Conditions: Atopic Dermatitis
Keywords: atopic dermatitis adolescent adults in-home telemedicine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 77
Healthy volunteers: no

Brief summary:
This is a randomized, double blind, vehicle controlled Phase 2 study with a 4-week open label extension in adolescent and adult participants with atopic dermatitis and head and/or neck involvement. It is intended to compare the efficacy and safety of ruxolitinib cream 1.5% BID versus vehicle cream, then further evaluate ruxolitinib cream as maintenance during the open label extension period.

Detailed description:

Arms:
arm 1: Participants will be treated with ruxolitinib cream 1.5% or vehicle cream twice a day (BID) in a double-blind fashion. arm 2: Patients will be treated with Ruxoltinib cream 1.5% twice per day (BID) during the open label extension period. Participants who complete the double-blind period will continue into this open-label extension period for an additional 4 weeks of treatment.

Interventions: intervention 1: Ruxolitinib cream intervention 2: Vehicle
Intervention descriptions: intervention 1: Ruxolitinib cream 1.5% applied twice a day (BID)" intervention 2: Vehicle cream applied twice a day (BID) to affected areas

Protocol document:
Prot_000.pdf: 
Official Title: A Phase 2, Efficacy and Safety Study of Ruxolitinib Cream in Participants with Facial and/or Neck
Atopic Dermatitis Involvement
NCT Number:
 
NCT05127421
Document Date: Protocol Version 3: 04-Aug-2022


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Clinical Study Protocol 
TITLE PAGE 
INCB 18424-215 
A Phase 2, Efficacy and Safety Study of Ruxolitinib Cream in 
Participants With Facial and/or Neck Atopic Dermatitis Involvement 
Product: 
Ruxolitinib cream (INCB018424) 
IND Number: 
 
Phase of Study: 
2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, Delaware, USA 19803 
Original Protocol: 
19 MAY 2021 
Protocol Amendment 1: 
28 JUL 2021 
Protocol Amendment 2: 
04 AUG 2022 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, applicable Good Clinical Practices, and applicable laws 
and country-specific regulations in which the study is being conducted. 
The 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 18424-215 Protocol Amendment 2 (dated 04 AUG 2022) 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 ..........................................................................................................7 
1. 
PROTOCOL SUMMARY ............................................................................................9 
2. 
INTRODUCTION ......................................................................................................13 
2.1. 
Background .................................................................................................................13 
2.2. 
Study Rationale ...........................................................................................................14 
2.2.1. 
Scientific Rationale for Study Design ........................................................................14 
2.2.2. 
Justification for Dose ..................................................................................................16 
2.3. 
Benefit/Risk Assessment ............................................................................................16 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................18 
4. 
STUDY DESIGN .......................................................................................................19 
4.1. 
Overall Design ............................................................................................................19 
4.2. 
Overall Study Duration ...............................................................................................20 
4.3. 
Study Termination ......................................................................................................20 
5. 
STUDY POPULATION .............................................................................................21 
5.1. 
Inclusion Criteria ........................................................................................................21 
5.2. 
Exclusion Criteria .......................................................................................................22 
5.3. 
Lifestyle Considerations .............................................................................................23 
5.4. 
Screen Failures ............................................................................................................24 
5.5. 
Replacement of Participants .......................................................................................24 
6. 
STUDY TREATMENT ..............................................................................................25 
6.1. 
Study Treatments Administered .................................................................................25 
6.1.1. 
Study Drug Application ..............................................................................................26 
6.2. 
Preparation, Handling, and Accountability ................................................................26 
6.3. 
Measures to Minimize Bias:  Randomization and Blinding .......................................27 
6.4. 
Study Treatment Compliance .....................................................................................27 
6.5. 
Dose Modifications .....................................................................................................28 
6.5.1. 
Criteria and Procedures for Application Interruptions of Study Drug .......................28 
6.5.2. 
Criteria for Permanent Discontinuation of Study Drug ..............................................28 


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6.6. 
Concomitant Medications and Procedures .................................................................28 
6.6.1. 
Permitted Medications and Procedures ......................................................................29 
6.6.2. 
Restricted Medications and Procedures ......................................................................29 
6.6.3. 
Prohibited Medications and Procedures .....................................................................30 
6.7. 
Treatment After the End of the Study .........................................................................30 
7. 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
WITHDRAWAL ........................................................................................................31 
7.1. 
Discontinuation of Study Treatment ...........................................................................31 
7.1.1. 
Reasons for Discontinuation .......................................................................................31 
7.1.2. 
Discontinuation Procedures ........................................................................................31 
7.2. 
Participant Withdrawal From the Study .....................................................................32 
7.3. 
Lost to Follow-Up.......................................................................................................33 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................34 
8.1. 
Administrative and General Procedures .....................................................................34 
8.1.1. 
Informed Consent Process ..........................................................................................34 
8.1.2. 
Screening Procedures ..................................................................................................35 
8.1.3. 
Interactive Response Technology Procedure ..............................................................35 
8.1.4. 
Distribution of Reminder Notification and eDiary .....................................................35 
8.1.5. 
Demography and Medical History ..............................................................................36 
8.1.5.1. 
Demographics and General Medical History .............................................................36 
8.1.5.2. 
Disease Characteristics and Treatment History ..........................................................36 
8.2. 
Efficacy Assessments .................................................................................................36 
8.2.1. 
Full-Body Photography ..............................................................................................36 
8.2.2. 
Eczema Area and Severity Index ................................................................................36 
8.2.3. 
Investigator's Global Assessment ...............................................................................37 
8.2.4. 
Body Surface Area ......................................................................................................37 
8.2.5. 
Medical Resource Utilization and Health Economics ................................................37 
 
37 
 
37 
 
38 
 
38 
8.4.1. 
Location of Atopic Dermatitis-Affected Areas ..........................................................38 
8.5. 
Safety Assessments .....................................................................................................38 


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8.5.1. 
Adverse Events ...........................................................................................................38 
8.5.2. 
Vital Signs ..................................................................................................................39 
8.5.3. 
Laboratory Assessments .............................................................................................39 
8.5.3.1. 
Pregnancy Testing ......................................................................................................41 
8.5.3.2. 
Serology ......................................................................................................................41 
8.6. 
Pharmacokinetic Assessments ....................................................................................41 
8.7. 
Pharmacodynamic and Translational Assessments ....................................................41 
8.8. 
Unscheduled Visits .....................................................................................................41 
8.9. 
End of Treatment and/or Early Termination ..............................................................42 
8.10. 
Safety Follow-Up ........................................................................................................42 
9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................43 
9.1. 
Definition of Adverse Event .......................................................................................43 
9.2. 
Definition of Serious Adverse Event ..........................................................................44 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events .........45 
9.4. 
Reporting of Serious Adverse Events .........................................................................47 
9.5. 
Events of Clinical Interest ..........................................................................................48 
9.6. 
Emergency Unblinding of Treatment Assignment .....................................................49 
9.7. 
Pregnancy ...................................................................................................................49 
9.8. 
Warnings and Precautions ..........................................................................................50 
9.9. 
Product Complaints ....................................................................................................50 
9.10. 
Treatment of Overdose ...............................................................................................50 
10. 
STATISTICS ..............................................................................................................51 
10.1. 
Sample Size Determination ........................................................................................51 
10.2. 
Populations for Analysis .............................................................................................51 
10.3. 
Level of Significance ..................................................................................................51 
10.4. 
Statistical Analyses .....................................................................................................51 
10.4.1. 
Primary Analysis ........................................................................................................51 
10.4.2. 
Secondary 
Analyses .........................................................................52 
10.4.3. 
Safety Analyses ..........................................................................................................52 
10.5. 
Interim Analysis ..........................................................................................................52 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................53 


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11.1. 
Investigator Responsibilities .......................................................................................53 
11.2. 
Data Management .......................................................................................................54 
11.3. 
Data Quality Assurance ..............................................................................................56 
11.4. 
Data Privacy and Confidentiality of Study Records ...................................................56 
11.5. 
Financial Disclosure ...................................................................................................57 
11.6. 
Publication Policy .......................................................................................................57 
11.7. 
Study and Site Closure................................................................................................58 
12. 
REFERENCES ...........................................................................................................59 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS AND DEFINITIONS ............................................62 
APPENDIX B. PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................64 
LIST OF TABLES 
Table 1: 
Primary and Secondary Objectives and Endpoints .......................................................9 
Table 2: 
Key Study Design Elements .........................................................................................9 
Table 3: 
Schedule of Activities .................................................................................................11 
Table 4: 
Objectives and Endpoints ...........................................................................................18 
Table 5: 
Study Treatment Information .....................................................................................25 
Table 6: 
Investigator's Global Assessment ...............................................................................37 
Table 7: 
Required Laboratory Analytes ....................................................................................40 
Table 8: 
Populations for Analysis .............................................................................................51 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................10 


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LIST OF ABBREVIATIONS 
Abbreviations and 
Special Terms 
Definition 
AD 
atopic dermatitis 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice daily 
BSA 
body surface area 
CFR 
Code of Federal Regulations 
ClinRO 
clinician-reported outcome 
CMH 
Cochran-Mantel-Haenszel 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DB 
double-blind 
DCT 
decentralized trial 
DNA 
deoxyribonucleic acid 
EASI 
Eczema Area and Severity Index 
EASI75 
≥ 75% improvement in EASI score 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
FTU 
fingertip units 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HCVAb 
hepatitis C virus antibody 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 


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Abbreviations and 
Special Terms 
Definition 
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 
IRB 
institutional review board 
IRT 
interactive response technology 
Itch NRS 
Itch Numerical Rating Scale 
ITT 
intent-to-treat 
JAK 
Janus kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
not applicable 
NCI 
National Cancer Institute 
OL 
open-label 
PDE4 
phosphodiesterase-4 
 
 
RNA 
ribonucleic acid 
RSI 
Reference Safety Information 
SAE 
serious adverse event 
SCORAD 
Scoring Atopic Dermatitis 
SoA 
schedule of activities 
SOP 
standard operating procedure 
SPF 
sun protection factor 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
UV 
ultraviolet 
VC 
vehicle-controlled 
WBC 
white blood cell 
WOCBP 
woman of childbearing potential 
 


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1. 
PROTOCOL SUMMARY 
Protocol Title:  A Phase 2, Efficacy and Safety Study of Ruxolitinib Cream in Participants With 
Facial and/or Neck Atopic Dermatitis Involvement 
Protocol Number:  INCB 18424-215 
Objectives and Endpoints: 
Table 1 presents the primary and secondary objectives and endpoints. 
Table 1: 
Primary and Secondary Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To establish the efficacy of ruxolitinib cream in 
participants with AD on the face and/or neck. 
Proportion of participants who achieve an EASI75 
of the head and neck region at Week 4. 
Secondary 
To further assess efficacy of ruxolitinib cream 
for the treatment of AD on the face, neck, and 
other body areas. 
• Proportion of participants who achieve an 
EASI75 of the head and neck region at Weeks 2 
and 8. 
• Proportion of participants who achieve an overall 
EASI75 at Weeks 2, 4, and 8. 
To assess the safety and tolerability of ruxolitinib 
in participants with AD on the face and/or neck. 
The type, frequency, and severity of AEs, 
including the evaluation of vital signs. 
Overall Design: 
Table 2 presents the key study design elements.  Further study details are presented after the 
table. 
Table 2: 
Key Study Design Elements 
Study Phase 
Phase 2 
Clinical Indication 
Treatment of patients with facial atopic dermatitis 
Population 
Male and female participants aged 12 to 70 years who have been diagnosed 
with AD for at least 6 months and present with active eczematous changes 
on the face and/or neck, who have an overall and face and/or neck IGA score 
of 2 or 3 at screening and baseline, and who have AD affecting ≥ 0.5% of 
the total BSA on the face and/or neck (excluding scalp).  Participants with 
active AD lesions on their face and/or neck (fulfilling the % BSA criterion) 
who also have AD on other body areas (excluding the scalp) may be 
included if their total BSA involvement is ≤ 20%. 
Number of 
Participants 
Approximately 75 participants will be randomized 2:1 between 2 treatment 
groups.  The participants will be stratified by face and/or neck IGA score at 
screening (IGA 2 or 3).  Participants with a screening face and/or neck IGA 
score of 2 will constitute approximately 25% of the overall study population. 


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Table 2: 
Key Study Design Elements (Continued) 
Study Design 
Decentralized, randomized, 4-week, DB VC period followed by a 4-week, 
OL period and a 30-day, post-treatment, safety follow-up visit. 
Estimated Duration of 
Study Participation 
Estimated total duration of participation is approximately 17 weeks, 
including up to 5 weeks for screening, 4 weeks of DB treatment, 4 weeks of 
OL treatment, and 30 days for safety follow-up. 
DSMB/DMC 
No 
Coordinating 
Principal Investigator 
NA (1 site) 
Treatment Groups and Duration: 
Eligible participants will be randomized 2:1 to ruxolitinib cream 1.5% or vehicle cream BID and 
stratified by the face and/or neck IGA score (2 vs 3) measured at screening.  Participants will 
apply blinded study drug starting at baseline (Day 1) through Week 4.  Participants will then 
enter the OL period during which they will apply ruxolitinib 1.5% cream BID from Week 4 
through Week 8. 
The study design schema is presented in Figure 1 and the SoA is detailed in Table 3.  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 
Visit Day (Range) 
Screening Period 
DB VC Period 
Open-Label 
Period 
Safety 
Follow-Up 
Notes 
Screening 
Days −35 to −1 Randomization 
Day 1 
(Baseline) 
Week 2 
(± 3 d) 
Week 4 
(± 3 d) 
(EOT 1) 
Week 8 
(± 3 d) 
(EOT 2) 
30 Days 
(+ 3 d) After 
Last Dose 
Administrative procedures 
Informed consent (including 
assent; electronic) 
X 
 
 
 
 
 
 
See Section 8.1.1. 
Consent is a separate virtual visit 
ahead of screening.  
Contact IRT 
 
X 
X 
 
X 
X 
 
See Section 8.1.3.  
Inclusion/exclusion criteria 
review 
X 
X 
 
 
 
 
 
See Section 5. 
Demography and medical and 
disease history 
X 
 
 
 
 
 
 
See Section 8.1.5. 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
See Section 6.6. 
Apply study drug 
 
 
X 
 
Study drug will be applied BID from 
Day 1 through Week 8. 
See Section 6. 
Medication eDiary 
 
 
X* 
X 
X 
X 
 
*Instructions for medication eDiary 
will be reviewed on Day 1 visit. 
Medication diary will be completed 
from the first application of study 
drug in the VC period through the 
end of the OL period. 
Assess eDiary and study drug 
compliance 
 
 
X* 
X 
X 
X 
 
*Itch NRS eDiary compliance will 
be assessed at baseline. 
Collect study drug 
 
 
 
 
X 
X 
 
Mobile healthcare provider will 
arrange for return of study drug to 
depot. 


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Table 3: 
Schedule of Activities (Continued) 
Visit Day (Range) 
Screening Period 
DB VC Period 
Open-Label 
Period 
Safety 
Follow-Up 
Notes 
Screening 
Days −35 to −1 Randomization 
Day 1 
(Baseline) 
Week 2 
(± 3 d) 
Week 4 
(± 3 d) 
(EOT 1) 
Week 8 
(± 3 d) 
(EOT 2) 
30 Days 
(+ 3 d) After 
Last Dose 
Safety assessments 
AE assessment 
X 
 
X 
X 
X 
X 
X 
See Section 9. 
Vital signs/body weight/height 
X 
 
X 
X 
X 
X 
X 
Height and weight at screening only 
(see Section 8.5.2). 
Efficacy assessments 
Full body photography 
X 
 
X 
X 
X 
X 
X 
See Section 8.2.1. 
EASI score 
Head and neck 
Overall 
X 
 
X 
X 
X 
X 
X 
See Section 8.2.2. 
%BSA 
Face and/or neck 
Overall 
X 
 
X* 
X 
X 
X 
X 
See Section 8.2.4. 
*BSA to be assessed independently 
in real time during the baseline visit 
before dose administration (see 
Section 7.2). 
Laboratory assessments 
Chemistry 
X 
 
 
 
 
 
 
See Table 7. 
Hematology 
X 
 
 
 
 
 
 
See Table 7. 
Serology 
X 
 
 
 
 
 
 
See Section 8.5.3.2. 
FSH 
X 
 
 
 
 
 
 
Women of nonchildbearing potential 
only (see Section 8.5.3.1) 
Serum pregnancy test 
X 
 
 
 
 
 
 
WOCBP only (see Section 8.5.3.1). 
Urine pregnancy test 
 
 
X 
 
X 
X 
X 
WOCBP only (see Section 8.5.3.1). 
Note:  Visits will be a combination of telemedicine and mobile healthcare provider visits. 


