream during the VC period.  This is particularly important for the 7 days immediately prior to 
the Day 1/baseline, Week 2, Week 4, and Week 8 visits; therefore, Itch NRS scores are required 
for at least 4 of those 7 days during each of these 4 weeks to allow evaluation of participant 
eligibility and the Itch NRS endpoints. Detailed directions for the administration of a diary will 
be provided in the Study Reference Manual. 


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8.4. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (see Table 3 [VC period] 
and Table 4 [LTS period]). 


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See Section 6.5 for guidelines regarding the management of relevant laboratory or other safety 
assessment abnormalities. 
8.4.1. 
Adverse Events 
Adverse events will be monitored from the time the participant signs the ICF (or assent) until at 
least 30 days after the last application of study cream.  Adverse events that begin or worsen after 
informed consent should be recorded on the Adverse Events Form in the eCRF regardless of the 
assumption of a causal relationship with the study cream.  Conditions that were already present 
at the time of informed consent 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 cream/procedures, or that caused the participant to discontinue the 
study cream.  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 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). 
8.4.2. 
Physical Examinations 
During the study, participants will be assessed by the investigator or medically qualified 
designee per institutional standard of care.  Physical examinations will be conducted at the 
timepoints listed in Table 3 and Table 4. 
8.4.2.1. 
Comprehensive Physical Examination 
At the screening visit and Week 52/EOT or ET visit, 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. 
8.4.2.2. 
Targeted Physical Examination 
At the visits indicated in the SoA (see Table 3 [VC period] and Table 4 [LTS period]), a targeted 
physical examination will be a symptom-directed evaluation (ie, conducted only if indicated by 


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symptoms, AEs, or other findings); clinically significant abnormalities (in the investigator's 
judgment) are to be reported as AEs and documented on the Adverse Events Form in the eCRF. 
8.4.3. 
Vital Signs, Height, and Weight 
Vital signs, height, and weight will be measured as outlined in the SoA (see Table 3 [VC period] 
and Table 4 [LTS period]). 
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.  Abnormal vital sign results 
identified after the first application of study cream constitute an AE if they are considered 
clinically meaningful, induce clinical signs or symptoms, or require concomitant therapy. 
Height and weight will be assessed at the baseline, Week 8/ET, Week 24, and Week 52/EOT/ET 
visits.  Individual growth measurements from the preceding year should be collected, if at all 
possible, from each participant's physician prior to the baseline visit.  If these measurements 
cannot be obtained, the reason should be documented.  Height will be measured using a 
stadiometer.  The stadiometer should be calibrated, and a wall-mounted one is recommended.  
Participants should be measured without socks and 3 measurements taken to the nearest 0.1 cm.  
The average of the 3 height measurements of individual participants should be entered into the 
EDC.  At the end of the study, these growth measurements will be compared against each 
participant's growth measurements from the previous year prior to entry into this trial. 
8.4.4. 
Laboratory Assessments 
See Table 11 for the list of clinical laboratory tests to be performed and the SoA (see Table 3 and 
Table 4) for the timing and frequency.  Day 1 testing will be performed only if the interval 
between this visit and screening is > 2 weeks.  A central laboratory will perform all clinical 
laboratory assessments for safety (blood chemistries and hematology assessments) 
 
  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 SoA (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 application of study 
cream, 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 11: 
Required Laboratory Analytes 
Serum Chemistries 
Hematology 
Serology 
• Albumin 
• Alkaline phosphatase 
• ALT 
• AST 
• Bicarbonate 
• Blood urea nitrogen or urea 
• Calcium 
• Chloride 
• Creatinine 
• Glucose 
• Lactate dehydrogenase 
• Phosphorus 
• Potassium 
• Sodium 
• 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 count 
 
Differential count, including: 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
• HIV antibody 
Pregnancy Testing 
Female participants who have 
reached menarche will have a 
urine test conducted at all 
required visits.  A positive urine 
test must be confirmed by a 
serum test. 
Note:  Additional tests may be required, as agreed upon by the investigator and sponsor, based on emerging safety data or to rule 
out a diagnosis. 
 
 
 
 
. 
8.4.4.2. 
Pregnancy Testing 
A urine pregnancy test will be required for all female participants who have reached menarche.  
The urine pregnancy test will be performed locally as outlined in the SoA (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.  Day 1 testing will be performed only if the interval between this visit and 
screening is > 2 weeks. 
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 treatment and continue participation in the study. 
If a pregnancy is confirmed by a serum pregnancy test, see Section 9.6 for reporting 
requirements. 
8.4.4.3. 
Serology 
An HIV assessment will be performed at the screening visit to rule out HIV infection; required 
analytes are shown in Table 11.  Serology and virology tests should be performed early in the 


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screening process due to the length of time needed to obtain the results.  Additional tests may be 
performed if clinically indicated. 
 
 
 
 
 
 
8.7. 
Unscheduled Visits 
Unscheduled study visits may occur at any time medically warranted, including when 
participants develop new areas of AD.  Any assessments performed at those visits should be 
recorded in the eCRF. 


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If the participant develops new areas of AD, documentation of the new BSA may occur at an 
unscheduled visit if appropriate. 
8.8. 
End of Treatment and/or Early Termination 
The EOT coincides with the Week 52 visit.  A participant that completes the Week 52/EOT visit 
will have reached the end of treatment with study cream. 
If a decision is made that the participant will permanently discontinue study cream prior to the 
Week 52/EOT visit, then the ET visit should be conducted.  If the ET visit coincides with a 
regular study visit, then the ET evaluations will supersede those of that scheduled visit, and the 
data should be entered in the ET page in the eCRF.  If this decision does not coincide with a 
regular visit, reasonable efforts should be made to have the participant return to the site to have 
the ET procedures completed. 
8.9. 
Follow-Up 
8.9.1. 
Safety Follow-Up 
The safety follow-up period is the interval between the Week 52/EOT or ET visit and the 
scheduled follow-up visit, which should occur 30 days after the Week 52/EOT or ET visit, with 
the following 2 exceptions: 
• Follow-up visit should occur at the Week 52/EOT visit for participants who have 
been in an observation/no treatment cycle with an IGA score of 0 (clear) from 
Week 48 or earlier until Week 52 
• Follow-up visit should occur 30 days after the last application of study cream if the 
Week 52/EOT or ET visit was not performed. 
Adverse events and SAEs must be reported up until 30 days after the last application of study 
cream; ongoing AEs and SAEs must be followed up 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. 


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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 it is considered drug-related. 
• An AE can therefore be any unfavorable or unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
cream. 
Additional Guidance for Events Meeting the Adverse Event Definition 
• Any safety assessments (eg, vital sign 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) are to be reported as an AE. 
• Abnormal laboratory test results are to be reported as an AE if they are considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes in 
study cream.  Whenever possible, a diagnosis (eg, anemia, thrombocytopenia) should be recorded in 
the eCRF rather than the abnormal laboratory test result (eg, low hemoglobin, platelet count 
decreased). 
• Exacerbation of a chronic or intermittent pre-existing condition/disease, including either an increase 
in the frequency and/or intensity of the condition, is to be reported as an AE. 
• New conditions detected or diagnosed after the start of study cream administration are to be reported 
as an AE. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction are to be reported as 
an AE. 
• Signs and/or symptoms from dosing errors of a study cream (eg, overdose) or a concomitant 
medication are to be reported as an AE. 
• "Lack of efficacy" or "failure of expected pharmacological action" 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. 
• A condition that leads to a medical or surgical procedure (eg, endoscopy, appendectomy) will be 
reported as an AE if it occurs after obtaining informed consent.  If the condition is present before 
entering the study, then it should be captured as medical history. 
• Pre-existing diseases or conditions with expected fluctuations in signs or symptoms should be 
reported as an AE only if the investigator judges the fluctuation to have worsened more than 
expected during study participation. 


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9.2. 
Definition of Serious Adverse Event 
If an event is not an AE per the 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 occurs.  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 (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 or planned surgery (eg, stent replacement, hip surgery) is not 
considered an SAE. 
Hospitalization for medical interventions in which no unfavorable medical occurrence occurred 
(ie, elective procedures or routine medical visits) are not considered SAEs. 
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. Is an important medical event 
An important medical event is 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 new invasive or 
malignant cancers; 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. 


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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 is signed should be recorded on the 
Adverse Event Form in the eCRF.  Adverse events/SAEs should be reported for enrolled participants, 
but only SAEs need to be reported for screen failure participants.  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 diagnostic 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 Adverse Event Form in the eCRF. 
• There may be rare 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 by the 
site staff on the copies of the medical records before submission.  These records can be submitted to 
Incyte Pharmacovigilance by email/fax per the contact information listed as per SAE Completing 
Guidelines. 
• 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 following: 
• The severity grade (CTCAE v5.0 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 cream:  suspected 
(yes) or not suspected (no).  See below for further instructions on the assessment of causality. 
• The start and end dates, unless unresolved at the final safety follow-up visit. 
• The action taken with regard to study cream 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). 
• 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 the Adverse Event Form and the treatment 
should be specified on the appropriate eCRF (eg, Prior/Concomitant Medications, Procedures and 
Non-Drug Therapy). 


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Assessment of Intensity 
The severity of AEs will be assessed using CTCAE v5.0 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 medically 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 cream and each occurrence of 
each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are medical 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 possibility of a relationship. 
• The investigator will also consult the Reference Safety Information in the IB for study cream in 
making his/her assessment. 
• Alternative causes, such as underlying or concurrent disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study cream 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 based on the available information 
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 
submit 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. 
• Once an AE is detected, it should be followed in the AE eCRFs 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 cream, 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. 
• 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 SAE information will be recorded in the originally completed eCRF and reported to 
Incyte Pharmacovigilance (either via email/fax) until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up. 
• Any updated SAE data (including SAEs being downgraded to nonserious) will be submitted to the 
sponsor (or designee) within 24 hours of receipt of the information. 
9.4. 
Reporting of Serious Adverse Events 
All SAEs, regardless of suspected causality (eg, relationship to study cream or study 
procedure[s]), occurring after the participant has signed the ICF/assent through 30 days after the 
last application of study cream, 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 study 
participation (ie, after the safety follow-up visit or 30 days after the last application of study 
cream).  However, if the investigator learns of any SAE, including a death, at any time during 
this period, and after a participant has been discharged from the study, and he/she considers the 
event to be reasonably related to the study cream 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 toward the safety of participants and the safety of a study 
cream under clinical investigation are met. 
If the SAE is not documented in the Reference Safety Information of the IB for the study cream 
(new occurrence) and is thought to be related to the study cream, 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 


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involved in any study with the same drug that this SAE has been reported.  Suspected 
unexpected serious adverse reactions will be collected and reported to the competent authorities 
and relevant ethics committees in accordance with Directive 2001/20/EC or as per national 
regulatory requirements in participating countries. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study cream 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 report within 24 hours of learning of its occurrence any SAE via the EDC 
system (primary method) or by completing the Serious Adverse Event Report Form in English (only 
if the EDC system is not available).  The contact information for Incyte Pharmacovigilance by 
email/fax is listed in the Study Reference Manual or as per the Incyte Reference Guide for 
Completing the Serious Adverse Event Report Form. 
• In circumstances where the EDC system is not accessible for reporting SAE information (initial 
and/or follow-up SAE information) to the sponsor within 24 hours, refer to the Incyte Reference 
Guide for Completing the Serious Adverse Report Form.  Once the EDC system is functional, the 
SAE report should be retrospectively added to the EDC system and follow-up should be completed 
through the EDC.  The original copy of the Serious Adverse Event Report Form and the email or 
facsimile confirmation sheet must be kept at the study site (refer to the Incyte Reference Guide for 
Completing the Serious Adverse Report Form or Study Reference Manual for details and for the 
email address or fax number). 
• Follow-up information is also recorded in the eCRF and transmitted to Incyte Pharmacovigilance via 
the EDC system.  The follow-up report should include information that was not provided previously, 
such as the outcome of the event, treatment provided, action taken with study cream 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. 
• Contacts for SAE reporting can be found in the Study Reference 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 Manual.  
The IRT system has an option to select for "Participant Unblinding" in the event that a 
participant's treatment needs to be unblinded in the case of a medical emergency.  The 


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investigator/subinvestigator will proceed to either final confirmation or cancellation of the 
subjecting unblinding procedure.  After providing a final confirmation to unblind the selected 
participant, the investigator/subinvestigator will proceed to enter their IRT password as a final 
security measure.  Once a valid password has been entered for the user's account, IRT will 
display the participant's unblinded information to the user. 
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 cream, unless there are ethical reasons to have the 
participant remain on the study cream.  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 the study 
cream 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 cream, the following procedures should be followed in order to ensure safety: 
• The study cream must be discontinued immediately (female participants only). 
• 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 cream 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 its 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. 


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9.7. 
Warnings and Precautions 
Special warnings or precautions for the study cream, derived from safety information collected 
by the sponsor or its designee, are presented in the ruxolitinib cream 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. 
There are no study-specific special warnings or precautions in this study. 
9.8. 
Treatment of Excessive Use 
There has been no clinical experience with overdose resulting from excessive use of ruxolitinib 
cream.  Treatment of excessive use should consist of general supportive measures. 
9.9. 
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. 


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10. 
STATISTICS 
10.1. 
Sample Size Determination 
Approximately 315 participants will be randomized 2:2:1 to ruxolitinib cream 1.5% BID, 
ruxolitinib cream 0.75% BID, or vehicle cream BID.  The sample size calculation is based on the 
Fisher exact test for the primary efficacy endpoint.  Based on the results from the 2 pivotal 
studies, INCB 18424-303 and INCB 18424-304, the response rate of IGA-TS at Week 8 is 
assumed to be 51% and 47% for the active arms (1.5% BID and 0.75% BID, respectively) versus 
14% 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 
providing adequate power for efficacy variables, the sample size is determined to provide a large 
database for safety evaluations. 
10.2. 
Populations for Analysis 
Table 12 presents the populations for analysis. 
Table 12: 
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.  In general, the following are important 
protocol deviations that may significantly affect the primary analysis: 
Missing data for the primary endpoint 
Overall application compliance less than 80% during the VC period 
Participants with one or more such deviations will be excluded from the PP 
population.  In addition, important protocol deviations related to inclusion/exclusion 
criteria, discontinuation criteria, and use of prohibited concomitant medications will 
be reviewed.  Decisions as to whether any of these deviations warrant exclusion 
from the PP population will be made prior to unblinding. 
Safety 
The safety evaluable population includes all participants who applied study cream 
at least once.  Treatment groups for this population will be determined according to 
the actual treatment the participant received on Day 1. 
LTS evaluable 
All analyses for the LTS period will be conducted with the LTS evaluable 
population, which includes all participants who applied study cream at least once 
during the LTS period. 
 
 
 
 
 
. 


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10.3. 
Level of Significance 
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 by Bretz et al (2009).  This method will guarantee a strong control of the family-wise 
error rate. 
In Step 1, 2 families of 4 elementary hypotheses tests at Week 8 are grouped according to 
treatment comparison between each ruxolitinib cream group and the vehicle cream group, where 
•
Family 1 (1.5% BID vs vehicle):
−
H11:  proportion of participants who achieve IGA-TS
−
H12:  proportion of participants with a ≥ 4-grade improvement in Itch NRS score
over baseline
•
Family 2 (0.75% BID vs vehicle):
−
H21:  proportion of participants who achieve IGA-TS
−
H22:  proportion of participants with a ≥ 4-grade improvement in Itch NRS score
over baseline
Step 2 has 2 families of 4 hypotheses tests: 
•
Family 3 (1.5% BID vs vehicle and 0.75% BID vs vehicle on Day 7 Itch NRS):
−
H13:  proportion of participants with a ≥ 4-grade improvement in Itch NRS score
over baseline to Day 7 (Week 1) between 1.5% BID and vehicle
−
H23:  proportion of participants with a ≥ 4-grade improvement in Itch NRS score
over baseline to Day 7 (Week 1) between 0.75% BID and vehicle
•
Family 4 (1.5% BID vs vehicle and 0.75% BID vs vehicle on Day 3 Itch NRS):
−
H14:  proportion of participants with a ≥ 4-grade improvement in Itch NRS score
over baseline to Day 3 between 1.5% BID and vehicle
−
H24:  proportion of participants with a ≥ 4-grade improvement in Itch NRS score
over baseline to Day 3 between 0.75% BID and 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 key secondary endpoint will be tested only if the associated primary
endpoint is rejected.  For any treatment strength, if the 2 related null hypotheses can be rejected,
then the fixed sequence for the other treatment strength can be conducted at the 2-sided α = 0.05
level.  If all null hypotheses in Family 1 and 2 are rejected, in Step 2, the endpoints in Family 3
(H13 and H23) will be tested using Bonferroni-Hochberg's procedure with overall 2-sided
α = 0.05 level. If both hypotheses in Family 3 are rejected, the endpoints in Family 4 (H14 and
H24) will be tested similarly using Bonferroni-Hochberg's procedure with overall 2-sided
α = 0.05 level. The approach is visualized in Figure 9.


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Figure 9: 
Control of the Overall Type I Error Rate 
Step 1: 
 
Step 2: 
 
10.4. 
Statistical Analyses 
The SAP will be developed and finalized before database lock and will describe the participant 
populations to be included in the analyses and procedures for accounting for missing, unused, 
and spurious data.  This section is a summary of the planned statistical analyses of the primary 
and secondary endpoints. 