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2. 
INTRODUCTION 
2.1. 
Background 
Atopic dermatitis is a chronic, recurring, inflammatory skin disease characterized by significant 
pruritus, epidermal barrier disruption, and an impaired innate immune response that results in 
enhanced penetration of allergens and pathogens through the skin (De Benedetto et al 2011, 
Eichenfield et al 2014a, Gittler et al 2012, Howell 2007, Lio et al 2014, Palmer et al 2006).  
Worldwide, up to 25% of children and up to 12% of adults have AD (Eichenfield et al 2014a, 
Hanifin et al 2007, Harrop et al 2007, Rönmark et al 2012).  Atopic dermatitis is the most 
common disease of the skin, and its incidence in industrialized countries appears to be increasing 
(Ellis et al 2002, Laughter et al 2021).  In the US, the prevalence of AD in adults is estimated to 
be 7.2% (Chiesa Fuxench et al 2019, Silverberg et al 2015).  It is not clear how many adolescents 
suffer from AD, as this age subgroup is usually not reported separately from the overall pediatric 
population.  However, one study (Shaw et al 2011) gave the estimated frequency rate of AD in 
adolescents 13 to 17 years of age as 8.6%.  Fewer than 20% of adults with AD develop the 
disease in adulthood (Ozkaya 2005), which indicates the vast majority of adult patients with AD 
have never grown out of their childhood/adolescent affliction (Williams and Strachan 1998). 
According to the recent Global Burden of Disease project, AD is 1 of the 50 most prevalent 
diseases worldwide (Hay et al 2014), and it has the highest disease burden among skin diseases 
as measured by disability-adjusted life years (Laughter et al 2021).  Atopic dermatitis is 
associated with significantly diminished quality-of-life owing in large part to chronic itch and 
associated sleep disturbances (Silverberg et al 2015, Silverberg et al 2018b, Zuberbier 
et al 2006).  Chronic itch has been shown to have profound economic, educational, and 
occupational impacts on patients with AD. 
Although not life-threatening in and of itself, AD is associated with numerous allergic/atopic 
comorbidities, some of which may be life-threatening (Eichenfield et al 2014a, Gustafsson 
et al 2000, Spergel 2010).  In addition, an increasing number of publications have stipulated that 
AD may be associated with other systemic and non–skin-related conditions, including 
psychiatric and metabolic complications (Deckert et al 2014, Kauppi et al 2019, Paller et al 2018, 
Shalom et al 2019, Silverberg et al 2011, Silverberg et al 2015, Silverberg et al 2018a, Strom 
et al 2016, Yaghmaie et al 2013).  It may also be a risk factor for cardiovascular diseases (Ivert 
et al 2019, Standl et al 2017).  These comorbid conditions may be related to the chronic pruritus 
experienced by patients. 
The management of AD is guided by many factors, including severity of flares, extent of disease, 
symptoms, and impact on quality of life.  Basic management (ie, education of patients about skin 
hydration, the use of emollients, and avoidance of factors that worsen the disease) is used in 
patients with mild disease, and topical anti-inflammatory medications are added when 
nonpharmacologic interventions are not sufficient to control inflammation and itching.  In 
patients with severe or recalcitrant disease, phototherapy and/or systemic therapies may be 
added. 
Topical agents are the mainstay of AD treatment.  The current prescription topical 
anti-inflammatory medication armamentarium includes topical corticosteroids, topical 


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calcineurin inhibitors, and a PDE-4 inhibitor, crisaborole ointment (Eucrisa® 2020).  The former 
classes of medications are effective in treating signs (erythema, induration/papulation, and 
oozing/crusting) and symptoms of AD but may be associated with adverse effects. 
Topical corticosteroids of any potency may cause skin atrophy, purpura, telangiectasia, striae, 
focal hypertrichosis, and acneiform or rosacea-like eruptions (Eichenfield et al 2014b).  Topical 
corticosteroids may also cause hypothalamic-pituitary-adrenal axis suppression.  The risk of 
cutaneous adverse effects increases with higher-potency agents, occlusion, use on thinner skin, 
and advanced age, and the risk of systemic side effects increases with prolonged continuous use. 
The topical calcineurin inhibitors, tacrolimus ointment (Protopic® 0.03% and 0.1% ointment) and 
pimecrolimus cream (Elidel® 1% cream), are used in the second-line setting for their 
steroid-sparing properties.  Skin burning and pain are common application-site reactions 
following application of topical calcineurin inhibitors (Eichenfield et al 2014b, Elidel 2020, 
Protopic 2019).  In addition, topical calcineurin inhibitors carry a boxed warning that rare cases 
of malignancy (eg, skin cancer and lymphoma) have been reported in patients treated with these 
agents, although a causal relationship has not been established. 
To minimize adverse effects, the use of topical corticosteroids on sensitive skin areas (eg, the 
face) and the long-term use of topical corticosteroids and topical calcineurin inhibitors are not 
recommended (Eichenfield et al 2014b). 
Crisaborole ointment, which is indicated for patients 3 months of age and older with mild to 
moderate AD, has no such safety limitations but was shown to have modest efficacy 
(Eucrisa 2020). 
Thus, there remains a significant medical need for topical therapies that provide both rapid and 
long-term control of the signs and symptoms of the disease, specifically on sensitive skin areas 
such as the face and neck. 
2.2. 
Study Rationale 
This study is designed to further evaluate the efficacy and safety of ruxolitinib cream in 
individuals with AD affecting at least 0.5% of the total BSA on the face and/or neck. 
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).  Ruxolitinib 1.5% 
cream is approved by the FDA for the treatment of AD in nonimmunocompromised patients 
≥ 12 years of age whose disease is not adequately controlled with topical prescription therapies, 
or when those therapies are not advisable (Opzelura™ 2021).  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. 
2.2.1. 
Scientific Rationale for Study Design 
Two Phase 3 pivotal studies (INCB 18424-303 and INCB 18424-304) demonstrated that 
ruxolitinib 1.5% cream BID was statistically significantly superior to vehicle after 8 weeks of 
treatment for the primary endpoint, IGA-TS (a score of 0 or 1 with ≥ 2 grade improvement from 
baseline), and key secondary endpoints, including a 75% improvement in the EASI and at least a 
4-point improvement in the Itch NRS (Papp et al 2020).  The 1.5% strength was also superior in 


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efficacy to the 0.75% strength with nondifferentiating safety profiles of both regimens.  The 
purpose of this study is to further investigate and confirm the efficacy and safety of ruxolitinib 
cream (1.5%) when applied to affected areas on the face and neck. 
This study will be a fully DCT.  The benefits of a DCT include enhancing the participant's 
experience, minimizing day-to day disruption, eliminating travel burden, potentially increasing 
participant diversity, and improving participant retention.  All visits will be conducted remotely 
via telemedicine (telephone and/or video) or in-home visits by a trained mobile healthcare 
provider.  Efficacy assessments will be performed by an investigator/rater (dermatologist; central 
reader) using high-quality digital photographs.  A validation study demonstrated excellent 
agreement between assessment of AD severity using EASI, SCORAD, IGA, and BSA during 
in-home visits and via digital photographs (Hughes et al 2019). 
This study will enroll both male and female participants ≥ 12 years of age with both an overall 
and a face and/or neck IGA score of 2 or 3 and AD affecting at least 0.5% of the total BSA on 
the face or neck.  Participants in the Phase 3 studies had AD involvement of 3% to 20% BSA 
(excluding the scalp) and an IGA score of 2 to 3 at baseline.  Although approximately 39% of 
participants with AD in the Phase 3 studies reported prior facial involvement, the efficacy 
assessments in these studies (eg, IGA-TS and EASI) were based on the all (total) AD-affected 
areas.  The study population for this trial will be similar to the Phase 3 study population with the 
exception that in this study, all participants must have AD lesions on the face and/or neck region 
involving at least 0.5% of their total BSA in that area. 
The clinical endpoints in the study will be similar to those in the Phase 3 studies, except the 
primary endpoint will be the proportion of individuals who achieve EASI75 in the head and neck 
region 
will be included as secondary 
endpoints. 
The selection of a vehicle control for 4 weeks is based on the chronic, relapsing nature of AD 
and the low risk to participants of using a vehicle for 4 weeks.  Moreover, this duration of 
treatment is anticipated to be sufficient for the evaluation of treatment effect in this specific body 
location.  The 4-week, OL extension will allow participants who were randomized to vehicle the 
ability to receive treatment and the participants randomized to active to continue treatment if 
clearance (IGA = 0) was not achieved in 4 weeks.  It is also expected to decrease dropout rates in 
the vehicle arm by offering an incentive to participants to remain in the study beyond the initial 
4-week, DB VC period. 
In the Phase 3 AD studies, efficacy was seen as early as the first postbaseline visit, Week 2, and 
continued through Week 8.  The assessment of efficacy at 4 weeks is supported by the data from 
the Phase 3 studies. 
Based on the low bioavailability of ruxolitinib cream following twice-daily applications for up to 
8 weeks in individuals with AD and the absence of clinically meaningful laboratory findings 
(hematology and chemistry) in the Phase 3 studies that could be attributed to the therapy with 
ruxolitinib cream, laboratory tests will be collected at screening only. 


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2.2.2. 
Justification for Dose 
Data from the Phase 3 pivotal studies in participants ≥ 12 years of age with AD were the basis 
for the selection of the 1.5% BID regimen in this study.  Overall, ruxolitinib 1.5% cream was 
found to be more efficacious than its 0.75% strength, while the safety and tolerability profiles of 
both treatment arms were comparable and nondifferentiating.  Of note, the Phase 3 efficacy and 
safety findings were on par and thus fully confirmatory to the outcomes of the earlier Phase 2 
dose range-finding study. 
The efficacy and safety outcomes from the pivotal Phase 3 studies are summarized below: 
• Ruxolitinib 1.5% cream BID was statistically significantly superior to the vehicle at 
Week 8 for IGA-TS, EASI75, and ≥ 4-point improvement in Itch NRS score. 
• The antipruritic effect of ruxolitinib cream showed a rapid onset with evidence of a 
treatment effect on daily Itch NRS scores as early as Day 1 (ie, within 12 hours after 
the first application of study drug). 
• The consistent treatment effects of ruxolitinib 1.5% cream on IGA-TS, EASI75, and 
Itch NRS score were also observed across all subgroups irrespective of demographic 
and baseline characteristics, which supports the generalizability of benefit to patients 
aged 12 years and older who may use ruxolitinib cream. 
• Safety data from the Phase 3 VC AD studies demonstrate that ruxolitinib 1.5% cream 
applied BID continuously for 8 weeks in adolescent and adult participants with AD 
was safe and well-tolerated. 
Based on the Phase 3 data, the proposed treatment regimen for the current study is ruxolitinib 
1.5% cream BID. 
2.3. 
Benefit/Risk Assessment 
Safety data on the use of ruxolitinib cream are available from 2350 participants who applied 
ruxolitinib cream across multiple indications.  In AD, the safety database consists of 
1463 participants who applied ruxolitinib cream, evaluated in clinical studies.  No safety 
concerns for ruxolitinib's strength were identified in the 1463 participants with AD who applied 
ruxolitinib cream.  In addition, ruxolitinib cream was also found to be well-tolerated and safe in 
participants with extensive AD lesions, in other words, those involving at least 25% of the 
participant's total BSA (maximum use trial; INCB 18424-103). 
In summary, ruxolitinib cream did not present with any clinically meaningful tolerability issues, 
including its use on the face and/or neck area, or concerning safety findings. 
The most commonly reported TEAEs while receiving ruxolitinib treatment were upper 
respiratory tract infection in 104 participants (7.1%), nasopharyngitis in 103 participants (7.0%), 
and headache in 39 participants (2.7%); all other TEAEs were reported in ≤ 2% of participants.  
All SAEs were reported for 1 participant each (0.1%). 
The majority of participants had good local tolerability with ruxolitinib cream use.  Few 
application site reactions were reported:  application site pain (6 participants; 0.4%); application 
site pruritus (4 participants; 0.3%); application site erythema (2 participants; 0.1%); and 
application site folliculitis, application site irritation, application site papules, application site 


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paresthesia, and application site urticaria (1 participant each; 0.1%).  All application site 
reactions among participants with AD were Grade 1 or 2 in severity. 
Local tolerability studies (INCB 18424-105, INCB 18424-107, and INCB 18424-108) in healthy 
participants demonstrated that ruxolitinib 1.5% cream was not phototoxic and did not induce 
photosensitization.  However, due to the theoretical risk of skin reaction when exposure to 
ruxolitinib is combined with sun exposure, participants should be cautioned to avoid prolonged 
exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc), and 
when outdoors, should be advised to wear loose-fitting clothing that protects the treated area 
from the sun. 
Current approved topical therapies for AD remain suboptimal due to their efficacy limitations 
and safety concerns, particularly for long-term use, specifically for sensitive areas such as the 
face and neck.  Based on the Phase 3 data, participants in this trial may benefit from a rapid 
reduction in itch and the inflammatory signs of AD with ruxolitinib cream, which is generally 
safe and well-tolerated.  More detailed information about the known and expected benefits and 
risks and reasonably expected AEs of ruxolitinib cream may be found in the IB. 


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3. 
OBJECTIVES AND ENDPOINTS 
Table 4 presents the objectives and endpoints. 
Table 4: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To establish the efficacy of ruxolitinib cream in 
participants with AD on the face and/or neck. 
Proportion of participants who achieve an EASI75 
of the head and neck region at Week 4. 
Secondary 
To further assess efficacy of ruxolitinib cream for 
the treatment of AD on the face, neck, and other 
body areas. 
• Proportion of participants who achieve an 
EASI75 of the head and neck region at Weeks 2 
and 8. 
• Proportion of participants who achieve an 
overall EASI75 at Weeks 2, 4, and 8. 
To assess the safety and tolerability of ruxolitinib 
in participants with AD on the face and/or neck. 
The type, frequency, and severity of AEs, 
including the evaluation of vital signs. 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a decentralized, randomized, DB, VC study with a 4-week, OL period in adolescent and 
adult participants with AD (including AD on the face and/or neck) eligible for topical therapy.  
This study will be conducted through a single, stand-alone, virtual site in the US.  All study visits 
will be conducted in the participant's home with the assistance of a mobile healthcare provider 
and investigator or designee present through telemedicine (telephone and/or video visits). 
Prospective participants who are assessed as preliminarily eligible will be emailed a link to a 
secure portal to review the electronic version of the IRB-approved consent with the investigator 
or designee during a telemedicine visit.  If the individual agrees to participate, they will provide a 
handwritten signature executed to an electronic record.  The investigator will counter sign the 
ICF/assent in the same manner.  The participant will be able to download a copy of the 
ICF/assent, or the site can provide a copy via email.  The informed consent process will be 
documented by the investigator and maintained as part of the participant's source documentation. 
Following consent/assent, sample collection kits, instructions, and other study materials will be 
provided via direct-to-participant shipments.  Once eligibility is confirmed, the participant will 
be randomized during the screening period to allow time for the study drug to be shipped to the 
participant in time for the first dose administration on Day 1.  Prior to application of the first 
dose of study drug, the investigator will confirm participant can continue with study participation 
on baseline/Day 1. 
Participants will be randomized 2:1 to blinded treatment with ruxolitinib cream 1.5% BID or 
vehicle cream BID with stratification by screening face and/or neck IGA score (IGA 2 or 3).  
Participants with a screening face and/or neck IGA score of 2 will constitute approximately 25% 
of the overall study population. 
During the 4-week, DB VC period, participants will apply study treatment BID to all areas 
identified for treatment at the baseline visit even if the AD begins to improve and lesions 
decrease in size.  The mobile healthcare provider will take comprehensive photographs for the 
investigator to assess the AD-affected areas for the clinician-reported assessments detailed in 
Table 3.  After all the Week 4 study assessments are complete, participants who complete the 
Week 4 visit with no safety concerns will continue into the 4-week, OL period and will apply 
ruxolitinib cream 1.5% BID only to affected areas. 
Throughout the study, participants who develop additional areas of AD may treat those areas 
with approval from the investigator, as long as the total treated BSA does not exceed 20% and 
there are no safety concerns regarding the additional application of study drug.  Approval to treat 
additional areas will occur via telemedicine visits. 
If AD lesions clear during the 4-week, OL period, participants will stop treatment applications 
3 days after the lesions have disappeared and record the dates of these events in their diaries.  If 
the AD lesions recur, participants may restart treatment at home at the first sign of recurrence 
and record the date of study drug administration. 


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At Week 4, efficacy (the primary endpoint of the study) will be evaluated as the proportion of 
participants who achieve an EASI75 of the head and neck region.  Additional efficacy 
assessments and patient-reported outcomes will be conducted as outlined in the SoA (see 
Table 3). 
Participants will be assessed for safety and tolerability throughout the study by monitoring the 
type, frequency, and severity of AEs and measuring vital signs (see Table 3). 
Figure 1 presents the study design schema, and the SoA for the VC and OL periods is in Table 3. 
4.2. 
Overall Study Duration 
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 drug and has 
completed applicable safety follow-up assessments or is lost to follow-up. 
Participants will participate in the study for a duration of up to approximately 17 weeks as 
follows: up to 35 days in the screening period, 4 weeks in the DB VC period, 4 weeks in the 
OL period, and 30 (+ 3) days for follow-up after the last application of study drug. 
A participant is considered to have completed the study if they have completed all study visits 
including the safety follow-up visit. 
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 if, for example, required by regulatory decision.  
If the study is terminated prematurely, the sponsor will notify the investigators, the IRBs and 
IECs, and the regulatory bodies of the decision and reason for termination of the study. 


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5. 
STUDY POPULATION 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or participant safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential.  Prospective approval of 
Protocol deviations to recruitment and enrollment criteria, also known as Protocol waivers or 
exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Ability to comprehend and willingness to sign a written ICF for the study or written 
informed consent of the parent(s) or legal guardian and written assent from the participant 
when applicable. 
Note:  Adolescent participants who become legal adults during the study will be asked for 
their signed consent to continue the study. 
2. Adolescents and adults aged 12 to 70 years. 
3. Participants diagnosed with AD as defined by Hanifin and Rajka (1980) criteria based on 
patient-reported history and investigator assessment at study entry. 
4. AD for a duration of at least 6 months. 
5. Participants with an overall and a face and/or neck IGA score of 2 or 3 at screening. 
6. Participants with AD affecting the following at screening: 
a. ≥ 0.5% of the total BSA on the face and/or neck 
b. Up to a total of 20% BSA (face and/or neck plus other body areas) 
7. Participants with adequate venous access in areas unaffected by AD. 
8. Participants who agree to discontinue all other agents used to treat AD from screening 
through the final follow-up visit. 
9. Willingness to avoid pregnancy or fathering children based on the criteria below. 
a. Male participants with reproductive potential must agree to take appropriate 
precautions to avoid fathering children from screening through 90 days 
(a spermatogenesis cycle) after the last dose of study drug and must refrain from 
donating sperm during this period.  Permitted methods in preventing pregnancy (see 
Appendix A) should be communicated to the participants and their understanding 
confirmed. 
b. Female participants who are WOCBP must have a negative serum pregnancy test at 
screening, a negative urine pregnancy test before the first dose on Day 1, and must 
agree to take appropriate precautions to avoid pregnancy from screening through 
30 days (1 menstrual cycle) after the last dose of study drug and must refrain from 
donating oocytes during this period.  Permitted methods in preventing pregnancy (see 
Appendix A) should be communicated to the participants and their understanding 
confirmed.  
c. A female participant not considered to be of childbearing potential as defined in 
Appendix A is eligible. 


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5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Participants who have an unstable course of AD (spontaneously improving or rapidly 
deteriorating) as determined by the investigator over the previous 4 weeks prior to 
baseline. 
2. Participants with concurrent conditions and history of other diseases as follows: 
a. Immunocompromised (eg, lymphoma, acquired immunodeficiency syndrome, 
Wiskott-Aldrich Syndrome). 
b. Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, 
antiparasitics, antiprotozoals, or antifungals within 2 weeks before the baseline visit. 
c. Active acute bacterial, fungal, or viral skin infection (eg, herpes simplex, herpes 
zoster, chicken pox) within 1 week before the baseline visit. 
d. Any other concomitant skin disorder (eg, generalized erythroderma such as 
Netherton's 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. Other types of eczema. 
f. Chronic asthma requiring more than 880 µg/day of inhaled budesonide or equivalent 
high-dose of other inhaled corticosteroids. 
3. Any serious illness or medical, physical, or psychiatric condition(s) that, in the 
investigator's opinion, would interfere with full participation in the study, including 
administration of study drug and attending required study visits; pose a significant risk to 
the participant; or interfere with interpretation of study data. 
4. Participants using any of the following treatments within the indicated washout period 
before the baseline visit: 
a. 5 half-lives or 12 weeks, whichever is longer – for biologic agents (eg, dupilumab). 
b. 4 weeks – cyclosporine, methotrexate, azathioprine, or other systemic 
immunosuppressive or immunomodulating agents (eg, mycophenolate or tacrolimus). 
c. 4 weeks – systemic corticosteroids or adrenocorticotropic hormone analogs. 
d. 2 weeks – immunizations; sedating antihistamines unless on long-term stable regimen 
(nonsedating antihistamines are permitted). 
e. 1 week – use of topical treatments for AD (other than bland emollients) such as 
topical antipruritics (eg, doxepin cream), corticosteroids, calcineurin inhibitors, PDE4 
inhibitors, coal tar (shampoo), topical antibiotics, antibacterial cleansing body 
wash/soap.  Note:  diluted sodium hypochlorite "bleach" baths are allowed as long as 
they do not exceed 2 baths per week. 
5. Previous treatment with systemic or topical JAK inhibitors (eg, ruxolitinib, tofacitinib, 
baricitinib, filgotinib, lestaurtinib, pacritinib). 
6. Ultraviolet light therapy or prolonged exposure to natural or artificial sources of UV 
radiation (eg, sunlight or tanning booth) within 4 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. 


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7. Any of the following clinical laboratory test results at screening: 
a. Removed in Protocol Amendment 1. 
b. Removed in Protocol Amendment 1. 
c. Liver function tests:  
− AST or ALT ≥ 2.5 × ULN. 
− Total bilirubin > 1.5 × ULN unless Gilbert's Syndrome. 
d. Positive serology test result for HIV antibody. 
e. Cytopenias, defined as follows: 
− Hemoglobin < 10 g/dL 
− Absolute neutrophil count < 1000/µL 
− Platelet count < 100,000/µL 
f. Estimated glomerular filtration rate < 30 mL/min/1.73 m2 (using the Modification of 
Diet in Renal Disease equation). 
g. Any other clinically significant laboratory result that, in the opinion of the 
investigator, poses a significant risk to the participant. 
8. Evidence of HBV or HCV infection or risk of reactivation.  Participants cannot be 
positive for HBsAg, anti-HBcAb, or HCVAb, except in the cases below: 
• Participants with no prior history of HBV infection who have been vaccinated against 
HBV and who have a positive antibody (HBsAb) against HBsAg as the only evidence 
of prior exposure may participate in the study. 
• Participants with a history of HCV infection who are antibody-positive and have 
successfully completed treatment > 12 weeks before screening, and have no 
detectable HCV RNA, are allowed in the study. 
9. Participants who are pregnant (or who are considering pregnancy) or lactating. 
10. History of alcoholism or drug addiction within 1 year before screening, or current alcohol 
or drug use that, in the opinion of the investigator, will interfere with the participant's 
ability to comply with the administration schedule and study assessments. 
11. Removed in Protocol Amendment 1. 
12. 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 study. 
13. Participants who, in the opinion of the investigator, are unable or unwilling or unlikely to 
comply with the administration schedule and study evaluations. 
5.3. 
Lifestyle Considerations 
Prolonged exposure to natural or artificial sources of UV radiation (eg, sun lamps, tanning 
booths) 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. 


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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 
drug.  See Section 6.6.1 for additional guidance. 
Participants should abstain from physical activity that can cause significant sweating for 2 hours 
following study drug application.  Study drug should be applied at least 2 hours after shaving. 
Swimming during the DB 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 drug 
application. 
The participant's living environment should be suitable for study participation, eg having 
appropriate place for televisits, with internet connection.  In addition, participant's activities are 
to be compatible with visit schedule over the 3 months of study participation. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study, 
completed the screening visit, but are not subsequently entered in the study. 
Tests with results that fail eligibility requirements may be repeated once during screening if the 
investigator believes the result to be in error.  Additionally, a participant who fails screening may 
repeat the screening process 1 time if the investigator believes that there has been a change in 
eligibility status.  Participants who rescreen must reconsent (if rescreened > 35 days after the 
initial screening) and be assigned a new participant number. 
Participants who have been randomized but terminated early from the study prior to dose 
administration are not screen failures.  However, upon sponsor approval, they may be invited for 
a second participation in the study by reconsenting and rescreening.  They will be assigned a new 
participant number. 
5.5. 
Replacement of Participants 
No participants will be replaced at any time during this study. 


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6. 
STUDY TREATMENT 
6.1. 
Study Treatments Administered 
Information regarding study drug and administration is provided in Table 5.  Participants will 
record study drug administration in a daily diary. 
Table 5: 
Study Treatment Information 
 
Study Treatment 1 
Study Treatment 2 
Study treatment name: 
Ruxolitinib 
Vehicle 
Mechanism of action: 
JAK1/2 inhibitor 
NA 
Dosage formulation: 
Cream 
Cream 
Unit dose strength(s)/dosage level(s): 
1.5% 
NA 
Route of administration:  
Topical 
Topical 
Administration instructions: 
DB VC period:  Apply a thin film to affected areas identified 
at baseline in the morning and at least 1 hour before bedtime 
for 4 weeks. 
OL period:  Apply a thin film to affected areas only in the 
morning and at least 1 hour before bedtime as needed for 
4 weeks. 
Packaging and labeling 
Ruxolitinib and vehicle will be provided in 60-g tubes. 
Tubes will include labeling in the local language and will 
comply with the legal requirements of the country. 
Storage: 
Ambient (15°C-30°C/59°F-86°F) 
Status of treatment in participating 
countries: 
Investigational 
At randomization after eligibility has been confirmed, the %BSA assessed at screening will be 
used by the IRT system to calculate the number of tubes of study drug to be dispensed for initial 
supply. 
During the DB VC period, all areas identified at the baseline visit should continue to be treated 
through the end of the period (at Week 4) even if the area begins to improve or the AD resolves 
completely, unless the participant meets criteria for stopping study drug. 
During the OL period, starting at the Week 4 visit, only areas with active disease need to be 
treated.  If the lesions clear, participants should continue to apply study drug for an additional 3 
days to the areas of the body where lesions were last present.  After 3 days of applying study 
drug to area where the lesions resolved, treatment should be discontinued.  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.  The start and end dates 
of treatment applications and/or interruptions will be captured by the participant in the electronic 
medication diary. 


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At any time during the study, participants who develop additional areas of AD may treat these 
additional areas with approval of the investigator as long as the total treated BSA does not 
exceed 20% and there are no safety concerns.  Approval to treat additional areas can occur via 
telemedicine visit.  The new %BSA should be entered into the CRF.  The participant should be 
discontinued if total treated BSA is >20%. 
No other 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 Drug Application 
Participants should remove study drug from the tube in FTUs until all affected areas are covered 
by a thin even film.  The recommended maximum amount of the study drug per application 
should be calculated as:  total FTUs = total %BSA involvement / 2.  For example, a participant 
with 3% total BSA would apply a total of 1.5 FTUs. 
One FTU is the amount of topical study drug that is squeezed out from the tube along the 
participant's fingertip.  A fingertip is from the very end (tip) of the finger to the first crease in the 
finger.  One FTU is enough to apply a thin film of study drug to an area of skin twice the size of 
the flat of a participant's hand with the fingers together (or ~2% BSA). 
6.2. 
Preparation, Handling, and Accountability 
The investigator or designee, must confirm appropriate temperature conditions have been 
maintained during transit or storage for all study drug received and any discrepancies are 
reported and resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment.  Study treatment will be 
shipped directly to the participant who will received appropriate instruction on how to handle 
and store before the next visit.  All study treatment must be stored in accordance with the labeled 
storage conditions and should be stored in a location out of the reach of children. 
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 drug to the participants. 
• Inventory of study drug for the individual participants. 
• Participant use of the study drug, including tube counts from each supply dispensed. 
• Return of study drug to the investigator or designee by participants or remote 
healthcare worker. 
The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the participants were provided the 
specified study drug.  These records should include dates, quantities, and any available batch or 
serial numbers or unique code numbers assigned to the investigational product and study 
participants. 


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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 drug 
until verified by the study monitor (unless otherwise agreed to by the sponsor).  At the 
conclusion of the study, the investigator or designee will oversee shipment of any remaining 
study drug back to the sponsor or its designee for destruction according to institutional 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 drug is destroyed before monitor inspection, the 
monitors rely on documentation of destruction per the site SOP. 
Further guidance and information for the final disposition of unused study treatments are 
provided in the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias:  Randomization and Blinding 
All participants will be centrally assigned to study treatment using an IRT system (see 
Section 8.1.3).  The system will assign in a 2:1 ratio, stratified by screening face and/or neck 
IGA score (2 or 3).  Before the study is initiated, the telephone number and call-in directions for 
the IRT and/or the log in information and directions for the IRT will be provided to the site.  Full 
details will be provided in the IRT Manual. 
Study drug will be shipped directly to the participant once study eligibility is confirmed. 
Participants, investigators, and the sponsor will remain blinded to each participant's treatment 
assignment during the DB VC period.  Emergency unblinding will occur if an AE requires the 
investigator to be made aware of the participant's treatment assignment (see emergency 
unblinding procedures in Section 9.6 and refer to the IRT Manual). 
6.4. 
Study Treatment Compliance 
Compliance with all study-related treatments should be emphasized to the participant by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study.  
Compliance will be assessed by the site staff for frequency of administration of study drug by 
reviewing the participants' diaries.  Participants will also be questioned regarding study drug 
application technique, missed applications, and use of any additional topical or systemic 
prescriptions of other products or over-the-counter products.  Compliance with study drug will 
be evaluated based on the participant's adherence to the application regimen (evaluation of actual 
number vs prescribed number of applications), 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 treatment portion of 
the study.  Participants who are noncompliant during the DB or OL periods will be reinstructed 
by the investigator (or designee), and the sponsor should be consulted by the investigator for 
repeated non-compliance and 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 visit and subsequent study visits, the amount of  


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study drug to be applied is to be determined by weighing a tube before and after the participant 
applies a thin film of study drug to the affected areas. 
6.5. 
Dose Modifications 
No dose modifications are allowed during the study.  The only modifications to the treatment 
regimen are temporary or permanent discontinuation of the study drug.  In some circumstances, 
it may be necessary to temporarily interrupt treatment with study drug as a result of AEs that 
have an unclear relationship to the study drug. 
6.5.1. 
Criteria and Procedures for Application Interruptions of Study Drug 
Individual decisions regarding interruptions due to an AE should be made using clinical 
judgment in consultation with the medical monitor (whenever possible), taking into account 
relatedness of the AE to the study drug and the participant's underlying condition.  In addition to 
these guidance steps, safety concerns should be discussed with the sponsor (or representative) 
immediately upon occurrence or awareness. 
6.5.2. 
Criteria for Permanent Discontinuation of Study Drug 
The occurrence of unacceptable toxicity not caused by the underlying disease will require that 
the study drug be permanently discontinued.  Unacceptable toxicity is defined as follows: 
• The occurrence of an AE that is related to study drug that, in the judgment of the 
investigator or the sponsor's medical monitor, compromises the participant's ability to 
continue study-specific procedures or is considered to not be in the participant's best 
interest. 
• A worsening of AD that requires treatment with a prohibited concomitant medication 
(see Section 6.6.3) or total BSA to be treated > 20%. 
• A persistent AE requiring a delay of therapy for more than 14 days unless a greater 
delay has been approved by the sponsor. 
See Section 7 for discontinuation procedures. 
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 12 weeks before the first dose of study treatment and 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 more than 30 days after the last dose of study treatment 
should be recorded for SAEs until the SAE is no longer being followed.  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. 