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10.4.1. 
Primary Analysis 
The primary analysis will be based on the ITT population.  The primary alternative hypothesis 
(superiority of each active ruxolitinib arm, 1.5% BID or 0.75% BID, compared with vehicle) will 
be tested at a 2-sided α = 0.025 level using logistic regression.  This model will include the 
treatment group (1.5% BID, 0.75% BID, and vehicle) and stratification factors (baseline IGA 
score and age).  Exact logistic regression (Mehta and Patel 1995) will be used for all of the 
comparisons if any of the treatment strengths have an expected cell count < 5. 
The difference in IGA-TS rates (ruxolitinib cream/vehicle) at Week 8 will be computed.  The 
95% confidence interval for the difference will be computed based on a large-sample normal 
approximation with continuity correction.  All nonresponders during the VC 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.  Subgroup analysis by baseline characteristic (eg, IGA score, country, and 
age) will be performed.  Details will be provided in the SAP.  The following approaches may be 
performed for sensitivity analyses: 
• 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.  In the model, visits are nested within participants, which are further 
nested within sites. 
The primary endpoint binary response 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 score 
and age), 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. 
• Multiple imputation: 
Multiple imputation with missing at random assumption will be used as an alternative 
method to handle missing data.  A fully conditional specification method 
(van Buuren 2007) that assumes the existence of a joint distribution for all variables 
will be used to impute the IGA score.  A regression model including treatment group, 
stratification factors (baseline IGA score and age), and baseline and scheduled 
postbaseline scores up to Week 8 will be specified for the fully conditional 
specification method.  The imputation will be repeated a number of times to generate 
corresponding complete data sets, in order to reflect the uncertainty around the true 
values.  The primary endpoint binary response will be derived for each of the imputed 
datasets, and the logistic regression described in Section 10.4.1 will be applied.  The 
results will then be combined for the inference using Rubin's rule. 


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• Last observation carry forward: 
For the participants who are missing postbaseline assessments, the last observed 
nonmissing postbaseline values will be used to fill in missing values at Week 8.  Then 
the proposed logistic regression described in Section 10.4.1 will be applied to the 
imputed dataset. 
• Tipping point analysis: 
A tipping point sensitivity analysis will be conducted to examine the potential effects 
of missing data.  The missing primary endpoint binary response at Week 8 in each 
treatment group will be replaced by a range of values to see how far they must be 
changed for the results of the study to tip from significant to not. Between-treatment 
comparisons will be performed using a chi-square test. 
10.4.2. 
Secondary Analyses 
Secondary efficacy analyses will be conducted on 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 9.   
The Itch NRS score for baseline will be determined by averaging the 7 daily NRS scores directly 
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 directly 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 same 
nonresponder imputation method as specified in the primary analysis will be used to handle 
missing Week 8 itch data, and the logistic regression described in Section 10.4.1 will be applied 
to compare each ruxolitinib cream group and the vehicle cream group for the key secondary 
endpoint of Itch NRS score responses at Week 8.  
For the key secondary endpoints of Itch NRS score responses on Day 7 (Week 1) and Day 3, all 
participants who are missing Day 7 and/or Day 3 daily Itch NRS scores will be imputed using 
multiple imputation by fully conditional specification method.  The variables to be included in 
the imputation regression model are treatment group, stratification factor, baseline itch score, and 
postbaseline daily itch score on Day 1 to Day 7.  The details of the multiple imputation, 
including number of imputations and seed number, will be specified in the SAP.  After the 
missing values have been imputed, the binary variable for the ≥ 4-point improvement in Itch 
NRS score on Day 7 and Day 3 will be derived.  The logistic regression specified in 
Section 10.4.1 will be applied to each imputed dataset, and then the results will be combined for 
the inference. 
All other secondary 
 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. 


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10.4.3. 
Safety Analyses 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after the 
first application of study cream.  Analysis of AEs will be limited to TEAEs, but data listings will 
include all AEs regardless of their timing to study cream administration.  AEs will be tabulated 
by the MedDRA preferred term and system organ class.  Severity of AEs will be based on the 
National Cancer Institute CTCAE v5.0 using Grades 1 through 5. 
The subset of AEs considered by the investigator to have a relationship to study cream will be 
considered to be treatment-related AEs.  If the investigator does not specify the relationship of 
the AE to study cream, 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), height, and weight at each assessment 
time. 
 
 
 
 
10.5. 
Interim Analysis 
No formal interim analysis is planned for this study; however, the following analyses will be 
performed: 
• The primary analysis will occur after the primary database lock, when all participants 
have completed the VC period.  The sponsor will be unblinded after the primary 
database lock; however, investigators and participants will remain blinded to the 
individual study treatment assignment. 
• The final analysis will occur when all participants have completed or withdrawn from 
the study. 


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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 and health authorities 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 approval from both health authorities 
and the IRB/IEC 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 during the 
retention period 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. 
− 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. 


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11.1.1. 
Identification of the Coordinating Principal Investigator 
A coordinating principal investigator will be appointed by the sponsor before the end of the 
study.  As part of their responsibilities, the coordinating principal investigator will review the 
final CSR.  Agreement with the final CSR will be documented by the dated signature of the 
coordinating principal investigator. 
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 with 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.  Other data outside the EDC system required in the study conduct 
of the Protocol, such as documents or results transmitted to the sponsor via a central laboratory 
or specialized technical vendors and as designated by the sponsor, will have their own data flow 
management plans, study charters, 
, as applicable. 
The sponsor (or designee) will be responsible for the following: 
• Managing the integrity of the data and the quality of the conduct of the study, such as 
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. 
• Managing and reconciling the data generated and/or collected, including documents 
and results such as laboratory or imaging data analyzed centrally by a designated 
vendor of the sponsor. 
The investigator will be responsible for the following: 
• Recording, or ensuring the recording of, all relevant data relating to the study in the 
eCRF. 
• Delivering, or ensuring the delivery of, all other results, documents, data, know-how, 
or formulas relating to the study to the sponsor or designee electronically and/or 
centrally (eg, laboratory data, imaging data, 
 photographs, diary data) 
or as otherwise specified in the Protocol. 


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• Maintaining adequate and accurate source documents and trial records that include all 
pertinent observations on each of the site's trial participants.  Source data should be 
attributable, legible, contemporaneous, original, accurate, and complete.  Changes to 
source data should be traceable, should not obscure the original entry, and should be 
explained if necessary (eg, via an audit trail).  Source data are, in general, all 
information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained in source 
documents (original records or certified copies). 
• 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, sent to a central vendor designated by the sponsor, or as 
described in other study and data flow manuals. 
− Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected.  Source documents are filed and 
available at the investigator's site.  Examples of source documents are original 
documents, data, and records (eg, hospital records; electronic hospital records; 
clinical and office charts; laboratory notes; memoranda; participants' diaries or 
evaluation checklists; pharmacy dispensing records; recorded data from 
automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiches; photographic negatives; microfilm or 
magnetic media; x-rays; participants' files; and e-records/records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in 
the clinical trial). 
Data 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.  Current applicable medical records must be available. 
• Sending participants' data, either as unique samples, copies, or photographs, to be 
evaluated centrally or analyzed centrally, or both, by a qualified vendor designated by 
the sponsor. 
− As required by privacy and data protection regulations and Incyte's privacy 
policies, if any photographs of participants are to be taken, the photographs must 
be limited to the area of the face or the body that is strictly necessary and the 
photographs should be masked (ie, identifying features such as eyes, mouth, scars, 
tattoos, or unique markings or features should be either obscured with a black bar 
or digitally pixelated so as to not permit the reidentification of the participants and 
preserve their confidentiality) by a specially designated photography vendor prior 
to sending the photographs to Incyte or any other third-party vendors for analysis 
or further processing. 


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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 Quality Assurance 
The sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations). The sponsor or designee is responsible for the data management of this 
study, including quality checking of the data. Further, monitoring details describing strategy, 
including definition of study-critical data items and processes (eg, risk-based initiatives in 
operations and quality such as risk management and mitigation strategies and analytical risk-
based monitoring), methods, responsibilities, and requirements, including handling of 
noncompliance issues, Protocol deviations, and monitoring techniques (eg, central, remote, or 
on-site monitoring) are provided in the Clinical Monitoring Plan and Project Management Plan. 
Quality tolerance limits will be predefined in the Integrated Quality and Risk Management Plan 
to identify systematic issues that can impact participants' safety, efficacy results and analysis, 
and/or reliability of study results. These predefined parameters will be monitored during the 
study and can be adjusted during the study upon data review. Important deviations from the 
quality tolerance limits and remedial actions taken, including reporting to IRBs/IECs and health 
authorities if applicable, will be summarized in the CSR. 
11.4. 
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 personal information is handled in accordance with local data protection laws (including but 
not limited to HIPAA and GDPR) as applicable, and the sponsor operates comprehensive data 
privacy and data security programs that are applicable to this study.  Appropriate notice, or 
notice and consent (as may be required by each applicable jurisdiction), for collection, use, 


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disclosure, and/or transfer (if applicable) of personal information must be obtained in accordance 
with local data protection laws.  Appropriate data protection terms that comply with applicable 
laws will be included in relevant study agreements. 
To ensure confidentiality of records and protect personal data, 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. 
In the event of a data breach involving participant data, the sponsor or its designee will follow 
the sponsor's incident response procedures. The precise definition of a data breach varies in 
accordance with applicable law but may generally be understood as a breach of security leading 
to the accidental or unlawful destruction, loss, alteration, unauthorized disclosure of, or access to, 
personal data. In accordance with its incident response procedures, the sponsor will assess the 
breach to consider its notification and remediation obligations under applicable law. 
11.5. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject 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 Clinical 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. 
11.6. 
Publication Policy 
By signing the study Protocol, the investigator and their institution agree that the results of the 
study may be used by the sponsor, Incyte Corporation (Incyte), 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. 


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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. 
11.7. 
Study and Site Closure 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the Protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines. 
• Inadequate recruitment of participants by the investigator. 
• Discontinuation of further study treatment development. 


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12. 
REFERENCES 
Akdis CA, Adkis M, Bieber T, et al. Diagnosis and treatment of atopic dermatitis in children and 
adults: European Academy of Allergology and Clinical Immunology/American Academy of 
Allergy, Asthma and Immunology/PRACTALL Consensus Report. J Allergy Clin Immunol 
2006;118:152-169. 
Bissonnette R, Papp KA, Poulin Y, et al. Topical tofacitinib for atopic dermatitis: a phase IIa 
randomized trial. Br J Dermatol 2016;175:902-911. 
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med 2009;28:586-604. 
Chang YS, Chiang BL. Sleep disorders and atopic dermatitis: a 2-way street? J Allergy Clin 
Immunol 2018;142:1033-1040. 
 
 
 
Clinical Trials Facilitation and Coordination Group. Recommendations related to contraception 
and pregnancy testing in clinical trials. 2020. 
de la O-Escamilla NO, Sidbury R. Atopic dermatitis: update on pathogenesis and therapy. 
Pediatr Ann 2020;49:e140-e146. 
Dupixent (dupilumab) injection [prescribing information]. Regeneron Pharmaceuticals, Inc; 
June 2020. 
Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care for the management of atopic 
dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol 
2014;70:338-351. 
Eucrisa (crisaborole) ointment [prescribing information]. Pfizer Inc; April 2020. 
European Medicines Agency. Guidance on the Management of Clinical Trials During the 
COVID-19 (Coronavirus) Pandemic. 2020. 
Food and Drug Administration. Draft Guidance on Pimecrolimus. March 2012. 
Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol Suppl 
(Stockh) 1980;92:44-47. 
Hanifin JM, Reed ML, Eczema Prevalence and Impact Working Group. A population-based 
survey of eczema prevalence in the United States. Dermatitis 2007;18:82-91. 
Harrop J, Chinn S, Verlato G, et al. Eczema, atopy and allergen exposure in adults: a 
population-based study. Clin Exp Allergy 2007;37:526-535. 
Hay RJ, Johns NE, Williams HC, et al. The global burden of skin disease in 2010: an analysis of 
the prevalence and impact of skin conditions. J Invest Dermatol 2014;134:1527-1534. 
Hong CH, Joseph M, Kim VH, Lansang P, Lara-Corrales I. Approach to the assessment and 
management of pediatric patients with atopic dermatitis: a consensus document. Section II: 
comorbid disease in pediatric atopic dermatitis. J Cutan Med Surg 2019;23(suppl):12S-18S. 


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Howell MD, Kuo FI, Smith PA. Targeting the Janus kinase family in autoimmune skin diseases. 
Front Immunol 2019;10:2342. 
Kim BS, Howell MD, Sun K, Papp K, Nasir A, Kuligowski ME. Treatment of atopic dermatitis 
with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream. J Allergy Clin Immunol 
2020a;145:572-582. 
Kim BS, Sun K, Papp K, Venturanza M, Nasir A, Kuligowski ME. Effects of ruxolitinib cream 
on pruritus and quality of life in atopic dermatitis: results from a phase 2, randomized, 
dose-ranging, vehicle- and active-controlled study. J Am Acad Dermatol 2020b;82:1305-1313. 
Levy LL, Urban J, King BA. Treatment of recalcitrant atopic dermatitis with the oral Janus 
kinase inhibitor tofacitinib citrate. J Am Acad Dermatol 2015;73:395-399. 
 
 
Lyons JJ, Milner JD, Stone KD. Atopic dermatitis in children: clinical features, pathophysiology, 
and treatment. Immunol Allergy Clin North Am 2015;35:161-183. 
Mehta CR, Patel NR. Exact logistic regression: theory and examples. Stat Med 
1995;14:2143- 2160. 
Napolitano M, Fabbrocini G, Cinelli E, Stingeni L, Patruno C. Profile of baricitinib and its 
potential in the treatment of moderate to severe atopic dermatitis: a short review on the emerging 
clinical evidence. J Asthma Allergy 2020;13:89-94. 
Papp K, Szepietowski JC, Kircik L, et al. Efficacy and safety of ruxolitinib cream for the 
treatment of atopic dermatitis: results from two phase 3, randomized, double-blind studies.   
Presented at: 2nd Annual Revolutionizing Atopic Dermatitis Conference; April 5, 2020; 
Chicago, IL. 
Pruritus Resources. Numerical Rating Scale (NRS). Accessed July 28, 2021. 
http://www.pruritussymposium.de/numericalratingscale.html 
Ramirez FD, Chen S, Langan SM, et al. Assessment of sleep disturbances and exhaustion in 
mothers of children with atopic dermatitis. JAMA Dermatol 2019;155:556-563. 
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. 
van Buuren S. Multiple imputation of discrete and continuous data by fully conditional 
specification. Stat Methods Med Res 2007;16:219-242. 
van der Schans JV, Çiçek R, de Vries TW, Hak E, Hoekstra PJ. Association of atopic diseases 
and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses. Neurosci 
Biobehav Rev 2017;74:139-148. 


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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. 
Yaghmaie P, Koudelka CW, Simpson EL. Mental health comorbidity in patients with atopic 
dermatitis. J Allergy Clin Immunol 2013;131:428-433. 
Yang EJ, Beck KM, Sekhon S, Bhutani T, Koo J. The impact of pediatric atopic dermatitis on 
families: a review. Pediatr Dermatol 2019;36:66-71. 


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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For female participants in the study: 
The following methods that can achieve a failure rate of < 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 
ovulationa 
− 
oral 
− 
intravaginal 
− 
transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulationa 
− 
oral 
− 
injectable 
− 
implantableb 
• 
Intrauterine device (IUD)b 
• 
Intrauterine hormone-releasing system (IUS)b 
• 
Bilateral tubal occlusionb 
• 
Vasectomized partnerb,c 
• 
Sexual abstinenced 
Acceptable birth control methods that result in a failure rate of more than 1% per year include the followinge: 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of 
action 
• 
Male or female condom with or without spermicidef 
• 
Cap, diaphragm, or sponge with spermicidef 
For male participants in the study: 
Male participants should use a condom during treatment through 90 days after the end of systemic exposure.  
If the male participant has a partner that is of childbearing 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 during the study through 90 days after the end of relevant systemic exposure.  Male participants 
who have had a vasectomy qualify as having met the requirement for a highly effective birth control method. 
a Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the contraception 
method. 
b Contraception methods that in the context of this guidance are considered to have low user dependency. 
,c Vasectomized partner is a highly effective method provided of avoiding pregnancy that partner is the sole sexual partner of the 
study participant and that the vasectomized partner has received medical assessment of the surgical success. 
d 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 trial and the preferred and usual lifestyle of the 
participant. 
e Choices are for US and Canada participants only and include above < 1% failure rate methods. 
f A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods) are also 
considered acceptable, but not highly effective, birth control methods. 
Source:  Clinical Trials Facilitation and Coordination Group 2020. 