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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. 
• If sunscreen is needed, a mineral-based sunscreen (such as zinc oxide– or titanium 
oxide–based) with an SPF of at least 30 may be used at least 4 hours before and at 
least 2 hours after study drug application. 
• Bathing during the study should be limited to once daily for no longer than 
15 minutes and not within 2 hours following study drug 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. 
6.6.2. 
Restricted Medications and Procedures 
The following are permitted during the study under specified conditions: 
• Participants may continue using sedating antihistaminic drugs as long as their use is 
part of a pre-existing and well-established regimen.  There are no restrictions for use 
of nonsedating antihistamines. 
• Use of any over-the-counter, nonprescription preparations (including vitamins, 
minerals, and phytotherapeutic, herbal, or plant derived preparations) within 7 days 
before the baseline visit through the follow-up visit, unless deemed acceptable by the 
investigator. 
• Use of any prescription medication (including immunizations, phytotherapeutic, 
herbal, or plant-derived preparations) within 7 days before the baseline visit through 
the follow-up visit, unless deemed acceptable by the investigator. 
• Bleach baths are allowed as long as they do not exceed 2 baths per week and their 
frequency remains the same throughout the study. 
• Participants should not take baths or showers within 2 hours after study drug 
application. 
• Participants should apply study drug at least 2 hours after shaving. 
• Topical anti-infectives or other topical treatments applied to active AD lesions should 
not be used for at least 4 hours before and 2 hours after application of study drug. 
• Inhalation therapy for bronchial asthma or chronic obstructive pulmonary disease 
with the dose of budesonide or other equivalent inhaled corticosteroids may not 
exceed 880 μg. 


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• Participants may continue to use makeup but may not change or introduce makeup 
within 4 weeks before baseline and throughout the study. 
Note:  Makeup should not be used on affected areas within 30 minutes after 
application.  All makeup should be removed at least 1 hour prior to study visits. 
6.6.3. 
Prohibited Medications and Procedures 
The following are not permitted during the study: 
• Any investigational medication other than the study drug. 
• Any topical or systemic JAK or TYK2 inhibitor other than ruxolitinib cream 
(eg, ruxolitinib, tofacitinib, baricitinib, filgotinib, lestaurtinib, pacritinib, abrocitinib, 
brepocitinib). 
• Systemic immunosuppressive or immunomodulating biologic drugs (eg, adalimumab, 
etanercept, infliximab, golimumab, certolizumab, ustekinumab, secukinumab, 
brodalumab, ixekizumab, risankizumab, guselkumab, bimekizumab, iscalimab, 
bermekimab, rituximab, anakinra). 
• Systemic immunosuppressive or immunomodulating small-molecule drugs (eg, oral 
or injectable corticosteroids, methotrexate, cyclosporine, dapsone, azathioprine). 
• 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. 
• Allergen immunotherapy. 
• Phototherapy or tanning beds. 
• Live or live-attenuated vaccination. 
6.7. 
Treatment After the End of the Study 
There will be no treatment provided after the end of the study. 


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7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
7.1.1. 
Reasons for Discontinuation 
Participants must be discontinued from study treatment for the following reasons: 
• The participant becomes pregnant. 
• Disease worsens to the point where the extent of affected area to be treated exceeds 
20% BSA. 
• 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 public domain, may be solicited from or collected on the participant.  
Participants may choose to discontinue study treatment and remain in the study to be 
followed for progression. 
• Further participation would be injurious to the participant's health or well-being, in 
the investigator's medical judgment. 
• Unacceptable toxicity 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 drug 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 investigator, in collaboration with the medical monitor, will determine 
whether the participant should be discontinued from study treatment. 
• If a participant is noncompliant with study procedures or study drug/treatment 
handling or administration in the investigator's opinion, the sponsor should be 
consulted for instruction on handling the participant. 
7.1.2. 
Discontinuation Procedures 
In the event that the decision is made to permanently discontinue the study treatment, the EOT 
visit should be conducted.  Reasonable efforts should be made to have the participant complete 
the follow-up visit.  These visits are described in Table 3.  The last date of the last dose of study 
drug and the reason for discontinuation of study drug will be recorded in the eCRF. 


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If a participant is discontinued from study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for discontinuation must be documented in the participant's medical 
record (source document) and the primary reason for discontinuation must be 
included in the eCRF. 
• The EOT visit should be performed and date recorded. 
• The status of the participant should be updated to EOT in the IRT. 
• Participants must be followed for safety until the time of the follow-up visit or until 
study drug–related toxicities 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/efficacy assessments. 
7.2. 
Participant Withdrawal From the Study 
At the baseline visit (Day 1), a participant will be withdrawn from the study prior to receiving 
first dose of study drug if the following occur: 
• Participant's overall and face/neck IGA score is 1 or 4 or 
• Participant's BSA is < 0.5% of the total BSA on the face and/or neck or 
• Participant's BSA is > a total of 20% BSA (face and/or neck plus other body areas) 
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 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.  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. 
See Table 3 for data to be collected at the time of study withdrawal and follow-up and for any 
further evaluations that need to be completed.  If no visit is completed at time of withdrawal, the 
participant should return investigational product per sponsor's instructions. 


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7.3. 
Lost to Follow-Up 
After consent is signed, a participant will be considered lost to follow-up if he/she is not able to 
attend for one scheduled visit and is unable to be contacted by the study site to reschedule, 
despite all efforts from site staff to contact. 
The following actions must be taken if a participant fails to be available for a required 
telemedicine and in-home healthcare worker study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant.  These contact attempts 
should be documented in the participant's medical record. 
• Should the participant continue to be unreachable, they will be considered to be lost 
to follow-up and have withdrawn from the study. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Administrative and General Procedures 
8.1.1. 
Informed Consent 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. 
Note:  Adolescent participants who become legal adults during the study will be 
asked for their signed consent to continue in the study and in the event of lack thereof, 
will be discontinued from further participation. 
− Informed consent/assent must be obtained using the IRB/IEC-approved version in 
a language that is native and understandable to the participant.  A template will be 
provided by the sponsor or its designee.  The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF template.  The ICF must 
include a statement that the sponsor or its designee and regulatory authorities have 
direct access to participant records. 
− The ICF/assent must contain all required elements and describe the nature, scope, 
and possible consequences of the study in a form understandable to the study 
participant. 
• Participants must be informed that their participation is voluntary.  Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent/assent that meets the applicable requirements and regulations for the country 
in which the study is being conducted as well as the IRB/IEC or study center. 
• The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection laws.  The level of disclosure 
must also be explained to the participant. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
• The medical record (source document) 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/assent must also sign the ICF. 
• Participants must provide consent to the most current version of the ICF/assent during 
their participation in the study. 
• A copy of the ICF(s)/assent 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 
> 35 days after the initial screening) and must be assigned a new participant number. 


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8.1.2. 
Screening Procedures 
Screening is the interval between signing the ICF/assent and the day the participant is dosed in 
the study (Day 1).  Screening may not exceed 35 days.  Assessments that are required to 
demonstrate eligibility may be performed over the course of 1 or more days during the screening 
process. 
Procedures conducted as part of the participant's routine clinical management (eg, blood count, 
imaging study) and obtained before signing of the ICF may be used for screening purposes 
provided the procedure meets the Protocol-defined criteria and has been performed in the 
timeframe of the study (ie, within 35 days of Day 1).  For participants who are enrolled in the 
study, information associated with eligibility requirements must be entered into the appropriate 
eCRF pages. 
Results from the screening visit evaluations will be reviewed to confirm eligibility before 
randomization.  At the baseline visit (Day 1), a participant will be confirmed that they can 
continue with study participation (eg, meeting disease activity requirements regarding IGA and 
BSA, and prior and concomitant medication requirements) prior to the first administration of 
study drug.  Tests with results that fail eligibility requirements may be repeated once during 
screening if the investigator believes the results to be in error.  For screening assessments that are 
repeated, the most recent available result before randomization will be used to determine 
eligibility. 
See Sections 5.4 and 5.5 for information regarding screen failures and replacement of 
participants, respectively. 
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 2 letter country code (US), 3-digit site ID, and 3-digit participant number.  
Site staff should contact the IRT to obtain the participant ID number during screening.  Upon 
determining that the participant is eligible for study entry, the IRT will be contacted to obtain the 
treatment assignment.  Additionally, the IRT will be contacted as detailed in Table 3 to update 
the study drug supply.  Additional details are provided in the IRT Manual. 
8.1.4. 
Distribution of Reminder Notification and eDiary 
Participants will be provided with a reminder notification for each visit.  The reminder 
notification will indicate the date/time of the next visit and will also remind the participant that 
they should not apply their study drug within 1 hour of each visit. 
An electronic study medication diary (eDiary) will be used by each participant in order to record 
their twice per day application of study drug.  The completed eDiary will be reviewed during 
each of the participant's study visits and data uploaded as well as compliance with eDiary 
completion will be confirmed by the study staff. 


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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 
that is considered to be clinically significant by the investigator. 
8.1.5.2. 
Disease Characteristics and Treatment History 
A disease-targeted medical and treatment history will be collected at screening.  Details 
regarding the participant's history of AD, including date of diagnosis, relevant disease 
characteristics, and prior treatments, including systemic treatments, radiation, and surgical 
procedures, will be recorded.  A medical history of other conditions related to AD will also be 
collected at this time. 
8.2. 
Efficacy Assessments 
The investigator or designee will independently assess the ClinROs (EASI,
nd %BSA 
involvement) via the digital photographs.  Rater performing the assessment will be distinct from 
the investigator conducting the televisit.  If possible, the same rater should perform the 
assessment for the same participant at every visit.  At the baseline visit, clinical assessments (eg, 
IGA, BSA) need to be completed during the visit prior to first study drug application. 
8.2.1. 
Full-Body Photography 
For the ClinRO assessments (EASI,
nd BSA), full body photographs will be captured by 
the mobile healthcare provider at the visits designated in Table 3.  The photograph set will 
undergo a quality-control process to ensure photographs are of sufficient quality for ClinRO 
assessments.  The rater (a dermatologist) will rate the participant's AD severity using the 
specified ClinRO assessments described in Sections 8.2.2, 8.2.3, and 8.2.4.  The mobile 
healthcare provider will be trained to take a standard set of full-body photographs.  A reference 
guide will be provided to the mobile nurse for photo capture during the remote visit.  An 
investigator will provide oversight during the photography capture process to determine in 
real-time if the photographs obtained are of sufficient quality.  Photographs not meeting the 
assessment standard will be retaken during the same session. 
The investigator or designee will document in the eCRF the specific affected areas of the face 
(forehead, cheeks, chin, nose, eyelids, periocular, and mouth) and other body areas based on the 
photographs. 
8.2.2. 
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 score for the head and neck region 
ranges from 0 to 7.2.  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 


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separately for erythema (E), induration/papulation/edema (I), excoriations (Ex), and 
lichenification (L) for an average degree of severity of each sign in each region. 
The severity strata for the EASI are as follows:  0 = clear; 0.1 to 1.0 = almost clear; 1.1 to 
7.0 = mild; 7.1 to 21.0 = moderate; 21.1 to 50.0 = severe; and 50.1 to 72.0 = very severe. 
8.2.3. 
Investigator's Global Assessment 
The IGA is an overall eczema severity rating on a 0 to 4 scale that will be assessed overall and 
for the face and/or neck, during visits as detailed in Table 3.  The severity strata are shown in 
Table 6. 
Table 6: 
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 
The IGA-TS is defined as an IGA score of 0 or 1 with at least a 2-grade improvement from 
baseline. 
8.2.4. 
Body Surface Area 
At the visits designated in Table 3, the %BSA involvement on the face and/or neck and overall 
will be determined to the nearest 0.1%.  Participants with AD affecting ≥ 0.5% of their total BSA 
on the face and/or neck at screening and baseline and up to a total 20% overall total BSA are 
eligible for the study. 
8.2.5. 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics parameters are not evaluated in this study. 
 
 
  
 
 
 
 


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8.5. 
Safety Assessments 
See Section 6.5 for guidelines regarding the management of other safety assessment 
abnormalities. 
8.5.1. 
Adverse Events 
Adverse events will be monitored from the time the participant signs the ICF until at least 
30 days after the last dose of study drug.  Adverse events for enrolled participants 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 drug.  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 drug/procedures, or that caused the participant to discontinue the 
study drug.  Care will be taken not to introduce bias when detecting AEs and/or SAEs.  
Open-ended and nonleading verbal questioning of the participant, such as "How are you 
feeling?" is the preferred method to inquire about AE occurrences.  Adverse events may also be 
detected when they are volunteered by the participant during the screening process or between 
visits or through physical examinations, laboratory tests, or other assessments.  The definition, 
reporting, and recording requirements for AEs are described in Section 9. 


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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). 
8.5.2. 
Vital Signs 
Vital signs, height, and weight will be measured as outlined in the SoA (see Table 3). 
Vital sign measurements include blood pressure, pulse, respiratory rate, and body temperature.  
At screening, vital sign measurements should be obtained before blood collection for laboratory 
tests.  If vital signs cannot be taken before blood collection for laboratory tests, there must be a 
minimum of 30 minutes from the completion of the blood collection procedures to the beginning 
of the vital signs collection.  Blood pressure and pulse will be taken with the participant in the 
recumbent, semirecumbent, or sitting position after 5 minutes of rest. 
Abnormal vital sign results identified after the first dose of study drug constitute an AE if they 
are considered clinically meaningful, induce clinical signs or symptoms, require concomitant 
therapy, or require study drug interruption or discontinuation. 
8.5.3. 
Laboratory Assessments 
See Table 7 for the list of clinical laboratory tests to be performed at screening.  A central 
laboratory will perform all clinical laboratory assessments for safety (ie, chemistry, hematology 
assessments, and serology).  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).  Information regarding 
collection, processing, and shipping of samples for laboratory assessment is provided in the 
Laboratory Manual. 
Screening laboratory assessments must be performed within 35 days before Day 1.  If performed 
more than 35 days before Day 1, then the tests must be repeated and eligibility confirmed before 
study drug administration on Day 1. 


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Table 7: 
Required Laboratory Analytes 
Serum Chemistries 
Hematology 
Serology/Infection 
Pregnancy Testing (Urine and Serum) 
• Albumin 
• Alkaline phosphatase 
• Alanine aminotransferase 
• Aspartate aminotransferase 
• Blood urea nitrogen or urea 
• Creatine kinase 
• Creatinine 
• Glucose 
• Total bilirubin 
• Direct bilirubin (if total bilirubin 
is elevated above ULN) 
Complete blood count, including: 
• Hemoglobin 
• Hematocrit 
• Platelet count 
• Red blood cell count 
• WBC count 
 
Differential count, including: 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
 
Absolute values must be provided for: 
• WBC differential laboratory results 
• HBsAg 
• HBsAb 
• HBcAb 
• HCVAb 
• HCV RNA 
• HIV 
• Human chorionic gonadotropin 
(WOCBP only) 
• FSH (women of nonchildbearing 
potential only) 
Note:  Additional tests may be required, as agreed by investigator and sponsor, based on emerging safety data or to rule out a diagnosis. 


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8.5.3.1. 
Pregnancy Testing 
At screening, post-menopausal women of nonchildbearing potential will have an FSH 
assessment (see Appendix A).  Women of childbearing potential will have serum and urine 
pregnancy testing performed throughout the study as outlined in the SoA (see Table 3), as 
medically indicated (eg, in case of loss of menstrual cycle, when pregnancy is suspected).  If a 
urine pregnancy test is positive, the results should be confirmed with a serum pregnancy test. 
If the serum pregnancy test is negative after a urine test was positive, the investigator will assess 
the potential benefit/risk to the participant and determine whether it is in the participant's best 
interest to resume study drug and continue participation in the study. 
If a pregnancy is confirmed by a serum pregnancy test, see Section 9.7 for reporting 
requirements. 
8.5.3.2. 
Serology 
Hepatitis B and C and HIV screening assessments will be performed at the screening visit to rule 
out infection; required analytes are shown in Table 7.  Generally, hepatitis and HIV tests should 
be performed early in the screening process due to the length of time needed to obtain the results.  
Additional tests may be performed if clinically indicated. 
Eligibility criteria for participants with a history of HCV infection should generally require 
participants to have completed curative antiviral treatment and require HCV viral quantitative 
RNA below the limit of quantification 12 weeks after the end of HCV therapy.  A participant 
who is HCVAb-positive but HCV RNA-negative due to prior treatment or natural resolution is 
eligible. 
Reactivation of HBV can occur in chronic carriers of HBV infection (HBsAg-positive, 
undetectable or low HBV DNA, and normal ALT) who are not on HBV therapy or in individuals 
who have serologic evidence of a resolved prior HBV infection (ie, HBsAg-negative and 
anti-HBc–positive).  While HBsAg-negative, anti-HBc–positive participants are at lower risk of 
HBV reactivation compared with HBsAg-positive participants, risk of HBV reactivation should 
be considered in all participants.  Participants with no prior history of HBV infection who have 
been vaccinated against HBV and who have a positive antibody against HBV surface antigen as 
the only evidence of prior exposure may participate in the study. 
8.6. 
Pharmacokinetic Assessments 
Pharmacokinetic parameters will not be evaluated in this study. 
8.7. 
Pharmacodynamic and Translational Assessments 
Pharmacodynamic parameters are not evaluated in this study. 
8.8. 
Unscheduled Visits 
Unscheduled study visits may occur at any time at the investigator's (or designee's) discretion 
and appropriate clinical and laboratory tests may be performed as clinically indicated.  Any 
assessments performed at those visits should be recorded in the eCRF. 


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8.9. 
End of Treatment and/or Early Termination 
When the participant permanently discontinues study drug, whether the participant is terminating 
the study early or the participant has completed the study, the EOT visit (at Week 4 EOT1 for 
end of DB VC period and at Week 8 EOT2 for end of OL period) should be conducted.  If the 
EOT visit coincides with a regular study visit, the EOT evaluations will supersede those of that 
scheduled visit, and the data should be entered in the EOT visit in the eCRF.  If a participant 
withdraws from the study before or on Week 4, EOT1 should be conducted.  If a participant 
withdraws from the study after Week 4 and before or on Week 8, EOT2 should be conducted.  
The participant should be encouraged to complete the follow-up visit. 
8.10. 
Safety Follow-Up 
The safety follow-up period is the interval between the EOT visit and the scheduled follow-up 
visit, which should occur 30 (+ 3) days after the EOT visit (or after the last dose of study drug if 
the EOT visit was not performed).  Reasonable efforts should be made to have the participant 
complete the follow-up visit and report any AEs that may occur during this period.  Adverse 
events and SAEs must be reported up until at least 30 days after the last application of study drug 
or until toxicities resolve, return to baseline, or are deemed irreversible, whichever is longer.  
Reasonable efforts should be made to have the participant complete 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 drug. 
Additional Guidance for Events Meeting the Adverse Event Definition 
• Any safety assessments (eg, vital signs measurements), including those that worsen from baseline, 
considered clinically significant in the medical and scientific judgment of the investigator (ie, not 
related to progression of underlying disease) 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 drug.  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 drug 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 drug (eg, overdose) or a concomitant 
medication are to be reported as an AE. 
• "Lack of efficacy," "disease progression," or "failure of expected pharmacological action" will not be 
reported as an AE or SAE.  Such instances will be captured in the efficacy assessments. 
• 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.  AEs/SAEs should be reported for enrolled participants, but only 
SAEs need to be reported for screen failure participants.  For enrolled participants, conditions that 
were present at the time informed consent was given should be recorded on the Medical History 
eCRF.  For detailed information refer to the eCRF guidelines. 
• 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 in the Study Reference 
Manual or 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 drug:  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 drug as a result of the AE/SAE(s). 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown). 
• 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 drug 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 RSI in the IB or Product Information for study drug/treatment, 
or marketed products, respectively, 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 drug 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 drug, the interventions required to 
treat the event, and the outcome. 
• When the severity of an AE changes over time for a reporting period (eg, between visits), each 
change in severity will be reported as a separate AE. 
• 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. 
• 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 
Regardless of suspected causality (eg, relationship to study drug or study procedure[s]), all SAEs 
occurring after the participant has signed the ICF through the last safety visit or at least 30 days 
after the last application of study drug must be reported to the sponsor (or designee) 
immediately, without undue delay but not later than within 24 hours of obtaining knowledge of 
its occurrence unless otherwise specified by the protocol.  The investigator will submit any 
updated SAE data to the sponsor (or designee) immediately, without undue delay but not later 
than within 24 hours of it being available. 
Investigators are not obligated to actively seek SAE information after the safety follow-up visit 
or 30 days after the last application of study drug.  If the investigator learns of any SAE, 
including death, at any time during this period, and he/she considers the event to be reasonably 
related to the study drug or study participation, then 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 regarding an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a study 
drug under clinical investigation are met. 
If the SAE is not documented in the RSI of the IB for the study drug (new occurrence) and is 
thought to be related to the study drug, the sponsor or its designee may urgently require further 
information from the investigator for expedited reporting to health authorities.  The sponsor or its 


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designee may need to issue an Investigator Notification to inform all investigators involved in 
any study with the same drug that this SAE has been reported.  Suspected unexpected serious 
adverse reactions will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC or as per national regulatory requirements 
in participating countries. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study drug 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 an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB 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 drug because of the 
SAE (eg, dose reduced, interrupted, or discontinued), or participant disposition (eg, continued or 
withdrew from study participation).  Each recurrence, complication, or progression of the original 
event should be reported as follow-up to that event, regardless of when it occurs. 
9.5. 
Events of Clinical Interest 
Not applicable. 


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9.6. 
Emergency Unblinding of Treatment Assignment 
In case of a medical emergency, for a participant's safety management, the procedure for 
emergency unblinding is provided to the investigator in the IRT Manual.  If a participant's 
treatment assignment is unblinded, the sponsor or its designee should be notified immediately by 
telephone for awareness. 
If an investigator, the site personnel performing assessments, or a participant is unblinded, then 
the participant must discontinue study drug unless there are ethical reasons to have the 
participant remain on the study treatment.  In these cases, the investigator must obtain specific 
approval from the sponsor's (or its designee's) medical monitor for the participant to continue in 
the study. 
9.7. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that the study drug 
may have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a participant during maternal or paternal exposure to study 
drug, the following procedures should be followed in order to ensure safety: 
• The study drug must be discontinued immediately (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 drug to any pregnancy outcome, as well as follow-up to the first well-baby 
visit or the duration specified in local regulations, whichever is later.  Refer to the Incyte 
Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy of a study participant must be recorded on the 
Serious Adverse Event Report Form and submitted to the sponsor or 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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9.8. 
Warnings and Precautions 
Special warnings or precautions for the study drug, derived from safety information collected by 
the sponsor or its designee, are presented in the IB.  Additional safety information collected 
between IB updates will be communicated in the form of Investigator Notifications.  Any 
important new safety information should be discussed with the participant during the study as 
necessary.  If new significant risks are identified, they will be added to the ICF. 
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. 
9.10. 
Treatment of Overdose 
There has been no clinical experience with overdose of ruxolitinib cream.  Treatment of 
overdose should consist of general supportive measures. 


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10. 
STATISTICS 
10.1. 
Sample Size Determination 
Approximately 75 participants will be randomized 2:1 to ruxolitinib cream 1.5% BID or vehicle 
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 -304, the 
response rate of EASI75 at Week 4 on head and neck is assumed to be 55% for the active arm of 
1.5% BID versus 15% for placebo.  Using a 2-sided alpha of 0.05, the sample size will have a 
> 90% power to detect a difference between the active treatment group versus vehicle.  In 
addition, to provide adequate power for efficacy variables, the sample size is determined to 
provide a large database for safety evaluation. 
10.2. 
Populations for Analysis 
The populations for analysis are provided in Table 8. 
Table 8: 
Populations for Analysis 
Population 
Description 
FAS 
The FAS includes all participants enrolled in the study who will have at least 
1 application of study drug.  The FAS will be used for the summary of 
demographics, baseline characteristics, participants disposition, and analyses of all 
efficacy and safety data. 
OL-evaluable 
The OL-evaluable population includes all participants who applied at least 1 dose of 
ruxolitinib cream during the OL period.  All analyses for the OL period will be 
conducted with the OL-evaluable population. 
10.3. 
Level of Significance 
A hypothesis test will be conducted for the primary analysis at the 2-sided alpha = 0.05 level.  In 
addition, 95% CI will be reported, if applicable. 
10.4. 
Statistical Analyses 
10.4.1. 
Primary Analysis 
The primary endpoint of this study is the proportion of participants who achieve an EASI75 of 
the head and neck region at Week 4.  The primary analysis will be based on the FAS population.  
The primary alternative hypothesis (superiority of ruxolitinib 1.5% BID compared with vehicle) 
will be tested using a CMH test stratified by the stratification factor (screening face and/or neck 
IGA score).  Odds ratio in response rates (ruxolitinib cream vs vehicle) at Week 4 will also be 
computed, and p-values will be provided.  The difference in proportion of participants who 
achieve an EASI75 score of the head and neck region (ruxolitinib cream vs vehicle) at Week 4 
will also be computed. 
All nonresponders in the DB treatment period, as well as all participants who discontinue study 
treatment at any time before the timepoint of interest, or withdraw from the study for any reason, 
will be defined as nonresponders for the nonresponder imputation analysis. 


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10.4.2. 
Secondary 
 Analyses 
All secondary 
efficacy variables will be summarized using descriptive statistics.  
For categorical measurements, summary statistics will include sample size, frequency, and 
percentages.  For continuous measurements, summary statistics will include sample size, mean, 
median, standard deviation, standard error of the mean, minimum, and maximum.  Continuous 
efficacy endpoints, including the actual measurement, change from baseline, and percentage 
change from baseline may also be analyzed by the mixed-effect model with repeat measurement. 
10.4.3. 
Safety Analyses 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first dose of study drug.  Analysis of AEs will be limited to TEAEs, but data listings will include 
all AEs regardless of their timing to study drug administration.  Adverse events will be tabulated 
by the MedDRA preferred term and system organ class.  Severity of AEs will be based on the 
NCI CTCAE v5.0 using Grades 1 through 5. 
The subset of AEs considered by the investigator to have a relationship to study drug will be 
considered to be treatment-related AEs.  If the investigator does not specify the relationship of 
the AE to study drug, then the AE will be considered treatment-related.  The incidence of AEs 
and treatment-related AEs will be tabulated. 
Descriptive statistics and mean change from baseline will be determined for vital signs (blood 
pressure, pulse, respiratory rate, and body temperature) at each assessment time. 
10.5. 
Interim Analysis 
No formal interim analysis is planned in this study. 


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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
11.1. 
Investigator Responsibilities 
• The Protocol, Protocol amendments, ICF, IB, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements, the 
policies and procedures established by the IRB/IEC, and institutional requirements. 
• Any amendments to the Protocol will require approval from both health authorities 
and 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. 


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− All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations.  
The sponsor will retain the original eCRF data and audit trail. 
11.2. 
Data Management 
Data management will be performed in a validated EDC system.  The investigator will be 
provided with access to an EDC system so that an eCRF can be completed for each participant. 
The site will be provided 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, or biomarker plans, 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, biomarker data, photographs, diary data) 
or as otherwise specified in the Protocol. 
• 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). 


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• 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, or 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. 
• 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. 


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− 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. 
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, 
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, 


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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 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 his/her 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. 
The results of this study may be published or presented at scientific meetings.  If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission.  
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined in line with International Committee of Medical Journal Editors 
authorship requirements. 


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


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12. 
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adult population. J Invest Dermatol 2019;139:583-590. 
Clinical Trial Facilitation and Coordination Group. Recommendations related to contraception 
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De Benedetto A, Rafaels NM, McGirt LY, et al. Tight junction defects in patients with atopic 
dermatitis. J Allergy Clin Immunol 2011;127:773-786.e1-7. 
Deckert S, Kopkow C, Schmitt J. Nonallergic comorbidities of atopic eczema: an overview of 
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Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic 
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Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care for the management of atopic 
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ELIDEL (pimecrolimus) Cream [prescribing information]. Bausch Health Companies Inc; 
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and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin 
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Gustafsson D, Sjöberg O, Foucard T. Development of allergies and asthma in infants and young 
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Hanifin JM, Reed ML, Eczema Prevalence and Impact Working Group. A population-based 
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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. 


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Howell MD. The role of human beta defensins and cathelicidins in atopic dermatitis. Curr Opin 
Allergy Clin Immunol 2007;7:413-417. 
Hughes ME, Aralis H, Bruhn KW, et al. A reliability study using network-oriented research 
assistant (NORA®) to evaluate the use of digital photographs in the assessment of atopic 
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10.1016/j.jaad.2019.01.043. 
Ivert LU, Johansson EK, Dal H, et al. Assoication between atopic dermatitis and cardiovascular 
disease: a nationwide register-based case-control study from Sweden. Acta Derm Venerol 
2019;99:865-870. 
Kauppi S, Jokelainen J, Timonen M, et al. Adult patients with atopic eczema have a high burden 
of psychiatric disease: a Finnish nationwide registry study. Acta Derm Venereol 
2019;99:647-651. 
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. 
Laughter MR, Maymone MBC, Mashayekhi S, et al. The global burden of atopic dermatitis: 
lessons from the Global Burden of Disease Study 1990-2017. Br J Dermatol 2021;184:304-309. 
Lio PA, Lee M, LeBovidge J, Timmons KG, Schneider L. Clinical management of atopic 
dermatitis: practical highlights and updates from the atopic dermatitis practice parameter 2012. 
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Mehta CR, Patel NR. Exact logistic regression: theory and examples. Stat Med 
1995;14:2143- 2160. 
Opzelura (ruxolitinib)1.5% [prescribing information. Incyte Corporation; September 2021. 
Ozkaya E. Adult-onset atopic dermatitis. J Am Acad Dermatol 2005;52:579-582.  
Paller A, Jaworski JC, Simpson EL, et al. Major comorbidities of atopic dermatitis: beyond 
allergic disorders. Am J Clin Dermatol 2018;19:821-838. 
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Genet 2006;38:441-446. 
Papp K, Szepietowski JC, Kircik L, et al. Efficacy and safety of ruxolitinib cream for the 
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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 
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Ruxolitinib Cream Investigator's Brochure. Wilmington, DE: Incyte Corporation. 
Shalom G, Dreiher J, Kridin K, et al. Atopic dermatitis and the metabolic syndrome: a 
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Shaw TE, Currie GP, Koudelka CW, et al. Eczema prevalence in the United States: data from the 
2003 National Survey of Children's Health. J Invest Dermatol 2011;131:67-73. 
Silverberg JI, Garg NK, Paller AS, Fishbein AB, Zee PC. Sleep disturbances in adults with 
eczema are associated with impaired overall health; a US population-based study.  J Invest 
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Silverberg JI, Gelfand JM, Margolis DJ, et al. Association of atopic dermatitis with allergic, 
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Spergel JM. Epidemiology of atopic dermatitis and atopic march in children. Immunol Allergy 
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Standl M, Tesch F, Baurecht H, et al. Association of atopic dermatitis with cardiovascular risk 
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Strom MA, Fishbein AB, Paller AS, et al. Association between atopic dermatitis and attention 
deficit hyperactivity disorder in U.S. children and adults. Br J Dermatol 2016;175:920-929. 
Williams HC, Strachan DP. The natural history of childhood eczema: observations from the 
British 1958 birth cohort study. Br J Dermatol 1998;139:834-839. 
Yaghmaie P, Koudelka CW, Simpson EL. Mental health comorbidity in patients with atopic 
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS AND DEFINITIONS 
Definitions 
WOCBP:  A woman who is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below) 
Women in the following categories are not considered WOCBP: 
• Premenarchal 
• Premenopausal with 1 of the following:a 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
• Postmenopausal 
− A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. 
o A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or HRT.  However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range is required. 
− Females on HRT and whose menopausal status is in doubt will be required to use 1 of the nonhormonal, 
highly effective contraception methods if they wish to continue their HRT during the study.  Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment. 
For male participants of reproductive potentialb 
The following methods during the Protocol-defined timeframe in Section 5.1 are highly effective: 
• Use of a male condom plus partner use of an additional contraceptive method when having penile-vaginal 
intercourse with a woman of childbearing potential who is not currently pregnant. 
• Vasectomy with medical assessment of the surgical success (verified by site personnel's review of the 
participant's medical records) 
• Sexual abstinencec 
− Abstinence from penile-vaginal intercourse 
The following are not acceptable methods of contraception: 
• Periodic abstinence (calendar, symptothermal, post ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method. 
• Male condom with cap, diaphragm, or sponge with spermicide. 
• Male and female condom used together. 
Note:  Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal 
intercourse or use a male condom during each episode of penile penetration.   