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APPENDIX C. COVID-19 PANDEMIC MITIGATION STRATEGIES AND 
INSTRUCTIONS 
The COVID-19 global pandemic presents numerous challenges to the conduct of ongoing 
clinical trials.  In line with the FDA and European Medicines Agency's Guidance on the 
Management of Clinical Trials During the COVID-19 (Coronavirus) Pandemic (2020), the 
following Protocol considerations are provided to ensure participant safety is maintained and 
adequate benefit/risk analyses are applied relative to the completion of study procedures and 
maintaining the investigational product supply chain. 
Recognizing the flexibility required to manage the impact of the pandemic on this clinical trial, 
additional details will be added to respective study reference manuals and project plan 
documents and communicated to the investigative sites as needed.  For any additional questions, 
please confer with the medical monitor. 
Number of Study Participants 
The evolving situation of the pandemic may result in a substantial number of participants 
dropping out of the study early, which could affect the data integrity of the trial.  Because of this 
risk, the sponsor may decide to recruit additional participants in the study, beyond the expected 
number, to mitigate such risk. 
Study Visits 
There are a number of on-site visits that would be required to ensure study validity.  If there are 
local travel restrictions or isolation requirements, or the investigator determines it to be unsafe 
for participants to attend the scheduled study visit, the site staff may conduct certain visits via 
telemedicine (phone or video calls) to minimize participant risk as follows: 
• VC period 
− The following visits must be performed in person: 
o Screening 
o Day 1 (Baseline) – if baseline visit cannot be performed on-site within the 
screening period of 28 (+ 7) days, the participant will be considered to have 
failed screening.  Participants who fail screening due to COVID-19 may be 
rescreened (see Section 5.4) at a later time, if feasible. 
o Week 8/ET (with a window of ± 7 days) 
− The following visits may be conducted via telemedicine, if necessary: 
o Week 2 
o Week 4 
• LTS period 
− The following visits should be in person whenever possible: 
o Week 24 ( ± 7 days) 
o Week 52/EOT/ET (± 10 days) 
− Other visits during the LTS period may be conducted via telemedicine if 
necessary. 


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• Telemedicine visits 
− At a minimum, a review of AEs, concomitant medications, and study cream 
application compliance must be completed and recorded in the EDC. 
− No efficacy assessments can be performed even if the telemedicine visit is a video 
call or photography of the active lesion is provided.  Note:  The presence or 
absence of active AD lesions may be verified through a video call, if available. 
− Participants should continue to complete the daily Itch NRS, 
 
 in 
their diary if the visit affected is during the VC period.  If the participant is in the 
LTS period of the study, the start and end dates of treatment cycles must be 
recorded. 
− All assessments not performed will be recorded in the EDC as protocol deviations 
and reason documented as COVID-19. 
Investigational Medicinal Product Dispensing and Distribution 
In order to ensure the continuity of providing participants with clinical supplies, should they not 
be able to attend an onsite study visit, within the constraints imposed by the pandemic, the site 
staff may decide to supply study treatment to participants as follows: 
• Adequate supplies of study cream can be shipped to the participant by the study staff 
using a third-party service with approval from the participant.  The third-party vendor 
will be agreed upon with the sponsor. 
• The participant may request, with prior arrangement/agreement with the site, an 
authorized individual (a relative or delegate) to retrieve the study cream from the 
study site if the participant is unable to personally to do so. 
Clinical Trial Monitoring 
Study monitoring visits may be postponed; however, the site monitor will continue to employ 
off-site monitoring practices such as routine communication methods (eg, phone calls, emails, 
video visits) with the sites to get information on trial progress, participant status, and issue 
resolution as detailed in the Data Monitoring Guidelines, Remote source data verification. 
If the study site monitor cannot be on-site to perform the final drug accountability for 
reconciliation purposes, and the operation cannot be postponed, it may be performed by a 
pharmacist from the hospital pharmacy or by the study coordinator/data manager with suitable 
training.  The study cream can be returned to the sponsor by the hospital pharmacy directly or 
destroyed in accordance with local practices, if applicable, and with sponsor approval. 


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Direct Contracts With Third Parties/Specialized Service Companies 
If necessary, direct contracts can be established with third-party local physicians to conduct 
activities related to the clinical management of participants for whom the investigator is 
responsible and maintains oversight.  In such situations, the investigator is required to provide 
the local physician with a delegation letter listing all delegated activities.  The sponsor, through 
the study investigator or institution, will reimburse the local physician for the test/procedures 
conducted outside of the standard of care. 
Reimbursement of Extraordinary Expenses 
The sponsor will arrange to reimburse the participant (participant's parent[s]/legal guardian) for 
any extraordinary expenses for AEs that are related to study cream, keeping appropriate 
documentation as evidence (eg, travel expenses for the local laboratory visit[s], the costs of local 
[proximate] laboratory tests). 


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APPENDIX D. BODY SURFACE AREA CALCULATION GUIDES 
1. Handprint Method (use of participant's hand) 
 
2. BSA Calculation Guides 
a) BSA for Children ≥ 3 and < 11 Years of Age 
 
0.1% BSA 
▪ 1% BSA = the palm plus 5 digits, with 
fingers tucked together and thumb 
tucked to the side (handprint) 
▪ Thumb as 0.1% BSA. 


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b) BSA for Infants ≥ 3 Months and < 3 Years of Age 
 
 


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APPENDIX E. ECZEMA AREA AND SEVERITY INDEX 
The EASI score examines 4 areas of the body and weights them as follows: 
• Subjects 8 years of age and older: 
− Head/Neck (H) = 0.1, Upper limbs (UL) = 0.2, Trunk (T) = 0.3, and Lower 
limbs (LL) = 0.4. 
• Subjects 0 to 7 years of age: 
− Head/Neck (H) = 0.2, Upper limbs (UL) = 0.2, Trunk (T) = 0.3, and Lower limbs 
(LL) = 0.3. 
The percentage of area involved for each of the 4 body regions is weighted as follows:  0 = no 
eruption, 1 = some to < 10%, 2 = 10% to 29%, 3 = 30% to 49%, 4 = 50% to 69%, 5 = 70% to 
89%, and 6 = 90% to 100%. 
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 with:  0 = none, 1 = mild, 2 = moderate, and 3= severe, with half-step allowed. 
 


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EASI Score Calculation Tool for 8 Years of Age and Older 
Body Region 
Erythema 
(0-3) 
Edema/ 
Papulation 
(0-3) 
Excoriation 
(0-3) 
Lichenification 
(0-3) 
Region 
Score 
(0-6) 
Multiplier 
Score per Body 
Region 
Head/neck 
(               + 
+ 
+ 
                                ) 
X 
X 0.1 
 
Trunk 
(               + 
+ 
+ 
                                ) 
X 
X 0.3 
 
Upper limbs 
(               + 
+ 
+ 
                                ) 
X 
X 0.2 
 
Lower limbs 
(               + 
+ 
+ 
                                ) 
X 
X 0.4 
 
The final EASI score is the sum of the 4 region scores: 
 
____________ 
   (0-72) 
EASI Score Calculation Tool for 0 to 7 Years of Age 
Body Region 
Erythema 
(0-3) 
Edema/ 
Papulation 
(0-3) 
Excoriation 
(0-3) 
Lichenification 
(0-3) 
Region 
Score 
(0-6) 
Multiplier 
Score per Body 
Region 
Head/neck 
( 
      + 
+ 
+ 
                   ) 
X 
X 0.2 
 
Trunk 
( 
      + 
+ 
+ 
                   ) 
X 
X 0.3 
 
Upper limbs 
( 
      + 
+ 
+ 
                   ) 
X 
X 0.2 
 
Lower limbs 
( 
      + 
+ 
+ 
                   ) 
X 
X 0.3 
 
The final EASI score is the sum of the 4 region scores: 
 
____________ 
   (0-72) 
 


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APPENDIX F. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment 1 
06 MAY 2021 
Amendment 2 
02 AUG 2021 
Amendment 3 
19 AUG 2021 
Amendment 4 
06 APR 2022 
Amendment 5 
29 JUL 2022 
Amendment 6 
22 FEB 2023 
Amendment 6 (22 FEB 2023) 
Overall Rationale for the Amendment: 
The primary purpose of the amendment is to add 2 key secondary endpoints.  Details of these 
and other minor changes are listed below. 
1. Section 1, Protocol Summary (Table 1:  Primary and Key Secondary Objectives and 
Endpoints); Section 3, Objectives and Endpoints (Table 7:  Objectives and 
Endpoints); Section 10.3, Level of Significance; Section 10.4.2, Secondary Analyses 
Description of change:  The proportion of participants with a ≥ 4-point improvement in 
Itch NRS score from baseline to Day 7 (Week 1) and from baseline to Day 3 were added 
as key secondary endpoints.  Statistical details were also added for these 2 additional key 
secondary endpoints. 
Rationale for change:  To include an alpha-controlled assessment of early itch reduction 
with ruxolitinib cream.  
2. Section 1, Protocol Summary (Table 2:  Key Study Design Elements) 
Description of change:  
, MD, was added as the coordinating principal 
investigator. 
Rationale for change:  A coordinating principal investigator is required. 
3. Section 10.2, Populations for Analysis 
Description of change:  Overall application compliance, which is an example of 
important protocol deviations that may significantly affect the primary analysis as part of 
the definition of the PP population, was modified from less than 60% to less than 80%. 
Rationale for change:  
 
4. Incorporation of administrative changes.  Other regulatory guidance and 
administrative changes have been incorporated throughout the Protocol and are noted in 
the redline version of the amendment. 


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Amendment 5 (29 JUL 2022) 
Overall Rationale for the Amendment: 
The primary purpose of the amendment is to increase the overall sample size.  The changes have 
no safety implications for this population of participants.  Details of these and other minor 
changes are listed below. 
1. Section 1, Protocol Summary (Table 2:  Key Study Design Elements; 
Figure 1:  Study Design Schema); Section 10.1, Sample Size Determination 
Description of change:  The sample size for this trial is being increased from 250 to 
315 participants. 
Rationale for change:  The evaluable population for the key secondary endpoint 
(proportion of participants with a ≥ 4-point improvement in Itch NRS score from baseline 
to Week 8) requires participants 6 years of age or older who have nonmissing baseline 
Itch NRS scores.  It was discovered that this subgroup was under-enrolled at a time when 
the overall enrollment was close to final.  Based on the enrollment status on 
14 JUL 2022, among 255 participants screened, approximately 116 participants were 
qualified in that subgroup.  To ensure enough power for this key secondary endpoint, at 
least 180 participants are required in this subgroup, and to achieve that the overall 
population will be increased from 250 to 315. 
The sample size calculation of 180 in this subgroup is based on the results from the 
2 pivotal studies, INCB 18424-303 and INCB 18424-304, in which the response rate for 
the key secondary endpoint at Week 8 is assumed to be 52% and 42% for the active arms 
(ruxolitinib 1.5% cream BID and ruxolitinib 0.75% cream BID, respectively) versus 16% 
for vehicle cream BID.  Using a 2-sided alpha of 0.025, the sample size will have > 90% 
power to detect a difference between ruxolitinib 1.5% cream BID versus vehicle cream 
BID and 70% power to detect a difference between ruxolitinib 0.75% cream BID versus 
vehicle cream.  In addition to providing adequate power for all efficacy variables, the 
sample size increase is also providing a larger database for safety evaluation. 
2. Section 1, Protocol Summary (Table 3:  Schedule of Activities:  Vehicle-Controlled 
Period); Section 5.1, Inclusion Criteria (Inclusion Criterion 8); Section 8.2.3, Target 
Lesion Identification; Section 8.2.4, Photography 
Description of change:  Instructions were added such that only participants who are 
participating in photography are required to identify and measure target lesions at the 
screening and baseline visits. For participants not participating in photography, the 
identification and measurement of target lesions are optional. 
Rationale for change:  Clarification was added that only participants who are 
participating in photography are required to identify and measure target lesions.  


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3. Section 5.1, Inclusion Criteria (Inclusion Criterion 6); Section 8.2.7, Itch Numerical 
Rating Scale 
Description of change:  Instructions were added such that participants who are aged 
6 years to < 12 years must record Itch NRS scores for at least 4 of the 7 days immediately 
prior to the Day 1/baseline, Week 2, Week 4, and Week 8 visits. 
Rationale for change:  Clarification added in order to adequately calculate average 
baseline and weekly Itch NRS scores. 
4. Section 9.4, Reporting of Serious Adverse Events 
Description of change:  Removed the last study visit as a possible last timepoint for 
reporting SAEs so that all SAEs are reported through 30 days after the last application of 
study cream. 
Rationale for change:  Changed in order to align with other sections for AE/SAE 
reporting timelines. 
5. Incorporation of administrative changes.  Other regulatory guidance and 
administrative changes have been incorporated throughout the Protocol and are noted in 
the redline version of the amendment. 


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Amendment 4 (06 APR 2022) 
Overall Rationale for the Amendment: 
The primary purpose of the amendment is to 
.  These changes have no 
safety implications for this population of participants.  Details of these and other minor changes 
are listed below. 
1. Section 1, Protocol Summary (Table 1:  Primary and Key Secondary Objectives and 
Endpoint); Section 3, Objectives and Endpoints (Table 7:  Objectives and 
Endpoints); Section 10.3, Level of Significance; Section 10.4, Primary Analysis 
Description of change:  The endpoint of the proportion of participants who achieve 
EASI75 at Week 8 has been moved from the key secondary endpoints to the other 
secondary endpoints.  The gatekeeping testing strategy described in Section 10.3 and the 
primary analysis description in Section 10.4 have been modified accordingly. Further, the 
gatekeeping testing strategy has been modified so that the primary and key secondary 
endpoints are both tested for the 1.5% ruxolitinib cream strength before testing for the 
0.75% strength. 
Rationale for change:  
. 
2. Section 1, Protocol Summary (Table 3:  Schedule of Activities:  Vehicle-Controlled 
Period) 
Description of change:  Exceptions for dispensing and applying the study cream at site 
visits were updated to include Week 8 if the IGA score is 0. 
Rationale for change:  Clarification that at the Week 8 visit, if the IGA score is 0, no 
study cream should be applied. 
3. Section 1, Protocol Summary (Table 3:  Schedule of Activities:  Vehicle-Controlled 
Period); Section 5.4, Screen Failures; Section 8.1.1, Informed Consent Process; 
Section 8.1.2, Screening Procedures 
Description of change:  Participants on prior medications requiring a 4-week washout 
period will have a 35-day screening window and must reconsent if rescreened ≥ 35 days 
after the initial screening. 
Rationale for change:  To clarify that the 35-day screening window pertains to the 
4-week washout period noted in Exclusion Criterion 5b. 
4. Section 1, Protocol Summary (Table 4:  Schedule of Activities:  Long-Term Safety 
Period) 
Description of change:  Added clarification that application of study cream at site visits 
only pertains to participants with active AD lesions at the time of visit. 
Rationale for change:  Clarification to be consistent with Section 6.1. 


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5. Section 1, Protocol Summary (Table 4:  Schedule of Activities:  Long-Term Safety 
Period); Section 8.9.1, Safety Follow-Up 
Description of change:  Clarified that participants who are in an observation/no 
treatment cycle from the Week 48 visit or earlier until the Week 52/EOT visit can 
complete the safety follow-up and Week 52/EOT visits at the same time. 
Rationale for change:  For consistency with changes previously made to Section 4.1. 
 
 
 
. 
  
. 
7. Section 4.1, Overall Design 
Description of change:  Removed the option for the investigator (in consultation with 
the medical monitor) to determine if a participant experiencing a lack of efficacy after 
8 weeks of continuous treatment in the LTS period should be discontinued, to match the 
language in Section 7.1.1. 
Rationale for change:  
. 
8. Section 5.2, Exclusion Criteria 
Description of change:  Exclusion Criterion 6c has been modified to clarify that 
COVID-19 vaccination is allowed before the baseline visit. 
Rationale for change:  Clarification. 
9. Section 5.2, Exclusion Criteria 
Description of change: Exclusion Criterion 6d has been modified to note that the 
frequency of "bleach" baths must remain the same throughout the study. 
Rationale for change: Consistency with Section 6.6.2. 
10. Section 5.2, Exclusion Criteria; 
 
 
Description of change:  Exclusion Criterion 11, which excluded participants with 
inadequate venous access in nonlesional areas for laboratory blood draws, has been 
removed. 
 
 
 
Rationale for change:  
 
 
 
 
 
 
 
 


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11. Section 6.1, Study Treatments Administered 
Description of change:  Further instructions have been added regarding approval to treat 
additional areas of AD with study cream. 
Rationale for change:  Providing additional guidance. 
12. Section 6.5, Dose Modifications 
Description of change:  Clarification has been provided to the dose-modification rules. 
Rationale for change:  Providing additional guidance. 
13. Section 6.5.1, Criteria and Procedures for Application Interruptions and 
Adjustments of Study Cream 
Description of change:  Added caution that participants should be closely monitored for 
the development of signs and symptoms of infection and added instructions for study 
cream interruption in case of infection. 
Rationale for change:  Added for consistency with current US labeling. 
14. Section 6.6.2, Restricted Medications and Procedures 
Description of change:  Clarification has been provided to indicate that the use of 
allergen immunotherapy is allowed if the participant is on a stable dose at baseline and 
continues at the same dose. 
Rationale for change:  Previously, allergen immunotherapy was not recommended, but 
the sponsor felt that it should be allowed throughout the study if a stable dose. 
15. Section 6.6.2, Restricted Medications and Procedures; Section 6.6.3, Prohibited 
Medications and Procedures 
Description of change:  The use of systemic corticosteroids is no longer completely 
prohibited. Short-term use in response to an AE for participants in the LTS period is now 
allowed, and the decision to keep the participant in the study (or early termination) will 
be made in consultation with the medical monitor. 
Rationale for change:  The sponsor believes that the short-term use of systemic 
corticosteroids will not impact assessment of the long-term safety of ruxolitinib cream 
16. Section 8.2.7, Itch Numerical Rating Scale 
Description of change:  The definition for baseline itch has been updated to state that the 
average must include Itch NRS values for at least 4 of the 7 days. 
Rationale for change:  The sponsor believes that having Itch NRS values for at least 4 of 
the 7 days directly before baseline is an appropriate minimum for the calculation of the 
average baseline Itch NRS score for assessment of Inclusion Criterion 6. 