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For female participants who are WOCBP 
The following methods during the Protocol-defined timeframe in Section 5.1 that can achieve a failure rate of less 
than 1% per year when used consistently and correctly are considered as highly effective birth control methods: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation.d 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulationd 
− oral 
− injectable 
− implantablee 
• Intrauterine devicee 
• Intrauterine hormone-releasing systeme 
• Bilateral tubal occlusione 
• Vasectomized partnere,f 
• Sexual abstinencec  
a Documentation can come from the site personnel's review of the participant's medical records, medical examination, or medical 
history interview. 
b If the male participant has a partner with child-bearing potential the partner should also use contraceptives. 
c In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments.  The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the 
participant. 
d Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may reduce the 
efficacy of the contraception method. 
e Contraception methods that in the context of this guidance are considered to have low user dependency. 
f Vasectomized partner is a highly effective method of avoiding pregnancy provided that partner is the sole sexual partner of the 
WOCBP study participant and that the vasectomized partner has received medical assessment of the surgical success. 
Source:  Clinical Trials Facilitation and Coordination Group (2020). 


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APPENDIX B. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment 1: 
28 JUL 2021 
Amendment 2: 
04 AUG 2022 
Amendment 2 (04 AUG 2022) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to align the protocol design with the DCT study 
delivery model.  Additional changes are summarized below. 
1. Section 1, Protocol Summary (Table 2:  Key Study Design Elements; 
Table 3:  Schedule of Activities; Figure 1:  Study Design Schema); Section 4.2, 
Overall Study Duration; Section 5.4, Screen Failures; Section 8.1.1, Informed 
Consent Process; Section 8.1.2, Screening Procedures; Section 8.5.3, Laboratory 
Assessments 
Description of change:  Updated screening window 35 days (5 weeks). 
Rationale for change:  To accommodate the screening activities in the DCT model, 
especially to allow time for study drug delivery to participants' home. 
2. Section 1, Protocol Summary (Table 2:  Key Study Design Elements; 
Table 3:  Schedule of Activities; Figure 1:  Study Design Schema); Section 4.2, 
Overall Study Duration; Section 6.6, Concomitant Medications and Procedures; 
Section 8.5.1, Adverse Events; Section 8.10, Safety Follow-Up; Section 9.4, 
Reporting of Serious Adverse Events 
Description of change:  Updated safety follow-up and follow-up after the last 
application of study drug to 30 days. 
Rationale for change:  To be consistent with safety reporting requirements. 
3. Section 1, Protocol Summary (Table 2:  Key Study Design Elements); Section 4.1, 
Overall Design; Section 5.1, Inclusion Criteria (Inclusion Criteria 5 and 6); 
Section 6.1, Study Treatments Administered 
Description of change:  Clarified when randomization occurs. 
Rationale for change:  In the DCT model, a participant is randomized during the 
screening period, not at baseline, after eligibility is confirmed from the screening visit. 


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4. Section 1, Protocol Summary (Table 3:  Schedule of Activities); Section 4.1, Overall 
Design; Section 7.2, Participant Withdrawal From the Study; Section 8.1.2, 
Screening Procedures; Section 8.2, Efficacy Assessments 
Description of change:  Revised IGA and BSA assessments to be performed during 
baseline prior to dose administration. 
Rationale for change:  Assessments perform at baseline will be used to confirm 
participant eligibility to continue with the study.  Participants with disease activity 
outside of the protocol-defined range at the baseline visit will be early terminated and 
withdrawn from the study, and not deemed as a screen failure. 
5. Section 1, Protocol Summary; Section 5.4, Screen Failures; Section 6.2, Preparation, 
Handling, and Accountability; Section 7.3, Lost to Follow-Up; Section 8.1.2, 
Screening Procedures; Section 8.1.4, Distribution of Reminder Notification and 
eDiary 
Description of change:  Minor revisions and clarifications made to text. 
Rationale for change:  To align with DCT model. 
 
 
 
7. Section 1, Protocol Summary (Table 3:  Schedule of Activities) 
Description of change:  Added that study drug will also be collected during Week 4 at 
the end of the DB VC period. 
Rationale for change:  The study drug collection during Week 4 was inadvertently 
excluded from the table. 
8. Section 2.2, Study Rationale 
Description of change:  Updated to include the details of the approval of ruxolitinib 
1.5% cream. 
Rationale for change:  To provide most up to date information. 
9. Section 2.2.1, Scientific Rationale for Study Design; Section 8.2, Efficacy 
Assessments 
Description of change:  Revised to include a rater in addition to an investigator for 
efficacy assessments. 
Rationale for change:  To clarify that clinical assessments are assessed independently by 
rater(s) and not the investigator(s). 


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10. Section 5.2, Exclusion Criteria (Exclusion Criterion 4b) 
Description of change:  Updated washout to 4 weeks. 
Rationale for change:  To be consistent with other ruxolitinib cream study protocol(s) 
considering the short half-life of these immunomodulating agents. 
11. Section 5.2, Exclusion Criteria (Exclusion Criterion 7c) 
Description of change:  Revised criteria to clarify the exception for the ULN of total 
bilirubin applies to participants with Gilbert's Syndrome. 
Rationale for change:  To clarify the relationship between the total versus direct 
bilirubin criteria. 
12. Section 5.2, Exclusion Criteria (Exclusion Criterion 8); Section 8.5.3, Laboratory 
Assessments (Table 7:  Required Laboratory Analytes); Section 8.5.3.2, Serology 
Description of change:  Revised HBV and HCV criteria for participants who are 
positive for HCVAb, which requires additional laboratory assessments of HCV RNA.  
Updated language to be consistent with the laboratory testing procedures and clarified 
requirements for test results. 
Rationale for change:  Due to DCT model, all required HBV and HCV tests are to be 
performed at the same time (ie, no reflective tests).   
13. Section 5.3, Lifestyle Consideration 
Description of change:  Updated to address participant's living environment and 
schedule. 
Rationale for change:  Study will be conducted through televisits and mobile nurse 
home visits.  Suitable living environments (eg, internet connect) are important for study 
conduct. 
14. Section 5.4, Screen Failures 
Description of change:  Added that participants that were terminated before dose 
administration could be rescreened upon sponsor approval. 
Rationale for change:  Due to DCT model, the baseline visit is separate from 
randomization.  A participant may be terminated from the study after randomization but 
before baseline visit/dose administration due to various reasons.  Upon sponsor approval, 
a participant can be rescreened. 
15. Section 6.1, Study Treatments Administered; Section 6.5.2, Criteria for Permanent 
Discontinuation of Study Drug; Section 7.1.1, Reasons for Discontinuation 
Description of change:  Updated follow-up action to discontinue study treatment when 
total BSA to be treated exceeds 20%.  
Rationale for change:  To be consistent with other ruxolitinib cream AD protocols. 


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16.  Section 6.3, Measures to Minimize Bias:  Randomization and Blinding 
Description of change:  Clarified that stratified by screening face and/or neck IGA score 
Rationale for change:  In the DCT model for this study, only screening IGA is available 
at randomization.  Participants are stratified based on screening IGA score. 
17. Section 10.2, Population for Analysis (Table 8: Population Analysis); Section 10.4.1, 
Primary Analysis 
Description of change:  The FAS population replaced both the ITT and safety 
populations. 
Rationale for change:  For the DCT model for this study, randomization occurs in the 
screening period and not on Day 1/baseline; therefore, using ITT may include 
randomized but participants who are terminated from the study early (eg, due to not 
meeting disease activity criteria at baseline or other reasons) without any baseline values 
for analysis.  Therefore, change from baseline analysis with ITT may not be feasible.  
The FAS will allow for a meaningful definition of change from baseline in the endpoints. 
18. Section 10.4.1, Primary Analysis 
Description of change:  Change primary analysis from logistic regression to CMH 
analysis. 
Rationale for change:  To better characterize the effect size of the efficacy endpoints. 
19. 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 1 (28 JUL 2021) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to revise Exclusion Criterion 7 to create consistency 
across other atopic dermatitis protocols and for ease of recruitment, minimizing screen failures 
for nonsignificant clinical laboratory results.  Additional changes are summarized below. 
1. Section 1, Protocol Summary (Treatment Groups and Duration); Section 6.3,  
Measures to Minimize Bias:  Randomization and Blinding 
Description of change:  The words "and age" were removed from the description of 
randomization and stratification of participants.  
Rationale for change:  This study will only stratify by face and/or neck IGA score 
(2 vs 3). 
2. Section 5.2, Exclusion Criteria (Exclusion Criterion 2f)  
Description of change:  Added "day" to 880 µg (880 µg/day). 
Rationale for change:  Clarification. 
3. Section 5.2, Exclusion Criteria (Exclusion Criterion 4e) 
Description of change:  Added a topical antipruritic and PDE4 inhibitors to the 1-week 
washout period before baseline. 
Rationale for change:  In order to mitigate any risk to the participant and interference 
with interpretation of study data. 
4. Section 5.2, Exclusion Criteria (Exclusion Criteria 7 and 11) 
Description of change:  Clarified that Exclusion Criterion 7 applies to laboratory results 
at screening; deleted Exclusion Criteria 7a (any value < 0.75 × LLN [other than 
bilirubin]) and 7b (any value > 2.5 × ULN); clarified that Exclusion Criterion 7c applies 
to liver function tests and added AST or ALT ≥ 2.5 × ULN; moved Exclusion Criterion 
11 to 7d; and added Exclusion Criteria 7e, 7f, and 7g regarding cytopenias at screening, 
estimated glomerular filtration rate, and any other clinical significant laboratory result 
that, in the opinion of the investigator, poses a significant risk to the participant, 
respectively.  
Rationale for change:  Original Exclusion Criterion 7a was overly restrictive; Criteria 7c 
through 7g were added/moved to be consistent with exclusion criteria from other atopic 
dermatitis protocols.  Exclusion Criterion 11 was moved because it is an 
investigator-determined clinically significant abnormal value. 
5. 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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SAP_001.pdf: 
Official Title: A Phase 2, Efficacy and Safety Study of Ruxolitinib Cream in Participants with Facial and/or Neck                     
Atopic Dermatitis Involvement
NCT Number: NCT05127421
Document Date: : Original Statistical Analysis Plan: 26-Sep-2023


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Statistical Analysis Plan 
 
 
TITLE PAGE 
INCB 18424-215 
A Phase 2, Efficacy and Safety Study of Ruxolitinib Cream in 
Participants with Facial and/or Neck Atopic Dermatitis Involvement 
 
Product: 
Ruxolitinib 
IND Number: 
EudraCT Number: 
2021‐000489‐14 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
United States 
Protocol Version: 
Protocol Amendment 02 dated 04 AUG 2022 
CRF Approval Date: 
15 MAR 2022 
SAP Version: 
Original 
SAP Author: 
 
 Biostatistician 
Date of Plan: 
26 SEP 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 ..........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................6 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS .................................7 
2.1. 
Protocol and Case Report Form Version ......................................................................7 
2.2. 
Objectives and Endpoints .............................................................................................7 
3. 
STUDY DESIGN .........................................................................................................8 
3.1. 
Randomization ..............................................................................................................8 
3.2. 
Control of Type I Error .................................................................................................9 
3.3. 
Sample Size Considerations .........................................................................................9 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................10 
4.1. 
Scheduled Study Evaluations and Study Periods ........................................................10 
4.1.1. 
Day 1 ...........................................................................................................................10 
4.1.2. 
Study Day ...................................................................................................................10 
4.1.3. 
Baseline Value ............................................................................................................10 
4.1.4. 
Handling of Missing and Incomplete Data .................................................................10 
4.2. 
Variable Definitions ....................................................................................................11 
4.2.1. 
Body Mass Index ........................................................................................................11 
4.2.2. 
Prior and Concomitant Medication .............................................................................11 
5. 
STATISTICAL METHODOLOGY ...........................................................................12 
5.1. 
General Methodology .................................................................................................12 
5.2. 
Treatment Groups .......................................................................................................12 
5.3. 
Analysis Populations ..................................................................................................12 
5.3.1. 
Full Analysis Set .........................................................................................................12 
5.3.2. 
Open-Label Evaluable Population ..............................................................................12 
6. 
BASELINE, EXPOSURE, AND DISPOSITION ......................................................13 
6.1. 
Demographics, Baseline Characteristics, and Disease History ..................................13 
6.1.1. 
Demographics and Baseline Characteristics ...............................................................13 
6.1.2. 
Baseline Disease Characteristics ................................................................................13 
6.1.3. 
Disease History ...........................................................................................................13 


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6.1.4. 
Medical History ..........................................................................................................14 
6.2. 
Disposition of Participant ...........................................................................................14 
6.3. 
Protocol Deviations ....................................................................................................14 
6.4. 
Exposure .....................................................................................................................14 
6.5. 
Study Drug Compliance..............................................................................................14 
6.6. 
Prior and Concomitant Medication .............................................................................15 
7. 
EFFICACY .................................................................................................................15 
7.1. 
General Considerations ...............................................................................................15 
7.2. 
Efficacy Hypothesis ....................................................................................................15 
7.3. 
Analysis of the Primary Efficacy Parameters .............................................................15 
7.3.1. 
Primary Efficacy Measure ..........................................................................................15 
7.3.1.1. 
Eczema Area and Severity Index Score ......................................................................15 
7.3.2. 
Primary Efficacy Analyses .........................................................................................16 
7.3.3. 
Subgroup Analyses for Primary Endpoint ..................................................................16 
7.3.4. 
Sensitivity and Supportive Analyses for Primary Endpoint .......................................16 
7.4. 
Analysis of Secondary Efficacy Parameters ...............................................................16 
 
16 
 
16 
 
16 
7.5.1.2. 
Investigator's Global Assessment ...............................................................................17 
 
17 
 
18 
 
18 
8. 
SAFETY AND TOLERABILITY ..............................................................................19 
8.1. 
General Considerations ...............................................................................................19 
8.2. 
Adverse Events ...........................................................................................................19 
8.2.1. 
Adverse Event Definitions ..........................................................................................19 
8.2.2. 
Adverse Event Summaries ..........................................................................................20 
8.3. 
Clinical Laboratory Tests ...........................................................................................21 
8.3.1. 
Laboratory Value Definitions .....................................................................................21 
8.4. 
Vital Signs ..................................................................................................................21 
9. 
PLANNED ANALYSES ............................................................................................22 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................22 


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22 
10.2. 
Changes to the Statistical Analysis Plan .....................................................................22 
11. 
REFERENCES ...........................................................................................................23 
APPENDIX A. PLANNED TABLES AND FIGURES .............................................................24 
 
LIST OF TABLES 
Table 1: 
Objectives and Endpoints .............................................................................................7 
Table 2: 
Investigator's Global Assessment ...............................................................................17 
Table 3: 
Criteria for Clinically Notable Vital Sign Abnormalities for 12 to 15 Years .............21 
Table 4: 
Criteria for Clinically Notable Vital Sign Abnormalities for 16 to 17 Years .............21 
Table 5: 
Criteria for Clinically Notable Vital Sign Abnormalities for ≥ 18 Years ...................21 
Table 6: 
Statistical Analysis Plan Versions ..............................................................................22 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema ...................................................................................................8 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AD 
atopic dermatitis 
AE 
adverse event 
ASR 
application site reaction 
BID 
twice daily 
BMI 
body mass index 
BSA 
body surface area 
CI 
confidence interval 
CMH  
Cochran-Mantel-Haenszel 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBVC 
double-blind vehicle-controlled 
EASI 
Eczema Area and Severity Index 
EASI75 
≥ 75% improvement in EASI score 
FAS 
full analysis set 
eCRF 
electronic case report form 
IGA 
Investigator's Global Assessment 
IGA-TS 
Investigator's Global Assessment Treatment Success 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRI 
nonresponder imputation 
NRS 
numerical rating scale 
OL 
open-label  
 
 
PT 
preferred term 
rux 
ruxolitinib 
SAP 
Statistical Analysis Plan 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
VC 
vehicle-controlled 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
INCB 18424-215 is a decentralized, randomized, DBVC study with a 4-week, OL period in 
adolescent and adult participants with AD (including AD on the face and/or neck) eligible for 
topical therapy. 
This study will be conducted through a single, stand-alone, virtual site in the US. All study visits 
will be conducted in the participant's home with the assistance of a mobile healthcare provider 
and investigator or designee present through telemedicine (telephone and/or video visits). 
Participants will be randomized 2:1 to blinded treatment with ruxolitinib 1.5% cream BID or 
vehicle cream BID with stratification by the participant's face and/or neck IGA score (IGA 2 or 
3) at screening. Participants with a face and/or neck IGA score of 2 at screening will constitute 
approximately 25% of the overall study population. 
Two Phase 3 pivotal studies (INCB 18424-303 and INCB 18424-304) demonstrated that 
ruxolitinib 1.5% cream BID was statistically and significantly superior to vehicle cream after 
8 weeks of treatment, reaching the primary endpoint, IGA-TS, with a score of 0 or 1 with 
≥ 2-grade improvement from baseline, as well as key secondary endpoints. Key secondary 
endpoints included a 75% improvement in the EASI and at least a 4-point improvement in 
Itch NRS (Papp et al 2020). The ruxolitinib 1.5% cream was consistently more efficacious than 
the ruxolitinib 0.75% cream; however, the safety and tolerability profiles of both regimens were 
comparable and nondifferentiating. 
The purpose of this study is to further investigate and confirm the efficacy and safety of 
ruxolitinib 1.5% cream when applied to affected areas on the face and neck. 
The purpose of this SAP is to provide details of the statistical analyses that have been outlined in 
the INCB 18424-215 Protocol. The Department of Biostatistics at Incyte 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 18424-215 Protocol Amendment 2 dated 04 AUG 2022 and CRFs 
approved 15 MAR 2022. 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 on the face and/or neck. 
Proportion of participants who achieve an EASI75 
of the head and neck region at Week 4. 
Secondary 
To further assess efficacy of ruxolitinib cream 
for the treatment of AD on the face, neck, and 
other body areas. 
Proportion of participants who achieve an EASI75 
of the head and neck region at Weeks 2 and 8. 
Proportion of participants who achieve an overall 
EASI75 at Weeks 2, 4, and 8. 
To assess the safety and tolerability of 
ruxolitinib in participants with AD on the face 
and/or neck. 
The type, frequency, and severity of AEs, including 
the evaluation of vital signs. 


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3. 
STUDY DESIGN 
This is a decentralized, randomized, DBVC study with a 4-week, OL period in adolescent and 
adult participants with AD (including AD on the face and/or neck) eligible for topical therapy. 
This study will be conducted through a single, stand-alone, virtual site in the US. All study visits 
will be conducted in the participant's home with the assistance of a mobile healthcare provider 
and investigator or designee present through telemedicine (telephone and/or video visits). 
During the 4-week DBVC period, participants will apply ruxolitinib 1.5% cream BID, or vehicle 
cream BID, to all areas identified for treatment at the baseline visit; this treatment will be 
followed by participants even if the AD begins to improve and the lesions decrease in size. 
Mobile healthcare providers will take comprehensive photographs. The investigator will use 
these photos to assess the AD-affected areas for the Week 4 clinician-reported assessments. The 
participants who complete the study with no safety concerns through Week 4 will then continue 
into the 4-week, OL period, where individuals will apply ruxolitinib cream 1.5% BID only to 
affected areas. 
The cumulative duration of this study will be approximately 17 weeks as follows: up to 35 days 
in the screening period; 4 weeks in the DBVC period; 4 weeks in the OL period; and 30 days 
(+ 3, as needed) for follow-up after the last application of the study drug. 
At Week 4, efficacy (the primary endpoint of the study) will be evaluated as the proportion of 
participants who achieve an EASI75 of the head and neck region. Additional efficacy 
assessments and patient-reported outcomes will be conducted. 
Figure 1 presents the study design schema. 
Figure 1: 
Study Design Schema 
 
3.1. 
Randomization 
In the DBVC period, the Interactive Response Technology system will assign approximately 
75 participants in a 2:1 ratio to ruxolitinib 1.5% cream BID and vehicle cream BID, respectively. 
Additionally, participants will be stratified by face and/or neck IGA score (2 or 3) at screening. 
Participants with a face and/or neck IGA score of 2 at screening will constitute approximately 
25% of the overall study population. 


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3.2. 
Control of Type I Error 
For the primary analysis, the overall 2-sided Type I error of 0.05 will be used. 
3.3. 
Sample Size Considerations 
Approximately 75 participants will be randomized 2:1 (ie, ruxolitinib 1.5% cream BID to 
vehicle cream BID, respectively). The sample size calculation is based on the Fisher's exact test 
for the primary efficacy endpoint. Based on the results from the 2 pivotal studies, 
INCB 18424-303 and -304, the response rate of EASI75 at Week 4 on the head and neck is 
assumed to be 55% for the active arm of ruxolitinib 1.5% cream BID versus 15% for vehicle 
cream BID. Using a 2-sided alpha of 0.05, the sample size will have a > 90% power to detect a 
difference between the ruxolitinib 1.5% cream BID versus vehicle cream BID. In addition, to 
provide adequate power for efficacy variables, the sample size is determined to provide a large 
database for safety evaluation. 


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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. 
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 safety analyses, participants who cross-over treatment in 
OL period, baseline is the last nonmissing measurement obtained before or on the first 
administration of study treatment in OL 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. 
4.1.4. 
Handling of Missing and Incomplete Data 
For response endpoints, all nonresponders, as well as all participants who are missing 
postbaseline values, will be defined as nonresponders for the NRI analysis. 
For other endpoints, missing observations will be handled as detailed in the specific sections 
addressing each analysis. 


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4.2. 
Variable Definitions 
4.2.1. 
Body Mass Index 
Body mass index will be calculated as follows: 
BMI (kg/m2) = [weight (kg)] / [height (m)]2 
4.2.2. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication started before the first application of 
study treatment. 
Concomitant medication is defined as any nonstudy medication that is started accordingly: 
• Before the date of first application of study treatment and is ongoing throughout the 
study or ends on/after the date of first application of study treatment. 
• On/after the date of first application of study treatment and is ongoing or ends during 
the course of study treatment. 
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after the first application of study treatment. In the listing, it will be indicated 
whether a medication is prior-only, concomitant-only, or both prior and concomitant. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant. 


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5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS® software (SAS Institute Inc, Cary, NC; v9.1) 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, DBVC study followed by an OL period. Data will be summarized based on 
the treatment (ruxolitinib 1.5% cream BID or vehicle cream BID) that the participant actually 
applied (ie, FAS). 
During the DBVC period, the treatment groups will be ruxolitinib 1.5% cream BID and 
vehicle cream BID. The treatment groups for the OL period will be ruxolitinib 1.5% cream BID 
to ruxolitinib 1.5% cream BID, and vehicle cream BID to ruxolitinib 1.5% cream BID. 
5.3. 
Analysis Populations 
5.3.1. 
Full Analysis Set 
The FAS will include all participants who are randomized and applied the study drug at least 
once. Treatment groups for this population will be determined according to the actual treatment 
the participant applied on Day 1 regardless of assigned study treatment. 
The FAS population will be used for the summary of demographics, baseline characteristics, and 
participant disposition, and analyses of all efficacy and safety data. 
5.3.2. 
Open-Label Evaluable Population 
The OL-evaluable population will include all participants who applied ruxolitinib cream at least 
once during the OL period. 
All analyses for the OL period will be conducted with the OL-evaluable population. 


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6. 
BASELINE, EXPOSURE, AND DISPOSITION 
Appendix A provides a list of planned tables, figures, and listings. Sample data displays are 
included in a separate document. 
6.1. 
Demographics, Baseline Characteristics, and Disease History 
6.1.1. 
Demographics and Baseline Characteristics 
The following demographics and baseline characteristics will be summarized for the FAS 
population in the DBVC period: age, sex, race, ethnicity, weight, height, and BMI. 
6.1.2. 
Baseline Disease Characteristics 
The following baseline disease characteristics will be summarized for the FAS population in the 
DBVC period: 
• Time since first onset of AD 
• Prior history of asthma (no/yes) 
• Prior allergies (no/yes) and type of allergy 
• History of contact dermatitis (no/yes) 
• Common complications of AD 
• Prior treatments for AD 
• Time since onset of current flare of AD 
• Prior therapy for AD given in the past 30 days (no/yes) 
• Total % BSA involvement in current AD episode 
• Total % BSA involving face and/or neck in the current episode 
• Facial and/or neck involvement during the past episodes/flares (no/yes) 
• Number of AD episodes/flares over the last 12 months 
• Average duration of episodes/flares 
• IGA score (2/3) at screening 
• Baseline IGA score (2/3) 
• Baseline facial and/or neck IGA (2/3) 
• Baseline EASI score 
• Baseline face and/or neck EASI score 
• Baseline Itch NRS score 
6.1.3. 
Disease History 
Not applicable. 


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6.1.4. 
Medical History 
For participants in the FAS, medical history will be summarized by assigned treatment group. 
This summary will include the number and percentage of participants with medical history event 
for each body system/organ class as documented on the eCRF. 
6.2. 
Disposition of Participant 
The number and percentage of participants who were randomized, who were treated, who 
completed the period, who discontinued study treatment with a primary reason for 
discontinuation, and who withdrew from the study with a primary reason for withdrawal will be 
summarized for the FAS population in the DBVC period. 
The number and percentage of participants who were treated, who completed the period, who 
discontinued study treatment with a primary reason for discontinuation, and who withdrew from 
the study with a primary reason for withdrawal will be summarized for the OL-evaluable 
population in the OL period. 
6.3. 
Protocol Deviations 
Protocol deviations recorded on the eCRF will be summarized and listed for the FAS and 
OL-evaluable populations. 
6.4. 
Exposure 
For participants in the FAS and OL-evaluable population, descriptive statistics will be provided. 
That is, by treatment group for duration of treatment, average daily weight of study drug, and 
total weight of study drug. 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 FAS population, the overall compliance (%) for the application of 
ruxolitinib cream or vehicle cream during the DBVC period will be calculated 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. 


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6.6. 
Prior and Concomitant Medication 
Prior medications and concomitant medications will be coded using the WHO Drug Dictionary. 
The number and percentage of participants in the FAS population during the DBVC period will 
be summarized by WHO drug class and WHO drug term for each prior and concomitant 
medication. 
For participants in the OL period, only concomitant medications will be summarized. Prior 
medications for AD will be summarized by treatment group, as well as listed for the 
FAS population. 
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 change from 
baseline (if available) will be analyzed. 
All by-visit analyses will include the follow-up period, if the data are available. 
7.2. 
Efficacy Hypothesis 
Not applicable. 
7.3. 
Analysis of the Primary Efficacy Parameters 
Digital photographs will be used to evaluate clinician-reported outcome assessments (eg, EASI, 
and BSA). 
7.3.1. 
Primary Efficacy Measure 
7.3.1.1. 
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 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 disease severity strata for the EASI are as follows: 0 = clear; 0.1 to 1.0 = almost clear; 
1.1 to 7.0 = mild; 7.1 to 21.0 = moderate; 21.1 to 50.0 = severe; 50.1 to 72.0 = very severe. 
Specifically for head and neck region, EASI score ranges from 0 to 7.2. 
The categorical variable EASI75 of the head and neck region will be equal to 1, if the percentage 
improvement from baseline of the EASI score is ≥ 75% or greater and will be equal to 0 for 
percentage improvement of less than 75% for the head and neck region. 


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Additionally, the categorical variable EASI75 for the entire body (ie, overall) will be equal to 1 if 
the percentage improvement from baseline of the EASI score is ≥ 75% or greater, and equal to 
0 for percentage improvement of less than 75% for the entire body. 
7.3.2. 
Primary Efficacy Analyses 
The primary endpoint is the proportion of participants who achieve EASI75 of the head and neck 
region at Week 4. The primary analysis will be based on the FAS population in the DBVC 
period. The primary alternative hypothesis (superiority of ruxolitinib 1.5% cream BID compared 
with vehicle cream BID) will be tested at a 2-sided α = 0.05 level using the CMH test stratified 
by the stratification factor (ie, the participant's face and/or neck IGA score at screening). 
Odds ratio in response rates (ruxolitinib cream vs vehicle) at Week 4 will be computed and 
provided, as well as the p-values. The difference in proportion of participants who achieve an 
EASI75 score of the head and neck region (ruxolitinib cream vs vehicle) at Week 4 will also be 
computed. The 95% CI for the difference will be computed based on a large-sample normal 
approximation with continuity correction. The p-value and stratum-adjusted EASI75 response 
rate difference with 95% CI will be provided. 
All nonresponders during the DBVC period, as well as all participants who discontinue study 
treatment at any time before Week 4, or withdraw from the study for any reason, will be defined 
as nonresponders for the NRI analysis. 
7.3.3. 
Subgroup Analyses for Primary Endpoint 
Not applicable. 
7.3.4. 
Sensitivity and Supportive Analyses for Primary Endpoint 
Not applicable. 
7.4. 
Analysis of Secondary Efficacy Parameters 
All secondary efficacy variables will be summarized using descriptive statistics. 
For categorical measurements, summary statistics will include sample size, frequency, and 
percentages. 
 
 
 
 
 
 
 
 
 
 
 


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7.5.1.2. 
Investigator's Global Assessment 
The IGA is an overall eczema severity rating on a 0 to 4 scale that will be used during treatment 
period visits to assess a participant's face and/or neck. 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: Food and Drug Administration 2012. 
The IGA-TS is defined as an IGA score of 0 or 1 with ≥ 2 grade improvement from baseline for 
both overall and the face and/or neck region. 
 
 
 
 
 
 
 
 
 
 
 


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8. 
SAFETY AND TOLERABILITY 
Appendix A provides a list of planned tables figures, and listings. Sample data displays are 
included in a separate document. 
8.1. 
General Considerations 
The analyses in this section will be provided for the FAS and OL-evaluable populations in the 
DBVC and OL periods. 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. 
Unless otherwise stated, table summaries will be limited to AEs occurring within 30 days of the 
last application of study drug or the first application in the OL period (if available) of the study, 
whichever is earlier. 
8.2. 
Adverse Events 
8.2.1. 
Adverse Event Definitions 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first application of the study drug. 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 National Cancer Institute CTCAE v5 (Grades 1 to 5). 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 the study drug will be 
considered to be treatment-related AEs. If the investigator does not specify the relationship of the 
AE to the study drug, the AE will be considered to be treatment-related. The incidence of AEs 
and treatment-related AEs will be tabulated. Serious AEs will also be tabulated. 
Any missing onset date, causality, or severity must be queried for resolution. Unresolved missing 
causality and severity will be handled according to the following rules: 
• An unresolved missing causality will be considered treatment-related. 
• An unresolved missing severity will be identified as an unknown severity. 
For purposes of analysis, all AEs will be considered TEAEs unless the AE can unequivocally be 
defined as not treatment-emergent. 
Application site reaction is an AE that occurs at the site of drug application. A summary of ASRs 
will be provided. 