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17. Section 8.4.3, Vital Signs, Height, and Weight 
Description of change:  It was clarified that at each visit in which the participant's height 
is measured, it is the average of 3 measurements that should be entered in the EDC rather 
than each of the 3 measurements. 
Rationale for change:  Previously, it was implied that all 3 measurements at a given visit 
should be recorded, whereas only 1 value (the average) is required. 
18. 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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Amendment 3 (19 AUG 2021) 
Overall Rationale for the Amendment: 
The primary purpose of the amendment is to 
 concerning Amendment 1.  
These changes have no safety implications for this population of participants.  Details of these 
and other minor changes are listed below. 
1. Section 1, Protocol Summary (Table 2:  Key Study Design Elements); Section 4.1, 
Overall Design 
Description of change:  Added details of the countries where the study will be 
conducted as well as the number of sites. 
Rationale for change:  
. 
2. Section 4.1, Overall Design 
Description of change:  Clarified that participants who are in an observation/no 
treatment cycle from the Week 48 visit or earlier until the Week 52/EOT visit can 
complete the safety follow-up and Week 52/EOT visits at the same time. 
Rationale for change:  The intent of the safety follow-up visit is to assess participants at 
least 30 days after the last application of study treatment; for participants who do not 
apply study treatment from the Week 48 visit onward due to having no active AD lesions, 
the Week 52/EOT visit would occur at approximately 30 days or more after the last 
application of study treatment.  Hence, it is appropriate to combine the Week 52/EOT and 
safety follow-up visits for these participants. 
3. Section 5.2, Exclusion Criteria 
Description of change:  Exclusion Criterion 3 was changed in Amendment 2 to state that 
exclusionary laboratory test results had to be clinically significant.  This is not the case, 
so "clinically significant laboratory results" has been replaced with "clinical laboratory 
test results," which was the language used in Amendment 1. 
Rationale for change:  A change made in Amendment 2 was deemed inappropriate, and 
the text reverted to that used in Amendment 1. 
4. Section 6.1, Study Treatments Administered 
Description of change:  For participants whose total areas of AD to be treated exceed 
20% BSA in either the VC period or LTS period, the option to treat these additional areas 
has been removed, and instructions have been added that these participants should be 
discontinued from study treatment. 
Rationale for change:  The intent was only to allow participants to treat areas of AD up 
to a maximum of 20% BSA in this study, so the 2 instances that suggested otherwise 
needed to be corrected. 


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5. Section 7.1.1, Reasons for Discontinuation 
Description of change:  Added a reason for discontinuation:  if the extent of AD to be 
treated (ie. any body part excluding the scalp) exceeds 20% BSA during either the VC 
period or the LTS period. 
Rationale for change:  Participants are only allowed to treat areas of AD up to a 
maximum of 20% BSA in this study, so it has been made clear that if the extent of AD 
exceeds 20% BSA, a participant must be discontinued from study treatment. 
6. Section 10.2, Populations for Analysis (Table 12:  Populations for Analysis) 
Description of change:  Added examples of protocol deviations that would exclude 
participants from the PP population. 
Rationale for change:  
. 
7. Section 10.4.1, Primary Analysis 
Description of change:  Added full details of the planned sensitivity analyses for the 
handling of missing data and the tipping point analysis. 
Rationale for change:  
. 
8. 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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Amendment 2 (02 AUG 2021) 
Overall Rationale for the Amendment: 
The primary purpose of the amendment is to revise Exclusion Criterion 3, which is overly 
restrictive, to create consistency across the AD program and for ease of recruitment, minimizing 
screen failures for nonsignificant clinical laboratory results.  These changes have no safety 
implications for this population of participants.  Additional changes are listed below. 
1. Protocol Summary (Table 3:  Schedule of Activities: Vehicle-Controlled Period; 
Table 4:  Schedule of Activities:  Long-Term Safety Period) 
Description of change:  Added guidance to study drug application during site visits 
during the VC period; clarified BSA and IGA assessments and ranges at the Week 8 visit; 
deleted Day 1/baseline compliance check; 
 
 
; added recommendation on use of a topical anesthetic prior to blood draw; 
and specified serologic testing for HIV at screening. 
Rationale for change:  To provide additional guidance for clarity and correct an 
administrative error (Day 1/baseline compliance check). 
2. Protocol Summary (Table 3:  Schedule of Activities: Vehicle-Controlled Period); 
Section 5.2, Exclusion Criteria (Exclusion Criterion 6); Section 6.1, Study 
Treatments Administered; Section 61.1, Study Treatment Application Guidance; 
Section 6.5, Dose Modifications; Section 6.5.1, Criteria and Procedures for 
Application Interruptions and Adjustments of Study Drug; 
 
; 
Section 8.4.4.2, Pregnancy Testing 
Description of change: 
• Protocol Summary and Section 8.4.4.2:  Clarified that Day 1 pregnancy testing will 
be performed only if the interval between screening and Day 1 is > 2 weeks. 
• Section 5.2:  Changed inactivated vaccines and live vaccines to live-attenuated 
vaccines and added topical antipruritics to the 1-week washout period before baseline. 
• Section 6.1:  Added allowance for study drug applications to be approximately 
8 hours apart. 
• Section 6.1.1:  Updated application instructions to use a fingertip to apply study drug 
in small amounts. 
• Section 6.5 and Section 6.5.1:  Added text that changes in frequency of application 
are not allowed and that treatment may be temporarily withheld at a lesional site but 
may be continued elsewhere and must be recorded as a dose interruption in the AE 
eCRF page. 
 
 
 
Rationale for change:  To provide additional guidance for clarity. 


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3. Section 5.2, Exclusion Criteria (Exclusion Criteria 2 and 3) 
Description of change:  Added "day" to 880 µg (880 µg/day) to Exclusion Criterion 2g; 
moved the criterion regarding medical history of hepatitis B virus or hepatitis C virus 
from Exclusion Criterion 4 to Exclusion Criterion 2i; revised Exclusion Criterion 3 to 
apply to clinically significant laboratory test results at screening; deleted Exclusion 
Criterion 3a (any value < 0.75 × LLN [other than bilirubin]); moved Exclusion Criterion 
3b to Exclusion Criterion 3d and revised "any value > 2.5 × ULN" to "AST or ALT 
≥ 2.5 × ULN"; added Exclusion Criterion 3d heading "liver function tests"; revised 
Exclusion Criterion 3e to change the estimated GFR from < 15 to < 30 mL/min/1.73 m2; 
added Exclusion Criteria 3c and 3g regarding cytopenias at screening and any other 
clinically significant laboratory result that, in the opinion of the investigator, poses a 
significant risk to the participant, respectively; and moved Exclusion Criterion 9 
regarding serologic testing for HIV to Exclusion Criterion 3f. 
Rationale for change:  Exclusion Criteria 2 were revised for updates and clarification; 
Exclusion Criteria 3 were revised, added, or moved to be consistent with exclusion 
criteria from other AD protocols.  In addition, original Exclusion Criteria 3a and 3b were 
overly restrictive; Exclusion Criterion 3d was revised to group the 2 liver function tests 
for clarity; and Exclusion Criterion 3e, per recommendation by Canada Health 
Authorities, was revised to provide a more conservative estimated GFR value. 
4. Section 6.5.1, Criteria and Procedures for Application Interruptions and 
Adjustments of Study Drug (Table 9:  Guidelines for Interruption and Restarting of 
Treatment Applications if Adverse Event Is Deemed Related to the Study Drug) 
Description of change:  Deleted ALT and AST (> 3 × ULN), revised ANC to < 750/μL 
(without fever) and < 1000/μL (with fever), and updated AST or ALT (from > 5 to > 20 
× ULN). 
Rationale for change:  To provide a more succinct guideline because ALT and AST 
> 3 × ULN is covered by "any other Grade 3 or higher laboratory abnormality" 
assessment, to define ANC levels with fever or without fever, and to update AST or ALT 
to > 20 × ULN to be consistent with CTCAE v5.0 grading. 
5. Section 6.6.2, Restricted Medications and Procedures; Section 6.6.3, Prohibited 
Medications and Procedures 
Description of change:  Moved allergen immunotherapy and live-attenuated 
vaccinations from prohibited medications to restricted medications. 
Rationale for change:  Allergen immunotherapy and immunizations with a 
live-attenuated vaccine are standard of care for this pediatric population and therefore 
may be allowed during the VC period should the investigator deem it necessary. 


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6. Appendix C, COVID-19 Pandemic Mitigation Strategies and Instructions (Study 
Visits) 
Description of change:  
 
 
Rationale for change:  Administrative error. 
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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Amendment 1 (06 MAY 2021) 
Overall Rationale for the Amendment: 
The primary purpose of the amendment is to incorporate revisions requested by the Canadian 
Health Authority and to address European regulatory requirements.  Additional changes are 
summarized below. 
1. Protocol Summary (Table 3:  Schedule of Activities:  Vehicle-Controlled Period; 
Table 4:  Schedule of Activities:  Long-Term Safety Period); Section 8.1.5.1, 
Demographics and General Medical History; Section 8.4.3, Vital Signs, Height, and 
Weight 
Description of change:  Added guidance to capture height and weight of not only each 
participant, but also both parents of each participant (if available), and to record these 
data in the EDC. 
Rationale for change:  To provide clarity that the growth measurements will be entered 
into the EDC and evaluated at the end of the study. 
 
 
 
 
 
 
  
 
 
  
 
 
 
3. Section 2, Introduction 
Description of change:  Revised the order of the sections for clarity and added text. 
• Moved Section 2.2, Study Rationale, to Section 2.3. 
• Moved Section 2.2.1, Scientific Rationale for Study Design, to Section 2.3.1. 
• Moved Section 2.2.2, Justification for the Selected Treatment Regimen, to Section 
2.3.2. 
• Moved Section 2.2.2.2, INCB 18424-303 and INCB 18424-304, to Section 2.2.1 and 
changed the heading to INCB 18424-303 and INCB 18424-304:  Phase 3 
Adolescent/Adult Studies. 
• Moved Section 2.2.2.3, INCB 18424-102:  Pharmacokinetic Pediatric Study, to 
Section 2.2.2. 
• Created Section 2.2, Pivotal Phase 3 Studies and Pilot Pediatric Study, for Section 
2.2.1, INCB 18424-303 and INCB 18424-304:  Phase 3 Adolescent/Adult Studies, 
and Section 2.2.2, INCB 18424-102:  Pharmacokinetic Pediatric Study. 


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• Moved Section 2.2.2.1, INCB 18424-206, to part of Section 2.3.2, Justification for the 
Selected Treatment Regimen, and added text to provide further information for the 
justification of the selected treatment regimen. 
Rationale for change:  Administrative corrections. 
4. Section 5.2, Exclusion Criteria (Criteria 2h, 3b, and 3d) 
Description of change: 
• Exclusion Criterion 2h:  Added a criterion to exclude participants who are on 
maintenance dialysis. 
• Exclusion Criterion 3b:  Added text to clarify that the laboratory test criterion for the 
ULN does not include for serum creatinine levels. 
• Exclusion Criterion 3d:  Added a clinical laboratory test criterion for the lower limit 
of the estimated GFR. 
Rationale for change:  To address Canadian Health Authority request. 
5. Section 5.2, Exclusion Criteria (Criteria 6c) 
Description of change:  Clarified the requirement for inactivated vaccines. 
Rationale for change:  To simplify the immunization requirement. 
6. Section 6.1, Study Treatments Administered; Section 6.1.1, Study Treatment 
Application Guidance 
Description of change:  Deleted text regarding redispensing of study drug, replaced 
Figure 8 (Fingertip Unit of a Cream), and deleted the study drug application instructions. 
Rationale for change:  To simplify the study drug dispensing process, to provide a better 
representation of the cream, and to avoid overlap of information that will be included in 
the Study Manual. 
7. Section 8.4.4.1, Blood Sample Collection 
Description of change:  Deleted capillary sampling. 
Rationale for change:  To minimize laboratory sampling options. 
8. Section 8.1.5.2, Medical and Treatment History 
Description of change:  Added text for clarity on what would be defined as 
documentation needed for previous AD medication history.  Defined the collective 
meaning of "inadequate response" for clarity of data collected. 
Rationale for change:  To address European regulatory requirements (for the intended 
target population/indication). 


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9. Appendices 
Description of change:  Revised the appendices as follows. 
 
 
 
• Moved original Appendix B (COVID-19 Pandemic Mitigation Strategies and 
Instructions) to Appendix C. 
• Moved original Appendix C (Body Surface Area Calculation Guides) to Appendix D. 
• Deleted original Appendix D (Centers for Disease Control And Prevention Growth 
Charts [for the US Region]) and Appendix E [United Kingdom–World Health 
Organization Growth Charts [for the EU Region]) 
• Changed original Appendix F (Eczema Area and Severity Index) to Appendix E. 
  
 
 
 
10. Appendix C, COVID-19 Pandemic Mitigation Strategies and Instructions 
Description of change:  
 
Rationale for change:  
 
 
11. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 


Signature Page for VV-CLIN-011993 v12.0
Signature Page for VV-CLIN-011993 v12.0
Approval Task
22-Feb-2023 21:32:24 GMT+0000
Approval Task
22-Feb-2023 21:35:13 GMT+0000
Approval Task
22-Feb-2023 22:17:59 GMT+0000
Approval Task
Document Preparer
22-Feb-2023 22:53:22 GMT+0000
Approval Task
23-Feb-2023 02:45:14 GMT+0000

SAP_001.pdf: 
Official Title:    A Phase 3, Double-Blind, Randomized, Vehicle-Controlled, Efficacy 
and Safety Study of Ruxolitinib Cream Followed by a Long-Term (Safety 
Extension Period in Children (Ages ≥ 2 Years to < 12 Years) With Atopic 
Dermatitis
NCT Number: 
 NCT04921969 
Document Date: 
 Statistical Analysis Pan Original: 02-June-2023


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Statistical Analysis Plan 
TITLE PAGE 
INCB 18424-305 
Topical Ruxolitinib Evaluation in Atopic Dermatitis Study 3 
(TRuE-AD3) 
A Phase 3, Double-Blind, Randomized, Vehicle-Controlled, Efficacy 
and Safety Study of Ruxolitinib Cream Followed by a Long-Term 
Safety Extension Period in Children (Ages ≥ 2 Years to < 12 Years) 
With Atopic Dermatitis
Product: 
Ruxolitinib Cream 
IND Number 
 
EudraCT Number: 
2021‐000489‐14 
Phase of Study: 
3 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
United States 
Protocol Version: 
Protocol Amendment 6 dated 22 FEB 2023 
CRF Approval Date: 
10 JAN 2023 
SAP Version: 
Original 
SAP Author: 
 
, Biostatistics 
Date of Plan: 
02 JUN 2023 
This study is being conducted in compliance with Good Clinical Practice, 
including the archiving of essential documents. 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS.................................9 
2.1. 
Protocol and Case Report Form Version ......................................................................9 
2.2. 
Objectives and Endpoints .............................................................................................9 
3. 
STUDY DESIGN .......................................................................................................12 
3.1. 
Randomization ............................................................................................................13 
3.2. 
Control of Type I Error ...............................................................................................13 
3.3. 
Sample Size Considerations .......................................................................................15 
3.4. 
Schedule of Assessments ............................................................................................15 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................16 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................16 
4.1.1. 
Day 1 ...........................................................................................................................16 
4.1.2. 
Study Day ...................................................................................................................16 
4.1.3. 
Baseline Value ............................................................................................................16 
4.1.4. 
Last Available Value ..................................................................................................17 
4.1.5. 
Handling of Missing and Incomplete Data .................................................................17 
4.2. 
Variable Definitions ....................................................................................................17 
4.2.1. 
Body Mass Index ........................................................................................................17 
4.2.2. 
Prior and Concomitant Therapy ..................................................................................17 
5. 
STATISTICAL METHODOLOGY ...........................................................................18 
5.1. 
General Methodology .................................................................................................18 
5.2. 
Treatment Groups .......................................................................................................18 
5.3. 
Analysis Populations ..................................................................................................18 
5.3.1. 
Intent-to-Treat Population ..........................................................................................18 
5.3.2. 
Per Protocol Population ..............................................................................................18 
5.3.3. 
Safety Population ........................................................................................................18 
 
19 
5.3.5. 
Long-Term Safety Evaluable Population ...................................................................19 


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19 
 
19 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES ...............................................................................................................20 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease History .............20 
6.1.1. 
Demographics .............................................................................................................20 
6.1.2. 
Baseline Disease Characteristics ................................................................................20 
6.1.3. 
Prior Therapies for Atopic Dermatitis ........................................................................21 
6.1.4. 
Medical History ..........................................................................................................21 
6.2. 
Disposition of Participants ..........................................................................................21 
6.3. 
Protocol Deviations ....................................................................................................21 
6.4. 
Exposure .....................................................................................................................22 
6.5. 
Study Drug Compliance .............................................................................................22 
6.6. 
Prior and Concomitant Therapies ...............................................................................22 
7. 
EFFICACY .................................................................................................................23 
7.1. 
General Considerations ...............................................................................................23 
7.2. 
Analysis of the Primary Efficacy Parameters .............................................................23 
7.2.1. 
Primary Efficacy Measures .........................................................................................23 
7.2.1.1. 
Investigator's Global Assessment ...............................................................................23 
7.2.2. 
Primary Efficacy Analyses .........................................................................................23 
7.2.3. 
Subgroup Analyses for the Primary Endpoint ............................................................24 
7.2.4. 
Sensitivity and Supportive Analyses for the Primary Endpoint .................................24 
7.2.4.1. 
Longitudinal Logistic Regression With Repeated Measures ......................................24 
7.2.4.2. 
Multiple Imputation ....................................................................................................25 
7.2.4.3. 
Last Observation Carried Forward .............................................................................25 
7.2.4.4. 
Tipping Point Analysis ...............................................................................................25 
7.3. 
Analysis of the Key Secondary Efficacy Parameters .................................................26 
7.3.1. 
Key Secondary Efficacy Measures .............................................................................26 
7.3.1.1. 
Itch Numerical Rating Scale Score .............................................................................26 
7.3.2. 
Key Secondary Efficacy Analysis ..............................................................................26 
7.4. 
Analysis of Secondary Efficacy Parameters ...............................................................27 
7.4.1. 
Secondary Efficacy Measures .....................................................................................27 
7.4.1.1. 
Eczema Area and Severity Index Score ......................................................................27 


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7.4.2. 
Secondary Efficacy Analysis ......................................................................................27 
7.4.2.1. 
Categorical Efficacy Endpoints ..................................................................................27 
7.4.2.2. 
Time-to-Event Efficacy Endpoints .............................................................................28 
 
28 
 
28 
 
28 
 
 
29 
 
 
29 
 
29 
 
30 
 
30 
 
 
31 
 
32 
 
32 
 
33 
 
33 
 
34 
 
34 
 
35 
 
.36 
 
36 
 
36 
 
36 
. 
36 
9. 
SAFETY AND TOLERABILITY ..............................................................................37 
9.1. 
General Considerations ...............................................................................................37 
9.2. 
Adverse Events ...........................................................................................................37 
9.2.1. 
Adverse Event Definitions ..........................................................................................37 
9.2.2. 
Adverse Event Summaries ..........................................................................................38 
9.3. 
Clinical Laboratory Tests ...........................................................................................39 


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9.3.1. 
Laboratory Value Definitions .....................................................................................39 
9.3.2. 
Laboratory Value Summaries .....................................................................................39 
9.4. 
Body Weight and Height ............................................................................................40 
9.5. 
Vital Signs ..................................................................................................................40 
10. 
PLANNED ANALYSES ............................................................................................41 
11. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................42 
11.1. 
Changes to Protocol-Defined Analyses ......................................................................42 
11.2. 
Changes to the Statistical Analysis Plan .....................................................................42 
12. 
REFERENCES ...........................................................................................................43 
APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS ........................................44 
 
LIST OF TABLES 
Table 1: 
Objectives and Endpoints .............................................................................................9 
Table 2: 
Investigator's Global Assessment ...............................................................................23 
Table 3: 
Criteria for Clinically Notable Vital Sign Abnormalities for 
Ages ≥ 7 to < 12 Years ...............................................................................................40 
Table 4: 
Criteria for Clinically Notable Vital Sign Abnormalities for 
Ages ≥ 2 to < 7 Years .................................................................................................41 
Table 5: 
Statistical Analysis Plan Versions ..............................................................................42 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................12 
Figure 2: 
Control of Overall Type I Error Rate .........................................................................14 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ANC 
absolute neutrophil count 
AD 
atopic dermatitis 
AE 
adverse event 
ANOVA 
analysis of variance 
ASR 
application site reaction 
BID 
twice daily 
BSA 
body surface area 
 
 
CI 
confidence interval 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
EASI 
Eczema Area and Severity Index 
 
 
EASI75 
≥ 75% improvement in EASI score 
 
 
eCRF 
electronic case report form 
EOT 
end of treatment 
 
 
ET 
early termination 
FDA 
Food and Drug Administration 
 
 
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 
LTS 
long-term safety 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
mixed-model repeated measures 
NRI 
nonresponder imputation 
NRS 
numerical rating scale 
 
 
 
 
 
 


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Abbreviation 
Term 
ANC 
absolute neutrophil count 
 
 
PP  
per protocol 
 
 
PT 
preferred term 
 
 
SAP 
Statistical Analysis Plan 
SOC 
system organ class 
TCI 
topical calcineurin inhibitor 
TCS 
topical corticosteroid 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 
 
 
VC 
vehicle-controlled 


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1. 
INTRODUCTION 
Study INCB 18424-305 is a randomized, double-blind, vehicle-controlled study with an 
LTS period in pediatric participants aged ≥ 2 to < 12 years with AD eligible for topical therapy. 
This Phase 3 study will be conducted at roughly 60 sites in the United States and Canada. 
Approximately 315 participants will be randomized 2:2:1 to blinded treatment with either 
ruxolitinib 1.5% cream BID, ruxolitinib 0.75% cream BID, or vehicle cream BID; stratification 
will be by baseline IGA score and age. Enrollment will be capped such that no more than 
approximately 25% of randomized participants have a baseline IGA score of 2. At least 40% of 
the overall study population will consist of children aged ≥ 2 to 6 years. In this trial, participants 
will apply blinded study treatment for 8 weeks followed by a randomized 44-week LTS 
extension period. In the LTS period, participants initially randomized to vehicle cream will apply 
either ruxolitinib 0.75% or 1.5% cream BID; this will replicate the design of the earlier pivotal 
studies (INCB 18424-303 and INCB 18424-304) in adolescents and adults with AD. 
The purpose of this SAP is to provide details of the statistical analyses that have been outlined in 
the INCB 18424-305 Protocol. The Department of Biostatistics or designee will execute the 
scope of this plan 
 
. 


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2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on INCB 18424-305 Protocol Amendment 6 dated 22 FEB 2023 and CRFs 
approved 10 JAN 2023. Unless superseded by an amendment, this SAP will be effective for all 
subsequent Protocol amendments and eCRF versions. 
2.2. 
Objectives and Endpoints 
Table 1 presents the objectives and endpoints. 
Table 1: 
Objectives and Endpoints 
Objectives  
Endpoints 
Primary 
To establish the efficacy of ruxolitinib cream in 
participants with AD. 
Proportion of participants who achieve IGA-TS at 
Week 8. 
Key Secondary 
To further assess the treatment effects of ruxolitinib 
cream. 
• Proportion of participants with a ≥ 4-point 
improvement in Itch NRS score from baseline to 
Week 8. 
• Proportion of participants with a ≥ 4-point 
improvement in Itch NRS score from baseline to 
Day 7 (Week 1). 
• Proportion of participants with a ≥ 4-point 
improvement in Itch NRS score from baseline to 
Day 3. 
Secondary 
To evaluate the safety and tolerability of ruxolitinib 
cream. 
The type, frequency, and severity of AEs and changes 
from baseline in physical examinations, vital signs, 
height, weight, and laboratory data for hematology and 
serum chemistry. 
To further evaluate the efficacy of ruxolitinib cream. 
• Proportion of participants who achieve IGA-TS at 
Weeks 2 and 4. 
• Proportion of participants with a ≥ 4-point 
improvement in Itch NRS score from baseline to 
Weeks 2 and 4. 
• Proportion of participants who achieve EASI75 at 
Weeks 2, 4, and 8. 
• Time to achieve Itch NRS score improvement of at 
least 2 or 4 points. 


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Table 1: 
Objectives and Endpoints (Continued) 
Objectives  
Endpoints 


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Table 1: 
Objectives and Endpoints (Continued) 
Objectives  
Endpoints 
 


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3. 
STUDY DESIGN 
This is a randomized, double-blind, VC study with an LTS period in pediatric participants aged 
≥ 2 to < 12 years with AD eligible for topical therapy. For participants who meet all study 
inclusion criteria and none of the exclusion criteria, study drug will be assigned at the 
Day 1/baseline visit. Participants will be randomized 2:2:1 to blinded treatment with either 
ruxolitinib 0.75% cream BID, ruxolitinib 1.5% cream BID, or vehicle cream BID, with 
stratification by baseline IGA score and age. Enrollment will be capped, such that no more than 
approximately 25% of randomized participants have a baseline IGA score of 2. At least 40% of 
the overall study population will consist of children aged ≥ 2 to 6 years. 
Participants who complete Week 8 assessments with no additional safety concerns will continue 
into the 44-week LTS period with the same treatment regimen, except those initially randomized 
to vehicle cream who will be rerandomized (1:1) in a blinded manner to 1 of the 2 active 
treatment groups (ruxolitinib 0.75% or 1.5% cream BID). The IGA score required for 
participants to enter the LTS period is 0 to 4, and participants must have a %BSA in the range of 
0% to 20% (excluding the scalp). 
Following the end of treatment (Week 52/EOT or ET), all participants will have a safety 
follow-up visit 30 days later (or 30 days after the last application of study treatment if the 
Week 52/EOT or ET visit was not performed); this visit will evaluate the safety and duration of 
response (refer to Protocol Amendment 6). 
Figure 1 presents the study design schema. 
Figure 1: 
Study Design Schema 
 


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3.1. 
Randomization  
In the VC period, the IRT system will assign approximately 315 participants in a 2:2:1 ratio to 
ruxolitinib 1.5% cream BID, ruxolitinib 0.75% cream BID, or vehicle cream BID, respectively. 
Additionally, participants will be stratified by baseline IGA score (2 or 3) and age (2-6 years or 
7 to < 12 years). 
Participants who complete Week 8 assessments with no safety concerns will continue into the 
44-week LTS period with the same treatment regimen, except that those initially randomized to 
vehicle cream who will be rerandomized (1:1) in a blinded manner to 1 of the 2 active treatment 
groups (ruxolitinib 0.75% or 1.5% cream BID). 
3.2. 
Control of Type I Error 
For the primary and key secondary analyses, an overall 2-sided Type I error of 0.05 will be used. 
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 by Bretz et al (2009). The method will guarantee a strong control of the family-wise 
error rate. 
In Step 1, 2 families of 4 elementary hypotheses tests at Week 8 are grouped according to 
treatment comparison between each ruxolitinib cream group and the vehicle cream group, where 
• Family 1 (1.5% BID vs vehicle): 
− H11: proportion of participants who achieve IGA-TS 
− H12: proportion of participants with a ≥ 4-grade improvement in Itch NRS score 
over baseline 
• Family 2 (0.75% BID vs vehicle): 
− H21: proportion of participants who achieve IGA-TS 
− H22: proportion of participants with a ≥ 4-grade improvement in Itch NRS score 
over baseline  
Step 2 has 2 families of 4 hypotheses tests: 
• Family 3 (1.5% BID vs vehicle and 0.75% BID vs vehicle on Day 7 Itch NRS): 
− H13: proportion of participants with a ≥ 4-grade improvement in Itch NRS score 
over baseline to Day 7 (Week 1) between 1.5% BID and vehicle 
− H23: proportion of participants with a ≥ 4-grade improvement in Itch NRS score 
over baseline to Day 7 (Week 1) between 0.75% BID and vehicle 
• Family 4 (1.5% BID vs vehicle and 0.75% BID vs vehicle on Day 3 Itch NRS): 
− H14: proportion of participants with a ≥ 4-grade improvement in Itch NRS score 
over baseline to Day 3 between 1.5% BID and vehicle 
− H24: proportion of participants with a ≥ 4-grade improvement in Itch NRS score 
over baseline to Day 3 between 0.75% BID and vehicle 


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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 a Bonferronized 
2-sided α = 0.025 level. The key secondary endpoint will be tested only if the associated primary 
endpoint is rejected. For any treatment strength, if the 2 related null hypotheses can be rejected, 
then the fixed sequence for the other treatment strength can be conducted at the 2-sided α = 0.05 
level. If all null hypotheses in Family 1 and 2 are rejected, in Step 2, the endpoints in Family 3 
(H13 and H23) will be tested using Bonferroni-Hochberg's procedure with overall 2-sided 
α = 0.05 level. If both hypotheses in Family 3 are rejected, the endpoints in Family 4 (H14 and 
H24) will be tested similarly using Bonferroni-Hochberg's procedure with overall 2-sided 
α = 0.05 level. The approach is visualized in Figure 2. 
Figure 2: 
Control of Overall Type I Error Rate 
Step 1: 
 
Step 2: 
 


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3.3. 
Sample Size Considerations 
Approximately 315 participants will be randomized 2:2:1 to blinded treatment with either 
ruxolitinib 1.5% cream BID, ruxolitinib 0.75% cream BID, or vehicle cream BID. The sample 
size calculation is based on the Fisher exact test for the primary efficacy endpoint. Based on the 
results from the 2 pivotal studies in adolescents and adults with AD (INCB 18424-303 and 
INCB 18424-304), the response rate of IGA-TS at Week 8 is assumed to be 51% and 47% for 
the active arms (ie, 1.5% BID and 0.75% BID, respectively) versus 14% 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 the vehicle. In addition to providing 
adequate power for efficacy variables, the sample size is determined to provide a large database 
for safety evaluations. 
3.4. 
Schedule of Assessments 
Refer to Protocol Amendment 6 dated 22 FEB 2023 for a full description of all study procedures 
and assessment schedules for this study. 


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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 the VC 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.  
For participants who continue in the LTS period, baseline for LTS is defined as follows: 
• For efficacy evaluation, baseline is the last nonmissing measurement obtained before 
or on the day of first application of study treatment in the VC period. 
• For safety evaluation, for participants who cross over from vehicle to ruxolitinib 
cream, baseline is the last nonmissing measurement obtained before or on the day of 
first application of ruxolitinib cream in the LTS period; for participants on ruxolitinib 
cream in both periods, baseline is the last nonmissing measurement obtained before 
or on the day of first application of study treatment in the VC period. 
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 
In general, values for missing dates will not be handled unless methods for handling missing 
dates are specified in this section or relevant sections. The original reported dates collected on 
the eCRF should be used in all relevant listings. The following rules will be used for handling 
partial dates for analyses requiring dates. 
For response endpoints, all nonresponders, as well as all participants who are missing 
postbaseline values at Week 8, 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 or MI under the missing-at-random assumption. The 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 will be calculated as follows: 
Body mass index (kg/m2) = (weight [kg] / (height [m])2 
4.2.2. 
Prior and Concomitant Therapy 
Prior therapy is defined as any nonstudy therapy started before the first application of study 
treatment.  
Concomitant therapy is defined as any nonstudy therapy 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 therapy could also be classified as "both prior and concomitant therapy" if the end date is 
on or after the first application of study treatment. In the listing, it will be indicated whether a 
therapy is prior only, concomitant only, or both prior and concomitant. 
For the purposes of analysis, all therapies will be considered concomitant therapies unless the 
therapies 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; v9.1 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, first quartile, third 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, VC 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. 
For 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 their 
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 in the VC period. 
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 the 
primary endpoint in the VC 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 ruxolitinib cream or vehicle cream at least once 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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5.3.5. 
Long-Term Safety Evaluable Population 
All participants who applied study drug at least once during the LTS period will constitute the 
LTS evaluable population. All efficacy and safety analyses for the LTS period will be conducted 
with the LTS evaluable population.  
 
 
 
 
 
 


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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 and listed for the ITT population during the VC 
period and the LTS evaluable population during the LTS period: age, age group, sex, race, 
ethnicity, weight, height, and body mass index. 
6.1.2. 
Baseline Disease Characteristics 
The following baseline disease characteristics summarized and listed 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 
• Time since onset of current AD episode 
• Prior therapy for AD given in the past 30 days (no/yes) 
• Total %BSA involvement in current AD episode 
• Facial and/or neck involvement (no/yes) during past episodes 
• Number of AD episodes/flare-ups over the last 12 months 
• Average duration of episodes/flare-ups over the last 12 months 
• Baseline IGA score (2, 3) 
• Baseline EASI score 
• Baseline Itch NRS score 
 
 


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6.1.3. 
Prior Therapies for Atopic Dermatitis 
Prior therapies for AD, including medication and other types of therapies during the 12 months 
prior to the screening visit, will be coded using the WHO Drug Dictionary and summarized and 
listed by treatment group for the ITT population. The type of treatment and reason for 
discontinuation will be summarized as well. Prior therapies for AD in the past 30 days will be 
summarized in a similar way. 
6.1.4. 
Medical History 
For participants in the ITT population during the VC period, medical history will be summarized 
and listed 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, who were treated, who 
completed the VC period, who discontinued study treatment, or who withdrew from the study 
during the VC period with a primary reason for discontinuation will be summarized and listed 
for the ITT population during the VC period. 
The number and percentage of participants who were treated, who completed the LTS period, 
who were ongoing treatment during the LTS period, who discontinued study treatment, or who 
withdrew from the study during the LTS period with a primary reason for discontinuation, will 
be summarized and listed for the LTS evaluable population in the LTS period. 
6.3. 
Protocol Deviations 
In general, the following are important protocol deviations that may significantly affect the 
primary analysis: 
• Missing data for the primary endpoint 
• Overall application compliance < 80% during the VC period 
• Did not apply any study cream in the VC period 
• IGA assessment 14 days out of the target visit date at Week 8 (Day 57 ±7)  
Participants with any of the deviations listed above will be excluded from the PP population. 
Additionally, important protocol deviations, such as those related to inclusion/exclusion criteria, 
discontinuation criteria, and the use of prohibited concomitant medications, will be reviewed. 
Decisions as to whether any of these deviations warrant exclusion from the PP population will be 
made prior to unblinding. 
Protocol deviations will be summarized and listed by treatment groups in the VC and 
LTS periods separately. 