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8.2.2. 
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 ASRs 
• Number (%) of participants reporting any serious TEAEs 
• Number (%) of participants reporting any Grade 3 or higher TEAEs 
• Number (%) of participants reporting any treatment-related TEAEs 
• Number (%) of participants who temporarily interrupted study drug because of 
TEAEs 
• Number (%) of participants who permanently discontinued study drug because of 
TEAEs 
• Number (%) of participants who had a fatal TEAE 
The following summaries will be produced by MedDRA term (if 2 or fewer participants appear 
in a table, a listing may be appropriate): 
• Summary of TEAEs by SOC and PT 
• Summary of TEAEs by PT in decreasing order of frequency 
• Summary of ASRs by PT in decreasing order of frequency 
• Summary of Grade 3 or higher AEs by SOC and PT 
• Summary of Grade 3 or higher AEs by PT in decreasing order of frequency 
• Summary of serious TEAEs by SOC and PT 
• Summary of serious TEAEs by PT in decreasing order of frequency 
• Summary of treatment-related TEAEs by SOC and PT 
• Summary of treatment-related TEAEs by PT in decreasing order of frequency 
• Summary of Grade 3 or higher treatment-related TEAEs by SOC and PT 
• Summary of treatment-related serious TEAEs by SOC and PT 
• Summary of TEAEs with a fatal outcome by SOC and PT 
• Summary of TEAEs leading to dose interruption of study drug by SOC and PT 
• Summary of TEAEs leading to discontinuation of study drug by SOC and PT 


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8.3. 
Clinical Laboratory Tests 
8.3.1. 
Laboratory Value Definitions 
All laboratory assessments will be performed using a central laboratory, except for urine 
pregnancy tests (as applicable). Laboratory values will be summarized descriptively, as well as 
listed, for the FAS population at screening; non-numeric test values will be tabulated when 
necessary. 
8.4. 
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 for the FAS and OL-evaluable populations. 
Criteria for clinically notable vital sign abnormalities will be defined in Table 3, Table 4, and 
Table 5. The abnormal values for participants exhibiting clinically notable vital sign 
abnormalities will be listed along with their assigned treatment group. Alert vital signs are 
defined as an absolute value outside the defined range and percentage change > 25%. The 
abnormal values for participants exhibiting alert vital sign abnormalities will be listed. 
Table 3: 
Criteria for Clinically Notable Vital Sign Abnormalities for 12 to 15 Years 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 131 mmHg  
< 110 mmHg  
Diastolic blood pressure 
> 83 mmHg  
< 64 mmHg  
Pulse 
> 100 bpm  
< 60 bpm  
Temperature 
> 38.0ºC  
< 35.5ºC  
Respiratory rate 
> 20 breaths/min  
< 8 breaths/min  
Table 4: 
Criteria for Clinically Notable Vital Sign Abnormalities for 16 to 17 Years 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 120 mmHg  
< 90 mmHg  
Diastolic blood pressure 
> 85 mmHg  
< 50 mmHg  
Pulse 
> 100 bpm  
< 45 bpm  
Temperature 
> 38.0ºC  
< 35.5ºC  
Respiratory rate 
> 20 breaths/min  
< 8 breaths/min  
Table 5: 
Criteria for Clinically Notable Vital Sign Abnormalities for ≥ 18 Years 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg  
< 85 mmHg  
Diastolic blood pressure 
> 100 mmHg  
< 40 mmHg  
Pulse 
> 100 bpm  
< 45 bpm  
Temperature 
> 38ºC  
< 35.5ºC  
Respiratory rate 
> 20 breaths/min  
< 8 breaths/min  


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9. 
PLANNED ANALYSES 
No formal interim analysis is planned for this study. 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN 
All versions of the SAP are listed in Table 6. 
Table 6: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
26 SEP 2023 
 
 
 
 
 
 
 
 
 
10.2. 
Changes to the Statistical Analysis Plan 
Not applicable. 


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11. 
REFERENCES 
Charman C, Venn A, and Williams H. The patient-oriented eczema measure: development and 
initial validation of a new tool for measuring atopic eczema severity from the patients' 
perspective. Arch Dermatol 2004;140:1513-1519. 
Food and Drug Administration. Draft Guidance on Pimecrolimus. 2012. 
Papp K, Szepietowski J, 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. Second Annual 
Revolutionizing Atopic Dermatitis Conference; 2020. Chicago, IL. 


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APPENDIX A. PLANNED TABLES AND FIGURES 
This appendix provides a list of the planned tables, figures, and listing for the Clinical Study 
Report. Shells are provided in a separate document for tables that are not in the most current 
Standard Safety Tables v1.13. 
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 and Demographic Characteristics 
1.1 Disposition 
1.1.1 
Analysis Populations 
FAS 
X 
1.1.2.1 
Summary of Participant Disposition in the Double-Blind 
Vehicle-Controlled Period 
FAS 
X 
1.1.2.2 
Summary of Participant Disposition in the Open-Label Period 
OL-Evaluable 
X 
1.2 Demography 
1.2.1 
Summary of Demographics 
FAS 
X 
1.3 Baseline Characteristics 
1.3.1 
Summary of Baseline Disease Characteristics 
FAS 
X 
1.4 Prior Medication and Concomitant Medication 
1.4.1 
Summary of Prior Medications  
FAS 
X 
1.4.2 
Summary of Prior Medications for Atopic Dermatitis  
FAS 
X 
1.4.3.1 
Summary of Concomitant Medications for Double-Blind 
Vehicle-Controlled Period 
FAS 
X 
1.4.3.2 
Summary of Concomitant Medications in the Open-Label Period 
OL-Evaluable 
X 
1.5 Others 
1.5.1 
Summary of General Medical History  
FAS 
X 
1.5.2 
Summary of Protocol Deviations During Double-Blind 
Vehicle-Controlled Period 
FAS 
X 
1.5.3 
Summary of Protocol Deviations During Open-Label Period 
OL-Evaluable 
X 
Efficacy 
2.1 EASI 
2.1.1 
Summary and Analysis of Participants Who Achieved EASI75 of 
the Head and Neck Region During the Treatment Period 
FAS 
 
2.1.3 
Summary and Analysis of Participants Who Achieved an Overall 
EASI75 During the Treatment Period 
FAS 
 


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Exposure and Safety 
3.1 Study Drug Exposure 
3.1.1.1 
Summary of Exposure in the Double-Blind Vehicle-Controlled 
Period 
FAS 
X 
3.1.1.2 
Summary of Exposure in the Open-Label Period 
OL-Evaluable 
X 
3.1.1.3 
Summary of Exposure During the Treatment Period 
FAS 
X 
3.1.2.1 
Summary of Study Drug Compliance in the Double-Blind 
Vehicle-Controlled Period 
FAS 
 
3.2 Adverse Events 
3.2.1.1 
Overall Summary of Treatment-Emergent Adverse Events in the 
Double-Blind Vehicle-Controlled Period 
FAS 
X 
3.2.1.2 
Overall Summary of Treatment-Emergent Adverse Events in the 
Open-Label Period 
OL-Evaluable 
X 
3.2.1.3 
Overall Summary of Treatment-Emergent Adverse Events During 
the Treatment Period 
FAS 
X 
3.2.2.1 
Summary of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term in the Double-Blind 
Vehicle-Controlled Period 
FAS 
X 
3.2.2.2 
Summary of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term in the Open-Label Period 
OL-Evaluable 
X 
3.2.2.3 
Summary of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term During the Treatment 
Period 
FAS 
X 
3.2.3.1 
Summary of Application Site Reactions by MedDRA Preferred 
Term in Decreasing Order of Frequency in the Double-Blind 
Vehicle-Controlled Period 
FAS 
X 
3.2.3.2 
Summary of Application Site Reactions by MedDRA Preferred 
Term in Decreasing Order of Frequency in the Open-Label Period 
OL-Evaluable 
X 
3.2.3.3 
Summary of Application Site Reactions by MedDRA Preferred 
Term in Decreasing Order of Frequency During the Treatment 
Period 
FAS 
X 
3.2.4.1 
Summary of Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency in the 
Double-Blind Vehicle-Controlled Period 
FAS 
X 
3.2.4.2 
Summary of Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency in the 
Open-Label Period 
OL-Evaluable 
X 
3.2.4.3 
Summary of Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency During the 
Treatment Period 
FAS 
X 
3.2.5.1 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term in the 
Double-Blind Vehicle-Controlled Period 
FAS 
 
3.2.5.2 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term in the 
Open-Label Period 
OL-Evaluable 
 


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Table No. 
Title 
Population 
Standard 
3.2.5.3 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
During the Treatment Period 
FAS 
 
3.2.6.1 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing Order of 
Frequency in the Double-Blind Vehicle-Controlled Period 
FAS 
X 
3.2.6.2 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing order of 
Frequency in the Open-Label Period 
OL-Evaluable 
X 
3.2.6.3 
Summary of Grade 3 or Higher Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing order of 
Frequency During the Treatment Period 
FAS 
X 
3.2.7.1 
Summary of Serious Treatment-Emergent Adverse Events By 
MedDRA System Organ Class and Preferred Term in the 
Double-Blind Vehicle-Controlled Period 
FAS 
X 
3.2.7.2 
Summary of Serious Treatment-Emergent Adverse Events By 
MedDRA System Organ Class and Preferred Term in the 
Open-Label Period 
OL-Evaluable 
X 
3.2.7.3 
Summary of Serious Treatment-Emergent Adverse Events By 
MedDRA System Organ Class and Preferred Term During the 
Treatment Period 
FAS 
X 
3.2.8.1 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing order of Frequency in the 
Double-Blind Vehicle-Controlled Period 
FAS 
X 
3.2.8.2 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing order of Frequency in the 
Open-Label Period 
OL-Evaluable 
X 
3.2.8.3 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing order of Frequency During 
the Treatment Period 
FAS 
X 
3.2.9.1 
Summary of Treatment-Related Treatment-Emergent Adverse 
Events By MedDRA System Organ Class and Preferred Term in 
the Double-Blind Vehicle-Controlled Period 
FAS 
X 
3.2.9.2 
Summary of Treatment-Related Treatment-Emergent Adverse 
Events By MedDRA System Organ Class and Preferred Term in 
the Open-Label Period 
OL-Evaluable 
X 
3.2.9.3 
Summary of Treatment-Related Treatment-Emergent Adverse 
Events By MedDRA System Organ Class and Preferred Term 
During the Treatment Period 
FAS 
X 
3.2.10.1 
Summary of Treatment-Related Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing Order of 
Frequency in the Double-Blind Vehicle-Controlled Period 
FAS 
X 
3.2.10.2 
Summary of Treatment-Related Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing Order of 
Frequency in the Open-Label Period  
OL-Evaluable 
X 
3.2.10.3 
Summary of Treatment-Related Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing Order of 
Frequency During the Treatment Period 
FAS 
X 
3.2.11.1 
Summary of Grade 3 or Higher Treatment-Related 
Treatment-Emergent Adverse Events By MedDRA System Organ 
FAS 
X 


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Table No. 
Title 
Population 
Standard 
Class and Preferred Term in the Double-Blind Vehicle-Controlled 
Period 
3.2.11.2 
Summary of Grade 3 or Higher Treatment-Related 
Treatment-Emergent Adverse Events By MedDRA System Organ 
Class and Preferred Term in the Open-Label Period 
OL-Evaluable 
X 
3.2.11.3 
Summary of Grade 3 or Higher Treatment-Related 
Treatment-Emergent Adverse Events By MedDRA System Organ 
Class and Preferred Term During the Treatment Period 
FAS 
X 
3.2.12.1 
Summary of Treatment-Related Serious Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred 
Term in the Double-Blind Vehicle-Controlled Period 
FAS 
 
3.2.12.2 
Summary of Treatment-Related Serious Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred 
Term in the Open-Label Period 
OL-Evaluable 
 
3.2.12.3 
Summary of Treatment-Related Serious Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred 
Term During the Treatment Period 
FAS 
 
3.2.13.1 
Summary of Treatment-Emergent Adverse Events With a Fatal 
Outcome by MedDRA System Organ Class and Preferred Term in 
the Double-Blind Vehicle-Controlled Period 
FAS 
 
3.2.13.2 
Summary of Treatment-Emergent Adverse Events With a Fatal 
Outcome by MedDRA System Organ Class and Preferred Term in 
the Open-Label Period 
OL-Evaluable 
 
3.2.13.3 
Summary of Treatment-Emergent Adverse Events With a Fatal 
Outcome by MedDRA System Organ Class and Preferred Term 
During the Treatment Period 
FAS 
 
3.2.14.1 
Summary of Treatment-Emergent Adverse Events Leading to Dose 
Interruption by MedDRA System Organ Class and Preferred Term 
in the Double-Blind Vehicle-Controlled Period 
FAS 
 
3.2.14.2 
Summary of Treatment-Emergent Adverse Events Leading to Dose 
Interruption by MedDRA System Organ Class and Preferred Term 
in the Open-Label Period 
OL-Evaluable 
 
3.2.14.3 
Summary of Treatment-Emergent Adverse Events Leading to Dose 
Interruption by MedDRA System Organ Class and Preferred Term 
During the Treatment Period 
FAS 
 
3.2.15.1 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Study Drug by MedDRA System Organ Class 
and Preferred Term in the Double-Blind Vehicle-Controlled Period 
FAS 
X 
3.2.15.2 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Study Drug by MedDRA System Organ Class 
and Preferred Term in the Open-Label Period 
OL-Evaluable 
X 
3.2.15.3 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Study Drug by MedDRA System Organ Class 
and Preferred Term During the Treatment Period 
FAS 
X 
3.3 Laboratory 
3.3.1.1 
Summary of Laboratory Values at Screening 
FAS 
X 
3.4 Vital Signs 
3.4.1.1 
Summary of Systolic Blood Pressure in the Double-Blind 
Vehicle-Controlled Period 
FAS 
X 
3.4.1.2 
Summary of Systolic Blood Pressure in the Open-Label Period 
OL-Evaluable 
X 


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Table No. 
Title 
Population 
Standard 
3.4.2.1 
Summary of Diastolic Blood Pressure in the Double-Blind 
Vehicle-Controlled Period 
FAS 
X 
3.4.2.2 
Summary of Diastolic Blood Pressure in the Open-Label Period 
OL-Evaluable 
X 
3.4.3.1 
Summary of Pulse in the Double-Blind Vehicle-Controlled Period 
FAS 
X 
3.4.3.2 
Summary of Pulse Pressure in the Open-Label Period 
OL-Evaluable 
X 
3.4.4.1 
Summary of Respiratory Rate in the Double-Blind 
Vehicle-Controlled Period 
FAS 
X 
3.4.4.2 
Summary of Respiratory Rate in Open-Label Period  
OL-Evaluable 
X 
3.4.5.1 
Summary of Body Temperature in the Double-Blind 
Vehicle-Controlled Period 
FAS 
X 
3.4.5.2 
Summary of Body Temperature in the Open-Label Period 
OL-Evaluable 
X 
Figures 
Figure No. 
Title 
Population 
4.1.1 
Proportion of Participants Who Achieved EASI75 of the Head and Neck Region 
During the Treatment Period 
FAS 
4.1.3 
Proportion of Participants Who Achieved an Overall EASI75 During the Treatment 
Period 
FAS 
Listings 
Listing No. 
Title 
2.1.1 
Participant Enrollment and Disposition Status 
2.1.2 
Participant Inclusion and Exclusion Criteria Violations 
2.2 
Protocol Deviations 
2.3 
Analysis Population 
2.4.1 
Demographic Characteristics 
2.4.2 
Baseline Disease Characteristics 
2.4.3 
Prior and Concomitant Medications 
2.4.4 
Prior Medications for Atopic Dermatitis 
2.4.5 
Medical History 
2.5 
Study Drug Exposure and Compliance 


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Listing No. 
Title 
Efficacy 
2.6.1 
Head and/or Neck EASI Score 
2.6.2 
Total EASI Score 
2.6.3 
Itch NRS Score 
 
 
 
 
 
 
Adverse Events 
2.7.1 
Adverse Events 
2.7.2 
Adverse Events Leading to Drug Discontinuation 
2.7.3 
Serious Adverse Events 
2.7.4 
Treatment-Related Adverse Events 
2.7.5 
Adverse Events With a Fatal Outcome 
2.7.6 
Adverse Events Leading to Interruption of Study Drug 
2.7.8 
Adverse Events with Grade 3 or Higher 
Laboratory Data 
2.8.1 
Clinical Laboratory Values – Hematology 
2.8.2 
Clinical Laboratory Values – Serum Chemistry 
2.8.3 
Abnormal Clinical Laboratory Values – Hematology 
2.8.4 
Abnormal Clinical Laboratory Values – Serum Chemistry 
Vital Signs 
2.9.1 
Vital Signs 
2.9.2 
Abnormal Vital Sign Values 
2.9.3 
Alert Vital Sign Values