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6.4. 
Exposure 
For participants in the safety population during the VC period and in the LTS evaluable 
population in the LTS period, descriptive statistics will be provided (ie, by treatment group for 
the duration of treatment, the average daily amount of cream applied [g], and the total amount of 
cream applied [g]). 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 
For participants in the safety population, overall compliance (%) for the application of ruxolitinib 
cream or vehicle cream during the VC period will be calculated for all participants 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 and the total number of intended applications is the 
number of planned applications minus the number of interrupted applications. Overall 
compliance will be summarized and listed for the safety population during the VC period. 
6.6. 
Prior and Concomitant Therapies 
For participants in the ITT population during the VC period, prior and concomitant therapies will 
be coded using the WHO Drug Dictionary and summarized as number and percentage of 
participants with prior and concomitant therapies by WHO drug class and WHO drug term. 
For participants in the LTS period, only concomitant therapies will be summarized. Concomitant 
therapies for AD will also be summarized by treatment groups in the VC and LTS periods.  


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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 safety follow-up period, if the data are available. 
7.2. 
Analysis of the Primary Efficacy Parameters 
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: FDA 2012. 
The IGA-TS is defined as an IGA score of 0 or 1 with ≥ 2-grade improvement from baseline. 
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 score and age). The 
unadjusted p-values between each treatment group versus vehicle will be calculated based on the 
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 < 5. 


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The odds ratio and 95% CI at Week 8 for the response rates (ruxolitinib cream/vehicle) will be 
computed for the above model. Additionally, the difference in IGA-TS response rates 
(ruxolitinib cream − vehicle) at Week 8 will be computed. The 95% CI for the difference will be 
computed based on a large-sample normal approximation with continuity correction. 
All nonresponders during the VC period, as well as all participants missing the Week 8 
assessment and who discontinue study treatment at any time before Week 8, or discontinue from 
the study for any reason, will be defined as nonresponders for the nonresponder imputation 
analysis. 
The primary outcome will also be examined for the PP population using the same model as the 
primary analysis. 
7.2.3. 
Subgroup Analyses for the Primary Endpoint 
Subgroup analysis will be performed based on the following participant-demographic and 
baseline disease-characteristic variables for those participants whose data are available: 
• Baseline IGA score (2, 3) 
• Baseline EASI score (≤ 7, > 7) 
• Age (2 to 6 years, 7 to < 12 years) 
• Sex (male, female) 
• Race 
• Country (United States or Canada) 
• Prior TCS therapy (yes/no) 
• Prior TCI therapy (yes/no) 
• Prior systemic therapy (yes/no) 
• Prior AD therapy (yes/no) 
7.2.4. 
Sensitivity and Supportive Analyses for the Primary Endpoint 
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 
• Level 3: site, 
where visits are nested within participants and participants are further nested within sites. 
The binary response (IGA-TS) of each participant at Weeks 2, 4, and 8 will be included as the 
dependent variable. Treatment (1.5% BID, 0.75% BID, and vehicle BID), randomization 
stratification factors (baseline IGA score and age), visit, and treatment-by-visit interaction will 


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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. A full conditional specification method (van Buuren 2007) that assumes the 
existence of a joint distribution for all variables will be used to impute the IGA score. A 
regression model including treatment group, stratification factor age group, and baseline and 
scheduled postbaseline IGA scores up to Week 8 will be specified for the fully conditional 
specification method. The imputation will be repeated 40 times to generate corresponding 
complete datasets in order to reflect the uncertainty around the true values. The primary endpoint 
binary response will be derived for each of the imputed datasets per the definition in 
Section 7.2.1.1 and the logistic regression described in Section 7.2.2 will be applied. The results 
will then be combined for the inference using Rubin's rule. 
The following sample SAS code will be used for the MI: 
proc mi data=mi_wide seed=18424305 nimpute=40 out=impute_IGA; 
    class trt01p agestrata; 
var trt01p agestrata avalBASELINE avalWEEK2 avalWEEK4   avalWEEK8; 
fcs REGPMM nbiter=30; 
run; 
7.2.4.3. 
Last Observation Carried Forward 
For participants who are missing postbaseline values, the last observed nonmissing value will be 
used to fill in missing values at Week 8. The proposed logistic regression described in 
Section 7.2.2 will then be applied to the imputed dataset. 
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 binary IGA-TS response in each treatment group at Week 8 will be replaced 
by a range of values from the most conservative case to the most aggressive case. The most 
conservative case is that all the missing participants in active treatment groups are nonresponders 
and all the missing participants in the vehicle group are responders, while the most aggressive 
case is the other way around. For each scenario, between-treatment comparisons will be 
performed using a chi-square test. If there are N missing responses in the 1.5% BID arm and 
Mmissing responses in the vehicle arm, the following process will be used to determine the 
tipping point and a similar process will be implemented for the 0.75% BID arm versus the 
vehicle arm: 
• Missing responses in the 1.5% BID arm will be imputed with a range of values from 
0 to N. 
• Missing responses in the vehicle arm will be imputed with a range of values from 0 to 
M. 


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• Treatment comparisons between the 1.5% BID arm and the vehicle arm will be 
analyzed in each of the (N + 1) × (M + 1) imputed datasets using a chi-square test, 
which will result in a (N + 1) × (M + 1) table; columns will represent the number of 
responses imputed for the 1.5% BID arm and rows will represent the number of 
responses imputed for the vehicle arm. A separate table will be generated to compare 
the 0.75% BID arm with the vehicle arm following the same process. 
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-daily patient-reported measure of itch intensity assessed using an 
11-point scale (0 = no itch to 10 = worst imaginable itch). Participants aged 6 years or older 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 directly 
before Day 1 (Day –7 to Day –1) for all the by-visit summaries. The by-visit Itch NRS score for 
postbaseline visits will be determined by averaging the 7 daily NRS scores directly 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. For all daily itch related analyses, including time to achieve Itch NRS score 
improvement of at least 2 or 4 points analyses, baseline will be defined as the last available Itch 
NRS score during the week prior to Day 1 (Day −7 to Day −1). 
The proportion of participants with a clinically relevant change in itch, defined as a ≥ 4-point 
improvement in by-visit or daily Itch NRS score from baseline, will be summarized by treatment 
group for participants with baseline Itch NRS score ≥ 4. 
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 Section 3.2. 
The same nonresponder imputation method as specified in the primary analysis will be used to 
handle missing Week 8 itch data, and the logistic regression described in Section 7.2.2 will be 
applied to compare each ruxolitinib cream group and the vehicle cream group for the key 
secondary endpoint of ≥ 4-point improvement in Itch NRS score response at Week 8. 
For the key secondary endpoints of Itch NRS score responses on Day 7 (Week 1) and Day 3, all 
participants who are missing Day 7 and/or Day 3 daily Itch NRS scores will be imputed using 
multiple imputation by fully conditional specification method. The variables to be included in the 
imputation regression model are treatment group, stratification factor, baseline itch score, and 
postbaseline daily itch score on Day 1 to Day 7. The corresponding binary response on Day 7 
and Day 3 will be derived for each of the imputed datasets per the definition in Section 7.3.1.1. 
The logistic regression specified in Section 7.2.2 will be applied to each imputed dataset and 
then the results will be combined for the inference using Rubin's rule. 


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The following sample SAS code will be used for the MI: 
proc mi data=mi_wide seed=18424 nimpute=30 out=impute_itch; 
    class trt01p strat1 strat2; 
    var trt01p strat1 strat2 base avald1 avald2 avald3 avald4 avald5 
avald6 avald7; 
 
fcs regpmm nbiter=30; 
run; 
7.4. 
Analysis of Secondary Efficacy Parameters 
7.4.1. 
Secondary Efficacy Measures 
7.4.1.1. 
Eczema Area and Severity Index Score 
Atopic dermatitis will be assessed using the EASI scoring system, which is a validated scoring 
system that grades the physical signs of AD to provide a measure of AD severity (ranging from 
0 to 72). 
The weight of the body regions for the EASI scoring is based on age (< 8 years or ≥ 8 years): 
• For participants 8 years of age or older: head/neck (H) = 0.1, upper limbs (UL) = 0.2, 
trunk (T) = 0.3, and lower limbs (LL) = 0.4 
• For participants 7 years or younger: head/neck (H) = 0.2, upper limbs (UL) = 0.2, 
trunk (T) = 0.3, and lower limbs (LL) = 0.3 
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 with 0 = none, 1 = mild, 2 = moderate, and 3 = severe, with half-steps allowed.  
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; and 50.1 to 72.0 = very severe. 
The categorical variable EASI75 to indicate the EASI responder will be set 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%. 
 
 
7.4.2. 
Secondary Efficacy Analysis 
All secondary efficacy analyses will be conducted based on the ITT population in the VC period. 
7.4.2.1. 
Categorical Efficacy Endpoints 
For the following categorical parameters, summary statistics including sample size, frequency, 
and percentages will be presented by visit: 
• Proportion of participants achieving an IGA-TS 
• Proportion of participants with a ≥ 4-point improvement in Itch NRS score 
• Proportion of participants achieving EASI75 


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A logistic regression model with treatment and stratification factors as covariates will be fit at 
Week 8. The p-values between each ruxolitinib group versus vehicle will be calculated based on 
the Wald test. Exact logistic regression will be used for all of the comparisons if any of the dose 
levels have an expected cell count < 5. The NRI will be used to impute postbaseline missing 
values for binary outcomes based on IGA, Itch NRS, and EASI scores. 
7.4.2.2. 
Time-to-Event Efficacy Endpoints 
For the time to achieve Itch NRS score improvement of at least 2 or 4 points, a log-rank test 
stratified by randomization stratification factors will be used for between-treatment 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 treatment group. The number of participants, number of events, and number of 
censoring will be summarized by treatment group. The Kaplan-Meier 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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9. 
SAFETY AND TOLERABILITY  
Appendix A provides a list of planned tables figures, and listings. Sample data displays are 
included in a separate document. 
9.1. 
General Considerations  
The analyses in this section will be provided for the safety population in the VC period and for 
the LTS evaluable population in the LTS period. Cumulative TEAEs across the treatment periods 
(VC and LTS periods) will be summarized. Summary 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 reported on relatively few participants. 
9.2. 
Adverse Events  
9.2.1. 
Adverse Event Definitions 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first application of study drug and within 30 days after the last dose of study drug. For 
participants who cross over treatments, the first application date is period specific, and the end 
date is 30 days after the last application date in this period or the first application date in the next 
period, whichever comes first. Analysis of AEs (as discussed below) will be limited to TEAEs, 
but data listings will include all AEs regardless of their timing in relation to study drug 
administration. 
Adverse events will be tabulated by MedDRA PT and SOC. Severity of AEs will be graded 
using the NCI CTCAE v5. The CTCAE (Grade 1 to 5) 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 
treatment-related AEs. If the investigator does not specify the relationship of the AE to study 
drug, the AE will be considered treatment-related. The incidence of AEs and treatment-related 
AEs will be tabulated. In addition, 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. 
Application site reactions are AEs that occur at the site of drug application. A summary of ASRs 
will be provided. Exposure-adjusted summaries will also be provided for the safety population, 
including cumulative TEAEs and cumulative ASRs. 


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9.2.2. 
Adverse Event Summaries  
An overall summary of AEs by treatment group will include the following: 
• 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 in part of the 
treated areas because of TEAEs  
• Number (%) of participants who temporarily interrupted study drug in all of the 
treated areas because of TEAEs  
• Number (%) of participants who temporarily interrupted study drug in any of the 
treated areas 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 TEAEs by SOC and PT  
• Summary of Grade 3 or higher TEAEs 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  
• 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 in any of the treated 
areas by SOC and PT  
• Summary of TEAEs leading to dose interruption of study drug in part of the treated 
areas by SOC and PT  


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• Summary of TEAEs leading to dose interruption of study drug in all of the treated 
areas by SOC and PT  
• Summary of TEAEs leading to discontinuation of study drug by SOC and PT  
Subgroup analysis for TEAEs by age categories will also be provided. 
Adverse events of interest will be summarized in the following categories: 
• Cytopenias 
− Anemia 
− Thrombocytopenia 
− Neutropenia 
• Herpes zoster 
• Viral skin infections 
• Nonmelanoma skin neoplasms 
• Liver function test elevations 
• Malignancies 
• Major Adverse Cardiovascular Events 
• Venous and arterial thromboembolic events 
• Thrombocytosis and elevated mean platelet volume 
9.3. 
Clinical Laboratory Tests  
9.3.1. 
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. 
9.3.2. 
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. 


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All test results and associated normal ranges from central laboratories will be reported in SI 
units. All tests with numerical 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 nonmissing laboratory 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. 
Test results will be summarized and listed 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 the VC period, as well as the LTS period 
for the LTS evaluable population. Shift tables will be presented to show 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. 
9.4. 
Body Weight and Height 
Values at each scheduled visit, change, and percentage change from baseline for body weight 
and height will be summarized descriptively and listed. 
9.5. 
Vital Signs 
Values at each scheduled visit, change, and percentage change from baseline for vital signs, 
including systolic blood pressure, diastolic blood pressure, pulse, respiratory rate, and body 
temperature, will be summarized descriptively. 
Criteria for clinically notable vital sign abnormalities are defined in Table 3 and Table 4. 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 from baseline > 25%. The abnormal values for 
participants exhibiting alert vital sign abnormalities will be listed. 
Table 3: 
Criteria for Clinically Notable Vital Sign Abnormalities for 
Ages ≥ 7 to < 12 Years 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 120 mm Hg 
< 97 mm Hg 
Diastolic blood pressure 
> 80 mm Hg 
< 57 mm Hg 
Pulse 
> 118 bpm 
< 75 bpm 
Temperature 
> 38.0°C 
< 35.5°C 
Respiratory rate 
> 25 breaths/min 
< 18 breaths/min 
 


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Table 4: 
Criteria for Clinically Notable Vital Sign Abnormalities for 
Ages ≥ 2 to < 7 Years 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 112 mm Hg 
< 89 mm Hg 
Diastolic blood pressure 
> 72 mm Hg 
< 46 mm Hg 
Pulse 
> 120 bpm 
< 80 bpm 
Temperature 
> 38.0°C 
< 35.5°C 
Respiratory rate 
> 28 breaths/min 
< 20 breaths/min 
10. 
PLANNED ANALYSES 
No formal interim analysis is planned for this study. There are 2 formal planned analyses. 
• The primary analysis will occur after the primary database lock, when all participants 
have completed the VC period. The sponsor will be unblinded after the primary database 
lock; however, investigators and participants will remain blinded to the individual study 
treatment assignment. 
• The final analysis will occur when all participants have completed or withdrawn from the 
study. 


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11. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN 
All versions of the SAP are listed in Table 5. 
Table 5: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
02 JUN 2023 
11.1. 
Changes to Protocol-Defined Analyses 
Not applicable. 
11.2. 
Changes to the Statistical Analysis Plan 
Not applicable. 


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APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS 
This appendix provides a list of the planned tables, figures, and listings for the Clinical Study 
Report. Shells are provided in a separate document for tables that are not in the most current 
Standard Safety Tables. 
The list of tables, figures, and listings are to be used as guidelines. Modifications of the lists that 
do not otherwise affect the nature of the analysis will not warrant an amendment to the SAP. 
Tables 
Table No. 
Title 
Population 
Standard 
Baseline Demographic and Characteristic 
1.1.1 
Analysis Populations 
All 
X 
1.1.2.1 
Summary of Participant Disposition in the VC Period 
ITT 
X 
1.1.2.2 
Summary of Participant Disposition in the LTS Period 
LTS Evaluable 
X 
1.1.3 
Summary of Number of Participants Enrolled by Country and 
Site 
ITT 
X 
1.1.4.1 
Summary of Protocol Deviations During the VC Period 
ITT 
X 
1.1.4.2 
Summary of Protocol Deviations During the LTS Period 
LTS Evaluable 
X 
1.2.1 
Summary of Demographics and Baseline Characteristics in the 
VC Period 
ITT 
X 
1.2.2 
Summary of Demographics and Baseline Characteristics in the 
LTS Period 
LTS Evaluable 
X 
1.3 
Summary of Baseline Disease Characteristics 
ITT 
X 
1.4.1 
Summary of Prior Non-AD Medications 
ITT 
X 
1.4.2.1 
Summary of Prior Therapies for Atopic Dermatitis During the 
Past 12 Months 
ITT 
X 
1.4.2.2 
Summary of Prior Therapies for Atopic Dermatitis During the 
Past 12 Months by Therapy Type and Discontinuation Reason 
ITT 
X 
1.4.2.3 
Summary of Prior Therapies for Atopic Dermatitis During the 
Past 30 Days 
ITT 
X 
1.4.2.4 
Summary of Prior Therapies for Atopic Dermatitis During the 
Past 30 Days by Therapy Type and Discontinuation Reason 
ITT 
X 
1.4.3.1 
Summary of Non-AD Concomitant Medications During the VC 
Period 
ITT 
X 
1.4.3.2 
Summary of Non-AD Concomitant Medications During the LTS 
Period 
LTS Evaluable 
X 
1.4.3.3 
Summary of Concomitant Therapies for AD During the VC 
Period 
ITT 
X 
1.4.3.4 
Summary of Concomitant Therapies for AD During the LTS 
Period 
LTS Evaluable 
X 
1.5 
Summary of General Medical History  
ITT 
X 
1.6.1 
Summary of Participants With Assessments Affected by the 
COVID-19 Pandemic in the VC Period 
ITT 
X 
1.6.2 
Summary of Participants With Assessments Affected by the 
COVID-19 Pandemic in the LTS Period 
LTS Evaluable 
X 


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Table No. 
Title 
Population 
Standard 
Efficacy 
IGA 
2.1.1 
Summary and Analysis of Participants Achieving IGA-TS in the 
VC 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 
Summary and Analysis of Participants Achieving IGA-TS in the 
VC Period 
PP 
 
2.1.4 
Summary and Analysis of Participants Achieving IGA-TS by 
Baseline IGA Score in the VC Period 
ITT 
 
2.1.5 
Summary and Analysis of Participants Achieving IGA-TS by 
Baseline EASI Score in the VC Period 
ITT 
 
2.1.6 
Summary and Analysis of Participants Achieving IGA-TS by 
Country in the VC Period 
ITT 
 
2.1.7 
Summary and Analysis of Participants Achieving IGA-TS by 
Age Group in the VC Period 
ITT 
 
2.1.8 
Summary and Analysis of Participants Achieving IGA-TS by 
Sex in the VC Period 
ITT 
 
2.1.9 
Summary and Analysis of Participants Achieving IGA-TS by 
Race in the VC Period 
ITT 
 
2.1.10 
Summary and Analysis of Participants Achieving IGA-TS by 
Any Prior TCS Therapy in the VC Period 
ITT 
 
2.1.11 
Summary and Analysis of Participants Achieving IGA-TS by 
Any Prior TCI Therapy in the VC Period 
ITT 
 
2.1.12 
Summary and Analysis of Participants Achieving IGA-TS by 
Any Prior Systemic Therapy in the VC Period 
ITT 
 
2.1.13 
Summary and Analysis of Participants Achieving IGA-TS by 
Any Prior AD Therapy in the VC Period 
ITT 
 
 
 
 
 
 
 
 
 
 
 
2.1.15.1  
Summary of Participants in Each Category of IGA Score in the 
VC Period  
ITT  
 
2.1.15.2  
Summary of Participants in Each Category of IGA Score in the 
LTS Period  
LTS Evaluable 
 
EASI 
2.2.1 
Summary and Analysis of Participants Achieving EASI75 in the 
VC Period 
ITT 
 


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Table No. 
Title 
Population 
Standard 
2.2.5.1 
Summary of Participants in Each Category of EASI Score in the 
VC Period 
ITT 
 
Itch NRS Score 
2.3.1 
Summary and Analysis of Participants Achieving ≥ 4-Point 
Improvement in Itch NRS Score in the VC Period by Visit  
ITT with baseline 
Itch NRS Score 
≥ 4 
 
2.3.3 
Summary and Analysis of Time to ≥ 2-Point Improvement in 
Itch NRS Score in the VC Period  
ITT with daily 
baseline Itch 
NRS Score ≥ 2 
 
2.3.4 
Summary and Analysis of Time to ≥ 4-Point Improvement in 
Itch NRS Score in the VC Period  
ITT with daily 
baseline Itch 
NRS Score ≥ 4 
 
2.3.6 
Summary and Analysis of Participants Achieving ≥ 4-Point 
Improvement in Itch NRS Score from Day 1 to Day 7 
ITT with daily 
baseline Itch 
NRS Score ≥ 4 
 


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Table No. 
Title 
Population 
Standard 


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Table No. 
Title 
Population 
Standard 
Exposure, Adverse Events, Laboratory, and Vital Signs 
Exposure 
3.1.1.1 
Summary of Exposure During the VC Period  
Safety 
X 
3.1.1.2 
Summary of Exposure During the LTS Period 
LTS Evaluable 
X 
3.1.1.3 
Summary of Exposure From Baseline to Week 52 
Safety 
X 
3.1.2 
Summary of Study Drug Compliance During the VC Period 
Safety 
X 
Adverse Events 
3.2.1.1.1 
Overall Summary of Treatment-Emergent Adverse Events in the 
VC Period 
Safety 
X 
3.2.1.1.2 
Overall Summary of Treatment-Emergent Adverse Events by 
Age Group in the VC Period 
Safety 
X 
3.2.1.1.3 
Overall Summary of Treatment-Emergent Adverse Events in the 
LTS Period 
LTS Evaluable 
X 
3.2.1.1.4 
Overall Summary of Treatment-Emergent Adverse Events for 
Participants Who Applied Ruxolitinib Cream Throughout the 
Study (Baseline to Week 52) 
Safety 
X 
3.2.2.1.1 
Summary of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term in the VC Period 
Safety 
X 


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Table No. 
Title 
Population 
Standard 
3.2.2.1.2 
Summary of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term by Age Group in the 
VC Period 
Safety 
X 
3.2.2.1.3 
Summary of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term in the LTS Period 
LTS Evaluable 
X 
3.2.2.1.4 
Summary of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term for Participants Who 
Applied Ruxolitinib Cream Throughout the Study (Baseline to 
Week 52) 
Safety 
X 
3.2.3.1.1 
Summary of Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency in the VC 
Period 
Safety 
X 
3.2.3.1.2 
Summary of Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency by Age 
Group in the VC Period 
Safety 
X 
3.2.3.1.3 
Summary of Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency in the LTS 
Period 
LTS Evaluable 
X 
3.2.3.1.4 
Summary of Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency for 
Participants Who Applied Ruxolitinib Cream Throughout the 
Study (Baseline to Week 52) 
Safety 
X 
3.2.3.2.1 
Summary of Treatment-Emergent Adverse Events in ≥ 1% of 
Participants in Any Treatment Group by MedDRA Preferred 
Term in Decreasing Order of Frequency in the VC Period 
Safety 
X 
3.2.3.2.2 
Summary of Treatment-Emergent Adverse Events in ≥ 1% of 
Participants in any Treatment Group by MedDRA Preferred 
Term in Decreasing Order of Frequency by Age Group in the 
VC Period 
Safety 
X 
3.2.3.2.3 
Summary of Treatment-Emergent Adverse Events in ≥ 1% of 
Participants in Any Treatment Group by MedDRA Preferred 
Term in Decreasing Order of Frequency in the LTS Period 
LTS Evaluable 
X 
3.2.3.2.4 
Summary of Treatment-Emergent Adverse Events in ≥ 1% of 
Participants by MedDRA Preferred Term in Decreasing Order 
of Frequency for Participants Who Applied Ruxolitinib Cream 
Throughout the Study (Baseline to Week 52) 
Safety 
X 
3.2.3.3.1 
Summary of Application Site Reactions by MedDRA Preferred 
Term in Decreasing Order of Frequency in the VC Period 
Safety 
X 
3.2.3.3.2 
Summary of Application Site Reactions by MedDRA Preferred 
Term in Decreasing Order of Frequency by Age Group in the 
VC Period 
Safety 
X 
3.2.3.3.3 
Summary of Application Site Reactions by MedDRA Preferred 
Term in Decreasing Order of Frequency in the LTS Period 
LTS Evaluable 
X 
3.2.3.3.4 
Summary of Application Site Reactions by MedDRA Preferred 
Term in Decreasing Order of Frequency for Participants Who 
Applied Ruxolitinib Cream Throughout the Study (Baseline to 
Week 52) 
Safety 
X 


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CONFIDENTIAL 
Table No. 
Title 
Population 
Standard 
3.2.4.1.1 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term in 
the VC Period 
Safety 
X 
3.2.4.1.2 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term by 
Age Group in the VC Period 
Safety 
X 
3.2.4.1.3 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term in 
the LTS Period 
LTS Evaluable 
X 
3.2.4.2.2 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
for Participants Who Applied Ruxolitinib Cream Throughout 
the Study (Baseline to Week 52) 
Safety 
X 
3.2.5.1.1 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing Order of 
Frequency in the VC Period 
Safety 
X 
3.2.5.1.2 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing Order of 
Frequency by Age Group in the VC Period 
Safety 
X 
3.2.5.1.3 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing Order of 
Frequency in the LTS Period 
LTS Evaluable 
X 
3.2.5.1.4 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing Order of 
Frequency for Participants Who Applied Ruxolitinib Cream 
Throughout the Study (Baseline to Week 52) 
Safety 
X 
3.2.6.1.1 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term in the VC 
Period 
Safety 
X 
3.2.6.1.2 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term by Age 
Group in the VC Period 
Safety 
X 
3.2.6.1.3 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term in the LTS 
Period 
LTS Evaluable 
X 
3.2.6.1.4 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term for 
Participants Who Applied Ruxolitinib Cream Throughout the 
Study (Baseline to Week 52) 
Safety 
X 
3.2.7.1.1 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency in 
the VC Period 
Safety 
X 
3.2.7.1.2 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency by 
Age Group in the VC Period 
Safety 
X 
3.2.7.1.3 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency in 
the LTS Period 
LTS Evaluable 
X 


Incyte Corporation 
Page 51 of 61 
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CONFIDENTIAL 
Table No. 
Title 
Population 
Standard 
3.2.7.1.4 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency for 
Participants Who Applied Ruxolitinib Cream Throughout the 
Study (Baseline to Week 52) 
Safety 
X 
3.2.8.1.1 
Summary of Treatment-Related Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term in 
the VC Period 
Safety 
X 
3.2.8.1.2 
Summary of Treatment-Related Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term by 
Age Group in the VC Period 
Safety 
X 
3.2.8.1.3 
Summary of Treatment-Related Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term in 
the LTS Period 
LTS Evaluable 
X 
3.2.8.1.4 
Summary of Treatment-Related Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
for Participants Who Applied Ruxolitinib Cream Throughout 
the Study (Baseline to Week 52) 
Safety 
X 
3.2.9.1.1 
Summary of Treatment-Related Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing Order of 
Frequency in the VC Period 
Safety 
X 
3.2.9.1.2 
Summary of Treatment-Related Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing Order of 
Frequency by Age Group in the VC Period 
Safety 
X 
3.2.9.1.3 
Summary of Treatment-Related Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing Order of 
Frequency in the LTS Period 
LTS Evaluable 
X 
3.2.9.1.4 
Summary of Treatment-Related Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing Order of 
Frequency for Participants Who Applied Ruxolitinib Cream 
Throughout the Study (Baseline to Week 52) 
Safety 
X 
3.2.10.1.1 
Summary of Grade 3 or Higher Treatment-Related 
Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term in the VC Period 
Safety 
X 
3.2.10.1.2 
Summary of Grade 3 or Higher Treatment-Related 
Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term by Age Group in the VC 
Period 
Safety 
X 
3.2.10.1.3 
Summary of Grade 3 or Higher Treatment-Related 
Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term in the LTS Period 
LTS Evaluable 
X 
3.2.10.1.4 
Summary of Grade 3 or Higher Treatment-Related 
Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term for Participants Who Applied 
Ruxolitinib Cream Throughout the Study (Baseline to Week 52) 
Safety 
X 
3.2.11.1.1 
Summary of Treatment-Related Serious Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred 
Term in the VC Period 
Safety 
X 


Incyte Corporation 
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Table No. 
Title 
Population 
Standard 
3.2.11.1.2 
Summary of Treatment-Related Serious Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred 
Term by Age Group in the VC Period 
Safety 
X 
3.2.11.1.3 
Summary of Treatment-Related Serious Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred 
Term in the LTS Period 
LTS Evaluable 
X 
3.2.11.1.4 
Summary of Treatment-Related Serious Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred 
Term for Participants Who Applied Ruxolitinib Cream 
Throughout the Study (Baseline to Week 52) 
Safety 
X 
3.2.12.1.1 
Summary of Treatment-Emergent Adverse Events With a Fatal 
Outcome by MedDRA System Organ Class and Preferred Term 
in the VC Period 
Safety 
X 
3.2.12.1.2 
Summary of Treatment-Emergent Adverse Events With a Fatal 
Outcome by MedDRA System Organ Class and Preferred Term 
by Age Group in the VC Period 
Safety 
X 
3.2.12.1.3 
Summary of Treatment-Emergent Adverse Events With a Fatal 
Outcome by MedDRA System Organ Class and Preferred Term 
in the LTS Period 
LTS Evaluable 
X 
3.2.12.1.4 
Summary of Treatment-Emergent Adverse Events With a Fatal 
Outcome by MedDRA System Organ Class and Preferred Term 
for Participants Who Applied Ruxolitinib Cream Throughout 
the Study (Baseline to Week 52) 
Safety 
X 
3.2.13.1.1 
Summary of Treatment-Emergent Adverse Events Leading to 
Dose Interruption in Any of the Treated Areas by MedDRA 
System Organ Class and Preferred Term in the VC Period 
Safety 
X 
3.2.13.1.2 
Summary of Treatment-Emergent Adverse Events Leading to 
Dose Interruption in Any of the Treated Areas by MedDRA 
System Organ Class and Preferred Term by Age Group in the 
VC Period 
Safety 
X 
3.2.13.1.3 
Summary of Treatment-Emergent Adverse Events Leading to 
Dose Interruption in Any of the Treated Areas by MedDRA 
System Organ Class and Preferred Term in the LTS Period 
LTS Evaluable 
X 
3.2.13.1.4 
Summary of Treatment-Emergent Adverse Events Leading to 
Dose Interruption in Any of the Treated Areas by MedDRA 
System Organ Class and Preferred Term for Participants who 
Applied Ruxolitinib Cream Throughout the Study (Baseline to 
Week 52) 
Safety 
X 
3.2.13.2.1 
Summary of Treatment-Emergent Adverse Events Leading to 
Dose Interruption in Part of the Treated Areas by MedDRA 
System Organ Class and Preferred Term in the VC Period 
Safety 
X 
3.2.13.2.2 
Summary of Treatment-Emergent Adverse Events Leading to 
Dose Interruption in Part of the Treated Areas by MedDRA 
System Organ Class and Preferred Term by Age Group in the 
VC Period 
Safety 
X 
3.2.13.2.3 
Summary of Treatment-Emergent Adverse Events Leading to 
Dose Interruption in Part of the Treated Areas by MedDRA 
System Organ Class and Preferred Term in the LTS Period 
LTS Evaluable 
X 


Incyte Corporation 
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INCB 18424-305 Statistical Analysis Plan 
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Table No. 
Title 
Population 
Standard 
3.2.13.2.4 
Summary of Treatment-Emergent Adverse Events Leading to 
Dose Interruption in Part of the Treated Areas by MedDRA 
System Organ Class and Preferred Term for Participants Who 
Applied Ruxolitinib Cream Throughout the Study (Baseline to 
Week 52) 
Safety 
X 
3.2.13.3.1 
Summary of Treatment-Emergent Adverse Events Leading to 
Dose Interruption in All of the Treated Areas by MedDRA 
System Organ Class and Preferred Term in the VC Period 
Safety 
X 
3.2.13.3.2 
Summary of Treatment-Emergent Adverse Events Leading to 
Dose Interruption in All of the Treated Areas by MedDRA 
System Organ Class and Preferred Term by Age Group in the 
VC Period 
Safety 
X 
3.2.13.3.3 
Summary of Treatment-Emergent Adverse Events Leading to 
Dose Interruption in All of the Treated Areas by MedDRA 
System Organ Class and Preferred Term in the LTS Period 
LTS Evaluable 
X 
3.2.13.3.4 
Summary of Treatment-Emergent Adverse Events Leading to 
Dose Interruption in All of the Treated Areas by MedDRA 
System Organ Class and Preferred Term for Participants Who 
Applied Ruxolitinib Cream Throughout the Study (Baseline to 
Week 52) 
Safety 
X 
3.2.14.1.1 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Study Drug by MedDRA System Organ 
Class and Preferred Term in the VC Period 
Safety 
X 
3.2.14.1.2 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Study Drug by MedDRA System Organ 
Class and Preferred Term by Age Group in the VC Period 
Safety 
X 
3.2.14.1.3 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Study Drug by MedDRA System Organ 
Class and Preferred Term in the LTS Period 
LTS Evaluable 
X 
3.2.14.1.4 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Study Drug by MedDRA System Organ 
Class and Preferred Term for Participants Who Applied 
Ruxolitinib Cream Throughout the Study (Baseline to Week 52) 
Safety 
X 
3.2.15.1.1 
Summary of Treatment-Emergent Adverse Events of Interest by 
MedDRA System Organ Class and Preferred Term in the VC 
period 
Safety 
X 
3.2.15.1.2 
Summary of Treatment-Emergent Adverse Events of Interest by 
MedDRA System Organ Class and Preferred Term by Age 
Group in the VC period 
Safety 
X 
3.2.15.1.3 
Summary of Treatment-Emergent Adverse Events of Interest by 
MedDRA System Organ Class and Preferred Term in the LTS 
period 
LTS Evaluable 
X 
3.2.15.1.4 
Summary of Treatment-Emergent Adverse Events of Interest by 
MedDRA System Organ Class and Preferred Term for 
Participants Who Applied Ruxolitinib Cream Throughout the 
Study (Baseline to Week 52) 
Safety 
X 
3.2.16.1.1 
Summary of Treatment-Emergent Adverse Events of Interest by 
MedDRA Preferred Term in Decreasing Order of Frequency in 
the VC period 
Safety 
X 


Incyte Corporation 
Page 54 of 61 
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Table No. 
Title 
Population 
Standard 
3.2.16.1.2 
Summary of Treatment-Emergent Adverse Events of Interest by 
MedDRA Preferred Term in Decreasing Order of Frequency by 
Age Group in the VC period 
Safety 
X 
3.2.16.1.3 
Summary of Treatment-Emergent Adverse Events of Interest by 
MedDRA Preferred Term in Decreasing Order of Frequency in 
the LTS period 
LTS Evaluable 
X 
3.2.16.1.4 
Summary of Treatment-Emergent Adverse Events of Interest by 
MedDRA Preferred Term in Decreasing Order of Frequency for 
Participants Who Applied Ruxolitinib Cream Throughout the 
Study (Baseline to Week 52) 
Safety 
X 
Laboratory 
3.3.1.1.1 
Summary of Laboratory Values – Hematology in the VC Period 
Safety 
X 
3.3.1.1.2 
Summary of Laboratory Values – Hematology by Age Group in 
the VC Period 
Safety 
X 
3.3.1.1.3 
Summary of Laboratory Values – Hematology in the LTS 
Period  
LTS Evaluable 
X 
3.3.2.1.1 
Summary of Laboratory Values – Chemistry in the VC Period 
Safety 
X 
3.3.2.1.2 
Summary of Laboratory Values – Chemistry by Age Group in 
the VC Period 
Safety 
X 
3.3.2.1.3 
Summary of Laboratory Values – Chemistry in the LTS Period  
LTS Evaluable 
X 
3.3.3.1 
Shift Summary of Hematology Laboratory Values in CTCAE 
Grade – To the Worst Abnormal Value in the VC Period 
Safety 
X 
3.3.3.2 
Shift Summary of Hematology Laboratory Values in CTCAE 
Grade – To the Worst Abnormal Value in the VC Period by Age 
Group 
Safety 
X 
3.3.3.3 
Shift Summary of Hematology Laboratory Values in CTCAE 
Grade – To the Worst Abnormal Value in the LTS Period 
LTS Evaluable 
X 
3.3.4.1 
Shift Summary of Chemistry Laboratory Values in CTCAE 
Grade – To the Worst Abnormal Value in the VC Period 
Safety 
X 
3.3.4.2 
Shift Summary of Chemistry Laboratory Values in CTCAE 
Grade – To the Worst Abnormal Value in the VC Period by Age 
Group 
Safety 
X 
3.3.4.3 
Shift Summary of Chemistry Laboratory Values in CTCAE 
Grade – To the Worst Abnormal Value in the LTS Period 
LTS Evaluable 
X 
3.3.5.1 
Shift Summary of Hematology Values – To the Worst 
Abnormal Value in the VC Period 
Safety 
X 
3.3.5.2 
Shift Summary of Hematology Values – To the Worst 
Abnormal Value in the VC Period by Age Group 
Safety 
X 
3.3.5.3 
Shift Summary of Hematology Values – To the Worst 
Abnormal Value in the LTS Period 
LTS Evaluable 
X 
3.3.6.1 
Shift Summary of Chemistry Values – To the Worst Abnormal 
Value in the VC Period 
Safety 
X 
3.3.6.2 
Shift Summary of Chemistry Values – To the Worst Abnormal 
Value in the VC Period by Age Group 
Safety 
X 
3.3.6.3 
Shift Summary of Chemistry Values – To the Worst Abnormal 
Value in the LTS Period 
LTS Evaluable 
X 


Incyte Corporation 
Page 55 of 61 
INCB 18424-305 Statistical Analysis Plan 
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CONFIDENTIAL 
Table No. 
Title 
Population 
Standard 
Body Weight and Height 
3.4.1.1 
Summary of Body Weight and Height in the VC Period 
Safety 
X 
3.4.1.2 
Summary of Body Weight and Height in the LTS Period 
LTS Evaluable 
X 
Vital Signs 
3.5.1.1 
Summary of Systolic Blood Pressure in the VC Period 
Safety 
X 
3.5.1.2 
Summary of Systolic Blood Pressure in the LTS Period 
LTS Evaluable 
X 
3.5.2.1 
Summary of Diastolic Blood Pressure in the VC Period 
Safety 
X 
3.5.2.2 
Summary of Diastolic Blood Pressure in the LTS Period 
LTS Evaluable 
X 
3.5.3.1 
Summary of Pulse in the VC Period 
Safety 
X 
3.5.3.2 
Summary of Pulse in the LTS Period 
LTS Evaluable 
X 
3.5.4.1 
Summary of Respiratory Rate in the VC Period 
Safety 
X 
3.5.4.2 
Summary of Respiratory Rate in the LTS Period 
LTS Evaluable 
X 
3.5.5.1 
Summary of Body Temperature in the VC Period 
Safety 
X 
3.5.5.2 
Summary of Body Temperature in the LTS Period 
LTS Evaluable 
X 
Figures 
Figure No. 
Title 
Population 
IGA 
4.1.1 
Proportion of Participants Achieving IGA-TS in the VC Period 
ITT 
4.1.1.1 
Proportion of Participants Achieving IGA-TS by Baseline IGA Score in the 
VC Period 
ITT 
4.1.1.2 
Proportion of Participants Achieving IGA-TS by Baseline EASI Score in the 
VC Period 
ITT 
4.1.1.3 
Proportion of Participants Achieving IGA-TS by Country in the VC Period 
ITT 
4.1.1.4 
Proportion of Participants Achieving IGA-TS by Age Group in the VC Period 
ITT 
4.1.1.5 
Proportion of Participants Achieving IGA-TS by Sex in the VC Period 
ITT 
4.1.1.6 
Proportion of Participants Achieving IGA-TS by Race in the VC Period 
ITT 
4.1.1.7 
Proportion of Participants Achieving IGA-TS by Prior TCS Therapy in the 
VC Period 
ITT 
4.1.1.8 
Proportion of Participants Achieving IGA-TS by Prior TCI Therapy in the 
VC Period 
ITT 
4.1.1.9 
Proportion of Participants Achieving IGA-TS by Prior Systemic Therapy in 
the VC Period 
ITT 
4.1.1.10 
Proportion of Participants Achieving IGA-TS by Prior AD Therapy in the VC 
Period 
ITT 
4.1.1.11 
Forest Plot of Response Rate Difference in Achieving IGA-TS at Week 8: 
1.5% BID Versus Vehicle 
ITT 
4.1.1.12 
Forest Plot of Response Rate Difference in Achieving IGA-TS at Week 8: 
0.75% BID Versus Vehicle 
ITT 
EASI 


Incyte Corporation 
Page 56 of 61 
INCB 18424-305 Statistical Analysis Plan 
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CONFIDENTIAL 
Figure No. 
Title 
Population 
4.2.2 
Proportion of Participants Achieving EASI75 in the VC Period 
ITT 
Itch NRS 
4.3.1.1 
Proportion of Participants Achieving ≥ 4-Point Improvement in Itch NRS 
Score in the VC Period 
ITT with baseline 
Itch NRS score 
≥ 4 
4.3.1.2 
Proportion of Participants Achieving ≥ 2-Point Improvement in Itch NRS 
Score in the VC Period 
ITT with baseline 
Itch NRS score 
≥ 2 
4.3.2.1 
Mean and Standard Error Plot of Itch NRS Score by Visit in the VC Period 
ITT with age 
≥ 6 years 
4.3.3 
Kaplan-Meier Curve of the Time to ≥ 2-Point Improvement in Itch NRS 
Score in the VC Period 
ITT with daily 
baseline Itch NRS 
score ≥ 2 
4.3.4 
Kaplan-Meier Curve of the Time to ≥ 4-Point Improvement in Itch NRS 
Score in the VC Period 
ITT with daily 
baseline Itch NRS 
score ≥ 4 
4.3.6 
Proportion of Participants Achieving ≥ 4-Point Improvement in Itch NRS 
Score from Day 1 to Day 7 
ITT with daily 
baseline Itch NRS 
score ≥ 4 


Incyte Corporation 
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INCB 18424-305 Statistical Analysis Plan 
02 JUN 2023 
VV-CLIN-020148 
CONFIDENTIAL 
Figure No. 
Title 
Population 


Incyte Corporation 
Page 58 of 61 
INCB 18424-305 Statistical Analysis Plan 
02 JUN 2023 
VV-CLIN-020148 
CONFIDENTIAL 
Figure No. 
Title 
Population 
Laboratory 
4.13.1.1.1 
Box Plot of Hemoglobin (g/L) by Visit in the VC Period 
Safety 
4.13.1.1.2 
Box Plot of Hemoglobin (g/L) by Visit in the VC Period by Age Group  
Safety 
4.13.1.2.1 
Box Plot of Change From Baseline in Hemoglobin (g/L) by Visit in the VC 
Period 
Safety 
4.13.1.2.2 
Box Plot of Change From Baseline in Hemoglobin (g/L) by Visit in the VC 
Period by Age Group  
Safety 
4.13.1.3.1 
Box Plot of Percentage Change From Baseline in Hemoglobin (g/L) by Visit 
in the VC Period 
Safety 
4.13.1.3.2 
Box Plot of Percentage Change From Baseline in Hemoglobin (g/L) by Visit 
in the VC Period by Age Group  
Safety 
4.13.2.1.1 
Box Plot of Platelets (10^9/L) by Visit in the VC Period 
Safety 
4.13.2.1.2 
Box Plot of Platelets (10^9/L) by Visit in the VC Period by Age Group  
Safety 
4.13.2.2.1 
Box Plot of Change From Baseline in Platelets (10^9/L) by Visit in the VC 
Period 
Safety 
4.13.2.2.2 
Box Plot of Change From Baseline in Platelets (10^9/L) by Visit in the VC 
Period by Age Group  
Safety 
4.13.2.3.1 
Box Plot of Percentage Change From Baseline in Platelets (10^9/L) by Visit 
in the VC Period 
Safety 
4.13.2.3.2 
Box Plot of Percentage Change From Baseline in Platelets (10^9/L) by Visit 
in the VC Period by Age Group  
Safety 
4.13.3.1.1 
Box Plot of Neutrophils (10^9/L) by Visit in the VC Period 
Safety 
4.13.3.1.2 
Box Plot of Neutrophils (10^9/L) by Visit in the VC Period by Age Group  
Safety 
4.13.3.2.1 
Box Plot of Change From Baseline in Neutrophils (10^9/L) by Visit in the 
VC Period 
Safety 
4.13.3.2.2 
Box Plot of Change From Baseline in Neutrophils (10^9/L) by Visit in the 
VC Period by Age Group  
Safety 
4.13.3.3.1 
Box Plot of Percentage Change From Baseline in Neutrophils (10^9/L) by 
Visit in the VC Period 
Safety 
4.13.3.3.2 
Box Plot of Percentage Change From Baseline in Neutrophils (10^9/L) by 
Visit in the VC Period by Age Group 
Safety 


Incyte Corporation 
Page 59 of 61 
INCB 18424-305 Statistical Analysis Plan 
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CONFIDENTIAL 
Figure No. 
Title 
Population 
4.13.4.1.1 
Box Plot of Leukocytes (10^9/L) by Visit in the VC Period 
Safety 
4.13.4.1.2 
Box Plot of Leukocytes (10^9/L) by Visit in the VC Period by Age Group  
Safety 
4.13.4.2.1 
Box Plot of Change From Baseline in Leukocytes (10^9/L) by Visit in the VC 
Period 
Safety 
4.13.4.2.2 
Box Plot of Change From Baseline in Leukocytes (10^9/L) by Visit in the VC 
Period by Age Group  
Safety 
4.13.4.3.1 
Box Plot of Percentage Change From Baseline in Leukocytes (10^9/L) by 
Visit in the VC Period 
Safety 
4.13.4.3.2 
Box Plot of Percentage Change From Baseline in Leukocytes (10^9/L) by 
Visit in the VC Period by Age Group 
Safety 
4.13.5.1.1 
Box Plot of Lymphocytes (10^9/L) by Visit in the VC Period 
Safety 
4.13.5.1.2 
Box Plot of Lymphocytes (10^9/L) by Visit in the VC Period by Age Group  
Safety 
4.13.5.2.1 
Box Plot of Change From Baseline in Lymphocytes (10^9/L) by Visit in the 
VC Period 
Safety 
4.13.5.2.2 
Box Plot of Change From Baseline in Lymphocytes (10^9/L) by Visit in the 
VC Period by Age Group  
Safety 
4.13.5.3.1 
Box Plot of Percentage Change From Baseline in Lymphocytes (10^9/L) by 
Visit in the VC Period 
Safety 
4.13.5.3.2 
Box Plot of Percentage Change From Baseline in Lymphocytes (10^9/L) by 
Visit in the VC Period by Age Group 
Safety 
4.13.6.1.1 
Box Plot of Erythrocytes (10^12/L) by Visit in the VC Period 
Safety 
4.13.6.1.2 
Box Plot of Erythrocytes (10^12/L) by Visit in the VC Period by Age Group  
Safety 
4.13.6.2.1 
Box Plot of Change From Baseline in Erythrocytes (10^12/L) by Visit in the 
VC Period 
Safety 
4.13.6.2.2 
Box Plot of Change From Baseline in Erythrocytes (10^12/L) by Visit in the 
VC Period by Age Group  
Safety 
4.13.6.3.1 
Box Plot of Percentage Change From Baseline in Erythrocytes (10^12/L) by 
Visit in the VC Period 
Safety 
4.13.6.3.2 
Box Plot of Percentage Change From Baseline in Erythrocytes (10^12/L) by 
Visit in the VC Period by Age Group 
Safety 
4.13.7.1.1 
Box Plot of Reticulocytes/Erythrocytes (%) by Visit in the VC Period 
Safety 
4.13.7.1.2 
Box Plot of Reticulocytes/Erythrocytes (%) by Visit in the VC Period by Age 
Group  
Safety 
4.13.7.2.1 
Box Plot of Change From Baseline in Reticulocytes/Erythrocytes (%) by 
Visit in the VC Period 
Safety 
4.13.7.2.2 
Box Plot of Change From Baseline in Reticulocytes/Erythrocytes (%) by 
Visit in the VC Period by Age Group  
Safety 
4.13.7.3.1 
Box Plot of Percentage Change From Baseline in Reticulocytes/Erythrocytes 
(%) by Visit in the VC Period 
Safety 
4.13.7.3.2 
Box Plot of Percentage Change From Baseline in Reticulocytes/Erythrocytes 
(%) by Visit in the VC Period by Age Group 
Safety 


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INCB 18424-305 Statistical Analysis Plan 
02 JUN 2023 
VV-CLIN-020148 
CONFIDENTIAL 
Listings 
Listing No. 
Title 
Baseline Demographic and Characteristic 
2.1.1.1 
Participant Enrollment and Disposition Status in the VC Period 
2.1.1.2 
Participant Enrollment and Disposition Status in the LTS Period 
2.1.2 
Participant Inclusion and Exclusion Criteria Violations 
2.1.3 
Participants Who Discontinued Treatment or Discontinued From the Study Due to COVID-19 
2.1.4 
Participants With Assessments Affected by the COVID-19 Pandemic 
2.2 
Protocol Deviations 
2.3 
Analysis Populations 
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 
2.5.1 
Study Drug Exposure and Compliance in the VC Period 
2.5.2 
Study Drug Exposure in the LTS Period 
2.5.3 
Study Drug Exposure from Baseline to Week 52 
Efficacy 
2.6.1 
IGA Score 
2.6.2.1 
EASI Individual Scores 
2.6.2.2 
EASI Total Score 
2.6.3.1 
Itch NRS Daily Score 
 
  
2.6.3.3 
Time to Itch Response 


Incyte Corporation 
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INCB 18424-305 Statistical Analysis Plan 
02 JUN 2023 
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CONFIDENTIAL 
Listing No. 
Title 
Adverse Events 
2.7.1 
Adverse Events 
2.7.2 
Adverse Events Leading to Study 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 
Grade 3 or Higher Adverse Events 
2.7.8 
Application Site Reactions 
2.7.9 
Adverse Events of Interest 
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 
Body Weight and Height 
2.9.1 
Body Weight and Height 
Vital Signs 
2.10.1 
Vital Signs 
2.10.2 
Abnormal Vital Sign Values 
2.10.3 
Alert Vital Sign Values